01 March 2024, Volume 38 Issue 3
    

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  • Review
    Elena Moretti, Cinzia Signorini, Roberta Corsaro, Laura Liguori, Luciano Saso, Giulia Collodel
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1779-1795. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.142
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    Sperm cryopreservation is an important technique in preserving male fertility. Several methods for semen and sperm cryopreservation are available; however, the quality of thawed spermatozoa is poor and this is due to different mechanisms during the freezing-thawing process, including temperature changes, crystal ice formation, osmotic stress and oxidative stress (OS). OS is the result of an overproduction of reactive oxygen species (ROS) that, if present in high concentration, can damage the cellular structures and impair sperm function. Modulation of OS is an important issue in human sperm freezing. A large group of antioxidant molecules is used in cryopreservation processes as a pharmacological strategy to counteract the oxidizing effects of preservation procedures and thus protect sperm quality. The main body of the review comprises the analysis of different studies, starting from 2000 up to the present, dealing with the effects of different antioxidant compounds, including natural extract, used as supplement of cryopreservation media. Many studies have reported several beneficial effects of antioxidants that are added during freezing-thawing protocols on sperm cryo-damages; however, these improvements are not always evident. Over the past decade, the attention has been mainly focused on the phytoextracts and natural extracts. Phytoextracts can be obtained by waste products, which are a rich source of compounds with strong antioxidant activity. Because these by-products can be used in the industrial, cosmetic, nutraceutical, and human and animal reproductive fields, this topic of research is worthwhile implementing. The freezing and thawing protocols still have many pitfalls and the quality of thawed spermatozoa is not satisfactory. For this reason, new strategies to minimize cyodamages and to increase sperm cryostability are advisable to guarantee better sperm function and survival, permitting successful future clinical application.

  • Review
    Sarmistha Saha
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1797-1807. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.143
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    Alzheimer's disease (AD) and Parkinson's disease (PD), the two main causes of dementia, are neurodegenerative diseases in which neuroinflammation is a key factor. α-Synuclein (α-Syn), tau protein, and amyloid-β (Aβ) are among the misfolded proteins that accumulate in these illnesses, leading to mitochondrial dysfunction, oxidative stress and neuroinflammation. In this regard, NF-E2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), plays a crucial role in maintaining redox status, expression of antioxidant genes, and inflammatory response. All of the treatments that have been tried so far to stop protein aggregation have failed in clinical trials. As a result, dementia diagnosis and treatment remain difficult problems. Interestingly, tuning the Nrf2 system can affect the immunometabolic mechanisms and their potential medical applications. Now, it has been the subject of an increasing number of clinical investigations for inflammation and oxidative stress biomarkers and as a novel therapeutic target. However, targeting neuroinflammation by Nrf2 activators also has some limitations like limited pharmacokinetics and pharmacodynamics. Nanotechnology has gained significant interest in various applications, including sensors and therapeutic agents for targeted diseased sites. However, most nanostructures frequently become caught inside innate immune cells rather than reaching the intended target. This review will address these gaps by exploring the role of the Nrf2 pathway in neurodegenerative diseases and examine how custom-designed nanoscale materials can interact with biological systems and how this interaction can impact the nanostructures recognition by cells. Additionally, we will investigate the possible effects of dynamic alterations in the nanomaterials inside biological systems, with a focus on inflammation.

  • Review
    Azher Arafah
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1809-1829. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.144
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    Pharmacogenomics (PGx), a rapidly evolving field at the intersection of pharmacology and genomics, has the potential to revolutionize medical practice by investigating how an individual's genetic makeup influences their response to drugs. By optimizing drug selection, dosage, and treatment strategies based on an individual's genetic profile, pharmacogenomics aims to improve therapeutic outcomes, minimize adverse reactions, and enhance healthcare efficiency. Recent advancements in high-throughput genotyping technologies and the availability of genomic data have paved the way for personalized and targeted therapies. This review highlights pharmacogenomics's fundamental principles, applications, and challenges, emphasizing its potential to transform clinical practice and patient care. The field has made significant progress in understanding the impact of genetic variants on drug response, ranging from monogenic to complex polygenic variants. However, the implementation of pharmacogenomics in public health institutions remains limited. With continuous advancements and increasing integration of genomics into medicine, pharmacogenomics is poised to play a crucial role in precision medicine, improving drug efficacy, minimizing toxicity, and driving advancements in drug discovery and development.

  • Review
    Pronama Biswas, Asmita Saha, Bhoomika Sridhar, Anwesha Patel, Belaguppa Manjunath Ashwin Desai
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1831-1857. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.145
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    Quantum Dots (QDs) have emerged as promising nanomaterials with unique optical and physical properties, making them highly attractive for various applications in biomedicine. This review provides a comprehensive overview of the types, modes of synthesis, characterization, applications, and recent advances of QDs in the field of biomedicine, with a primary focus on bioimaging, drug delivery, and biosensors. The unique properties of QDs, such as tunable emission spectra, long-term photostability, high quantum yield, and targeted drug delivery, hold tremendous promise for advancing diagnostics, therapeutics, and imaging techniques in biomedical research. However, several significant hurdles remain before their full potential in the biomedical field, like bioaccumulation, toxicity, and short-term stability. Addressing these hurdles is essential to effectively incorporate QDs into clinical use and enhance their influence on healthcare outcomes. Furthermore, the review conducts a critical analysis of potential QD toxicity and explores recent progress in strategies and methods to mitigate these adverse effects, such as surface modification, surface coatings, and encapsulation. By thoroughly examining current research and recent advancements, this comprehensive review offers invaluable insights into both the future possibilities and the challenges that lie ahead in fully harnessing the potential of QDs in the field of biomedicine, promising a revolution in the landscape of medical diagnostics, therapies, and imaging technologies.

  • Review
    Nora Y Hakami
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1859-1873. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.146
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    Blood is vital fluid where cellular components are suspended within a non-cellular liquid matrix. The dysfunction or deficiency of these cellular components can cause serious morbidity and even mortality. Meanwhile, transfusion of blood components serves as a cornerstone during surgery, myelosuppression, and congenital disorders of the blood. However, donor-derived blood products are hindered by several challenges such as scarcity of supply, the requirement for matching, significant risks of pathogenic contamination, restricted shelf-life, and several other negative consequences. Currently, ongoing research focuses on addressing these issues, clinical interests have emerged in the bioengineering of artificial blood substitutes, aiming to mimic natural blood while avoiding the aforementioned concerns. Nanotechnology has offered innovative methods, including the development of synthetic red blood cells (RBCs) substitutes for oxygen transport, synthetic platelet substitutes for hemostasis, and synthetic white blood cells (WBCs) substitutes for immune responses. The study presents an overview of the role of nanotechnology in the production of synthetic blood substitutes, as well as an evaluation of the achievements and limitations of the existing state-of-the-art in this area. One area of research currently focuses on using cell culture technologies to make blood cells from stem cells, while another is investigating the use of nanotechnology to create blood cell replacements. In the near future, the product of ongoing research as well as comprehensive preclinical and clinical evaluations might lead to fully synthetic blood replacements for transfusion. Nanotechnology has offered a new perspective on the concept of artificial blood substitutes.

  • Review
    Xiaoyi Gu, Lemeng Sun, Lingling Zhao, Jiuwei Cui
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1875-1886. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.147
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    Chimeric antigen receptor (CAR)-T cell therapy has recently demonstrated promising outcomes for patients with malignant hematologic disorders. However, a significant number of these patients undergoing CAR-T cell therapy often present with symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS), a common reason for their hospitalization and need for intensive care, thereby impacting the broader application of this therapy. The early detection of neurological symptoms, identification of specific biomarkers, and effective handling of ICANS are crucial for optimizing the efficacy of CAR-T cell therapy. This review delves into the underlying mechanisms of ICANS, the initial recognition of its clinical indicators, and the strategies for its clinical management.

  • Review
    Yin-Di Wang, Chun-Xia He, Ye Zhang, Lu Xing, Peng-Quan Li, Hai-Qing Chu, Dong Zhao, Wei Qin, Hui-Jin Li, Hui-Ling Cao
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1887-1900. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.148
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    Diabetes poses a significant global threat to human health and life, emphasizing the crucial role of glycemic control in mitigating complications and mortality associated with the condition. While chemotherapeutic drugs effectively manage diabetes, their adverse effects have profound implications on the health and overall quality of life of the patients. In contrast, specific natural monomers have demonstrated promising anti-diabetic properties. This review highlights recent advancements in understanding the anti-diabetic effects of six groups of natural monomers, including alkaloids, plant polysaccharides, flavonoids, quinones, saponins, and terpenoids.

    The review synthesizes the latest research findings on the anti-diabetic potential of these natural monomers, elucidating their mechanisms of action. These mechanisms include the enhancement of insulin secretion, modulation of the expression of proteins involved in the signaling pathway, and regulation of glucose and lipid metabolism. Exploring these natural monomers contributes to the current understanding of anti-diabetic agents and holds promise for developing of novel drugs for managing diabetes.

  • Systematic Review
    Amita Bhadkaria, Poonam Mehta, Monika Mittal, Ambrish Mithal, Sushil Kumar Gupta, Singh Rajender, Naibedya Chattopadhyay
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1901-1917. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.149
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    Background: The growing skeleton of the fetus increases the mother's need for calcium during the pregnancy. An intricate system involving vitamin D and parathyroid hormone (PTH) regulates calcium transport from mother to fetus without compromising the maternal skeleton and is accomplished by dynamic adaptive changes during pregnancy. Vitamin D binding protein (VDBP) has a critical role in the bioavailability of vitamin D. We conducted a systematic review and meta-analysis to understand the temporal adaptive changes that occur in pregnancy in the context of vitamin D and calcium metabolism.

    Methods: Relevant studies were retrieved from PubMed, Google Scholar, and Cochrane till October 2023 and a random-effects model was used to draw the inference. A total of twenty studies consisting of 4559 healthy pregnant women were pooled for meta-analysis. Heterogeneity, sensitivity, and publication bias were analyzed.

    Results: Pregnant women had higher VDBP levels than the non-pregnant controls and displayed a trimester-dependent increase that declined following parturition, and vitamin D supplementation had no effect on it. The increase in VDBP was accompanied by an increase in total vitamin D but a decrease in metabolically active free vitamin D. The biologically active vitamin D increased from the second trimester reaching twice its control levels. PTH and alkaline phosphatase (ALP) increased while zinc, an essential cofactor required for the genomic action of vitamin D receptor, declined with the progression of pregnancy. There was significant heterogeneity between the studies but no evidence of publication bias was observed.

    Conclusion: As pregnancy progressed, VDBP, total vitamin D, biologically active vitamin D, PTH, and ALP increased while free vitamin D and zinc levels decreased. For the regulation of calcium homeostasis and vitamin D, the biologically active form of vitamin D was above the normal range. Moreover, this meta-analysis identified several hitherto unexplained adaptive changes in vitamin D and calcium metabolism during pregnancy.

  • Systematic Review
    Yi He, Wei Song
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1919-1931. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.150
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    Background: Immune dysfunction exacerbates the progression of heart failure, prompting the use of immunomodulatory drugs to regulate both immune and cardiac function of patients with heart failure. However, the existing therapeutic results are controversial. Therefore, this study aims to systematically evaluate the influence of immunomodulatory drugs on immune and cardiac function in patients with heart failure.

    Methods: A computerized search was performed on randomized controlled trials (RCTs) related to immunotherapy drugs in patients with heart failure published in Wanfang, China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and other databases from inception to November 2023. Quality assessment was performed using the Cochrane Manual of Systematic Review 5.3, and meta-analysis and sensitivity analysis were carried out using Stata 15.0.

    Results: 11 studies were included in this meta-analysis. Among patients with heart failure treated with immunomodulatory drugs, left ventricular end-diastolic dimension (LVEDD) [standardized mean difference (SMD) = –0.35, 95% confidence interval (CI): –0.66~–0.04], left ventricular end-systolic diameter (LVESD) [SMD = –0.27, 95% CI: –0.45~–0.10], high sensitivity C reactive protein (hsCRP) [SMD = –1.38, 95% CI: –2.09~–0.67], brain natriuretic peptide (BNP) [SMD = –0.43, 95% CI: –0.72~–0.15], tumor necrosis factor-α (TNF-α) [SMD = –0.73, 95% CI: –1.12~–0.33], interleukin-6 (IL-6) [SMD = –0.71, 95% CI: –0.87~–0.55) ], interleukin-1β (IL-1β) [SMD = –0.58, 95% CI: –0.78~–0.37] and quality of life scores (SMD = –0.32, 95% CI: –0.61~–0.0.04) were significantly inferior compared to the control group. Conversely, left ventricular ejection fraction (LVEF) [SMD = 0.62, 95% CI: 0.20~1.05] and 6-minute walking distance (6MWD) [SMD = 0.89, 95% CI: 0.58~1.21] were higher than the control group; There was no significant difference in interleukin-10 (IL-10) [SMD = 0.31, 95% CI: –0.26~0.88] or adverse events (OR = 1.15, 95% CI: 0.64~2.05) between the two groups.

    Conclusion: Immunomodulatory drugs can safely improve cardiac function, motor function, immune function, and quality of life in patients with heart failure.

  • Article
    Maryana Teufelsbauer, Sandra Stickler, Marie-Therese Eggerstorfer, Lukas Weigl, Gerhard Hamilton
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1933-1942. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.151
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    Background: Although <2% of breast cancers exhibit Kirsten rat sarcoma virus (KRAS) mutations, KRAS activity plays a role in triple-negative breast cancer (TNBC)/basal-like tumors. TNBC accounts for approximately 15% of breast tumors and is associated with a poor prognosis. Mutant KRAS G12D-triggered activation of the Rat sarcoma virus-Mitogen activated protein kinase (RAS-MAPK) pathway promotes immune evasion in TNBC by remodeling the tumor immune microenvironment (TIME). Specifically, CD11b+ myeloid suppressor cells promote KRAS G12D-driven cancer and enhance the infiltration of CD4+Gata3+ Th2 regulatory T cells. Of the breast cancer cell lines, only MDA-MB231 cells carry the KRAS G13D mutation. In this study, the efficacy of the KRAS G12D inhibitor MRTX1133 in inhibiting KRAS-driven growth and the migration of the MDA-MB-231 cell line was evaluated.

    Methods: The proliferation, chemosensitivity and migration of the MDA-MB-231 KRAS G13D cell line in response to MRTX1133 was compared with those of the MDA-MB-436 KRAS wildtype cell line using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assays and scratch assays. Furthermore, phosphorylation of cellular proteins and alterations in protein expression in response to KRAS/Son of Sevenless 1 (SOS1) inhibitors was detected using protein profiler western blot arrays.

    Results: MRTX1133 significantly inhibited (p < 0.05) the proliferation of MDA-MB-231 cells but not that of MDA-MB-436 cells. Similarly, migration of MDA-MB-231 but not that of MDA-MB-436 was retarded by this inhibitor. Furthermore, the SOS1 inhibitors BAY-293, BI-3406 and MRTX0902 exhibited high antiproliferative activity against MDA-MB-231 cells. In case of lung cancer, MRTX1133 was highly active against the BH1194 KRAS G12D Non-small cell lung cancer (NSCLC) cell line but demonstrated low activity against the BH1338 KRAS G13D NSCLC cell line. In phosphoprotein arrays, the phosphorylation of Extracellular signal-Regulated Kinases 1/2 (ERK 1/2), cAMP-response Element Binding protein (CREB), Glycogen Synthase Kinase 3 Alpha/ Beta (GSK-3α/β), and stress kinases was downregulated and in protein arrays, Epithelial Cell Adhesion Molecule (EpCAM), Interleukin 6 (IL-6), Granulocyte Macrophage-Colony Stimulating Factor 2 (GM-CSF), Macrophage-Colony Stimulating Factor 1 (M-CSF) and Vascular Endothelial Growth Factor A (VEGF) showed reduced expression in response to MRTX1133.

    Conclusions: KRAS G12D inhibition reprogrammed the TIME in pancreatic cancer experimental models, reversed tumor growth, increased CD8+ T cell infiltration, decreased myeloid infiltration and elicited sustained tumor regression in response to MRTX1133 combined with immune checkpoint inhibitors. The significant and selective activity of MRTX1133 against the KRAS G13C mutant MDA-MB-231 cell line appears to be linked to the presence of Cyclin Dependent Kinase Inhibitor 2A (CDKN2) deletions as well as of B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) and Tumor Protein P53 (TP53) mutations in contrast to NSCLC cell lines. Therefore, in selected cases of KRAS mutant TNBC, inhibition of KRAS G12D may be used synergistically with immunotherapy.

  • Article
    Floriana D’Angeli, Carlo Genovese, Alfio Distefano, Abdul Malik, Azmat Ali Khan, Simone Ronsisvalle, Federica Sipala, Giovanni Li Volti
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1943-1960. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.152
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    Background: Methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) strains can colonize the lower respiratory tract, causing severe bacterial pneumonia. Such infections frequently occur in oncologic patients affected by lung cancer. Therefore, the present study aimed to explore the potential antibacterial and cytotoxic properties of Opuntia ficus-indica acetone and Opuntia ficus-indica diethyl ether extracts (OFI AE and OFI DEE) against Staphylococcus aureus strains and human mucoepidermoid pulmonary carcinoma cell line H292, respectively. In addition, the antioxidant activity of the two extracts was evaluated.

    Methods: The antimicrobial activity of OFI AE and OFI DEE against MSSA and MRSA strains was evaluated through the microdilution method. The antibiofilm effect of OFI extracts was determined by the crystal violet assay. Moreover, the potential synergistic activity between OFI extracts and the antibiotic Gentamycin (GEN) was tested using the checkerboard assay. The cytotoxic activity against H292 cells was investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrasodium bromide (MTT) and flow cytometry assays. Furthermore, oxidative stress and antioxidant capacity of the extract were measured by extracellular reactive oxygen species (ROS) formation and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, respectively. Finally, the chemical composition of the two phytoextracts was analyzed by Ultra High-Performance Liquid Chromatography-Mass Spectrometry.

