20 August 2023, Volume 37 Issue 8

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  • Review
    Marta Kamalska, Iwona Krela-Kaźmierczak, Marek Karczewski, Agnieszka Dobrowolska, Torello Lotti
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3941-3948. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.389
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    Psoriasis and atopic dermatitis (AD) are the diseases of a chronic inflammatory-autoimmune origin. Their course is often unstable and fluctuating due to the alternating occurrence of exacerbations and remissions. Nerve growth factor (NGF) levels are increased in AD and psoriasis exacerbations, stress, and the early stage of romantic love. This phenomenon brings us closer to the thorough understanding of psychoneuroimmunology. Using PubMed, we manually searched for scientific work on psychoneuroimmunology, AD, psoriasis, and NGF tropomyosin receptor kinase A (TrkA). Having thoroughly studied the searching results, we selected 97 relevant articles. NGF not only takes part in neural growth, but is also involved in angiogenesis regulation, whereas increased vascularity is present in psoriasis. NGF increases in AD and psoriasis exacerbations and stress, whereas the stress is a well-known exacerbation trigger. NGF activity elevation occurs also in people experiencing the early stage of romantic love. All these facts cast some light on the obscure pathophysiology of psoriasis and AD, and corroborate the validity of notions related to psychoneuroimmunology. The discovery of NGF significance in psoriasis and AD caused the promising new class of drugs, namely, TrkA inhibitors, to emerge. They are indisputably worth attention, since the current methods are not fully satisfactory and present a number of contraindications and side effects. NGF is a significant factor contributing to the pathophysiology of AD and psoriasis and targeting it in patients exposed to stress, and also in those who have recently fallen in love, may be particularly beneficial.

  • Review
    Damilare Emmanuel Rotimi, Tomilola Debby Olaolu, Matthew Iyobhebhe, Adekemi Grace Oluwafemi, Olabisi Esther Bakare, Oluyomi Stephen Adeyemi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3949-3954. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.390
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    Male infertility is caused by a network of interconnected endogenous mechanisms. Around 50% of male infertility cases are idiopathic. However, oxidative stress (OS) and inflammation have been independently implicated in male infertility. For instance, reduced semen capacity was noted as OS increases the level of reactive oxygen species (ROS) and testicular inflammation increases the number of leukocytes which inhibit its capacity. It is worthy of note that inflammation is intimately connected with OS and together may initiate a vicious cycle with the ability to upend the homeostasis in the testicular system. It has been reported that ROS and reactive nitrogen species (RNS) facilitated by inflammatory cells at the site of inflammation are key factors in the initiation of testicular OS, while proinflammatory gene expressions are also elevated by a signalling pathway triggered by a variety of ROS/RNS. As a result, cellular damage could be exacerbated and male reproductive functions disrupted. Sperm from infertile men have shown higher ROS levels along with increased amounts of proinflammatory proteins and cytokines, thereby supporting the interlink between OS and inflammation. Over the last several decades, a significant number of studies have been conducted seeking to unravel the interplay between OS and inflammation, especially in the testis. This review, therefore, intends to discuss the interdependent interaction between OS and inflammation in testicular dysfunction.

  • Review
    Talip Çeter, Fatemeh Mollaamin, Majid Monajjemi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3955-3976. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.391
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    Although the types of scientific tests used change over time, saffron intake has been found to reduce symptoms of diabetes, cholesterol, Alzheimer's, depression, and many other diseases. The purpose of this study was to provide safe and well-controlled clinical tests to clearly analyze the potential mechanisms of the effects of saffron. Biological markers after saffron use are measured in relationship with the predicted health results, so that the results of various studies can be compared and explicated. Since the natural propagation of saffron does not occur quickly and its corms can be manually dug up, separated and replanted, biotechnological methods can increase the ability to generate large amounts of various saffron compounds, such as crocin, picrocrocin, crocetin and safranal, in vitro. Since pathogenic plants cause crop losses in agriculture environment, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated protein 9 (Cas9) can help with biotic and abiotic problems via a crop molecular reproduction plan, with improvement of the genes' responses to issues induced through viruses, fungi, and bacteria. Quantitative Structure Activity Relationship (QSAR) methods can be used for determining the maintenance times of ingredients for saffron extract through analyzing solid phase micro-extraction gas chromatography-mass spectrometry (SPME-GC-MS). QSAR is an accurate method for detecting relationships between the molecular properties of chemical reactions and biological systems. Bioinformatics tools can help the mechanism of the transcriptome of saffron based on the structural foundation of the flavor, color biogenesis, genomic establishment and biological gynoecium of saffron. The data extracted from bioinformatics websites can be used for constructing biological routes containing the biosynthesis of main ingredients of saffron, i.e., crocin, crocetin, safranal, picrocrocin. Omics-based technologies have been extensively discussed within biology and can be used for saffron. These studies have given rise to concepts for the better understanding of saffron growth and its therapeutic action. Molecular docking simulation has also been discussed to find the location of safranal inside lysozyme. The interaction of safranal with molecular biology was discussed by mixing approaches including CRISPR/Cas9, docking, bioinformatics and omics. This study provides a new approach that is fundamentally in agreement with the results obtained experimentally.

  • Article
    Maria Angela Tosca, Matteo Naso, Valentina Nosratian, Chiara Trincianti, Irene Schiavetti, Giorgio Ciprandi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3977-3982. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.392
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    Background: Asthma control is the goal of managing patients with asthma. However, half of asthmatic patients have partially or uncontrolled asthma. The present study investigated possible factors associated with asthma control over time in children.

    Methods: The study included children with partially controlled asthma and visited in July (a month characterized by negligible allergen exposure, scarce respiratory infections, and schools closing). Children were evaluated for three consecutive years. Clinical and functional parameters and asthma control grade were measured over time.