    Results: Our results show that both extracts inhibited the growth of MSSA and MRSA strains, although they were not able to counteract biofilm formation. However, the combination of the extracts with GEN potentiated the activity of the antibiotic treatment. Furthermore, OFI AE treatment showed a potent cytotoxic effect on H292 cells following ROS formation. Finally, both extracts showed no significant antioxidant activity and the chemical analysis revealed a high content of polyphenols and flavonoids, which could be responsible for the observed biological effects of the OFI extracts.

    Conclusions: OFI extracts are a promising natural source of antibacterial and anticancer agents endowed with beneficial effects on human health.

  • Article
    Fatemeh Mollaamin, Majid Monajjemi
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1961-1973. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.153
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    Background: This study focuses on a medication targeting the primary protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), aiming to inhibit in vitro viral replication across diverse experiments. At the onset of the coronavirus disease of 2019 (COVID-19) pandemic, only general therapy was available; however, an emergency application license has recently been granted for an oral antiviral in the U.S. Nirmatrelvir, an antiviral drug developed by Pfizer, operates as an orally effective 3 Cysteine-like protease inhibitor.

    Methods: This work evaluates the inhibitory potential of nirmatrelvir against the coronavirus when delivered using carbon nanomaterials. The direct electron transfer principle, elucidated through the quantum mechanics method of density functional theory (DFT), guides the drug delivery process. The evaluation involves the Becke, 3-parameter, Lee–Yang–Parr (B3LYP)/6-311+G (d,p) theoretical method to assess the affinity of carbon nanomaterials for nirmatrelvir using nuclear quadrupole resonance, nuclear magnetic resonance, thermodynamic specifications, and frontier molecular orbital theory.

    Results: Theoretical calculations demonstrated that carbon nanotubes effectively capture nirmatrelvir, as indicated by nuclear quadrupole resonance, nuclear magnetic resonance, thermodynamic specifications, and frontier molecular orbital theory using the B3LYP/6-311+G (d,p) method. This study suggests that combining carbon nanotube (CNT) and nirmatrelvir may offer a viable formula for drug delivery, supported by quantum mechanics computations and physicochemical properties of nuclear quadrupole resonance (NQR), nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet/visible (UV-VIS) approaches.

    Conclusions: In this work, network pharmacology, metabolite analysis, and molecular simulation were employed to elucidate the biochemical basis of the health-promoting effects of nirmatrelvir in drug delivery with CNT. This research article explores the efficacy of the drug, metabolites, and potential interactions of some medicinal plants with coronavirus-induced pathogenesis.

  • Article
    Omar Ortiz-Avila, Claudia Isabel García-Berumen, María del Consuelo Figueroa-García, Ricardo Mejía-Zepeda, Alfredo Saavedra-Molina, Esperanza Meléndez-Herrera, Christian Cortés-Rojo
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1975-1985. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.154
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    Background: Type 2 diabetes mellitus decreases blood adiponectin levels, which leads to mitochondrial dysfunction in the kidney and diabetic nephropathy. Strategies for enhancing blood adiponectin levels have been proposed as therapeutic approaches for the treatment of diabetic nephropathy. As oleic acid increases serum adiponectin levels, we determined whether avocado oil, a source of oleic acid, improves diabetic nephropathy by enhancing blood adiponectin levels and mitochondrial function in type 2 diabetic Goto-Kakizaki rats during a one-year follow up.

    Methods: Normoglycemic rats were fed standard rodent chow control (CTRL) group or standard rodent chow plus avocado oil (AVO) group for 3, 6, and 12 months while Goto-Kakizaki rats were fed standard rodent chow diabetic (DB) group or standard rodent chow plus avocado oil (DB + AVO group). The levels of 24 h-proteinuria, serum adiponectin, and insulin were assessed using enzyme-linked immunosorbent assay (ELISA) kits. The kidneys of rats were collected for histological analysis and mitochondrial isolation. Oxidative phosphorylation coupling in the isolated mitochondria was assessed using a polarographic method. Statistical differences between means were analyzed using analysis of variance (ANOVA) and Bonferroni's post hoc test.

    Results: Throughout the study period, adiponectin levels were lower in the DB group than in the CTRL group (p < 0.05). Adiponectin levels improved in the DB + AVO group compared to that in the DB group at months 3 and 6 of the study (p < 0.05). Insulin levels gradually decreased in a parallel manner in the DB and DB + AVO groups (p < 0.05). Proteinuria and glomerular degeneration progressively increased in the DB group during the study period. Proteinuria and glomerular degeneration decreased in the DB + AVO group compared to that in the DB group at months 3 and 6 of treatment. Mitochondrial function was impaired in the DB group at all stages of the study based on a notable decrease in respiration in the phosphorylated state (p < 0.05). This reduction was prevented in the DB + AVO group throughout the study (p < 0.05).

    Conclusions: Avocado oil could delay glomerular injury in the kidney and improve adiponectin levels and mitochondrial function in diabetic rats, independent of insulin levels. This finding suggests that avocado oil intake may be a nutritional strategy for attenuating diabetic nephropathy.

  • Article
    Li Li, Dongjian Huang, Hanyan Liu, Yuan Sun, Shaoying Li, Wenhong Zhang, Xi Zhang, Qiumian Ye, Man Li, Jianqiao Liu, Lian Liu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1987-1997. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.155
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    Background: Chromosomal abnormalities, such as changes in ploidy, aneuploidy, and structural changes, as well as duplication and deletion of microfragments, contribute to reduced implantation rate, pregnancy loss, and congenital disabilities in humans. In this study, we explored the significance of One preimplantation genetic testing (OnePGT) in preimplantation genetic testing (PGT).

    Methods: In this study, 20 embryos representing seven families undergoing PGT for monogenic disorders (PGT-M) and 11 embryos representing five families undergoing PGT for chromosomal structural rearrangements (PGT-SR) were selected for re-biopsy at our Reproductive Medicine Center. Moreover, blood samples were also obtained from the parents. For monogenic disease (MGD) analysis, 20 embryo samples (7 controls) and parental DNA samples were amplified. A whole-genome library was built and subsequently sequenced to obtain Single Nucleotide Polymorphism (SNP) data of ±2 Mb of the control embryo pathogenic gene loci and SNP data of parental samples. Furthermore, the embryos were screened for carrying any pathogenic gene loci, and the feasibility and accuracy of the OnePGT method relative to the original results in detecting MGDs were analyzed. However, in chromosomal structural rearrangement testing, 11 embryos (4 controls) and parental DNA samples were amplified, and the SNP data of ±2 Mb of chromosomal structural abnormalities were compared to differentiate the carrier embryo from normal ones. Additionally, the aforementioned embryo samples were analyzed for aneuploidy detection, and the accuracy of the aneuploidy detection through OnePGT was compared with the original results, as well as the degree of chimera coincidence.

    Results: The genetic results of embryos in patients with three MGDs (α-thalassemia, β-thalassemia, and spinal muscular atrophy), reciprocal chromosomal translocation, and Robertsonian translocation detected by the OnePGT method were consistent with those detected by the conventional method. Furthermore, compared to findings from the conventional method, OnePGT exhibited a 100% coincidence rate in distinguishing chromosomal translocation carrying embryos from normal, a 72% coincidence rate in the detection of aneuploidy, and a 50% coincidence rate in chimera.

    Conclusions: OnePGT is a novel, comprehensive, and effective three-in-one detection method for PGT.

  • Article
    Ting Sun, Ting Wang, Wenjing Shi, Jun Peng, Panling Xu, Ping Li, Juan Zhu, Bin Liu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 1999-2012. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.156
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    Background: The chemokine-like factor-like MARVEL transmembrane domain-containing family (CMTMs), a newly identified gene family, has been associated with reproduction, immunity, and the development of various cancer types, among other regulatory mechanisms. The aim of this study was to investigate the relationship between CMTM expression levels and prognosis and immune infiltration in pancreatic cancer.

    Methods: We comprehensively analyzed the prognosis and immune infiltration of pancreatic cancer patients associated with the CMTMs using online databases such as Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier (KM) Plotter, cBioPortal, Tumor Immune Estimation Resource (TIMER), Gene Multiple Association Network Integration Algorithm (GeneMANIA), Search Tool for Recurring Instances of Neighbouring Genes (STRING), and Metascape.

    Results: The results indicate that CMTM family genes are involved in multiple biological pathways in pancreatic adenocarcinoma (PAAD) patients. Chemokine-like factor (CKLF), CMTM1, CMTM2, CMTM3, and CMTM6 were negatively correlated with overall survival (OS) in PAAD patients, whereas low expression of CMTM1, CMTM3, CMTM6, and CMTM7 was associated with favorable recurrence-free survival (RFS). With the exception of CMTM8, the expression levels of other members of the CMTM family correlated with the infiltration of various immune cells in the tumor microenvironment.

    Conclusions: This research highlights that members of the CMTMs serve as potential prognostic markers for pancreatic cancer and suggests avenues for further immunotherapy investigation.

  • Article
    Dara Aldisi, Shaun Sabico, Amani Al-Farraj, Taghreed A. Basaeed, Kaiser Wani, Syed D. Hussain, Nasser M. Al-Daghri, Abeer Almiman, Philip G. McTernan
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2013-2024. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.157
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    Background: Evidence on the metabolic effects of functional foods such as kale and peas are limited in the Middle East, particularly in Saudi Arabia where obesity rates are high. We hypothesize that short term freeze-dried kale supplementation is superior to freeze-dried peas in improving indices of fatty acid binding protein 2 (FABP2) and cluster of differentiation (CD14) post-supplementation in Arab women with obesity. The present study aims to determine the acute impact of a two-week supplementation of freeze-dried kale versus freeze-dried peas in improving metabolic indices and gut-barrier function among obese Arab women.

    Methods: A total of 124 Saudi women with obesity were allocated to receive either freeze-dried kale (n = 62) or freeze-dried peas (n = 62) given in the form of 3-gram sachets three times daily for two weeks. Anthropometric measurements, 24-hr dietary recall, glucose, lipids and markers of gut barrier function were assessed at baseline and post-intervention.

    Results: A significant reduction in total caloric intake was observed in the kale group and not in the pea group overtime (p-values 0.02 and 0.38, respectively). This decrease in caloric intake in the kale group potentially explains the favorable weight loss observed (p = 0.01). Beneficial metabolic changes in terms of decreased triglycerides (p < 0.01) and glucose (p = 0.02) were also observed independent of weight loss in the kale group. These benefits were also noted in participants in the pea group [decreased total cholesterol (p < 0.01) and glucose (p = 0.02)], but without weight loss. Both groups achieved a decrease in their waist-hip ratio overtime with increased levels of FABP2 and CD14 post-supplementation, suggesting an enhanced gut barrier function.

    Conclusion: Both freeze-dried kale and pea supplementation appeared to improve gut health by increasing levels of FABP2 and CD14, however kale's additional health benefits in this study may arise due to its apparent natural appetite-suppressing effects, potentially leading to a reduction in daily caloric intake and weight loss.

    Clinical Trial Registration: The protocol has been registered in https://clinicaltrials.gov/ (NCT04904601).

  • Article
    Wenke Yin, Xiaoyan Song, Yue Xiang, Linli He
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2025-2034. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.158
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    Background: The expression of YTH domain-containing protein 2 (YTHDC2) has been reported to be elevated in various types of cancers, but its underlying mechanism of action remains unclear. In gastric cancer patients, YTHDC2 levels in tissues exhibit positive correlation with tumor invasion and recurrence. Tumor necrosis factor-α (TNF-α), produced by both cancer cells and the tumor microenvironment, exerts pleiotropic effects on tumorigenesis and tumor progression. Herein, we investigated the roles of YTHDC2 in inducing gastric cancer (GC) cell proliferation and metastasis due to TNF-α.

    Methods: GC cells were exposed to TNF-α followed by transfection with small interfering RNAs (siRNAs) si-NC, si-YTHDC2#1, si-YTHDC2#2, si-YTHDC2#1+vector or si-YTHDC2#1+OE-ZEB1 into human GC cell lines. These interventions aimed to knock down YTHDC2 or induce the overexpression of Zinc finger E-box-binding homeobox 1 (ZEB1). Various assays, including clone formation, transwell migration, cell counting kit-8 (CCK8) viability, western blot analysis, and wound healing, were conducted to elucidate the underlying mechanisms through which GC cells regulate YTHDC2. Furthermore, a murine heterotopic tumor model was employed to validate YTHDC2 functions.

    Results: The results showed that YTHDC2 was overexpressed in GC tissues and cells and TNF-α could induce YTHDC2 expression in GC cells. Knocking down YTHDC2 inhibited the proliferation and metastasis of GC cells following TNF-α exposure. Moreover, silencing YTHDC2 suppressed GC cell progression through Hypoxia-inducible factor 1-alpha (HIF-1α)/ZEB1 activation. These findings were confirmed in a murine heterotopic tumor model, where YTHDC2 suppression attenuated tumor growth in vivo.

    Conclusions: It was concluded that the expression of YTHDC2 may modulate the tumorigenesis and metastasis of GC. At the same time, targeting both YTHDC2 and ZEB1 may be a promising strategy for GC management.

  • Article
    Jiankun Wang, Fen Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2035-2044. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.159
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    Background: Cerebral infarction (CI) often leads to disability or cognitive deficits with limited effective therapeutic options. This study investigated the effect and mechanism of Notoginsenoside R1 (NGR1) on protecting cells from apoptosis in rat CI models.

    Methods: Sprague Dawley (SD) rats were used to establish CI models through middle cerebral artery occlusion (MCAO) treatment. Hematoxylin-eosin (H&E) staining was used to observe pathological changes. Cell apoptosis was assessed by Bcl-2 apoptosis regulator (Bcl-2)/Bcl-2 associated X (Bax), cleaved caspase-3, and cleaved caspase-9 levels determined by western blot and enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was used to evaluate levels of hes family bHLH transcription factor 1 (Hes1) and Notch receptor 1 (Notch1). Additionally, Notch1 pathway activation was regulated by the Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and Notch 1 activator valproic acid (VPA), and the consequent effect on brain cell apoptosis was determined.

    Results: In CI rat brains, the levels of cleaved caspase-3 and cleaved caspase-9 were elevated (p < 0.001), while Bcl-2/Bax was decreased (p < 0.001). NGR1 reversed these changes (p < 0.01). Hes1 and Notch1 levels were reduced in CI rat brains (p < 0.001) and were reversed by NGR1 (p < 0.001). Furthermore, compared to NGR1-treated CI rats, additional DAPT/VPA decreased/increased levels of Hes1, Notch1, Bcl-2/Bax (p < 0.001), and increased/decreased cleaved caspase-3 and cleaved caspase-9 levels (p < 0.001).

    Conclusion: NGR1 can decrease cell apoptosis in the brains of CI rats by activating the Notch1 signaling, presenting a novel therapeutic strategy with potential therapeutic targets for treating CI.

  • Article
    Bo Sun, Xia Wang, Hui Chen, Fujun Li, Wei Pan, Yanling Tu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2045-2054. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.160
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    Background: Cervical cancer (CC) is one of the prevalent cancers among females. The DEP domain containing 1 (DEPDC1) has been found to play a crucial role in the progression of cancers by promoting tumorigenesis. However, the regulatory role of DEPDC1 in CC progression remains unclear. Therefore, this study aimed to investigate the regulatory functions of DEPDC1, and its associated pathway in the progression of CC.

    Methods: Initially, using the UALCAN database, the higher expression level of DEPDC1 was confirmed in both CC and normal tissues. However, the expression levels of proteins were evaluated using immunohistochemistry (IHC) assay and western blot analysis. Moreover, the viability and proliferation capabilities of the cells were determined using cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays, respectively. Furthermore, the radiosensitivity of CC cells was evaluated using colony formation assay. The level of gamma-H2A histone family member X (γ-H2AX) was assessed within the small interfering RNA-negative control (si-NC), si-DEPDC1#1, si-NC+4 Gray (Gy), and si-DEPDC1#1+4 Gy groups using Immunofluorescence (IF) assay. The cell apoptosis was examined in the si-NC, si-DEPDC1#1, si-NC+4 Gy, and si-DEPDC1#1+4 Gy groups using flow cytometry. Additionally, in vivo assays were utilized to determine the growth of tumors within the short hairpin RNA-negative control (sh-NC), sh-DEPDC1, ionizing radiation (IR), and IR+sh-DEPDC1 groups of mice.

    Results: It was observed that CC patients with higher DEPDC1 expression level showed poor prognosis. The expression of DEPDC1, both at mRNA and protein level, was significantly elevated in CC tissues (p < 0.05). Moreover, silencing of DEPDC1 suppressed tumor cell growth and proliferation in CC (p < 0.05). Furthermore, radiosensitivity of CC cells was found at 0, 2, 4, 6 Gray-infrared radiation treatment (p < 0.05). However, it was observed that the radiosensitivity of both HeLa-radiation resistant (RR) and SiHa-RR cells was significantly enhanced following DEPDC1 knockdown (p < 0.05). Similarly, inhibition of DEPDC1 enhanced radiation-induced cell apoptosis in CC (p < 0.05) and retarded the forkhead box M1 (FOXM1)/ubiquitin-like plant homeodomain (PHD) and RING finger domain containing 1 (UHRF1) pathway, thereby influencing CC progression (p < 0.05). Additionally, the knockdown of DEPDC1 retarded tumor growth and promoted radiosensitivity in vivo (p < 0.05).

    Conclusion: The DEPDC1 accelerated cell growth and reduced radiosensitivity in CC by modulating the FOXM1/UHRF1 pathway. These findings suggest that DEPDC1 might be a potential bio-target for the treatment of CC.

  • Article
    Arijit Nandi, Nandita Mandal, Anwesha Das, Yadu Nandan Dey
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2055-2067. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.161
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    Background: The roots of Plumbago zeylanica (P. zeylanica) are widely utilized in the traditional medicine system, i.e., Ayurveda for the treatment of piles, inflammatory diseases, intestinal disorders, abdominal pain, and inflammation of the rectum. Previous experimental studies revealed the anti-inflammatory and antiarthritic activities of P. zeylanica. Because of the experimental and clinical effectiveness of the roots of P. zeylanica root in painful inflammatory conditions and rheumatic diseases, this study aimed to evaluate the network pharmacology to predict the phytoconstituents and signaling pathways of the antiarthritic effect of P. zeylanica.

    Methods: As per the first step in the network pharmacology analysis, the phytoconstituents were retrieved from the relevant database, and the drug targets as well as the disease targets were downloaded, from the relevant databases. From there, the common targets were obtained, and then, Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis to predict the pathways/processes by which these targets are involved in rheumatoid arthritis (RA). Further, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME/T), molecular docking, and dynamics studies of the resultant bioactive compounds of P. zeylanica with the regulated proteins were evaluated.

    Results: At first, using the network pharmacology analysis, the key target proteins in RA were predicted, then the key pathways were predicted using PPI, GO, and KEGG enrichment analysis in the treatment effects of P. zeylanica on RA. These key pathways used to be the responses to oxygen-containing compounds, organic response, and cellular response to a chemical stimulus which are synchronized by cancer, Phosphoinositide 3-kinases/Ak strain transforming (PI3K/AKT) signaling, lipid and atherosclerosis, microRNAs in cancer, calcium signaling and fluid shear stress and atherosclerosis pathways which indicates the involvement of abnormal proliferation of the immune cells and inflammation which are the characteristic features of rheumatoid arthritis. Further, the molecular docking, dynamics, Induced Fit Docking (IFD), and ADME/T studies revealed that the bioactive ingredients of P. zeylanica strongly bind with the essential target proteins in the ambience of rheumatoid arthritis.

    Conclusion: Hence, this study revealed computationally predicted the key targets of P. zeylanica phytoconstituents specific to its anti-inflammatory action in alleviating rheumatoid arthritis.

  • Article
    Xiaoyong Shen, Xunxia Zhu, Xiaoyu Chen, Fuzhi Yang, Zhao Zhang, Wen Gao
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2069-2078. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.162
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    Background: Protein phosphatase 4 (PP4) has been reported to be deeply involved in the development of malignancy. Protein phosphatase 4 regulatory subunit 1 (PP4R1) is an indispensable subunit of PP4, but its function in tumors remains unclear. In this study, we investigated the role of PP4R1 in non-small cell lung cancer (NSCLC).

    Method: Based on clinical samples and clinical data of NSCLC from the cancer genome atlas (TCGA) database, we first explored the role of PP4R1 in NSCLC. Next, we constructed PP4R1-overexpressed NSCLC cell lines (H1299 and A549), and explored the effects of PP4R1 on colony- and sphere-forming capacities. Subsequently, we performed RNA-seq and enrichment analyses, combined with corresponding rescue experiments, to further explore the underlying mechanisms by which PP4R1 affects the progression of NSCLC.

    Results: PP4R1 was significantly hyper-expressed in cancerous tissues from NSCLC patients, and higher PP4R1 level was negatively related to the overall survival of NSCLC patients. Cellular experiments proved that overexpressing PP4R1 promoted the cell mobility, colony-forming, and sphere-forming abilities of H1299 and A549 cells. Overexpression of PP4R1 led to the hyper-expression of octamer-binding transcription factor 4 (OCT4) and the activation of the mitogen-activated protein kinases/extracellular regulated kinase (MAPK/ERK) signaling pathway. Application of the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, U0126, significantly reversed the activation of ERK and the PP4R1-promoted cell mobility, cell growth, and sphere-forming abilities.

    Conclusion: In summary, PP4R1 upregulated the expression of OCT4 via the MAPK/ERK signaling pathway, and induced cancer stemness to promote cancer cell progression.

  • Article
    Jin Nie, Yi Liu, Liang Zhou, Luoxin Ma, Manzhu Jiang, Ling Gong, Zhu Li, Xinran Tan, Dong Ou, Bingyao Wang, Daishun Liu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2079-2094. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.163
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    Background: Lung squamous cell carcinoma (LUSC) is considered the second most prevalent subtype of non-small cell lung cancer (NSCLC), with a high frequency of somatic mutations and limited therapeutic options. Adaptor-associated protein complex 5 subunit sigma 1 (AP5S1) is a component of fifth adaptor proteins complexes. However, the correlation between AP5S1 expression and the occurrence, development, and tumor stemness in LUSC has rarely been studied. Therefore, this study aimed to elucidate the correlation between AP5S1 expression and the stemness of LUSC.

    Methods: The transcriptomic and functional clinic data of LUSC were accessed from various publicly accessible databases. The data were intensively analyzed using various bioinformatics tools and visualized employing statistical packages. Subsequently, the expression levels were validated through quantitative real-time polymerase chain reaction (qRT-PCR) using LUSC cell lines. The correlations between AP5S1 expression and prognosis, potential pathogenic mechanisms, tumor stemness, immune cell infiltration, DNA methylation, drug sensitivity, and malignant biological behavior in LUSC patients were assessed utilizing both bioinformatics approaches and various assays such as Cell Counting Kit-8 (CCK-8), colony formation, tumor sphere formation, and Transwell assays.

    Results: This study indicated a significant oncogenic role of AP5S1 in LUSC. Moreover, AP5S1 was confirmed as an independent prognostic risk factor for LUSC. Additionally, there was a strong association between AP5S1 expression and cancer stemness, immunity, DNA methylation, and drug treatment response. Furthermore, the knocking down of AP5S1 inhibited cell proliferation, migration, invasion, and stemness in LUSC in vitro.

    Conclusions: AP5S1 could be a promising prognostic indicator and a potential therapeutic target closely related to tumor stemness in LUSC patients.

  • Article
    Zhenyu Jia, Yongda Lu, Lu Zheng, Jiaqing Shen, Chenyue Tang, Yuqi Shi, Lijuan Qian, Tingting Xia
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2095-2104. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.164
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    Background: Colorectal cancer (CRC), ranking as the second leading cause of global cancer-related deaths, is marked by a high recurrence rate. Metabolic reprogramming, a characteristic feature of CRC, involves a shift from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis to fuel cell proliferation. However, the regulatory mechanisms of OXPHOS in CRC recurrence remain unclear.

    Methods: Proteomic analysis was conducted using CRC tissues from recurrent and non-recurrent patients. Candidate proteins identified through bioinformatic analysis were validated using Real-time quantitative PCR and western blot. Functional investigations were carried out through knockdown and overexpression strategies.

    Results: Our study revealed a correlation between CRC recurrence and reduced OXPHOS levels. Meanwhile, an upregulation of rapamycin-insensitive companion of mTOR (RICTOR) was observed in recurrent patients, correlating with a poorer CRC prognosis. RICTOR inhibited the expression of subunits of OXPHOS complexes, including NADH-ubiquinone oxidoreductase core subunit V2 (NDUFV2), NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUFB8), succinate dehydrogenase complex, subunit B (SDHB), and cytochrome c oxidase 5A (COX5A). Overexpression of RICTOR suppressed mitochondrial OXPHOS and promoted cell proliferation. Conversely, RICTOR knockdown reversed enhanced cell proliferation and inhibited subcutaneous tumor growth.

    Conclusion: In summary, our findings suggest that elevated RICTOR expression disrupts the assembly of the mitochondrial electron respiratory chain, consequently suppressing OXPHOS levels and ultimately promoting CRC recurrence.

  • Article
    Hamid Kabdy, Abdelmounaim Baslam, Anass Belbachir, Stefania Garzoli, Abderrahman Chait
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2105-2114. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.165
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    Background: Cannabis sativa L. is an annual plant from the Cannabaceae family. In Morocco, it has a long-standing traditional use. This study aimed to perform a chemical analysis of the Cannabis sativa essential oil (CSEO) and assess its acute toxicity, antioxidant properties, and analgesic effects.

    Method: Chemical analysis was conducted on the essential oil extracted from Cannabis sativa using gas chromatography-mass spectrometry (GC/MS) to identify its components. Subsequently, we carried out in vitro assessments of antioxidant activities using the 2,2-diphenyl-1-picrylhydrazyl radical scavenging method (DPPH), the iron reduction method, and the β-carotene assay. Concurrently, we conducted investigations into the antinociceptive activity using three distinct animal models: the writhing test, the formalin test, and the hot plate test, as well as the acute toxicity by determining the lethal dose 50 (LD50).

    Results: The GC/MS analysis of the CSEO allowed the identification of its major compounds, namely (E)-caryophyllene α-humulene and caryophyllene oxide. The antioxidant activity was also significant due to its ability to scavenge DPPH (IC50 = 1.16 ± 0.08 mg/mL) and reduce iron potency (IC50 = 1.49 ± 0.46 mg/mL) and IC50 = 1.8 ± 0.2 mg/mL for β-carotene/linoleic acid assay. Acute toxicity (LD50) was evaluated at 42.46 mg/kg, indicating a relatively high tolerance, while a significant analgesic effect was observed, persisting for 120 minutes.

    Conclusions: The study provides promising results for the essential oil of the Moroccan variety of Cannabis sativa (C. sativa), showing its potential therapeutic properties as an antioxidant, and analgesic agent.

  • Article
    Lidong Qi, Weizhong Lu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2115-2123. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.166
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    Background: Dental pulp stem cells (DPSCs) can improve periodontal tissue regeneration and have significant clinical application value in treating peri-implantitis. The Wnt signaling pathway is crucial for osteogenic differentiation of DPSCs. Berberine (BBR) has been found to promote the viability and differentiation of DPSC, whereas tumor necrosis factor-alpha (TNF-α) is a key factor affecting bone resorption. Additionally, Dickkopf 1 (DKK1) inhibits the Wnt canonical pathway. This study aims to explore how DKK1/TNF-α affects BBR-regulated osteogenic differentiation of DPSCs via the Wnt signaling pathway.

    Methods: We first evaluated the impact of varying doses of BBR, DKK1, and TNF-α on the viability of DPSCs through Cell Counting Kit-8 (CCK-8) experiments. Subsequently, we assessed the influence of DKK1/TNF-α/BBR on the osteogenic differentiation of DPSCs using alkaline phosphatase (ALP) staining, Alizarin Red staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot techniques. Finally, we investigated the effects of DKK1/TNF-α/BBR on Wnt signaling-related genes and proteins during DPSC osteogenic differentiation using qRT-PCR and Western blot.

    Results: The results showed that moderate to low concentrations of BBR, DKK1, and TNF-α enhanced the activity of DPSCs, while high concentrations of BBR, DKK1, and TNF-α inhibited DPSC proliferation. BBR promoted the osteogenic differentiation of DPSC by activating the Wnt/β-catenin pathway. DKK1 or TNF-α alone inhibited the promotional effect of BBR, while the combination of DKK1 and TNF-α reduced the inhibitory effect. TNF-α up-regulated the expression of the classical Wnt pathway and down-regulated the expression of the non-classical Wnt pathway. On the other hand, DKK1 inhibited the classical pathway and promoted the non-classical pathway.

    Conclusions: DKK1 reduced the inhibitory effect of TNF-α on BBR and promoted the osteogenic differentiation of DPSC through the Wnt signaling pathway. These findings provided a reference value for the treatment of bone resorption caused by peri-implantitis.

  • Article
    Haifeng Huang, Wenjia Guo, Ziwan Ning, Deao Xue, Haitao Xiao, Junqing Yang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2125-2138. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.167
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    Background: Type 2 diabetes mellitus has become a serious social concern, and diet-based therapies, such as those involving the Cyclocarya paliurus leave tea are gaining attention for preventing and alleviating diabetes mellitus. The objective of the present study was to determine the active components of this tea and understand the associated mechanism.

    Methods: The active fraction of C. paliurus was traced using the Cell Counting Kit-8 in response to streptozotocin-induced cell damage, and its components were identified using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Flow cytometry and western blotting were performed to examine the effects of the active fraction on streptozotocin-induced pancreatic β cell damage. A high-fat diet combined with streptozotocin-induced animal model was used to identify the effects of this extract against type 2 diabetes mellitus following 8 weeks of gavage administration.

    Results: The polyphenol fraction of C. paliurus protected against streptozotocin-induced cell damage and up-regulated cleaved caspase-3 and the Bax/Bcl-2 ratio in pancreatic β cells (p < 0.05). Moreover, this administration of the extract effectively reduced body weight, blood glucose level, and increased insulin sensitivity (p < 0.05). The treatment also alerted the abundance of gut microbiota, particularly by upregulating the abundance of Akkermansia and decreasing pathogenic bacteria genus Helicobacter (p < 0.05).

    Conclusions: Our findings suggested that the polyphenol fraction of C. paliurus could be a potential candidate for gut microbiota modulation as a dietary component for the prevention or management of type 2 diabetes mellitus.

  • Article
    Huan Jiang, Sihan Wang, Zhigang Zuo, Yutong Li, Yue Liu, Shaotai Wang, Xueqi Fu, Min Hu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2139-2149. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.168
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    Background: Root resorption, an unwanted side effect often seen in orthodontics, depends largely on osteoclasts. Osteoclastic protein tyrosine phosphatase (PTP-oc) plays a major role in controlling osteoclast activity. This study aimed to investigate the effects of Ursolic acid (UA), a novel PTP-oc inhibitor, on osteoclastogenesis and root resorption.

    Methods: UA was pinpointed using a PTP inhibition assay. Its inhibitory characteristics, inhibitor constant (Ki) against ∆PTP-oc, and selectivity were through an Inhibition Kinetics assay. The effects of UA on osteoclastogenesis were examined by treating human U937 histiocytic lymphoma cells with or without UA and then assessing osteoclastogenesis mediated by phorbol 12-myristate 13-acetate /1α, 25 di-hydroxy vitamin D3 (1,25(OH)2D3). The cell counting kit-8 (CCK-8) evaluated how a UA affects U937 cell proliferation in vitro. Osteoclast-like cell development was examined using tartrate-resistant acid phosphatase (TRAP) Staining, while Real-time-polymerase chain reaction (qPCR) was used to assess the expression of tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear factor-κB (RANK), matrix metalloproteinase-9 (MMP-9), cathepsin K (CK), and calcitonin receptor (CTR). Tyrosine kinase c-Src (c-Src) protein was measured using Western Blot. A rat model was used to study the levels of root resorption and tyrosine phosphorylation of c-Src (PY-527) by histology and immunohistochemistry.

    Results: UA displayed a strong and reversible inhibitory effect on PTP-oc in a competitive manner, showing selective in vitro (p < 0.001). The compound did not impact the viability of U937 cells at concentrations between 1–5 μM UA. UA's inhibition of osteoclastogenesis depends on its concentration, and the compound effectively suppresses the expression of osteoclast marker genes, TRAP, RANK, MMP-9, CK, and CTR. Additionally, the area of TRAP-positive cells was reduced. This effect is facilitated by inhibiting enzymatically active PTP-oc, which elevates the levels of c-Src tyrosine phosphorylation, thereby decreasing the activity of c-Src Protein Tyrosine Kinases (PTK). In animal studies, as UA concentration increased, there was a noticeable delay and weakening in root resorption. Finally, IHC staining results revealed that compared to the 0 μM UA (control) group, c-Src PY-527 in the model groups increased alongside the rise in UA concentration (p < 0.05).

    Conclusions: This study demonstrates that UA application effectively suppresses osteoclastogenesis and root resorption by inhibiting the enzymatic activity of PTP-oc. This effect is dose-dependent and may be mediated by the regulation of c-Src signaling pathway.

  • Article
    Chang Zhang, Yeli Wang, Yao Yu, Leilei Hao
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2151-2164. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.169
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    Backgrounds: Colon cancer is a leading cause of fatalities worldwide. The human plant homeodomain (PHD) finger protein 1 (PHF1) has been reported to play roles in various biological processes and the progression of several types of cancer. This study aims to investigate the impact of PHF1 on the progression of colon cancer and explore the underlying mechanisms.

    Methods: The differential expression of PHF1 in colon cancer tissues and cells was validated using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analyses. To assess the impact of PHF1 on colon cancer and the cell cycle pathway, as well as the reciprocal effect of cyclin-dependent kinase inhibitor 1A (CDKN1A)-mediated cell cycle regulation on PHF1 in colon cancer, the expression levels of PHF1 and cyclin-dependent kinase inhibitor 1A (CDKN1A) were modulated through specific small interference (si)RNA transfection. Cell proliferation was assessed using colony-forming and cell counting kit-8 (CCK-8) assays, while cell apoptosis was evaluated through the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and enzyme-linked immunosorbent assay (ELISA) to detect Bcl-2 (B-cell Leukemia/Lymphoma 2) and Bax (Bcl-2 associated X protein). Cell metastasis ability was determined using trans-well assays for cell migration and invasion, as well as lipid formation. Human Colorectal Carcinoma Cells (LOVO) were transfected and co-cultured with peripheral blood mononuclear cells (PBMCs) to elucidate the effects of PHF1 and the cell cycle on immunotherapy. This involved assessing the ratio of cells killed by immune cells, the proliferation of CD8+ T cells, and the percentages of CD107a+ and IFN-γ+ T cells.

    Results: PHF1 was found to be significantly overexpressed in both colon cancer tissues (p < 0.01) and cells (p < 0.01), demonstrating its capacity to activate the cell cycle pathway (p < 0.001). The upregulation of PHF1 led to increased cancer cell proliferation, invasion, and lipid formation (p < 0.001), while simultaneously decreasing colon cancer cell apoptosis (p < 0.001). Importantly, these effects were reversed when the cell cycle was suppressed (p < 0.01). Furthermore, in co-culture experiments where colon cancer cells with upregulated PHF1 were exposed to PBMCs, fewer colon cancer cells were killed (p < 0.001). There was also a reduction in the proliferation of CD8+ T cells (p < 0.001) and lower percentages of both CD8+ CD107a+ T cells (p < 0.001) and CD8+ IFN-γ+ T cells (p < 0.001). Notably, these outcomes were all reversed when the cell cycle pathway was suppressed (p < 0.001).