    Results: The study enrolled 37 children (12 females and 25 males; mean age 10.6 years). At the second follow-up, 30 (81.1%) children improved asthma control, such as they had controlled asthma, 5 (13.5%) did not have asthma control changes, and two (5.4%) worsened, such as they had uncontrolled asthma. No possible factor was associated with asthma control changes except the treatment adherence rate. Children with persistent partially controlled asthma or uncontrolled at the second follow-up had poor adherence to treatment rate.

    Conclusions: Asthma control requires careful management involving the application of guidelines and the closest involvement of the child and family to ensure adequate adherence to prescribed therapy.

  • Article
    Ruizhen Li, Wen Wu, Chunxia Cheng, Jiajing Liu, Xinli Liu, Chunmei Mi, Mailian Long
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3983-3993. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.393
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    Background: Gestational diabetes mellitus (GDM) has emerged as a social health issue that threatens pregnancy outcomes. Insulin resistance (IR) is considered to be a critical factor contributing to the development of GDM. It has been reported that signal transducer and activator of transcription 3 (STAT3) and IR are related. This study aimed to investigate the role of STAT3 in the modulation of IR in GDM.

    Methods: Ten cases of normal placenta and ten cases of GDM placenta were collected. The phosphorylation of STAT3 and lipopolysaccharide-induced TNF-α factor (LITAF) expression was measured by Western blot and immunohistochemistry. Trophoblast cells were treated with glucosamine to establish an IR cell model. Cell viability was detected by Cell Counting Kit-8 assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining. STAT3 effect on the LITAF promoter was explored by chromatin immunoprecipitation and dual-luciferase reporter assay. Trophoblast cells were treated with STAT3 inhibitors and transfected with LITAF overexpression plasmids to explore STAT3 and LITAF effect on IR and cellular activity in trophoblast cells. Insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and its phosphorylated proteins and glucose transporter 4 (GLUT4) protein expression were evaluated by Western blot.

    Results: LITAF and phosphorylation of STAT3 were increased in GDM placental tissue and IR cells (p < 0.05). Meanwhile, cell proliferation decreased, and phosphorylation levels of insulin signaling factors IRS-1, PI3K and AKT were reduced in GDM placentas, but cell apoptosis was increased (p < 0.05). STAT3 could target LITAF promoter, and STAT3 activation could increase LITAF expression (p < 0.05). STAT3 inhibitor treatment increased cell viability and reduced apoptosis and IR in glucosamine-treated trophoblast cells (p < 0.05). Overexpression of LITAF counteracted the action of STAT3 on trophoblast cells (p < 0.05).

    Conclusions: STAT3 inhibition suppressed trophoblast cell damage and IR in gestational diabetes by downregulating LITAF expression.

  • Article
    Yuanjiang Xie, Bo Zhang, Fujiang Zuo, Rufei Cao, Feifei Chang, Huahua Shi, Ting Li, Huijun Qin, Shuji Wang, Xun Min, Xiaolei Duan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 3995-4005. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.394
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    Background: Conserved Pif1 helicases play important roles in maintaining genome stability. Several studies have used prokaryotic-expressed human Pif1 (hPif1) to investigate its biochemical activities. However, the properties have only been revealed to a certain extent owing to difficulties in achieving native-like post-translational maturation. This study aimed to characterize the biochemical properties of the hPif1 helicase domain (hPif1-HD) expressed in insect cells.

    Methods: The binding characteristics of eukaryotic-expressed hPif1-HD were measured by a fluorescence polarization binding assay. The unwinding kinetics, DNA annealing and strand exchange assays were measured by the stopped-flow fluorescence resonance energy transfer (FRET) assay.

    Results: The results showed that the eukaryotic-expressed hPif1 exhibited some binding and unwinding preferences different from those in the prokaryotic-expressed protein. Furthermore, several novel biochemical characteristics were discovered, including that this helicase unwound Y-shaped DNA better than overhang DNA, hPif1-HD effectively annealed different substrates, and hPif1 preferentially unwound RNA/DNA heteroduplex over double-stranded DNA (dsDNA). Notably, human telomeric G-quadruplex (G4) was shown to be the best G4 substrate. It was discovered, for the first time, that G4 stimulated hPif1-mediated adjacent dsDNA unwinding.

    Conclusions: These findings suggest that eukaryotic-expressed hPif1 is more closely related to the binding and unwinding characteristics under physiological conditions, which could potentially expand our understanding of the enzymatic activity and reaction mechanism of hPif1.

  • Article
    Zhijian Jiao, Jiangrong Fan, Jun Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4007-4017. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.395
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    Background: To evaluate the effects of microRNA-503 (miR-503) on human nucleus pulposus cells (HNPCs) by targeting CXCL9 (CXC chemokine ligand 9) to regulate interleukin-1β (IL-1β) production.

    Methods: Enzyme-Linked Immunosorbent Assay (ELISA) and Quantitative Real-time PCR (qRT-PCR) assays were used to determine miR-503 and CXCL-9 levels in HNPCs treated with and without IL-1β. Efficacy of miR-503 on cell apoptosis, inflammation and extracellular matrix degradation was evaluated with in vitro experiments. To verify the target of miR-503 dual-luciferase reporter assay was performed. The miR-503/CXCL-9 regulatory axis in HNPCs was also assessed.

    Results: Low miR-503, collagen II and aggrecan, and high CXCL9 expression were detected in degenerative nucleus pulposus (NP) tissues and NP cells challenged by IL-1β. IL-1β treatment time-dependently suppressed cell viability and lowered miR-503 level in HNPCs. Conversely, miR-503 overexpression increased cell viability, but inhibited inflammation and cell apoptosis. The luciferase reporter assay identified CXCL9 as a miR-503 target. Moreover, miR-503 overexpression or transfection with si-CXCL9 decreased CXCL9 in HNPCs expression. Notably, blocking CXCL9 expression reversed the damage induced by IL-1β.

    Conclusions: This study suggests that miR-503 may restrain apoptosis, inflammation and extracellular matrix degradation in intervertebral disc degeneration (IDD) by targeting CXCL9.

  • Article
    RuiQiong Ke, Yan Wang, ShiHua Hong, LiXia Xiao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4019-4028. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.396
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    Background: Type 2 diabetes mellitus (T2DM) is mainly caused by glucose and lipid metabolism disorder. Understanding the molecular mechanisms of metabolic disorders is crucial for treating T2DM. This study investigated the effects of miR-337-3p on glycolipid metabolism in T2DM mice by targeting Dopamine receptor D1 (DRD1) expression and activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway.

    Methods: A T2DM mouse model was established by feeding C57BL/6 mice with high-fat diet and peritoneal injection of streptozotocin. miR-337-3p and DRD1 messenger RNA (mRNA) in T2DM mice were checked by the reverse transcription-qualitative polymerase chain reaction (RT-qPCR) method. The DRD1 protein and JAK/STAT expression were analyzed by Western blot. Lipid accumulation in liver tissue was determined by oil red O staining. Blood glucose, blood lipids, and liver glycogen levels were measured. Finally, the targeting relationship between miR-337-3p and DRD1 was studied via dual luciferase reporter assay.

    Results: Experimental data supported that miR-337-3p was downregulated in T2DM mice, while DRD1 was upregulated. Overexpressing miR-337-3p can reduce blood glucose and lipid levels, increase hepatic glycogen content, and reduce hepatic lipid accumulation in T2DM mice. DRD1 was targeted by miR-337-3p and could regulate the JAK/STAT pathway. Downregulating DRD1 has a healing effect on T2DM mice by reducing glucose and lipid metabolism. Furthermore, upregulating DRD1 abolishes the effect of upregulating miR-337-3p in T2DM mice.

    Conclusions: miR-337-3p is a key modifier of hepatic glucose and lipid metabolism and an activator of the JAK/STAT pathway by targeting DRD1, thereby exerting anti-diabetic effects in T2DM mice.

  • Article
    Hao Xiang, Ying Jin, Wei Zhuo, Jia-yu Yang, Hua-zhang Xiong, Ling Yan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4029-4040. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.397
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    Objectives: This study aimed to explore the effect and possible mechanisms of triggering receptor expressed on myeloid cells 1 (TREM1) on osteoarthritis (OA).

    Methods: An in vivo OA rat model was used, which was mediated by injecting 4% papain mixed with 0.3 mol/L L-cysteine. An in vitro study of OA chondrocytes was also conducted, which was induced by interleukin (IL)-1β treatment. Immunofluorescence staining was used to identify isolated chondrocytes. Hematoxylin-eosin (HE) staining and toluidine blue (TB) staining were adopted for evaluating the pathological injury of rats' articular cartilage tissue. The enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blot, cell counting kit-8 (CCK-8) and flow cytometry experiments were performed to evaluate the effects of TREM1 in OA progression in vivo and in vitro. Chondrocyte autophagy was observed by transmission electron microscopy (TEM).

    Results: The OA model group exhibited severe histopathological damage, high serum tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) levels, and decreased cell autophagy (downregulated autophagy-related gene 5 (ATG5), light chain 3 (LC3)-II and Beclin-1) in rat knee cartilage tissues. TREM1 was markedly overexpressed in OA samples. Transfection with si-TREM1 to knock down TREM1 significantly alleviated OA rats' histopathologic damage in articular cartilage, inhibited pro-inflammatory IL-6 and tumor necrosis factor α (TNF-α) levels, promoted autophagy, and increased IL-1β-induced chondrocyte activity and autophagy, and decreased cell apoptosis rate. Overexpression of TREM1 in chondrocytes induced by IL-1β presented the opposite effect. In addition, the knockdown of TREM1 was proved to suppress nuclear factor-κB (NF-κB) p65 expression in vivo and in vitro.

    Conclusions: TREM1 aggravates OA progression by inhibiting cell autophagy and promoting cell apoptosis and inflammation. This suggests that TREM1 could be a potential target for treating osteoarthritis.

  • Article
    Qiuyun Guo, Qianshan Ding
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4041-4049. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.398
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    Aim: To assess the suppressive effects of glabridin (GLA) on colorectal cancer (CRC) cells.

    Methods: After treating cultured CRC cell lines in vitro with different concentrations of GLA, cell proliferation was examined through cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, and cell migration and invasion were determined by Transwell migration and invasion assays. Quantitative polymerase chain reaction (qPCR) and Western blotting were carried out to detect expression levels of intercellular adhesion molecule 1 (ICAM1) mRNA (messenger ribonucleic acid) and phosphorylated (p)-signal transducer and activator of transcription 3 (STAT3) protein. ICAM1-associated downstream pathways were analyzed via the LinkedOmics database.

    Results: GLA inhibited proliferation, migration, and invasion of SW620 and HT-29 cells. Additionally, ICAM1 was found as a downstream target of GLA, and GLA suppressed the expression levels of ICAM1 and p-STAT3. ICAM1 overexpression reversed the effects of GLA on CRC cell multiplication, migration, invasion, and p-STAT3 protein expression.

    Conclusions: GLA restrains the malignant phenotypes of CRC cells via regulating ICAM1/p-STAT3 signaling pathway.

  • Article
    Hu Sun, Bing Chen, Hao Zhao, Hui Zhang, Wei Song, Yinghao Gu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4051-4062. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.399
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    Background: Glioblastoma (GBM) is a primary brain tumor. Lysyl oxidase-like 1 (LOXL1) has been confirmed to promote multiple tumor progression, but its function in GBM remains largely unknown. Therefore, we aimed to study the effects of LOXL1 on the biological behavior of GBM.