    Conclusions: PHF1 emerges as a potential marker for colon cancer, contributing to the progression of the disease through the activation of the cell cycle pathway. The suppression of PHF1 enhances the susceptibility of colon cancer to immunotherapy. These findings underscore the significance of PHF1 and the cell cycle pathway as viable targets for colon cancer treatment. Combining these targets with immunotherapy holds promise for the development of effective therapeutic strategies against colon cancer.

  • Article
    Azizah Salim Bawadood, Muhammad Afzal, Auwal Ibrahim Tanko, Fahad A. Al-Abbasi, Mustafa Zeyadi, May M. Alqurashi, Ryan A. Sheikh, Sami I. Alzarea, Nadeem Sayyed, Imran Kazmi
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2165-2179. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.170
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    Background: Chronic ethanol (EtOH) consumption results in a variety of central nervous system (CNS) deficits, including behavioral alteration and cognitive deficiencies like learning and memory problems. The current investigation aims to evaluate malvidin's ability to protect rats' memories from EtOH-induced impairments.

    Methods: A total of 24 male Wistar rats were randomly selected and allotted into 4 groups (n = 6): Group-I served as control and received saline solution (1 mL/kg p.o.), Group-II-EtOH control (2 mg/kg, i.p.) and Group-III and IV were treated with malvidin (lower-100 and higher-200 mg/kg dose p.o.) along with EtOH (2 mg/kg, i.p.) for 45 days. The efficacy of malvidin at higher and lower doses was evaluated using an experimentally induced EtOH-induced memory deficit model in rats. Spatial and working memory performance was assessed using the Y-maze and Morris water maze (MWM) tests. Biochemical markers were analyzed, including choline acetyltransferase (ChAT), acetylcholinesterase (AChE), glutathione (GSH), superoxide dismutase (SOD), nitrate, catalase (CAT), and malonaldehyde (MDA) levels. A ferric reducing/antioxidant power (FRAP) assay assessed antioxidant capacity. Glutamate (Glu) and gamma-aminobutyric acid (GABA) levels were measured to evaluate neurotransmitter function. Pro-inflammatory cytokine levels, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, were quantified to assess neuroinflammatory responses. Caspase-3 activity was measured as an apoptosis marker. Additionally, molecular docking simulations were performed to investigate potential interactions between malvidin and relevant molecular targets.

    Results: Malvidin at both dosage levels, demonstrated a significant (p < 0.001) attenuated EtOH-induced memory impairments in rats. That was evident through improved performance in Y-maze and MWM tests. Malvidin treatment at both concentrations substantially (p < 0.001) restored ChAT and antioxidant levels (GSH, SOD, CAT, and FRAP). Additionally, malvidin significantly (p < 0.001) reduced AChE levels, MDA levels, neuroinflammatory markers (IL-1β, TNF-α, and IL-6), and the apoptosis marker (caspase-3) when compared to the EtOH control group. Molecular docking studies suggested a potential interaction between malvidin and relevant targets involved in memory function and neuroinflammation. Malvidin had a favorable affinity towards glutamate, AChE, and ChAT with docking scores of –9.754, –9.329 and –8.234 kcal/mol.

    Conclusion: The findings of this study indicate that malvidin, especially at higher doses, exerts neuroprotective effects against EtOH-induced memory impairments in rats. The observed improvements in memory function may be associated with the restoration of cholinergic activity, oxidative stress modulation, neuroinflammation suppression, and potential interactions with crucial molecular targets. These findings hold significant promise for the advancement of novel neuroprotective therapeutics.

  • Article
    Yamin Zhang, Jianping Wang, Jin Yuan, Ruipeng Wu, Xiaojuan Hu, Fulin Gao, Yanqing Sun
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2181-2193. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.171
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    Background: The progression of Alzheimer's disease (AD) is closely linked to microglial pyroptosis. This study investigated the impact of somatostatin (SST) on microglial pyroptosis in AD and elucidated the underlying mechanisms.

    Methods: In-vitro AD cell models were established through sequential stimulation with 100 ng/mL lipopolysaccharide and 10 μM amyloid-β protein fragment 1-42 (Aβ1-42). The model cells which were transfected with or without silencing transformed mouse 3T3 cell murine double minute 2 (MDM2) or/and sirtuin 1 (Sirt1) overexpression plasmid, underwent SST treatment. Pro-inflammatory cytokines (interleukin 1β (IL-1β), interleukin 18 (IL-18)) were quantified using enzyme-linked immunosorbent assay, followed by the determination of lactate dehydrogenase (LDH) release. Intracellular Aβ1-42 deposition, NOD-like receptor family protein 3 (NLRP3)-mediated pyroptosis, and the MDM2/dipeptidyl peptidase 4 (DPP4)/Sirt1 axis were assessed using propidium iodide staining, immunofluorescence staining, and Western blot. The interaction between MDM2 and DPP4 was validated through ubiquitination analysis.

    Results: SST upregulated MDM2 and Sirt1 levels, leading to MDM2 ubiquitination and subsequent degradation of DPP4 in BV2 cells. Moreover, SST downregulated IL-1β and IL-18 levels, LDH release, Aβ1-42 deposition, and the expressions of DPP4, NLRP3, N-gasdermin D (N-GSDMD), and caspase-1 in AD model cells (p < 0.001). These effects were reversed by MDM2 silencing (p < 0.001). However, Sirt1 overexpression counteracted the effects of MDM2 silencing on SST-treated model cells by reducing pro-inflammatory cytokine production, LDH release, Aβ1-42 deposition, and NLRP3-mediated pyroptosis (p < 0.001).

    Conclusion: SST activates the MDM2/DPP4/Sirt1 axis to inhibit NLRP3-mediated microglial pyroptosis and thereby alleviates AD. This discovery presents a promising strategy for AD therapy.

  • Article
    Chengzi Tian, Baoyi Huang, Danying Lu, Yanxiang Kong, Jiayu Huang, Lin Ma
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2195-2207. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.172
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    Background: Inflammation plays a crucial role in the pathogenesis of obesity, and complete blood cell count (CBC)-derived inflammatory indices have increasingly been studied as a novel biomarker class. The relevance of these biomarkers to obesity and prognostic outcomes, however, remains uncertain. Therefore, the present study was designed to assess the associations among CBC-derived inflammatory biomarkers, obesity, cardiovascular disease (CVD) mortality, and all-cause mortality in the general public.

    Methods: The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to conduct this analysis with data collected from 1999–2018. The relationships between CBC-derived inflammatory biomarkers and obesity were analyzed by multivariate logistic regression. Furthermore, the correlations between these CBC-derived inflammatory biomarkers and both CVD and all-cause mortality in obese individuals were assessed employing a weighted regression approach. However, the linearity of these relationships was evaluated utilizing a restricted cubic spline (RCS) regression approach. Moreover, a random survival forest (RSF) model was used to estimate the relative significance of certain inflammatory biomarkers as risk factors associated with all-cause mortality in obese individuals.

    Results: Multivariate analyses showed that the highest quartile of CBC-derived inflammatory indices was independently associated with a higher prevalence of obesity. RCS regression analyses revealed non-linear associations of CBC-derived inflammatory indices with CVD and all-cause mortality in obese individuals. Furthermore, RSF models identified the [neutrophils + monocytes]/lymphocytes ratio (NMLR) as the most important predictor of all-cause mortality.

    Conclusion: These analyses revealed that high CBC-derived inflammatory biomarker levels were linked to an increase in the prevalence of both general and abdominal obesity. Among obese individuals, the relationship between elevated CBC-derived inflammatory biomarker levels and both CVD and all-cause mortality conformed to a non-linear “U” shape. Furthermore, NMLR emerged as the most relevant predictor for all-cause mortality.

  • Article
    Ning Yu, Jingjing Cao, Shengxian Jiao, Zongkai Wu, Han Yan, Ge Feng, Yaran Gao, Henan Pan, Hebo Wang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2209-2219. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.173
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    Background: Chronic cerebral hypoperfusion (CCH) is recognized as a significant contributor to dementia disease due to the pathological development of white matter lesions (WMLs). This study aimed to investigate cerebral perfusion changes and identify significant differentially expressed genes in the white matter (WM) of a CCH rat model.

    Methods: CCH was induced in rats through bilateral common carotid artery occlusion (BCCAO) in the BCCAO group while the Sham group underwent blood vessel isolation without ligation. The study involved three cohorts. Cohort 1 (6 rats per group) was longitudinally tracked to assess cerebral perfusion using magnetic resonance imaging arterial spin labeling sequence. Cohort 2 (10 rats per group) underwent cognition assessment via the Morris water maze test and evaluation of myelin damage using Luxol Fast Blue. Cohort 3 rats (6 per group) underwent high-throughput sequencing to identify differentially expressed genes, with expression verified at the gene and protein levels. Furthermore, WM apoptosis was determined via Caspase-3 (CASP3) expression using western blot and double-label immunofluorescence.

    Results: The CCH group exhibited significantly decreased WM perfusion, cognitive impairment, and myelin disorganization and loss (p < 0.05). High-throughput sequencing identified decreased expression of guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene which was subsequently validated by real-time polymerase chain reaction (qRT-PCR) and western blot (p < 0.01). Double-label immunofluorescence further corroborated decreased GNAS and increased CASP3 expression in the WM of the BCCAO group compared to the Sham group (p < 0.01).

    Conclusion: These findings suggest that GNAS may be a protective factor in the WM during CCH. By targeting the GNAS pathway, researchers may be able to develop more effective treatments to delay or inhibit disease progression.

  • Article
    Qinghua Li, Yuantao Wang, Junkai Zhu, Kai Yu, Yanhua Lu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2221-2233. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.174
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    Background: Burn injuries are closely associated with significant morbidity and mortality. Furthermore, immune and distributive shock, often correlated with severe burns, can lead to multiple organ failure. Therefore, this study aimed to investigate differentially expressed genes (DEGs) and develop a diagnostic model for burn injuries.

    Method: RNA-seq data and clinical information of both burn injury and control samples in GSE19743, GSE77791, and GSE37069 datasets were obtained from Gene Expression Omnibus (GEO). DEGs were identified using the limma package. Moreover, functional enrichment analysis was performed utilizing the WebGestaltR package, while protein-protein interaction (PPI) analysis was conducted using a Cytoscape package. A novel diagnostic model was developed employing the least absolute shrinkage and selection operator (Lasso) regression and eXtreme Gradient Boosting (XGBOOST) package using the data from the GSE77791 dataset.

    Result: A total of 1950 DEGs, 1033 DEGs, and 865 DEGs were identified between burn injury and control groups in GSE19743, GSE77791, and GSE37069, respectively. The DEGs were closely associated to immune of burn patients. Gene set enrichment analysis (GSEA) revealed that four immune-related pathways were impeded in the burn injury group. Moreover, the burn injury patients persistently exhibited an immunosuppressed state. PPI analysis determined 13 hub genes, six of which were used to establish diagnostic model. Furthermore, the model showed high accuracy, sensitivity, and specificity with F1-Score (all 1). Additionally, the model showed an area under the receiver operating characteristic (ROC) curve (AUC) of 1 in the GSE77791 dataset, which was successfully validated in the GSE19743 dataset.

    Conclusions: This study determined 13 hub genes associated with immune, six of which were used to develop a diagnostic model for predicting the status of burn injury patients.

  • Article
    Taomei Lian, Chao Liang, Xi Bai, Qiang Zhang, Xiaohua Cui, Zheng Li, Kunying Li
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2235-2247. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.175
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    Background: NudC domain containing 1 (NUDCD1) plays a significant regulatory role in pulmonary fibrosis (PF). Similarly, the expression patterns of Glutathione Peroxidase 4 (GPx4) and Fibroblast-specific protein 1 (FSP1) are closely associated with the fibrotic process. However, it is not clear whether the regulatory mechanism of NUDCD1 in PF is related to GPx4 and FSP1. Therefore, this study aimed to investigate the role of NUDCD1 in PF and delve into the underlying mechanism of this disease progression.

    Methods: Initially, expression levels of NUDCD1 were assessed in PF using Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blot analysis, and Hematoxylin and Eosin (H&E) techniques. Furthermore, a silica (SiO2)-induced pulmonary fibrosis cell model was developed. The cell models were subjected to various treatments, including Ferrostatin-1 (Fer-1) treatment, DNA methyltransferase inhibitor treatment, and transfection with siRNA and overexpression plasmid. Moreover, the effect of NUDCD1 knockdown was evaluated on iron death, apoptosis rates, and oxidative stress levels. Furthermore, the expression levels of NUDCD1, GPx4, and FSP1 were assessed in Type I alveolar epithelial (AECI) cells. Additionally, a bleomycin-induced PF mouse model was employed to assess the therapeutic effects of siRNA NUDCD1 transfection complex using various techniques, including qRT-PCR, Western blot analysis, H&E and Masson staining, and Enzyme-Linked Immunosorbent Assay (ELISA).

    Results: We observed that NUDCD1 was upregulated in PF. PF tissues exhibited severe collagen fiber deposition, significant cellular structural damage, and notable lipid oxidative damage (p < 0.01). Furthermore, Fer-1 and 5-Azacytidine (5-Aza) treatment significantly alleviated oxidative damage in PF and upregulated the expression of GPx4 and FSP1 (p < 0.05 and p < 0.01). Additionally, NUDCD1 knockdown significantly increased the expression of GPx4 and FSP1 (p < 0.01), while reducing the iron and Malondialdehyde (MDA) levels in the PF cell model (p < 0.05 and p < 0.01). Moreover, NUDCD1 knockdown reduced oxidative damage, mitigated cellular structural damage, and inhibited fibrosis in the PF animal model (p < 0.05 and p < 0.01). Additionally, reduced NUDCD1 level downregulated Alpha Smooth Muscle Actin (α-SMA) and Collagen I expression (p < 0.01), and upregulated GPx4 and FSP1 expression (p < 0.01).

    Conclusion: NUDCD1 was upregulated in PF. NUDCD1 mediated iron-dependent cell death by suppressing the expression of GPx4 and FSP1 genes through epigenetic mechanisms, thereby promoting the progression of PF.

  • Article
    Jianfeng Song, Yang Li, Fupeng Wu, Zichen Xie, Keyu Sun
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2249-2260. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.176
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    Background: Procyanidin B1 can attenuate inflammation, but its specific impact and mechanism on sepsis-related acute lung injury (ALI) are obscure. Therefore, this study aimed to explore the effect and mechanism of Procyanidin B1 on the lipopolysaccharide (LPS)-mediated human pulmonary alveolar epithelial cells (HPAEpiCs) injury.

    Methods: The effect of varying concentrations of Procyanidin B1 (50, 100, 150, or 200 μM) on the viability of HPAEpiCs cells and LPS-mediated HPAEpiCs was assessed using cell counting kit-8. After Procyanidin B1 treatment, the proliferation and apoptosis of LPS-mediated HPAEpiCs, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were evaluated employing colony formation assay, flow cytometer, and angiogenesis experiments. Endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and inflammation were examined using quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and western blot analysis. The effects of Procyanidin B1 and L-N-nitro-L-arginine methyl ester (L-NAME) on inflammation and eNOS/NO/cGMP pathway were assessed employing ELISA, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis.

    Results: Different concentrations of Procyanidin B1 (50, 100, 150, or 200 μM), which was not toxic to normal cells, enhanced LPS-mediated HPAEpiCs activity (p < 0.05), proliferation (p < 0.05), and eNOS expression (p < 0.01). However, Procyanidin B1 reduced apoptosis of LPS-mediated HPAEpiCs (p < 0.05) and stimulated angiogenesis of HUVEC (p < 0.01). Moreover, Procyanidin B1 repressed inflammation, endothelin-1 (ET-1), and inducible nitric oxide synthase (iNOS) levels and enhanced the NO production, cGMP, eNOS, and phosphorylated eNOS levels in LPS-mediated HPAEpiCs (p < 0.05). However, these effects were counteracted by L-NAME (p < 0.05).

    Conclusions: Procyanidin B1 protected HPAEpiCs from LPS-mediated inflammation damage by modulating the eNOS/NO/cGMP pathway.

  • Article
    Keserla Bhavani, Muthukumar A, Kuntal Das, Purushotham M, Mansour Almuqbil, Moneer E. Almadani, Syed Arif Hussain, Bader Hussain Alamer, Ebtesam Abdulrahman Jibreel, Syed Imam Rabbani, Syed Mohammed Basheeruddin Asdaq
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2261-2268. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.177
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    Background: Drug-induced acute liver damage is a contributing factor in nearly 50% of acute liver failures. Acute liver failure has been linked to pharmaceutical overdoses, particularly with paracetamol. Plant-based medication could be a possible agent for mitigating the effects of paracetamol overdose. The present study investigated Pimenta dioica (PD) berries extract for its hepatoprotective properties against paracetamol-induced liver toxicity in rats.

    Materials and Methods: Two chemicals, paracetamol and silymarin, were used in this study. Furthermore, fully mature berries of PD were used to extract the bioactive constituents in 90% ethanol. Moreover, male Wistar albino rats (n = 40) were used to assess the hepatoprotective activity. For this purpose, hepatotoxicity was induced by orally administering 2 g/kg body weight of paracetamol. The rats were divided into five groups. Group I (control group) received 1 mL/kg of 1% sodium carboxymethyl cellulose. Group II (hepatotoxic control group) received an oral dose of 2 g/kg of paracetamol. Group III was given silymarin at a dose of 100 mg/kg. Group IV and V received PD at 200 mg/kg and 400 mg/kg, respectively. The liver was surgically excised to calculate relative liver weight and histopathological examination in different rat groups. Blood samples were collected from the retro-orbital plexus on the 8th day of treatment and examined for serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) content, and gamma-glutamyl transferase (GGT) levels. The data were statistically analyzed using a one-way Analysis of Variance (ANOVA), with a p-value < 0.05 considered significant.