    Methods: The GBM-related data was obtained from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) databases. Survival analysis, gene set enrichment analysis, wound healing assay and transwell assay were performed. All statistical analyses were done using R v3.5.2. Clinical samples were collected from Zibo Central Hospital and real-time quantitative PCR (RT-qPCR), Western Blot and immunohistochemistry were conducted to verify LOXL1 expression in HA1800, U-87 and U-118 MG cell lines. The migration ability of tumor cells was determined by wound healing assay and Transwell assay.

    Results: Significantly higher LOXL1 expression was observed in GBM samples. According to the databases, GBM patients with higher LOXL1 expression had a worse prognosis. Among GBM patients with high and low LOXL1 expression (p < 0.05), the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway were significantly differentially enriched, along with 25 other pathways. LOXL1 overexpression significantly promoted GBM cell migration and invasion (p < 0.05).

    Conclusions: Overexpression of LOXL1 enhances the migration and invasion of GBM cells, promoting the malignant progression of the disease. High expression of LOXL1 predicts a poor prognosis in GBM patients.

  • Article
    Lijian Pang, Haoyang Zhang, Jingyu Wang, Xiande Ma, Ningzi Zang, Zhen Hua, Zhongxue Zhao, Yongming Liu, Xiaodong Lv
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4063-4077. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.400
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    Background: Nowadays, non-effective drugs have been confirmed for idiopathic pulmonary fibrosis (IPF) therapy. Previous experimental studies have shown that Shenlong Jianji (SLJJ) is a potentially effective Chinese herbal formula for IPF therapy. However, more research is needed to assess its therapeutic targets and intervention mechanisms.

    Methods: Active ingredients, corresponding targets of active ingredients and disease targets were assessed. Based on interrelation between active ingredient targets and disease targets, gene enrichment analyses were performed to assess the potential pharmacological mechanism of SLJJ for IPF. Overall, 144 Wistar adult rats were randomly divided into six groups (control group, model group, prednisone group and SLJJ high, medium, and low doses groups). Rats were given bleomycin (BLM) to trigger IPF. After treatment with corresponding medicine, histopathology changes of lung tissue were assessed using hematoxylin-eosin staining and masson's trichrome staining. Concentration of hydroxyproline (HYP) in lung tissue was analyzed using chloramine hydrolysis method. Lung function and blood gas analysis of rats in each group were also assessed in this study. Interferon-γ (IFN-γ) and Interleukin-4 (IL-4) content in serum were assessed using enzyme-linked immunosorbent assay. Protein and gene expressions of IFN-γ, IL-4, transforming growth factor-β1 (TGF-β1), transforming growth factor-βRII (TGF-βRII), Smad3, and Smad7 in lung tissue were assayed using western blotting and realtime-polymerase chain reaction.

    Results: 126 signaling pathways were obtained by gene enrichment analysis. Overall, SLJJ groups showed significant improvement on histopathology assessment and reduced HYP content in lung tissue compared to model group. SLJJ can also improve lung function and blood gas analysis results. Additionally, there was a decrease on IL-4 level and increase on IFN-γ level in serum, down-regulating IL-4, TGF-β1, TGF-βRII, Smad3 protein and mRNA expressions and up-regulating IFN-γ and Smad7 protein and mRNA expressions in lung tissue.

    Conclusions: Our findings suggest that SLJJ is a valid formula to alleviate BLM-induced IPF, while its partial mechanism might mediate by coordinating the IFN-γ/IL-4 balance and regulating the TGF-β1/Smads signaling pathways. The potential targets predicted by network pharmacology warrant further validation.

  • Article
    Ke-Lin Zhou, Shuo Dong, Guo-Bing Fu, Sheng Guo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4079-4092. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.401
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    Background: Major depressive disorder (MDD) is a highly prevalent and complex psychiatric disease concomitant with severe impairment in social functioning. Abdominal massage therapy (AMT), also known as Zhenfu (ZF), is an ancient and effective form of complementary and alternative medicine in China. Applied to the patient's abdomen, the fundamental technique of AMT uses rapid vibrations created by the hand which can be used to treat multiple diseases. This study aims to evaluate the antidepressant effects of AMT.

    Methods: In this study, 30 rats were randomly divided into three groups: the control group, the model group, and the abdominal massage therapy group. We first established a rat model of chronic unpredictable mild stress (CUMS) and observed the changes in depression-like behaviors. Then, Tandem Mass Tags (TMT)-based quantitative proteomics analysis was conducted to investigate the differentially expressed proteins in the hippocampus between CUMS and AMT rats to excavate potential antidepressant protein targets. Finally, we validated molecules of interest and detected proteins using parallel reaction monitoring (PRM) to further determine the related mechanisms. The expression of p11/Anxa2/Ahnak in the hippocampus was also measured by western blot and immunohistochemistry analysis.

    Results: Our study revealed the presence of depression-like behaviors in rats subjected to CUMS. In the TMT proteomic analysis, 78 differentially expressed proteins were identified: 55 were upregulated and 23 were downregulated. Functional analysis revealed that these proteins participate in Acute myeloid leukemia, the Toll-like receptor signaling pathway, Glycolysis/Gluconeogenesis, interleukin 17 (IL-17) signaling pathway and Metabolism of xenobiotics by cytochrome P450. Further independent analysis using PRM revealed that identified changes in Acss1, Tagln2, Serpina6, Cmbl, Serpinh1, Ampd3, Gstm7, Anxa2, AABR07034632.1, Apoa1, Ahnak that were distinctly correlated to CUMS and AMT groups. The expression of p11/Anxa2/Ahnak in the hippocampus was significantly downregulated in the CUMS rats (p < 0.01, p < 0.01, p < 0.01). AMT could significantly normalize these alternations with evident curative effects (p < 0.01, p < 0.01, p < 0.01).