    Results: It was observed that paracetamol significantly increased (p < 0.001) relative liver weight as well as liver biomarker enzymes such as ALP, ALT, AST, TB, and GGT. Furthermore, paracetamol caused histological alterations in the hepatocytes. Moreover, Pimenta dioica (PD) significantly inhibited (p < 0.001) paracetamol-induced changes in relative liver weight, liver biomarkers levels, and hepatocyte histopathology in a dose-dependent manner.

    Conclusion: These findings suggest that PD possesses hepatoprotective properties against paracetamol-induced hepatocellular damage. Although, based on the current findings, it is difficult to speculate on the precise mechanism of action, attenuation of paracetamol-induced generation of free radicals could be one of the mechanisms. Therefore, further investigation to identify potentially active components and to establish the precise mechanism of action for its hepatoprotective effect could make PD a novel candidate for therapeutic use.

  • Article
    Meng Xu, Shengnan Gao, Kai Wang, Zizhao Guo, Xiaolei Wang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2269-2279. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.178
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    Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and one of the malignant tumors with poor prognosis. To gain insights into HNSCC, we analyzed the proteome and phosphoproteome between cancerous and paracancerous normal tissue samples using quantitative mass spectrometry.

    Methods: Proteins were extracted from five pairs of tumor-normal samples and digested for data-independent acquisition mass spectrometry. Subsequently, phosphopeptides were enriched using TiO2 and prepared for phosphoproteome detection. A bioinformatics analysis was then conducted to identify potential biomarkers for HNSCC.

    Results: A total of 1239 protein groups and 2025 phosphorylation sites were differentially expressed. Among these, KRT16, MUC21, SH3BGRL2, ASL, and METTL7A were selected as biomarkers for HNSCC.

    Conclusions: This study presents a comprehensive and quantitative analysis using mass spectrometry of five pairs of NHSCC samples, including five adjacent non-cancerous tissues, unveiling five potential protein biomarkers for HNSCC.

  • Article
    Jing-fang Wang, Wen-hao Wang, Fang Wei, Wei-hong Zhao, Ke-yan Cheng, Li-li Zhang, Xin Bai, Rui Zhang, Wei-min Kong
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2281-2291. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.179
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    Background: Ovarian cancer (OC), the third most common gynecological tumor, has a high mortality rate. Epidemiological data suggest that metformin may be useful for treating OC patients, however, the relevant mechanisms remain unclear. This study aimed to decipher the mechanism of metformin in the treatment of OC.

    Methods: The OC cell lines A2780 and SKOV3 were subjected to metformin treatment (10 mM) alone or in combination with an mammalian target of rapamycin (mTOR) agonist (2 nM MHY1485), concurrently suppressing Cyclin B1 (CCNB1) expression. Then, Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell, and wound healing assays were performed to observe cell proliferation, migration, invasion, and apoptosis, respectively. In addition, Western blot and quantitative reverse transcription PCR (qRT-PCR) were used to test the expression of CCNB1, phosphatidylinositol-3-kinase (PI3K)/mTOR signaling pathway-related proteins, and epithelial-mesenchymal transition (EMT)-associated molecules (Vimentin, E-Cadherin).

    Results: Metformin significantly inhibited the OC cells proliferation, migration and invasion, while inducing apoptosis. Meanwhile, metformin significantly inhibited CCNB1 expression. Reducing CCNB1 expression enhanced the inhibitory effect of metformin on OC cells. Additionally, metformin inhibited the PI3K/mTOR signaling pathway proteins and Vimentin expression, while upregulating E-Cadherin expression. However, mTOR agonist partially reversed the effect of metformin on OC cells.

    Conclusions: Metformin reduced CCNB1 expression, inhibited EMT and the PI3K/mTOR signaling pathway, which in turn inhibited OC cell function.

  • Article
    Siyi Liu, Qiuying Li, Guiyan Zhang, Shitong Huang, Meifen Wu, Jian Zhuang, Liming Lei
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2293-2305. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.180
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    Background: Ductus arteriosus (DA) close depends on the mature development and extracellular matrix (ECM) accumulation of vascular smooth muscle cells (VSMCs). This study aims to explore the function and interaction of transforming growth factor β (TGF-β) and Notch signaling pathway on VSMCs.

    Methods: An in vitro experiment was conducted on mouse VSMCs and supplementations of TGF-β, Notch signaling pathway ligand (Jagged-1), and inhibitor SAHM1. Transfections were constructed on VSMCs with two siRNAs of Smad4 and overexpressed Smad4 plasmid. ELISA measured the reactive oxygen species (ROS) level. Cell apoptosis was evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry. Immunofluorescence (IF) analysis was used to detect the expression and localization of Smad4. The expression levels of ECM-related proteins and Smads were measured by western blotting and real-time quantitative PCR (RT-qPCR) analyses.

    Results: The higher concentration of TGF-β1 induced cell apoptosis (p < 0.001), increased ROS level (p < 0.001), and promoted ECM accumulation by regulating nuclear Smad4. Silencing Smad4 significantly impeded ECM accumulation induced by TGF-β1. The Notch pathway ligand Jagged-1 promoted ECM formation and activated Smad2–4 proteins, while Notch pathway inhibitor SAHM1 had the opposite effect. Further results confirmed that the Notch pathway induced Smad4 transcription (p < 0.001), thereby enhancing the function of the TGF-β1/Smads pathway. Moreover, Smad4 overexpression was found to induce ECM accumulation.

    Conclusions: Our present study explored the interaction of the Notch and TGF-β signaling pathways on ECM accumulation of VSMCs. The Notch pathway induced the transcription of Smad4, leading to enhanced ECM accumulation in VSMCs. This effect is achieved through co-regulation with TGF-β1.

  • Article
    Xin Chen, Bo Liu, Zengren Zhao, Meng He, Kuaiyun Yu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2307-2318. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.181
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    Background: Colorectal cancer (CRC) stands out as one of the most widespread and life-threatening malignancies globally. In recent years, significant attention has been directed towards the Yes-associated protein 1 (YAP1), identified as the central effector molecule in the Hippo signaling pathway, highlighting its crucial involvement in CRC development. Nevertheless, the role of hematopoietic SH2 domain-containing (HSH2D) in CRC, and its impact on tumor progression and resistance to chemotherapy by modulating YAP1, remains unclear. Therefore, this study aims to explore the role of HSH2D in CRC and assess its potential therapeutic significance.

    Methods: The study included the analysis of HSH2D expression levels in CRC tissues and cells by immunohistochemistry and western blot techniques. The influence of HSH2D on CRC cell proliferation and migration was examined using RNA interference and overexpression systems. The regulatory impact of HSH2D on YAP1 expression was assessed through real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and immunoblotting. In vitro cell experiments were conducted to unravel the mechanism by which HSH2D promotes CRC progression through YAP1. Lastly, the study investigated the role of HSH2D in modulating the sensitivity of CRC cells to cisplatin by chemosensitivity experiments.

    Results: The experimental findings demonstrated a notable elevation in HSH2D expression within both CRC tissues and cells. Overexpression of HSH2D was found to enhance the proliferation and migration capabilities of CRC cells, whereas silencing HSH2D had the opposite effect. Subsequent investigations unveiled that HSH2D upregulated YAP1 expression, and the tumor-promoting influence of HSH2D was, in part, dependent on YAP1. Furthermore, heightened HSH2D expression correlated with increased resistance of CRC cells to cisplatin.

    Conclusion: This study marks the initial identification of HSH2D upregulation in CRC and its role in advancing the progression and chemoresistance of CRC by modulating YAP1. HSH2D emerges as a promising novel target for CRC treatment, suggesting a potential therapeutic strategy. Future research should delve deeper into the specific interaction mechanisms between HSH2D and YAP1, aiming to effectively target this pathway for enhanced CRC treatment.

  • Article
    Xiu Zhang, Yu Chen, Jiale Mi, Kang Kang, Mingde Huang, Kai Chen
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2319-2330. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.182
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    Background: Pyrroline-5-Carboxylate Reductase 2 (PYCR2) demonstrates abnormal expression in various tumors and is intricately associated with tumor progression and prognosis. However, its expression and roles in esophageal squamous cell carcinoma (ESCC) remain unknown. The objective of this research is to explore the expression, effects, and underlying mechanisms of PYCR2 in ESCC.

    Methods: In this study, we performed immunohistochemical analysis on ESCC tissues to assess PYCR2 expression levels and their correlation with clinical parameters. Subsequently, we utilized in vitro assays and RNA sequencing to elucidate the functional roles of PYCR2 in ESCC cells. The primary objective was to comprehend the impact of PYCR2 on key cellular processes, including proliferation, migration, invasion, apoptosis, and its potential involvement in ferroptosis through the kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid-2 (NRF2) pathway.

    Results: Our findings suggest an upregulation of PYCR2 expression in ESCC, which correlates with a poorer prognosis in patients exhibiting increased PYCR2 levels (p < 0.05). Knocking down PYCR2 inhibits proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT), while concurrently promoting apoptosis (p < 0.05). Furthermore, our results indicate that PYCR2 knockdown induces ferroptosis by inhibiting the KEAP1-Nrf2 pathway.

    Conclusion: In conclusion, this study suggests that PYCR2 plays a crucial role in the malignant progression of ESCC and emerges as a promising new biomarker and potential therapeutic target in ESCC.

  • Article
    Hongxu Tian, Zhenying He, Ying Sun, Furong Zhao, Yun Wang, Lei Guo
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2331-2340. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.183
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    Purpose: DEXD/H box helicase 60 (DDX60) overexpression in oral squamous cell carcinoma (OSCC) specimens has been reported extensively. Nevertheless, the radiosensitization implications of high-level DDX60 expression in OSCC remain unknown. This study aimed to investigate the biological function of DDX60 and confirm whether the inhibition of DDX60 could enhance radiosensitivity.

    Methods: DDX60 expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis. After combination treatment of irradiation with or without DDX60-siRNA (small interfering RNA), the cell malignant behavior was determined using cell counting kit-8 (CCK-8) assay, flow cytometry, and transwell assays. The HSC6 xenograft models were utilized to measure the in vivo effects of combined treatment.

    Results: DDX60 was overexpressed in OSCC tissues and cells (p < 0.01, p < 0.05). HSC6 and SAS cells were transformed with DDX60-siRNA plasmids specifically reduced DDX60 gene expressions (p < 0.001, p < 0.01). DDX60 silencing notably hindered the proliferation and invasive abilities, and accelerated the apoptosis process (p < 0.01, p < 0.05). Suppression of DDX60 could enhance the 4 Gy irradiation-induced inhibiting in OSCC cell proliferation and invasion in HSC6 and SAS cells (p < 0.01, p < 0.05). Furthermore, the inhibition of DDX60 could promote the 4 Gy irradiation-induced apoptosis in HSC6 and SAS cells (p < 0.01, p < 0.05). Suppression of DDX60 also inhibited tumor growth in the HSC6 xenograft model (p < 0.01).

    Conclusions: The inhibition of DDX60 expression can promote radiosensitizing activity in human OSCC. Our results reveal that a multimodal therapy involving DDX60 expression inhibitors might be an effective radiosensitizer strategy in OSCC.

  • Article
    Yu Chang, Zu-rui Geng, Yu Wang, Lei Zhang, Xi-yang Liu, Zhao-ming Li, Ji-wei Li, Ming-zhi Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2341-2350. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.184
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    Background: The role of cytokines in predicting the diagnosis of extranodal nature killer/T-cell lymphoma-associated hemophagocytic syndrome (ENKL-LAHS) has been reported. This retrospective study aimed to analyze the cytokine profile in nasal type ENKL-LAHS.

    Methods: Sixty patients diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) were divided into two groups: ENKL-LAHS group (n = 30) and ENKL group (n = 30), based on the presence of lymphoma-associated hemophagocytic syndrome (LAHS). Peripheral blood cytokine levels were compared between the two groups. A logistic regression model was applied to assess the relationship between serum cytokine levels and ENKL-LAHS. The predictive values of serum cytokines for ENKL-LAHS were determined through receiver operating characteristic (ROC) curves.

    Results: Compared to the ENKL group, the ENKL-LAHS group exhibited significantly elevated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.001), granulocyte-colony stimulating factor (G-CSF) (p = 0.001), interferon-gamma (IFN-γ) (p = 0.003), interleukin (IL)-10 (p < 0.001), IL-15 (p < 0.001), IL-1 receptor antagonist (IL-1ra) (p < 0.001), IL-8 (p < 0.001), macrophage inflammatory protein 1α (MIP-1α) (p < 0.001), interferon-gamma inducible protein-10 (IP-10) (p < 0.001), MIP-1β (p < 0.001) and tumor necrosis factor α (TNF-α) (p < 0.001). Conversely, the levels of monocyte chemoattractant protein-1 (MCP-1) (p = 0.002) and soluble CD40 ligand (sCD40L) (p < 0.001) were significantly decreased. Logistic multivariate analysis revealed that the concentrations of cytokines IL-8 (p < 0.001), IL-10 (p = 0.016), IL-15 (p = 0.026), IFN-γ (p = 0.034), GM-CSF (p = 0.012), G-CSF (p = 0.001), sCD40L (p < 0.001), and TNF-α (p = 0.024) correlated with ENKL-LAHS. ROC curve analysis showed that the sCD40L/GM-CSF/IL-8 model exhibited better predictive value (the area under the curve (AUC): 0.973).

    Conclusion: sCD40L, GM-CSF, and IL-8 have a strong predictive value for ENKL-LAHS and can serve as reliable predictors for this condition.

  • Article
    Fanli Liu, Lei Zheng, Bo Zheng
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2351-2359. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.185
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    Background: Allergic rhinitis (AR) is a common autoimmune disease of the upper airway accompanied by prominent comorbid conditions. Cimifugin is a major constituent of Saposhnikovia divaricatae that is widely implied in the treatment of allergic diseases. This study aims to investigate the impacts of cimifugin on the process of AR and to ascertain the indistinct underlying mechanisms.

    Methods: Initially, AR mice models were developed and allergic symptoms in mice were observed. Hematoxylin and eosin (H&E) staining and toluidine blue staining were employed to assess the infiltration of eosinophils and mast cells in the nasal mucosa tissues of mice. Moreover, serum ovalbumin (OVA)-specific immunoglobulins levels, and levels of Th2 and Th1 cytokines were evaluated in the nasal lavage fluid using their corresponding enzyme-linked immunosorbent assay (ELISA) Kits. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay and western blot analysis were used to examine cell apoptosis. Furthermore, western blot analysis was used to determine the expression level of Sirtuin 2 (SIRT2) both in vitro and in vivo. Additionally, cell counting kit-8 (CCK-8) assay was utilized to examine cell viability and ELISA was used to estimate inflammatory levels. Moreover, reverse transcription-quantitative PCR (RT-qPCR), western blot analysis and IF assay were employed to determine the expression levels of mucin 5AC (MUC5AC).

    Results: It was noticed that cimifugin eased allergic symptoms and nasal mucosal inflammation, declined serum OVA-specific immunoglobulins and Th2 cytokines levels, and suppressed apoptosis in the OVA-induced AR murine model. Moreover, the cimifugin targeted SIRT2 and fortified SIRT2 expression both in vitro and in vivo. Furthermore, SIRT2 interference reversed the impacts of cimifugin on the inflammation and mucus production in interleukin-13 (IL-13)-exposed human nasal epithelial cells (hNECs).

    Conclusion: In conclusion, the cimifugin protected against OVA-triggered allergic symptoms and inflammation in AR by elevating SIRT2 expression.

  • Article
    Eman Fayad, Refaat A. Eid, Waleed K. Abdulsahib, Mohamed Samir A. Zaki, Dalal Nasser Binjawhar, Dalal Sulaiman Alshaya, Sarah Awwadh Altalhi, Ghadi Alsharif, Amir Helmy Elwishahy, Nahla H. El-shaer, Mohamed A. Soltan
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2361-2380. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.186
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    Background: Cyclin-dependent kinases regulatory subunit 2 (CKS2) has an essential biological function as it binds to the cyclin-dependent kinases' catalytic site, which in turn regulates the cell cycle. Hence, malfunction of CKS2 can be finally translated as an irregular cell cycle and malignancy progression. The current study aimed to comprehensively analyze the oncogenic roles of CKS2 in a pan-cancer model focusing on the interference of CKS2 expression with the infiltration of different immune components in the tumor microenvironment.

    Methods: Here, we applied a comprehensive bioinformatics analysis based on the available data in different databases to investigate the expression levels and the genetic, and epigenetic modifications that occurred to CKS2 and checked the possible correlation of those events with the abundance of immune factors with variable functions.

    Results: CKS2 was found to be overexpressed in multiple human cancers and that resulted in cancer progression in terms of stage and grade in addition to shorter patients' survival under different models. Enhanced infiltration and release of Myeloid-derived suppressor cell (MDSC) and Chemokine ligand 8 (CCL8) with the opposite trend in Natural killer (NK) cells and CCL14 correlated to CKS2 expression was detected as a potential immunological mechanism of CKS2 cancer progression induction. Additionally, the interaction network revealed cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinases regulatory subunit 1B (CKS1B), cell division cycle protein 20 (CDC20), G2/Mitotic-Specific Cyclin-B1 (CCNB1), and G2/Mitotic-Specific Cyclin-B2 (CCNB2) as proteins closely associated with CKS2, where that network represented the molecular mechanism for CKS2 tumor induction.

    Conclusions: Collectively, the current study nominates CKS2 and a potential biomarker and therapeutic target in a pan-cancer model.