    Conclusions: In summary, the current study explored the antidepressant-like effects of AMT in rats subjected to 21 consecutive days of CUMS. The results of TMT proteomic analysis demonstrated that AMT could ameliorate the symptoms of depression by modulating multiple molecular targets. Our results also provide new insights to further explore alternative therapeutic approaches for the treatment of depression.

  • Article
    Hui Qiao, Na Wang, Quanlin Guan, Peng Xie, Xiangkai Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4093-4103. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.402
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    Background: Gastric cancer (GC) remains the second most common cause of cancer-related death worldwide. The prognosis is dismal, with an average 5-year survival rate of less than 20%. This study aimed to explore the molecular mechanism of enolase 1 (ENO1) in the progression of GC by regulating the electron transfer flavoprotein dehydrogenase (ETFDH) signaling pathway.

    Methods: siRNA transfection was used to knock down ENO1/ETFDH in MKN45 and HGC27 cells. Cell Counting Kit-8 (CCK-8) assay, cell colony formation, and Transwell experiments were used to determine the role of ENO1 in GC cell proliferation and migration. The expression levels of mRNAs and proteins were quantified using RT-qPCR and western blot.

    Results: In this study, we identified a new ENO1/ETFDH axis involved in the progression of GC. ENO1 adversely regulated the expression of electron transfer flavoprotein dehydrogenase (ETFDH) in GC cells by regulating the stability of ETFDH mRNA. We then determined the impact of ETFDH on GC cell proliferation and migration in vitro. The results of CCK-8 assay, cell colony formation, and Transwell experiment all demonstrated that GC cell proliferation and migration were enhanced following ETFDH knockdown (p < 0.05), while GC cell growth was decreased by ETFDH overexpression (p < 0.05). The tumor suppressor function of ETFDH on GC development in vivo was also demonstrated by tumor xenograft models (p < 0.05).

    Conclusions: Our study suggests that the ENO1/ETFDH pathway may be a new target of GC treatment and that adjusting the ratio of ENO1 to ETFDH expression may be beneficial.

  • Article
    Zhuhui Huang, Wei Li, Kui Zhang, Ning Zhou, Yang Zhao, Yang Li, Shijun Xu, Lisong Wu, Taoshuai Liu, Jubing Zheng, Hongfeng Jiang, Ran Dong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4105-4115. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.403
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    Background: Though the saphenous vein is one of the most commonly used conduits in coronary artery bypass grafting (CABG), the short-term and long-term patency of vein grafts remains relatively low. The effects of cyclic stretch on the transcriptome profile of the saphenous vein and the role of transcription factors (TFs) have not been elucidated.

    Methods: Baseline information and the excess saphenous veins from 16 patients undergoing elective coronary artery bypass grafting were obtained. The patients were classified as normal control (NC) group and cyclic stretch (ST) group, according to manipulation procedures at harvest. Total RNA was extracted and RNA-seq (RNA sequencing, Transcriptome sequencing technology) performed to investigate changes in transcriptome profiles of venous samples that underwent cyclic stretch. Differentially expressed genes (DEGs), gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) enrichment were performed to study their potential function and pathways. We then used online databases to identify TFs and construct a protein-protein interaction (PPI) network, and identify hub TFs by Cytoscape software. Finally, hub TFs were validated using quantitative reverse transcription PCR (RT-qPCR), immunofluorescence, and western blot.

    Results: After cyclic stretch, 107 DEGs were identified, including 82 upregulated and 25 downregulated genes. The enrichment of graphene oxide suggests that DEGs are mainly enriched in cellular responses to mechanical stimuli and transcriptional activity. Then, nine differentially expressed TFs were identified after crossing the Encyclopedia of DNA Elements (ENCODE) database with DEGs, and six hub TFs were identified by Cytoscape software and its plug-in CytoHubba, including Early Growth Response Factor 3 (EGR3), activating transcription factor 3 (ATF3), transcription factor (JUN), Mouse Jun B oncogene (JUNB), Finkel Biskis Jinkins (FBJ) mouse osteosarcoma virus oncogenic gene homolog (FOS), and Finkel Biskis Jinkins (FBJ) mouse osteosarcoma virus oncogenic gene homolog B (FOSB). RT-qPCR demonstrated that ATF3 was significantly upregulated in the saphenous vein after cyclic stretch. Western blot further validated those results. Furthermore, immunofluorescence showed that the upregulated ATF3 was predominantly expressed in the tunica media of the saphenous vein.

    Conclusions: TFs were upregulated in the saphenous vein after cyclic stretch. This may regulate cellular responses to stimuli by regulating transcriptional activity. ATF3 was significantly upregulated in the tunica media of the saphenous vein, indicating it might be a potential biomarker and regulator of smooth muscle cell (SMC) activation caused by cyclic stretch.

  • Article
    Maochun Zhang, Jiao Chen, Hongwei Zhang, Yuanyuan Guo, Qing Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4117-4127. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.404
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    Background: Overall mortality of endometrial carcinoma (EC) has been increasing. Therefore, the correct preoperative diagnosis and accurate staging of EC are of great significance.

    Objective: This study aims to explore the diagnostic value of ultrasound associated with serum ratios of neutrophils to lymphocytes (NLR), platelets to lymphocytes (PLR), monocytes to lymphocytes (MLR) and carbohydrate antigen 125 (CA125) for endometrial carcinoma (EC).

    Methods: From 2018 to 2020, 104 patients with suspected EC diagnosed by ultrasound from the Affiliated Hospital of Sichuan Medical College were enrolled. All patients were examined by routine ultrasound, serum tumor markers CA125 and serum levels of NLR, PLR and MLR before operation. The size, boundary, internal echo and internal blood flow of the focus were recorded in detail. The correlation between NLR, PLR, MLR, CA125 and the occurrence of EC was analyzed by logistic regression. The receiver operating curve (ROC) and area under curve (AUC) were employed to evaluate the sensitivity and specificity of NLR, PLR, MLR, CA125 associated with ultrasound for diagnosing EC.

    Results: Among the 104 suspected cases, 64 were EC patients. The growth site, lesion shape and lesion range of 50% of the cancer foci were shown more clearly than those before radiography. There was a significant difference between high and low levels of NLR for surgical and pathological stages, histological types and myometrial invasion depth (p < 0.05). There was a significant difference between high and low levels of PLR for surgical and pathological stages, histological types and cervical involvement (p < 0.05). There was a significant difference between high and low levels of CA125 for surgical and pathological stages, histological types and depth of myometrial invasion (p < 0.05). Elevated levels of NLR, PLR, and CA125 were independent predictors of EC based on multivariate logistic regression analysis. ROC curve analysis revealed that the AUC value of ultrasound examination combined with NLR, PLR, MLR and CA125 for EC diagnosis was higher than other indexes.

    Conclusions: The diagnostic value of NLR, PLR, MLR and CA125 associated with ultrasound for EC is higher than ultrasound alone.

  • Article
    Huiying Chen, Xiaoyu Lin, Jialin Huang, Xiaoting Zhu, Jinlan Liu, Jinxia Chen, Jianqi Yi, Wanli Ye, Wenfeng Xu, Jiping Su
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4129-4148. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.405
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    Background: Sodium salicylate (SS) is known to cause injury to spiral ganglion neurons (SGN) through excitatory toxicity and calcium overload. Store-operated Ca2+ entry (SOCE) has been identified as a mediator of Ca2+ influx that can cause damage to various neurons, including SGN. This study aimed to investigate the role of SOCE and downstream molecules of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinase (JNK) pathways in the process of SS-induced elevation of intracellular calcium concentration ([Ca2+]i) in SGN.

    Methods: The expressions of ryanodine receptor 3 (RyR3), Orai calcium release-activated calcium channel 1 (Orai1) and Stromal interaction molecule 1 (Stim1) were tested on rat cochlear SGN cultured in vitro using immunofluorescence. The SGN were then exposed to SS, RyR agonist (caffeine), RyR antagonist (dantrolene), Orai1 antagonist (MRS1845), ERK and JNK phosphorylation inhibitor (1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)/5-[(5-Nitro-1,3-thiazol-2-yl)thio]-1,3,4-thiadiazol-2-amine (SU3327)). Intracellular calcium imaging, FqPCR and Western blotting were used to detect [Ca2+]i, mRNA and protein expressions of RyR3, Orai1, Stim1 and molecules of ERK and JNK pathways.

    Results: After 3 and 6 h of SS treatment, there was a significant increase in SGN [Ca2+]i, as well as significant upregulations of mRNA and proteins of RyR3, Stim1, and Orai1. Inhibition of RyR or Orai1 reversed these effects of SS. Additionally, SS led to enhanced phosphorylation of ERK and JNK in SGN, accompanied by increased expression of their downstream transcription factors ETS-like 1 transcription factor 1 (Elk-1), early growth response 1 (Egr-1), and v-jun avian sarcona virus 17 oncogene homolog (c-Jun). Furthermore, activation of RyR promoted ERK and JNK phosphorylation, and inhibition of ERK and JNK reduced the upregulation of RyR3, Stim1, and Orai1 expressions caused by SS.

    Conclusions: SS may enhance RyR3-SOCE and activate ERK and JNK signaling, leading to [Ca2+]i elevation in SGN.

  • Article
    Geng Geng, Miao Wang, Mengyao Dong, Xingqing Guo, Qinghao Li, Ming Ming
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4149-4160. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.406
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    Background: Neuroblastoma (NB) that arises from neuroblasts is recognized as the most frequently-occurring extracranial solid malignancy in infancy. We aimed to expound the impacts of apolipoprotein C1 (APOC1) on NB and the mechanisms related to Sry-related HMG-BOX-4 (SOX4).

    Methods: APOC1 expression in NB cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR) and western blot. After APOC1 depletion, cell counting kit-8 (CCK-8) and colony formation assays separately appraised cell viability and proliferation. Cell cycle was also evaluated by flow cytometry analysis. Concurrently, wound healing and Transwell assays separately measured cell migration and invasion. Thiobarbituric acid reactive substance (TBARS) assay kit was adopted for the measurement of lipid peroxidation. Intracellular Fe2+ was detected by a FerroOrange fluorescent probe. Western blot tested the expression of proteins involved in epithelial-to-mesenchymal transition (EMT) and ferroptosis. JASPAR, luciferase reporter and Chromatin immunoprecipitation (ChIP) assays respectively predicated and confirmed that SOX4 could bind to APOC1 promoter region. Then, the aforementioned experiments were performed again when APOC1 was silenced and SOX4 was further overexpressed simultaneously.

    Results: Significantly elevated APOC1 expression was observed in NB cells (p < 0.01 or p < 0.001). APOC1 knockdown restrained NB cell proliferation (p < 0.01 or p < 0.001) and induce the cell cycle arrest (p < 0.001). The capacities of cell migration and invasion were inhibited following APOC1 silencing (p < 0.001). Moreover, APOC1 absence elevated the lipid peroxidation and induced ferroptosis (p < 0.001). Further, SOX4 was confirmed to bind to APOC1 promoter (p < 0.001). Rescue experiments revealed that SOX4 overexpression attenuated the impacts of APOC1 deletion on the malignant cellular behaviors in NB (p < 0.01 or p < 0.001).

    Conclusion: To conclude, APOC1 transcriptionally activated by SOX4 exerted oncogenic effects on NB, providing an underlying targeted therapy for NB treatment.