  • Article
    Xiaoqian Wu, Wenjing Tang, Jin Shi, Jingjing Dai, Wubi Zhou, Wen Zhuang, Chuanli Ren, Yong Liang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2381-2390. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.187
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    Background: RNASEH2A, also known as ribonuclease H2 subunit A, plays a vital role in regulating tumorigenesis and progression. Nonetheless, our understanding of the biological roles of RNASEH2A in gastric cancer (GC) is still limited. Hence, this investigation aimed to explore the impact of RNASEH2A on various cellular processes, including proliferation, migration, invasion, and apoptosis, in GC cells derived from humans.

    Methods: RNASEH2A expression in GC tissues and cell lines was analyzed using the GEPIA database, immunohistochemistry, and immunocytochemistry. A total of 150 paired GC samples and adjacent normal tissues were collected for tissue microarray analysis. Various assays, including Cell Counting Kit-8 (CCK-8), scratch healing, transwell, western blotting, and Annexin V/Propidium iodide (PI) staining, were conducted to assess the influence of RNASEH2A on proliferation, migration, invasion, and apoptosis in GC cells.

    Results: The results showed that the expression level of RNASEH2A was upregulated in GC tissues and cells (p < 0.05). Furthermore, the T stage, N stage, cancer stage, and lymph node metastasis were positively correlated with RNASEH2A expression (p < 0.05). RNASEH2A silencing substantially decreased the proliferation, clone formation capacity, migration, and invasion, while increasing apoptosis in GC cells (p < 0.05).

    Conclusions: Our results indicate that RNASEH2A can promote GC cell proliferation, migration, and invasion, while inhibiting apoptosis, thereby contributing to the emergence of GC. RNASEH2A could be a therapeutic target for GC treatment strategies.

  • Article
    Shiming Dong, Cheng Liu, Xiaochen Bao, Nan Wang, Yiqun Fang, Meili Guo, Chun Liang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2391-2402. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.188
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    Background: Decompression sickness (DCS) is a common condition found in divers. However, the role of neutrophil extracellular traps (NETs) in the development of DCS is still unknown. This study sought to investigate the underlying mechanism of endothelial injury caused by NETs.

    Methods: A DCS mouse model was developed to assess the therapeutic effect of regadenoson (a selective A2A adenosine receptor agonist) in these models. The mice were divided into three groups: the control, model, and model+regadenoson (REG) groups. The DCS mouse model was established by applying a computer-controlled steel hyperbaric oxygen chamber to create a DCS-like environment. Moreover, the histopathological score of the lung tissues excised from treated mice was determined using Hematoxylin and Eosin (H&E) staining. Furthermore, the levels of tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), IL-16, IL-13, and IL-1β were evaluated using Real-time PCR. NETs were assessed using the double fluorescence staining method. Additionally, the activation levels of the phosphatidylinositol-3 kinase/a serine/threonine protein kinase (PI3K/AKT) signaling pathway were determined using Western blot analysis.

    Results: We found that regadenoson contributed to reducing lung inflammation and vascular endothelial injury. Additionally, regadenoson activated A2A receptors and upregulated the expression of prefoldin subunit 6 (PFDN6) protein (p < 0.05), thereby suppressing the formation of NETs. Moreover, NETs adversely affected the viability, and migration ability and caused cellular injury of endothelial cells by inhibiting a serine/threonine protein kinase (AKT) signaling pathway. However, regadenoson interrupted this effect by suppressing the formation of NETs. Moreover, regadenoson significantly reduced lung inflammation and endothelial damage (p < 0.05).

    Conclusions: Regadenoson holds promising potential in treating DCS.

  • Article
    Shanyu Gao, Xiaoming Liu, Congcong Liu, Lin Guo, Liwei Yan, Chunhua Chi, Jiulian Liu, Jiaxin Dong, Dingwei Zhen, Tong Liu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2403-2413. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.189
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    Background: Colon cancer (CC) is a prevalent malignant tumor, that is widely treated with chemotherapy drug, such as 5-fluorouracil+oxaliplatin (FOLFOX). However, the emergence of FOLFOX resistance poses a significant challenge to its therapeutic efficacy. This study aimed to investigate the effect of farnesyl-diphosphate farnesyltransferase (FDFT1) on the progression of FOLFOX-resistant CC cells.

    Methods: The human CC cells, including HCT-116 and HT-29, were used in establishing a chemotherapy-resistant cell model by their exposure to FOLFOX. Furthermore, these cells were transfected with either FDFT1-overexpression plasmid or empty vector. The impact of FDFT1 expression on the FOLFOX-resistant CC cells was evaluated by assessing the levels of cancer stem cell markers using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analysis. Furthermore, the colony formation and the DNA damage/condensation were examined employing the colony forming assay and 4′,6-diamidino-2-phenylindole (DAPI) nuclei staining method, respectively. Moreover, western blot analysis was used to determine the levels of chemotherapy-resistance-related proteins, cell proliferation-related epidermal growth factor receptor (EGFR), and autocrine/juxtacrine pathway-related transforming growth factor alpha (TGF-α). Finally, the apoptosis rate in the transfected cells was assessed utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and flow cytometry.

    Results: The FDFT1 was downregulated in FOLFOX-resistant cells (p < 0.01) and cell transfection successfully upregulated FDFT1 in FOLFOX-resistant cells (p < 0.01). Furthermore, FDFT1 overexpression substantially reduced cancer stem cell markers (p < 0.01), inhibited tumor sphere formation (p < 0.01), increased DNA condensation (p < 0.001), and suppressed drug-related proteins (p < 0.001) in FOLFOX-resistant cells. Moreover, overexpression of FDFT1 suppressed the cell proliferation and reduced the activity of autocrine/juxtacrine signaling in FOLFOX-resistant cells by downregulating EGFR (p < 0.001) and TGF-α (p < 0.001). Additionally, FDFT1 increased apoptosis in FOLFOX-resistant cells when exposed to FOLFOX (p < 0.01).

    Conclusion: This study revealed an inhibitory role of FDFT1 in FOLFOX-resistant CC cells. Overexpression of FDFT1 can reduce cancer stem cell markers and inhibit tumor proliferation. Additionally, overexpression of FDFT1 suppressed the activity of autocrine/juxtacrine signaling, leading to increased cell apoptosis. These findings suggest FDFT1 as a potential therapeutic target and offer new insights for improving the efficacy of FOLFOX.

  • Article
    Xing Wei, Haitao Liu, Weizhe Fan, Gang Guo
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2415-2426. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.190
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    Background: Stigmasterol has been reported to inhibit the growth and proliferation of various cancer types, including prostate cancer. However, its inhibitory mechanism in prostate cancer remains unclear. Therefore, this study aimed to investigate the underlying inhibitory mechanisms of stigmasterol in prostate cancer.

    Methods: Initially, PC-3 and DU145 cells were treated with various concentrations of stigmasterol (0, 1, 2, 5, 10, 20, 50, and 100 μM). After this, the cell viability of treated cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Moreover, the cell cycle, apoptosis rate, reactive oxygen species (ROS) production, Ca2+ levels in cytosol or mitochondria, and loss of mitochondrial membrane potential (MMP) were determined through functional experiments, including flow cytometry and JC-1 staining. Furthermore, apoptosis-related proteins were evaluated employing Western blot analysis. Additionally, to block mitochondrial Ca2+ influx, the cells were treated with 4, 4′-diisothiocyanostilbene-2, 2′-disulfonic acid (DIDS) before stigmasterol treatment. Rescue experiments were conducted to examine the expression of the c-Jun N-terminal kinase-2 (JNK2)/p38 pathway using Western blot analysis.

    Results: Stigmasterol shortened the G1 phase and expanded the G2/M phase, promoted cell apoptosis, induced ROS production, enhanced loss of MMP, increased Ca2+ overload, and up-regulated apoptosis-related proteins, including cleaved caspase-3, cleaved caspase-9, and cytochrome C, as well as Bcl2-associated X protein (Bax). However, DIDS treatment partially counteracted the afore-mentioned characteristics in prostate cancer cells induced by stigmasterol. Interestingly, DIDS treatment significantly reversed the stigmasterol-induced inhibition of JNK2 and p38 in PC-3 and DU145 cells.

    Conclusion: Stigmasterol promoted apoptosis in prostate cancer cells through ROS accumulation, loss of MMP, mitochondrial Ca2+ overload, and inhibition of the JNK2/p38 signaling pathway.

  • Article
    Yanxia Sun, Bo Yang, Hongmei Zheng, Heng Cai, Wenjuan Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2427-2434. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.191
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    Background: SRY-Box Transcription Factor 9 (SOX9) is involved in transforming growth factor (TGF)-β-induced atrial fibrosis, an important pathological feature of atrial fibrillation (AF). This study aims to investigate the role of SOX9 in AF.

    Methods: Sprague-Dawley rats were used to develop an AF model. The incidence and duration of AF were recorded using electrocardiography. Atrial fibrosis and tissue damage were analyzed through Masson staining and hematoxylin-eosin staining. The level of hydroxyproline was measured using spectrophotometric kits. Immunohistochemistry was performed to quantify SOX9 and α-smooth muscle actin (α-SMA). The expressions of inflammatory factors were calculated using quantitative real-time polymerase chain reaction (qRT-PCR), and the expressions of proteins related to the protein kinase B (AKT) signaling pathway and epithelial-to-mesenchymal transition were measured by Western blot.

    Results: AF was successfully induced in rats, characterized by the absence of P-wave and the presence of typical F-wave. Overexpression of SOX9 increased the incidence and duration of AF, as well as exacerbated atrial fibrosis and inflammatory damage. In contrast, the silencing of SOX9 had the opposite effects in the AF model rats. The levels of hydroxyproline and the expression levels of SOX9, α-SMA, and inflammatory factors were elevated in AF rats. Additionally, the elevation was further enhanced by SOX9 overexpression but suppressed by SOX9 silencing. SOX9 overexpression promoted the up-regulation of β-catenin, Collagen I, Vimentin, and phosphorylated proteins of Focal adhesion kinase (FAK)/AKT/S6 kinase (S6K), and the downregulation of E-cadherin. However, SOX9 silencing exerted opposite effects in AF rats.

    Conclusions: SOX9 deficiency improves atrial fibrosis and inflammation in AF rats and inhibits the AKT-S6K and β-catenin proteins.

  • Article
    Yachen Wang, Mingming Sun, Yi Li, Xiaodan Guo, Zhongzhi Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2435-2446. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.192
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    Background: Glaucoma, characterized by retinal ganglion cell axons and optic disc cupping degeneration, is strongly associated with elevated intraocular pressure. This study aimed to elucidate the potential role and underlying mechanisms of hydrostatic pressure in the activation of astrocytes.

    Methods: Astrocytes were subjected to 0 mmHg in the incubator or to hydrostatic pressure in 20, 30, 40, 50 and 60 mmHg in a pressurized incubator for 24 hours. Additionally, astrocytes were treated with varying concentrations of AG490 (10, 15, or 20 μM) under 40 mmHg pressure. The expressions of glial fibrillary acidic protein (GFAP), interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway-related proteins were analyzed using Western blot or real-time reverse transcription quantitative polymerase chain reaction.

    Results: Hydrostatic pressure significantly increased the mRNA and protein expression of GFAP (p < 0.05), elevated the mRNA levels of IL-1β, TNF-α, IL-6, and iNOS in astrocytes (p < 0.05), and enhanced the levels of IL-1β, TNF-α, IL-6, and NO in astrocytes supernatants (p < 0.05). Furthermore, the JAK2/STAT3 signaling pathway was activated in response to hydrostatic pressure (p < 0.05). Treatment with AG490 mitigated the effects of hydrostatic pressure on GFAP, IL-1β, TNF-α, IL-6, iNOS expression, and JAK2/STAT3 pathway activation (p < 0.05).

    Conclusions: Hydrostatic pressure induces the activation of astrocytes and inflammation through the promotion of the JAK2/STAT3 signaling pathway. Therefore, the JAK2/STAT3 pathway is a promising target to control the activation of astrocyte in glaucoma.

  • Article
    Ming Lin, Junjun Liu, Liangliang Lv
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2447-2455. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.193
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    Background: The cartilage degeneration and the other changes in joint components induced by osteoarthritis (OA) can result in disability. This study aims to elucidate the underlying mechanism and explore novel treatment options for OA.

    Methods: The chondrocytes were treated with H2O2 to induce OA. The cells were transfected with small interfering RNA targeting E26 transformation-specific proto-oncogene 2 (siETS2) to investigate the role of ETS2. The viability and apoptosis in the treated cells were examined using cell counting kit-8 assay and flow cytometry, respectively. Moreover, an enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factors. Cistrome was used to predict the binding interactions between Jun B proto-oncogene (JUNB) and ETS2, and Jaspar was employed to predict their binding sites. These binding interactions were validated using dual-luciferase reporter assay and chromatin immunoprecipitation analysis. Furthermore, Western blot analysis and quantitative real-time polymerase chain reaction were utilized to assess the expression levels of matrix metalloproteinase (MMP) 1/3/13, A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5), ETS2, and JUNB.

    Results: ETS2 and JUNB expressions were upregulated in H2O2-induced chondrocytes (p < 0.001). ETS2 silencing promoted viability while inhibiting apoptosis, inflammation, and extracellular matrix (ECM) decomposition in H2O2-mediated chondrocytes (p < 0.05). However, JUNB upregulation exhibited inverse effects (p < 0.05). A binding interaction was observed between ETS2 and JUNB, suggesting a positive correlation with it.

    Conclusion: Our results demonstrate that ETS2 facilitates cartilage degeneration in OA by upregulating JUNB expression. This suggests that ETS2 is a novel molecular mediator of OA and a potential therapeutic target for OA intervention.

  • Article
    Jingwei Li, Zifeng Dai, Cong Yan, Ying Li, Ziyu Xiong, Yuwen Wang, Jiayi Xu, Changbin Shi
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2457-2465. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.194
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    Background: Cerebral cavernous malformations (CCMs) are vascular malformations resulting from the deficiency of cerebral cavernous malformation genes (CCM1, CCM2, and CCM3) in endothelial cells. The genome-wide sequencing of CCM lesions indicated that the level of miRNA-21-5p was aberrantly overexpressed in CCM tissues. Therefore, this study aimed to explore the role of miR-21-5p in CCM.

    Methods: To establish the in vitro CCM model, CCM1 was silenced in human umbilical vein endothelial cells (HUVECs) by transfecting cells with small interfering RNA (siRNA) for CCM1. The regulatory effects of CCM1-deficiency on miR-21-5p levels were determined using Quantitative Real-Time PCR (qRT-PCR) analysis. The CCM1-siRNA, NC-siRNA, and miR-21-5p-siRNA were respectively delivered into the HUVECs, and the expression levels of the tight junction-related genes (ZO-1 and Claudin 5) were examined using qRT-PCR and Western blot analysis. Furthermore, the cell apoptosis ratio was assessed employing flow cytometry and cell viability was determined using Methyl Thiazolyl Tetrazolium (MTT) assay.

    Results: It was found that miRNA-21-5p downregulated the expression levels of zonula occludens-1 (ZO-1) and Claudin 5 in CCM (p < 0.05). However, miRNA-21-5p siRNA rescued the reduced expression levels of ZO-1 and Claudin 5 (p < 0.05) and promoted the apoptosis in CCM1-deficient endothelial cells (p < 0.05). Furthermore, the overexpression of tropomyosin 1 (TPM1), as a validated target of miRNA-21-5p, counteracted the miRNA-21-5p-induced cell apoptosis (p < 0.05) and hence upregulated the expression levels of ZO-1 and Claudin 5 (p < 0.05).

    Conclusions: In summary, the miRNA-21-5p/TPM1 axis was activated in CCM, regulated tight junction-associated proteins, and promoted cell apoptosis in CCM1-deficient endothelial cells. Thus, the miRNA-21-5p/TPM1 axis could be a novel potential target for treating CCM.

  • Article
    Jun Gu, Zicai Dong, Chunrong Zhao, Shiwu Dong
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2467-2479. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.195
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    Background: Osteoarthritis (OA) is a common chronic degenerative disease, and its incidence has risen in recent years. However, the specific pathogenesis of OA remains unclear. Studies have shown that interleukin-19 (IL-19) has an inhibitory effect on inflammation caused by colitis, psoriasis, and myocardial infarction. However, whether IL-19 has an inhibitory effect on OA caused by excessive inflammatory mediators is still unknown. This study aimed to investigate the downstream pathway regulation mechanism of IL-19 affecting OA progression by bioinformatics methods.

    Methods: Differentially expressed genes (DEGs) were identified using R language. Three OA synovial datasets (GSE55235, GSE55457, GSE55584) were downloaded from the Gene Expression Omnibus (GEO) database, including 20 normal and 26 OA synovial tissue samples. After the screening of DEGs, Gene Set Enrichment Analysis (GSEA) was performed. The effects of IL-19 on chondrocytes were detected by real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blot (WB), respectively, to investigate the gene and protein expression of apoptosis and inflammation factors. And weighted gene co-expression network analysis (WGCNA) was performed, followed by functional analysis. The improved Hulth modeling method was used to construct an OA rats model, and the expression levels of IL-19 and Janus kinase 3 (JAK3) mRNA and protein in synovial tissue were detected using qPCR and Western blot.

    Results: The immune infiltration of DEGs suggested the primary component of M2 macrophages in immune cells, IL-19 was markedly downregulated in OA, and immunofluorescence indicated the co-localization of IL-19 and M2 macrophages. Furthermore, the results revealed that the inhibition of IL-19 on IL-1β induced chondrocyte apoptosis and the expression of inflammatory cytokines. Following, the WGCNA analysis identified 8 distinct gene modules, among which the MEturquoise module showed a significant correlation with OA and was associated with IL-19 expression. Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the PI3K-Akt signaling pathway and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, well-known upstream signal pathways of IL-19 were associated with the MEturquoise module. Western blot and qPCR results showed a significant decrease in IL-19 and JAK3 mRNA and protein expression in OA rats.

    Conclusions: This study revealed the potential role of IL-19 and its upstream JAK3 regulatory pathways in the development of OA using bioinformatics methods.

  • Article
    Tao Chen, Jie Bao, Kailin Pan, Dan Xu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2481-2486. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.196
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    Background: The ABO and Rh systems are widely recognized as the most crucial systems in transfusion medicine and transplantation. Mismatching the Rh antigen-antibody system between the donor and the patient can lead to severe complications such as hemolytic transfusion reactions, hemolytic disease of the newborn (HDN), and autoimmune hemolytic anemia. This study aims to investigate the use of Rh antigen testing combined with the ABO blood grouping system in the transfusion therapy of patients with hematologic disorders.

    Methods: A total of 160 cases of blood disease patients requiring blood transfusion treatment were admitted to the First Hospital of Jiaxing between January and December 2021. They were randomly divided into two groups (n = 80). The control group received direct transfusion after routine testing matched with the blood of donors. The observation group used the Rh blood group antigen test card to detect Rh blood group system D, C, c, E and e antigens. The blood of donors with the same type of antigens was then selected for transfusion after cross-matching. The study compared the irregular antibody positivity rate, distribution of irregular positive antibodies, antibody potency change, the success rate of blood matching, hemoglobin (Hb), red cell hematocrit (HCT) before and after transfusion, and the total incidence of adverse reactions between the two groups.

    Results: The rate of irregular antibody positivity in the observation group (1.25%) was significantly lower than that in the control group (10.00%) (p < 0.05). The highest percentage of irregular positive antibodies was anti-E, at 37.50% in the control group. The success rate of blood matching was 97.50% in the observation group and 90.00% in the control group, which was statistically insignificant (p > 0.05). HCT and Hb after blood transfusion were significantly higher in the observation group than in the control group (p < 0.05). The total incidence of adverse reactions in the observation group (1.25%) was lower than in the control group (11.25%) (p < 0.05).

    Conclusions: Rh combined with ABO blood group system antigen testing before blood transfusion therapy in patients with hematologic diseases may effectively improve the success rate of blood matching. Additionally, homotypic blood transfusion can help improve HCT and Hb, reduce the incidence of adverse reactions, and provide a high degree of safety.

  • Article
    Jie Luo, Hong Cao
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2487-2501. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.197
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    Background: Triple-negative BrCa (TNBC) has been recognized as the most invasive type of breast cancer (BrCa), posing the worst outcomes with a minimal overall survival rate. The use of dexmedetomidine potentially affected BrCa surgery and dexmedetomidine was reported to have direct effects on TNBC cells. Therefore, this study aimed to explore the mechanisms underlying the effect of dexmedetomidine on TNBC.

    Methods: Through bioinformatic analysis, dexmedetomidine targets were predicted using The Cancer Genome Atlas data and SwissTargetPrediction database. These targets were validated in TBNC using both clinical samples and cell lines (MDA-MB-231, MCF7, and MCF10A). The cancer cell lines, and normal breast cell lines were divided into cancer and normal groups. Both groups were exposed to dexmedetomidine treatment. Furthermore, silencing and overexpression experimental models were used to determine the effect of dexmedetomidine treatment. Expression levels of target genes and their proteins were evaluated using qRT-PCR, western blot analysis, and immunohistochemistry. Cell Counting Kit-8 was used to determine the effect of dexmedetomidine on cells with target silencing. The binding model of the candidate targets was docked, and critical amino acids were mutated to validate the binding model.

    Results: Dexmedetomidine selectively inhibited cancer cells. Catalytic subunit of the DNA-dependent protein kinase (PRKDC), indoleamine 2,3-dioxygenase 1 (IDO1), opioid receptor kappa 1 (OPRK1), glutaminyl-peptide acyltransferase (QPCT), macrophage migration inhibitory factor (MIF), potassium voltage-gated channel subfamily H (Eag-related) member 2 (KCNH2), cholinergic receptor muscarinic 3 (CHRM3), and potassium intermediate/small conductance calcium-activated channel subfamily N member 4 (KCNN4) were identified as dexmedetomidine targets in TNBC. The expression levels of PRKDC, IDO1, MIF, KCNH2, CHRM3, and KCNN4 were found to be upregulated in TNBC tissues compared to the non-TNBC tissues (p < 0.05). Silencing of these genes reduced the sensitivity of TNBC cells to dexmedetomidine (p < 0.05). However, this effect was counteracted when the silenced genes were overexpressed, increasing the sensitivity of cells to dexmedetomidine (p < 0.05). Furthermore, a direct interaction of dexmedetomidine with IDO1 and CHRM3 was observed, impacting the sensitivity of cells to dexmedetomidine (p < 0.05).

    Conclusion: IDO1 and CHRM3 are direct targets of dexmedetomidine in TNBC.

  • Article
    Sarah Ali Abdelhameed Gouda, Basma Emad Aboulhoda, Nivin Sharawy, Mohamed Mansour Khalifa, Hend Abdallah, Laila Rashed, Omaima Mohammed Abdelwahed
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2503-2521. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.198
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    Background: Necroinflammation loop is a pathologic hallmark of organ dysfunction. That is owed to a distorted balance between the pro-inflammatory (M1) and the anti-inflammatory (M2) macrophages. We aimed to explore whether low-intensity pulsed ultrasound (LIPUS) and/or splenectomy could ameliorate necroinflammation by increasing M2 macrophages and modulating the exosomes-related proteins.

    Method: Rats were allocated into 2 groups: Sham and splenectomy (Splen). After that, rats were divided into LIPUS untreated and treated subgroups. Rats in each subgroup were subjected to either vehicle (sham, sham + LIPUS) or gentamicin (GM) (GM, GM + LIPUS, Splen + GM, Splen + GM + LIPUS). Biochemical and immunohistological analyses assessed macrophage polarization, necroptosis, exosomes-related markers, and exosomes-related proteins.

    Results: We found that LIPUS successfully reversed the effects of GM, LIPUS significantly-decreased (p < 0.05) necroinflammation markers through significant downshifting (p < 0.05) of M1 macrophage polarization, and noticeable modification (p < 0.05) of the exosome-related proteins (Milk fat globule-EGF factor 8 (MFG-E8), heat shock protein 70 (Hsp70)).

    Conclusion: Spleen could be a promising target for LIPUS via restoring M1/M2 balance and modulation of exosomes-related proteins.

  • Article
    Bo Yu, Jiaxing Yao, Weiye Fan, Chenlei Shi, Songpu Li, Fulin Dou, Xiyuan Sun, Ning Xu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2523-2541. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.199
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    Background: Immunogenic cell death (ICD)-related gene signatures demonstrate prognostic significance across multiple cancer types. Nevertheless, the differential expression of these genes in thyroid carcinoma (THCA) and their application in predicting the survival outcomes of individuals with THCA remain poorly understood. Therefore, this study aimed to explore the role of ICD-related genes in predicting the survival outcomes of THCA patients.

    Methods: The expression of ICD-related genes was analyzed using RNA-seq data and compared with clinicopathological features from The Cancer Genome Atlas-thyroid carcinoma cohort. The role of Fc receptor-like B (FCRLB) in thyroid cancer was identified using Methyl Thiazolyl Tetrazolium (MTT) assay, 7-amino-actinomycin D staining, and Annexin V-fluorescein isothiocyanate staining assay.

    Results: We identified FCRLB as a novel marker for predicting THCA survival. Moreover, bioinformatic analyses revealed a significant correlation between elevated FCRLB expression and increased levels of immune infiltration and somatic mutations, potentially contributing to a poorer prognosis in THCA (p < 0.05). Furthermore, we observed overexpression of FCRLB in THCA cells compared to thyroid epithelial cells (p < 0.05). Additionally, reduced proliferation, cell cycle arrest, and enhanced apoptosis were the outcomes of FCRLB knockdown in TPC-1 THCA cells (p < 0.05).

    Conclusions: These findings suggest that FCRLB overexpression predicts poor THCA survival and might contribute to THCA development.

  • Article
    Yongshan He, Jianlei Liu, Boruo Zhou, Heiying Jin, Jun Wang, Fule Liu, Shiyong Huang, Lin Yuan
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2543-2552. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.200
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    Background: Pachymic acid (PA), a purified triterpene extracted from the medicinal fungus Poria cocos, is known for its antiemetic, anti-inflammatory, and antitumor properties. However, the effect of PA on colorectal cancer and its underlying mechanism are yet to be elucidated. In this study, we delved into the chemotherapeutic effects and underlying mechanisms of PA on colorectal cancer.

    Methods: The impact of PA on the proliferation of cells in colon cancer was investigated employing the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU). Moreover, its role in the migration of colon cancer cells was assessed using the transwell assay. Bioinformatic analysis was performed to predict interferon alpha-inducible protein 6 (IFI6) binding miRNA and dual luciferase assay was used to validate this interaction. The IFI6-overexpressing cell lines were established and used to evaluate if PA regulates IFI6 to affect a serine/threonine protein kinase (AKT) and SMAD Family Member 3 (Smad 3) signaling pathways by western blot between control, PA + Vector and PA + IFI6-overexpression (OE) groups. Furthermore, miR-148a-5p inhibitor was applied to investigate the effect of PA on colorectal cancer cells.

    Results: PA showed antitumor effects in vitro by inhibiting colon cancer cell proliferation and metastasis in HT29 and DLD-1 cells (p < 0.01). Mechanistically, our data suggested that PA decreased colon cancer cell proliferation and metastasis by increasing miR-148a-5p expression to repress the levels of IFI6, AKT, and Smad 3 signaling pathways (p < 0.05). Moreover, overexpression of IFI6 and administration of miR-148a-5p inhibitors reversed the inhibitory effects of PA on the AKT and Smad-3 pathways (p < 0.01), indicating a critical role for IFI6 in colorectal cancer progression.

    Conclusion: Our study indicates PA as a potential therapeutic candidate for colorectal cancer growth and metastasis. This study provides a foundation for the potential application of PA in colorectal cancer therapy.

  • Article
    Baihui Shan, Xing Chai, Junjun Chen, Lei Zhu, Shu Wang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2553-2561. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.201
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    Background: Basal cell carcinoma (BCC) is one of the common malignant epithelial tumors. Integrin α5β1 plays a crucial role in the malignant progression of various human cancers. Therefore, this study aimed to investigate the impact of Integrin α5β1 on the growth and radiosensitivity of BCC cells.

    Methods: The α5β1 mRNA concentration in normal human epidermal keratinocytes PCS-200-11 and human skin BCC cell lines (TE354.T and A431) was appraised using Reverse Transcription Polymerase Chain Reaction (RT-qPCR). The cells were randomly divided into the normal cell culture (control subgroup), cells transfected with lentivirus containing pLEX-Multiple Cloning Site (MCS) (pLEX-MCS subgroup), cells transfected with lentivirus containing pLEX-α5β1 (pLEX-α5β1 subgroup), cell transfected with lentivirus containing pLEX-α5β1 and treated with 80 μmol/L Smoothened inhibitor SI4650 (pLEX-α5β1 + SI4650 subgroup). The impact of Integrin α5β1 on the cell viability was assessed utilizing Methylthiazolyldiphenyl-tetrazoliumbromide (MTT), 5-Ethynyl-2′-deoxyuridine (EdU), TdT-mediated dUTP Nick-End Labeling (TUNEL), flow cytometry, scratch assay, Transwell migration, and Transwell invasion assays. Furthermore, the TE354.T cells and A431 cells were randomly divided into the normal cell culture (control subgroup), cells were irradiated with 4 Gray (Gy) X-rays (4 Gy subgroup), and cell transfected with lentivirus containing pLEX-α5β1 and then irradiated with 4 Gy X-rays (pLEX-α5β1 + 4 Gy subgroup). The cell viability of BCC cells was determined using MTT and flow cytometry analysis. Additionally, the Hedgehog signaling pathway-related proteins were evaluated using western blot analysis.

    Results: The expression levels of α5β1 were increased in the BCC cell line. Moreover, α5β1 promoted cell viability while inhibiting apoptosis in BCC cells. Furthermore, the overexpression of α5β1 promoted the Hedgehog signaling pathway. The Smoothened (SMO) inhibitor SI4650 reversed the impact of α5β1 on promoting BCC cell activity while inhibiting cell apoptosis. Additionally, α5β1 reduced the sensitivity of BCC cells to 4 Gy X-ray irradiation.

    Conclusion: The expression levels of α5β1 were elevated in BCC cells, resulting in enhanced cell viability, abated apoptosis, and alleviated sensitivity to radiotherapy. This mechanism of action may be linked to the Hedgehog signaling pathway.

  • Article
    Yuqi Wang, Ruzhen Jia, Lei Shi, Junmei Jiang, Jian Ge
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2563-2570. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.202
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    Background: Gastric cancer (GC) is a prevalent malignancy of the digestive tract, posing substantial challenges and serious threats to human life. The crucial roles of Ras GTPase-activating protein-binding protein 1 (G3BP1) as an enhancer and Vezatin (VEZT) as a suppressor of cancer progression have been recognized. Therefore, this study aimed to elucidate the molecular mechanisms underlying the role of G3BP1/VEZT in GC cell activity and the consequent oxidative stress damage.

    Methods: The expression levels of G3BP1 and VEZT in GC cells were assessed utilizing Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and western blot assays. Subsequently, both G3BP1 and VEZT were knocked down in GC cells and their efficiency was evaluated using qRT-PCR. Additionally, methylation levels of the VEZT gene were evaluated using pyrosequencing technology. Moreover, DNA Methyltransferase 1 (DNMT1) enzyme activity, as well as levels of Reactive Oxygen Species (ROS), Malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), and Iron were assessed in GC cells utilizing Enzyme-Linked Immunosorbent Assay (ELISA). Furthermore, the proliferation activity and apoptosis levels of GC cells were determined by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry.

    Results: G3BP1 was upregulated and VEZT was downregulated in GC (p < 0.01, and p < 0.001). The knockdown of G3BP1 (si-G3BP1) led to a decrease in VEZ-silencing-induced DNA methylation level and DNMT1 activity (p < 0.05, and p < 0.01). The si-G3BP1 reversed the enhanced cell viability, decreased apoptosis rate, and decreased levels of ROS, MDA, and 4-HNE in GC cells induced by VEZT silencing (p < 0.01, and p < 0.001). Moreover, si-G3BP1 also reversed the elevation of Thioredoxin-dependent peroxide reductase (T-SOD), Glutathione (GSH), and Glutathione Peroxidase 4 (GPx4) levels induced by si-VEZT (p < 0.05, p < 0.01, and p < 0.001).

    Conclusion: Our study confirms the aberrant activation of G3BP1 and the suppression of VEZT in GC. Furthermore, we observed that G3BP1 affects the proliferation, apoptosis, oxidative stress-induced damage, and iron damage of GC cells by regulating the methylation level of VEZT.

  • Article
    Yunfei Wang, Mingyu Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2571-2580. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.203
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    Background: Melatonin (MLT) is a hormone that regulates circadian rhythms and has various biological functions. Recent studies have indicated that MLT also plays a significant role in the skeletal system by modulating bone formation and resorption. The aim of this study is to investigate the impact of MLT on the in vitro osteogenic differentiation of MC3T3-E1 cells, a mouse preosteoblast cell line, and the in vivo healing of fractures in mice.

    Methods: The mice underwent bilateral fibular fractures for a duration of 2 weeks. MLT was given at 14 days post-fracture, after which time they were sacrificed. Staining with hematoxylin and eosin (H&E) was used to analyze the callus. MC3T3-E1 cells were exposed to MLT for 7 days. The extent of osteogenic differentiation was assessed using alizarin red staining. The expressions of alkaline phosphatase (ALP), collagen type 1 alpha 1 chain (COL1A1), osteocalcin (OCN), and runt-related transcription factor 2 (Runx2) were detected using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Additionally, the expressions of tropomyosin receptor kinase A (TrkA), metallothionein-1 (MT1) and metallothionein-2 (MT2) in animal tissues and cells were detected by Western blotting.

    Results: The expression of murine (mouse) calvaria 3T3-E1 (MC3T3-E1) cells treated with MLT was observed. The MLT group exhibited a higher proportion of osteogenic differentiation than the Control group, as evidenced by alizarin red staining and qRT-PCR detection of osteogenic differentiation markers (p < 0.01). The Western blot analysis revealed a higher expression of MLT receptors in the MLT group than the control group (p < 0.01). TrkA expression was enhanced following MLT administration (p < 0.01). Additional studies revealed that the level of osteogenic differentiation in the overexpression tropomyosin receptor kinase A (OE-TrkA) group surpassed that of the MLT group (p < 0.001) but was decreased in the Si-TrkA group. MT1 and MT2 expressions were increased in the OE-TrkA group but were decreased in the Si-TrkA group (p < 0.001). Mechanical and histological tests in animal models demonstrated an augmentation in the level of osteoclast differentiation following MLT treatment (p < 0.01). The Western blots revealed an upregulation in TrkA expression following MLT treatment (p < 0.01). The utilization of TrkA activator and inhibitor revealed that MLT stimulated osteogenic differentiation and facilitated fracture healing through the activation of TrkA (p < 0.01).

    Conclusion: In summary, our study reveals that MLT stimulates the fracture healing in mice and the osteogenic differentiation of MC3T3-E1 cells through the activation of TrkA signaling pathway. Our findings suggest that MLT is a potential therapeutic agent for enhancing bone regeneration and repairing bone defects.

  • Article
    Kaicheng Liu, Shenyi Lu, Mingyang Jiang, Chuanliang Chen, Mingjing Xie, Yiji Jike, Ke Zhang, Xiaochong Zou, Zhandong Bo
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2581-2597. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.204
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    Background: Although immune checkpoint inhibitor (ICB) therapy has exhibited prolonged efficacy, it may have unexpected effects, particularly resistance development. The purpose of the study is to explore the specific prognostic value of anti-programmed cell death 1 (anti-PD-1) immunotherapy treatment response-related genes in melanoma and investigate the correlation of prognostic signature with immunotherapy and the tumor immune microenvironment (TIME).