  • Article
    Jun Li, Zhijie Xia, Shan Huang, Yan Zhang, Zhongfang Xia
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4161-4172. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.407
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    Objective: Presbycusis, the most prevalent sensory impairment in the elderly, is associated with the loss of mitochondrial (mt)DNA4977 (corresponding to the loss of mtDNA4834 in rats). Superoxide dismutase 2 (SOD2) is a key factor involved in aging. Therefore, this study aimed to investigate the relationship between SOD2 and aging-associated loss of mtDNA4834 in rats.

    Methods: A rat inner ear aging model was established by mimicking the aging-associated mtDNA4834 deletion mutation with D-galactose. In addition, SOD2 was either overexpressed or inhibited to investigate its effects on marginal cell (MC) damage in mtDNA4834-deficient rats. The expression and methylation status of SOD2 as well as the expression of SOD2 transcriptional regulatory elements in DNA4834 deletion mutant marginal cells (MCs) and normal MCs were compared. The effect of SOD2 expression on MC phenotype was simulated by transfection.

    Results: SOD2 was downregulated in mitochondrial DNA (mtDNA)-deficient MCs, and this process was associated with the methylation of the SOD2-encoding gene. In addition, the overexpression of SOD2 in mtDNA4834-deleted MCs resulted in increased cell viability and reduced apoptosis, as demonstrated by the upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins. Moreover, SOD2 overexpression suppressed mtDNA4834 deletion mutation and increased the copy number of mtDNA4834, whereas SOD2 silencing resulted in the opposite effect.

    Conclusion: These findings indicate that aging-related mtDNA4834 deletion is associated with SOD2 deficiency, suggesting that SOD2 is a potential target for the treatment of mtDNA4977 deletion-related presbycusis.

  • Article
    Jia Gu, Yongqing Ye, Yan Wang, Wenjian Zhan, Rutong Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4173-4187. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.408
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    Objective: Glioblastoma (GBM) is a tumor derived from aberrant proliferation of glial cells in the brain. The GTEx database revealed that long non-coding RNA (lncRNA) linear amplification using nonlinear components (LINC)01094 was highly expressed in GBM samples. Herein, this study aims to investigate the mechanism of LINC01094 in GBM in depth.

    Methods: Quantitative real-time PCR (RT-qPCR) was used to evaluate the expression levels of LINC01094, signal transducer and activator of transcription 3 (STAT3), microRNA-545-3p (miR-545-3p), and ubiquitin-conjugating enzyme E2N (UBE2N) in GBM cells. The role of LINC01094 in GBM was investigated both in vitro and in vivo. The regulatory mechanism of LINC01094 was determined using chromatin immunoprecipitation (ChIP), RNA pull down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter experiments.

    Results: LINC01094 is significantly up-regulated in GBM cell lines. Functionally, knockdown of LINC01094 hampers cell proliferation and tumor growth, while promoting cell apoptosis and enhancing cell radiosensitivity. Mechanistically, signal transducer and activator of transcription 3 (STAT3) enhances the transcription activity of LINC01094. LINC01094 regulates ubiquitin-conjugating enzyme E2N (UBE2N) expression via sponging miR-545-3p, thus regulating cell proliferation, apoptosis and radiosensitivity in GBM.

    Conclusion: STAT3/LINC01094/miR-545-3p/UBE2N axis plays a novel role in modulating tumorigenesis and radiosensitivity in GBM, which may provide a potential target for GBM treatment.

  • Article
    LanPing Gao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4189-4194. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.409
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    Background and Purpose: Neonatal respiratory distress syndrome (NRDS) commonly occurs in preterm infants with the involvement of MicroRNAs (miRNAs). This study evaluated the predictive significance of miR-3162-3p in NRDS onset and patient's prognosis.

    Methods: Cord blood samples were collected from 100 preterm infants, including 50 NRDS neonates and 50 control neonates. The miR-3162-3p expression was detected by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), and the diagnostic value and predictive accuracy of miR-3162-3p were evaluated by receiver operating characteristic (ROC) analysis. The association between miR-3162-3p with NRDS onset and clinical outcomes was assessed by univariate and multivariate logistic regression analysis.

    Results: miR-3162-3p levels showed an up-trend in NRDS neonates and were associated with disease severity. miR-3162-3p had high diagnostic accuracy in NRDS and was related to NRDS onset. In addition, miR-3162-3p was highly expressed in NRDS neonates with poor prognosis and could high-accurately predict clinical outcomes.

    Conclusion: High miR-3162-3p in umbilical cord blood of NRDS neonates is correlated with NRDS onset and clinical outcomes.

  • Article
    Jiachen Xu, Qianqi Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4195-4204. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.410
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    Background: In this study, we explore the potential mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) inhibition on autism spectrum disorder (ASD) using 5-aminoisoquinolinone (5-AIQ), a PARP-1 inhibitor that has been shown to ameliorate ASD in black and tan brachyury (BTBR) mice.

    Methods: ASD animal models were established in neonatal Wistar rats by using valproic acid (VPA) induction, and the model rats were treated with 5-AIQ. The social interaction of neonatal rats in the models was evaluated through a three-chamber social test. VPA-induced ASD cell models were constructed in primary cortical neurons bearing PARP-1/mitogen-activated protein kinase phosphatase 1 (MKP-1) knockdown, followed by 5-AIQ treatment. Expressions of PARP-1 and MKP-1 were assessed by quantitative real-time polymerase chain reaction. The viability and apoptosis were measured by cell counting kit-8 (CCK-8) and TdT-mediated dUTP nick end labeling (TUNEL) assays. Reactive oxygen species (ROS) production was evaluated through specific kits. Levels of 4-Hydroxynonenal (4-HNE), PARP-1, MKP-1, phosphorylated-p38 (p-p38), p38, c-caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) were analyzed through Western blot.