    Methods: The GSE78220 dataset was used for screening anti-PD-1 immunotherapy treatment response-related genes. The Cancer Genome Atlas specimens of patients with melanoma act as the training cohort, while the GSE65904 served as the validation cohort. Prognostic signatures based on seven anti-PD-1 immunotherapy treatment reaction-related genes were constructed in the training cohort using the least absolute shrinkage and selection operator (LASSO) regression. The overall survival of different risk groups was compared by Kaplan-Meier analysis. The effect of their clinicopathologic features and survival risk scores were evaluated using Cox regression. The immune microenvironment was analyzed using the CIBERSORT algorithm. The connection among clinical characteristics, gene expression level at checkpoints, and risk score was evaluated by correlation analysis. Immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) were employed to verify the expression level of seven genes.

    Results: The prognostic signature, comprising COL6A3, CCL8, FETUB, AGBL1, KIR3DL2, TMEM158, and NXT2, predicted poorer overall survival in the high-risk group. The results were consistent in the validation cohort. Different risk groups significantly changed the immune microenvironment and checkpoint gene expression. The risk score exhibited significantly negative correlation with T-cell and M1 macrophages, while displaying significantly positive correlation with M2 macrophages. Several immune checkpoint genes, such as CTL-4, PD-L1, and B7-H3 showed low expression patterns in the high-risk group. RT-qPCR and immunohistochemistry results further verified the feature gene.

    Conclusions: The prognostic features associated with anti-PD-1 immunotherapy treatment response-related genes can serve as innovative prognostic predictors, immune microenvironment, and responsiveness to ICB in patients with melanoma.

  • Article
    Jun Yang, Hong Huang, Jinlan Duan
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2599-2607. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.205
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    Background: Most cardiovascular diseases are age-related, accompanied by cell senescence in the cardiovascular system. Ionizing radiation (IR) has been reported to be involved in the dysfunction of endothelial cells (ECs) and smooth muscle cells. However, the specific mechanism is poorly defined. This study explores a possible mechanism of IR-induced cell senescence.

    Methods: Human umbilical vein ECs (HUVECs) and human aortic smooth muscle cells (HASMCs) were irradiated with 20 Gy X-rays for 6 days to induce cell senescence. Cell transfection was then used to overexpress or delete myeloid zinc finger 1 (MZF1) and neogenin 1 (NEO1) in HUVECs and HASMCs, along with the determination of their expressions. Cell viability, senescence associated-beta-galactosidase (SA-β-gal) levels, and expressions of senescence markers were determined to assess cell senescence.

    Results: In HUVECs and HASMCs, irradiation upregulated MZF1 and NEO1 expressions, inhibited cell viability, and elevated SA-β-gal level. However, MZF1 overexpression enhanced and MZF1 deletion reversed the effect of irradiation. Additionally, MZF1 deletion blocked NEO1 expression in irradiated HUVECs and HASMCs. NEO1 overexpression repressed cell viability, accelerated the SA-β-gal increase and upregulated expressions of cyclin dependent kinase inhibitor 2A/1A (p16/21), p53 and high mobility group AT-hook 1 (Hmga1) in irradiated HUVECs and HASMCs, which was counteracted by MZF1 deletion. Also, NEO1 overexpression reversed the effects of MZF1 deletion in irradiated HUVECs and HASMCs.

    Conclusion: MZF1 and NEO1 mediate IR-induced senescence of cardiovascular cells. This may provide a window for exploiting new targets in the therapy of age-related cardiovascular diseases.

  • Article
    Lin Zhong, Haixia Wang, Cuirong Lei, Ling Wang, Qin Tang, Yiqin Huang, Misi He, Dongling Zou
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2609-2619. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.206
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    Background: The poly ADP-ribose polymerase inhibitors (PARPi) are widely used for treating ovarian cancer. However, there is a need for additional clinical evaluation to determine the mechanisms underlying resistance and the potential benefits of PARPi re-challenge. Therefore, this study evaluated the potential therapeutic advantages of PARPi as a maintenance therapy for women with ovarian cancer who have acquired resistance to front-line PARP inhibitors.

    Methods: The clinical data of 479 epithelial ovarian cancer (EOC) patients were retrospectively reviewed from the database of Chongqing University Cancer Hospital, China. A cohort of patients diagnosed with platinum-sensitive recurrent ovarian cancer (PSOC) who had previously received PARPi maintenance therapy underwent a comprehensive analysis and 39 patients were selected for subsequent exploration. Among them, 16 patients received PARPi as second-line maintenance therapy after chemotherapy (Group A) and 23 did not receive any maintenance therapy (Group B). Disease response and safety profiles were recorded. Tumor tissues from a patient exhibiting resistance to fluzoparib were collected for next generation sequencing (NGS) analysis using the BGISEQ-500 (BGI, Beijing Genomics Institute) platform provided by BGI Inc. in Shenzhen, China.

    Results: Out of the total patients, 37 (94.9%) had received pretreatment with a maximum of two prior lines of chemotherapy. Twelve patients underwent optimal debulking cytoreductive surgeries. The clinical characteristics of the two groups, including age, federation international of gynecology and obstetrics (FIGO) stage, breast cancer susceptibility (BRCA) gene mutation status, and the condition of first-line PARPi, were well-matched. There was a statistically significant difference in progression free survival (PFS) between the two regimens. The mean PFS was 20 months (95% confidence interval (CI): 14–not available (NA)) in group A and 8 months (95% CI: 5–14) in group B, indicating superior clinical benefits with the rechallenge regimen. A difference was observed in PFS concerning re-cytoreductive surgery (RCRS) when considering a one-sided p < 0.1 as significant (p = 0.077). The tolerability of adverse events was acceptable. Genomic profiling showed that one patient had amplified radiation sensitive 52 (RAD52), myelocytomatosis oncogene (MYC), and fibroblast growth factor 6 (FGF6) genes after PARPi, which might be associated with resistance to fluzoparib.

    Conclusion: The rechallenge of PARPi is effective in the treatment of patients with ≤2 lines of PSOC who have previously demonstrated resistance to a front-line PARP inhibitor. Additionally, optimal cytoreductive surgery performed before PARP inhibitor rechallenge may be associated with improved progression-free survival in these patients.

  • Article
    Jiaran Wang, Ningzi Zang, Dongdong Fan, Jingyu Wang, Pin Li, Mei Wang, Ruizhi Yu, Yuwei Cui, Yingjie Li, Xiaodong Lv, Lijian Pang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2621-2633. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.207
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    Background: Idiopathic pulmonary fibrosis (IPF) is a challenging refractory interstitial lung disease, and acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a significant contributor to rapid clinical deterioration and mortality associated with IPF. The clinical application of Qingluo Yin can obviously improve the symptoms of wheezing and dyspnea in patients with AE-IPF, but its therapeutic mechanism of clearing heat and detoxifying, eliminating phlegm and dredging channels in the treatment of AE-IPF needs to be further explored. This study aimed to elucidate the therapeutic mechanisms of Qingluo Yin by examining its regulatory effect on miR-let-7d, impacting the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway and inhibiting epithelial-mesenchymal transformation in AE-IPF through animal experiments.

    Methods: An AE-IPF rat model was established through secondary bleomycin administration. Model effectiveness was evaluated through blood gas analysis and tissue staining. Lung CT and lung function assessments were used to assess lung volume and hypoxia status. The wet-dry weight ratio and lung coefficient were used to observe pulmonary tissue edema and fibrosis. Western blot analysis was used to determine protein expression levels of N-cadherin, alpha-smooth muscle actin (α-SMA), and E-cadherin in rat lung tissue to determine the degree of epithelial-mesenchymal transformation. Real-time Polymerase Chain Reaction (Real-time PCR) and Western blot were used to detect the levels of TGF-β1, Smad2, phosphorylation Smad2 (p-Smad2), Smad3, p-Smad3, high mobility group protein 2 (HMGA2), and miR-let-7d in rats to evaluate the impact of Qingluo Yin on AE-IPF.

    Results: Histopathological analysis revealed that Qingluo Yin could significantly improve the degree of alveolar inflammation and interstitial fibrosis in rats, alleviate the low partial pressure of arterial blood oxygen and decrease extracellular matrix deposition. Western blot analysis demonstrated that Qingluo Yin could significantly upregulate the expression level of E-cadherin protein and inhibit epithelial-mesenchymal transformation (EMT) (p < 0.05). Real-time PCR and Western blot revealed significant regulatory effects on the TGF-β1/Smads and key molecule miR-let-7d associated with the EMT pathway (p < 0.05). This intervention reduced the expression and transcription levels of TGF-β1, Smad2, Smad3, and HMGA2 proteins (p < 0.05) while targeting the regulation of miR-let-7d to inhibit AE-IPF.

    Conclusion: Qingluo Yin exhibits the potential to upregulate miR-let-7d, downregulate the expression of transcription factor HMGA2, inhibit the TGF-β1/Smads signaling pathway, and inhibit EMT, thereby presenting a promising therapeutic approach for treating AE-IPF.

  • Article
    Lin Chen, Luetao Zou, Miao Lei, Xiaojun Zhang, Wei Jiang, Zhenming Hu
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2635-2649. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.208
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    Background: Heme oxygenase (HO)-1, a stress-induced heat shock protease, has been implicated in the occurrence and progression of various tumors, though its impact on osteosarcoma remains unclear. This study aimed to elucidate the role of the HO-1 gene in regulating apoptosis in osteosarcoma cells and its associated mechanism.

    Method: Initially, bioinformatics analysis was employed to analyze the expression of HO-1 in osteosarcoma. Subsequently, human osteosarcoma cells (MG63 and HOS cell lines) were cultured in vitro to establish osteosarcoma cells transfected with adenovirus overexpressing HO-1. Cell activity was assessed using cell counting kit-8 (CCK-8) and colony formation assays. Western blotting was utilized to analyze levels of HO-1, microtubule-associated proteins light chain 3 (LC3), recombinant nucleoporin 62 (P62), transcription factor P65 (P65), B-cell lymphoma-2 (Bcl-2), Bcl-2 assaciated X protein (Bax), cleaved caspase-3, β-actin, and phosphorylation p65 (P65-RelA). Flow cytometry was conducted to examine distribution of cell cycle and cell apoptosis. Transmission electron microscopy (TEM) was employed to detect autophagy, while immunofluorescence was used to observe P65-RelA nuclear expression. Additionally, apoptosis of osteosarcoma cells was assessed via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Knockdown of P62 and treatment with an nuclear factor-k-gene binding (NF-κB) inhibitor (PDTC) preceded Western blotting analysis, and apoptosis was evaluated using TUNEL staining. P65-RelA levels were assessed through immunofluorescence assay. Finally, a tumor-bearing nude mouse model was employed to validate the role of HO-1 in osteosarcoma in vivo.

    Results: The GSE11414 and GSE12865 chips were selected from the Gene Expression Omnibus (GEO) database and analyzed using the GEO 2R tool. The results indicated low expression of HO-1 in osteosarcoma. An in vitro osteosarcoma cell model with HO-1 overexpression was successfully established. Overexpression of HO-1 inhibited autophagic flow, promoted apoptosis in MG63 and HOS cells (p < 0.001), and reduced cell proliferation. Immunofluorescence analysis revealed an elevation in P65-RelA nuclear levels. Furthermore, transmission electron microscopy showed a significant reduction in the number of autophagic lysosomes. This phenomenon was reversed by pyrrolidine dithiocarbamate (PDTC) and siRNA-P62. Animal experiments confirmed the inhibitory effect of HO-1 on osteosarcoma.

    Conclusion: HO-1 is downregulated in osteosarcoma. HO-1 impairs autophagic flux in osteosarcoma cells, leading to the accumulation of P62, which activates apoptosis through the P62/RelA pathway and inhibits osteosarcoma tumorigenesis and progression.

  • Article
    Peng Yao, Xingli Leng, Cuicui Li, Yubo Jiang, Si Yi, Lin Deng, Shaoqing Wang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2651-2659. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.209
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    Background: Vascular calcification (VC) is a significant risk factor for cardiovascular disease. The pathogenesis involves various factors such as hyperphosphatemia, oxidative stress, inflammation, and apoptotic cell death, leading to phenotypic changes in vascular smooth muscle cells (VSMCs) and subsequent calcification. This study aims to investigate the impact of roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), on the development of calcification in VSMCs induced by hyperphosphatemia in mice.

    Methods: Aortic VSMCs were cultured and exposed to high phosphate conditions to induce calcification. The cells were divided into control, high phosphate, and HIF-PHI plus high phosphate groups. Cell viability was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, and calcium content was measured through Von Kossa staining and the bicinchoninic acid (BCA) assay. The apoptotic rate was determined by flow cytometry, alkaline phosphatase concentration was determined by enzyme-linked immunosorbent assay (ELISA), and mitochondrial reactive oxygen species (ROS) levels were determined by Dichlorodihydrofluorescein acetoacetate (DCFH-DA). Protein expression levels were evaluated using immunoblotting techniques.

    Results: Compared to the control group, calcium deposition, calcium content, alkaline phosphatase, Runt-related Transcription Factor 2 (RUNX2) expression and apoptotic rate were significantly higher, while Alpha Smooth Muscle Actin (α-SMA) expression was significantly lower in the high phosphate group (p < 0.05). The HIF-PHI group showed an opposite trend to the high phosphate group in a dose-dependent manner (p < 0.05). The mitochondrial ROS and BCL2/adenovirus E1B 19kDa protein-interacting protein 3-like (BNIP3L) expression were significantly higher in the high phosphate group than in the control group (p < 0.05). Compared to the high phosphate group, the mitochondrial ROS was lower, while the protein expression levels of BNIP3L and Bcl-2 Interacting Protein 1 (Beclin-1) were higher in the HIF-PHI group (p < 0.05). HIF-1α protein expression was significantly higher in the high phosphate group than in the control group, which was increased by the treatment of HIF-PHI (p < 0.05).

    Conclusions: HIF-PHI ameliorates vascular calcification and apoptosis in high-phosphate induced viability of VSMCs by upregulation of HIF-1α expression, reduced mitochondrial ROS production and increased expression of autophagy-related proteins.

  • Article
    Yang Zhang, Tan Li, Feng Wang, Chuanjun Liao, Shenghan Song, Mingsheng Sun, Wangde Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2661-2672. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.210
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    Background: Diabetic foot ulcer (DFU), characterized by delayed wound healing, is a severe complication of diabetes mellitus. A report using single-cell sequencing technology revealed increased chitinase 3 like 1 (CHI3L1)-overexpressing fibroblasts in DFU patients with wound healing. Therefore, this study aimed to elucidate the role and mechanism of CHI3L1 in wound-healing process during DFU.

    Methods: DFU model rats were constructed with streptozotocin injection and scald wound formation. Subsequently, the rats were administered with adeno associated virus to overexpress signal transducer and activator of transcription 3 (STAT3). Human dermal fibroblasts (HDFs) were transfected with recombinant constructs as needed. Moreover, the binding of STAT3 to CHI3L1 was determined through bioinformatics analysis and dual-luciferase reporter assay. The trauma area, pathological changes, cell viability, migration, and protein levels of hypoxia-inducible factor-1 (HIF-1α), vascular endothelial growth factor (VEGF), and STAT3/CHI3L1/mitogen-activated protein kinase (MAPK) axis were assessed.

    Results: STAT3 overexpression significantly reduced trauma area and increased levels of HIF-1α and VEGF and the number of new vessels in DFU rats (p < 0.001). Moreover, overexpression of STAT3 enhanced proliferation, migration, VEGF secretion, and the expression levels of HIF-1α, VEGF, STAT3, CHI3L1, and phosphorylated p38 MAPK (p-p38) in DFU rats and HDFs (p < 0.001). STAT3 might bind with CHI3L1 in HDFs. The effect of CHI3L1 silencing on HDFs was opposite to that of STAT3 overexpression (p < 0.05). However, CHI3L1 silencing reversed the role of STAT3 overexpression (p < 0.001).

    Conclusion: STAT3 upregulation accelerates wound healing by promoting the proliferation and migration of fibroblasts by activating the CHI3L1/MAPK axis. These findings provide new drug targets for DFU treatment and unveil the underlying mechanism of delayed wound healing in DFU.

  • Article
    Mohammed Roubi, Salah-eddine Azizi, Mohammed Dalli, Ramzi A. Mothana, Mohammed F. Hawwal, Sidgi Hasson, Nadia Gseyra
    Journal of Biological Regulators and Homeostatic Agents. 2024, 38(3): 2673-2691. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.211
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    Background: The essential oil (EO) extracted from Citrus limon has gained attention for its potential bioactive properties due to its promising chemical composition. This study aimed to comprehensively evaluate the antioxidant and antimitotic activities of Citrus limon EO.

    Methods: Volatile compounds were thoroughly analyzed using headspace and gas chromatography techniques. Molecular docking studies identified D-limonene and α-bergamotene as having the highest antioxidant potential. Assessment of antioxidant capacity employed 2,2-diphenyl-1-picrylhydrazyl (DPPH) and β-Carotene bleaching assays, alongside the Total Antioxidant Capacity (TAC) assay. Absorption, distribution, metabolism, excretion and toxicity (ADMET) tests were conducted to confirm the EO's suitability for pharmaceutical applications. The antimitotic activity was evaluated using the Lepidium sativum test.

    Results: Results indicated a 1.99% essential oil yield, with D-limonene identified as the predominant constituent. In the DPPH assay, the half-maximal inhibitory concentration (IC50) value was 1.27 ± 0.03 mg/mL, and the β-carotene bleaching assay exhibited an IC50 value of 6.74 ± 0.12 mg/mL. The TAC assay determined the EO's total antioxidant capacity as 212.2 ± 1.35 μg Ascorbic acid (AA) eq/mg EO. The essential oil demonstrated significant antimitotic activity, reaching a maximum of 83.33% at a concentration of 250 μg/mL.

    Conclusions: These findings underscore the noteworthy antioxidant and antimitotic capabilities of Citrus limon essential oil, primarily attributed to D-limonene and other bioactive components.