    Results: The ability of social interaction among neonatal rats was suppressed in VPA-induced ASD animal models (p < 0.001). Expressions of 4-HNE, PARP-1, c-caspase-3, and Bax, as well as the ratio of p-p38/p38, were increased, while the expressions of MKP-1 and Bcl-2 were decreased in VPA-induced ASD animal models (p < 0.001). All these effects were reversed by 5-AIQ (p < 0.05). Suppressed viability, increased ROS production/apoptosis/ratio of p-p38/p38, upregulated PARP-1/c-caspase-3/Bax expression, and downregulated MKP-1/Bcl-2 expression in VPA-induced ASD cell models were reversed by 5-AIQ/small interfering RNA targeting PARP-1 (siPARP-1) (p < 0.01), while the effects of siPARP-1 were counteracted by small interfering RNA targeting MKP-1 (siMKP-1) (p < 0.001).

    Conclusions: PARP-1 inhibition ameliorates neuronal damage in VPA-induced models of ASD by the MKP-1/p38 pathway.

  • Article
    Jinxi Lu, Hongmei Yu, Xia Tao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4205-4210. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.411
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    Background: Gastric cancer (GC) is characterized by high malignancy and poor clinical prognosis. The identification of reliable prognostic indicators is crucial for assessing the condition of GC patients and developing evidence-based treatment strategies.

    Methods: This retrospective study analyzed clinical data from 168 GC patients at Wuhan Xinzhou District People's Hospital between February 2015 and February 2017. Thymidine kinase 1 (TK1) was detected, and systemic immune-inflammation indices (SII) were calculated for each patient. Receiver operating characteristic (ROC) curve analysis determined the cut-off values for SII and TK1, while Kaplan-Meier survival curves and logistic regression analysis identified factors impacting the clinical prognosis of GC patients.

    Results: Tumor size, tumor-node-metastasis (TNM) staging, lymph node metastasis, SII, and TK1 were significant factors influencing the 5-year survival rate of GC patients (p < 0.001), while gender, age, lesion location, and surgery did not significantly affect the 5-year survival rate (p > 0.05). Using a cut-off value of 781.985 for SII, patients were categorized into low and high SII groups, with the low SII group displaying longer survival time (p < 0.001). Similarly, a cut-off value of 2.445 for TK1 divided patients into low and high TK1 groups, with the low TK1 group exhibiting longer survival time (p < 0.001). Logistic regression analysis indicated that SII, TK1, and lymph node metastasis were independent factors affecting the prognosis of GC patients (p < 0.05).

    Conclusion: The lymph node metastasis, SII and TK1 are the key factors affecting the clinical prognosis of GC patients. It is believed that the changes in the patients' conditions can be predicted by monitoring the levels of SII and TK1, which can provide guidance for implementing the treatment and intervention measures, thus prolonging the survival period of patients.

  • Article
    Ting Wu, Shaojun Huang, Yumei Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4211-4218. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.412
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    Background: Colorectal cancer (CRC) is a malignant tumor with a significantly high incidence and mortality rate worldwide. Studies have found that quercetin has a significant effect in tumor treatment. However, the underlying molecular mechanism of quercetin remains unclear. The purpose of this study was to investigate the underlying molecular pathways involved in the therapeutic effects of quercetin in the treatment of CRC.

    Methods: We conducted in vitro experiments using quercetin at various concentrations to treat CRC cells. Transwell and plate clone formation assays were performed to detect the proliferation and migration ability of human CRC cells. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay was performed to evaluate cell apoptosis. Finally, molecular docking, western blot, and immunofluorescence assay were performed to detect the regulation mechanism.

    Results: Compared with the control group, the findings revealed significant decreases in cell proliferation and migration abilities, with increased apoptosis, in both the quercetin low, medium, and high dose groups, and the positive drug (rapamycin) group (p < 0.05). Moreover, with the increase of quercetin concentration, these effects became more pronounced, and no significant differences were observed between the quercetin high dose group and the positive drug group. According to western blot and immunofluorescence analysis, we observed that the cadherin 3 (CDH3) protein expression levels in quercetin medium and high dose groups were lower than in the control and quercetin low dose groups (p < 0.05).

    Conclusion: Overall, these results indicated that quercetin inhibited the proliferation and migration capabilities while increasing the apoptosis capability of CRC cells. This study provided a theoretical basis for the clinical application of quercetin and enhanced the research capabilities of our institution in CRC treatment.

  • Article
    Lin Zhu, Chunqin Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4219-4225. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.413
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    Objective: Chemotherapy-induced peripheral neuropathy (CIPN) often restricts the use of anti-cancer drugs due to its status as one of common toxic side effects. However, the precise pathogenesis of CIPN remains unclear, leading to a lack of definitive and effective preventative or treatment strategies. Accordingly, this study aims to assess CIPN early in ovarian cancer (OC) patients while exploring the impact of cold compress therapy on their extremities. The goal is to provide additional evidence to prevent and mitigate this toxic side effect.

    Methods: The study included 100 OC patients from the Fourth Hospital of Hebei Medical University, all undergoing chemotherapy with a paclitaxel and platinum-based regimen. Participants were divided into an intervention group (IG, n = 50, receiving cold compress treatment) and a control group (CG, n = 50, receiving standard chemotherapy care). The main evaluation measures were the total neuropathy score-clinical version (TNSc) and electromyography. We observed the incidences of CIPN after the second, fourth, and sixth chemotherapy courses, as well as at six months and one-year post-chemotherapy. Concurrently, blood samples were collected after the second, fourth, and sixth courses to measure nerve growth factor (NGF) levels. This helped evaluate the relationship between NGF and CIPN and whether serum NGF can predict early chemotherapy-induced peripheral nerve damage.

    Results: The IG, when compared with the CG, exhibited noticeably lower incidences of CIPN and TNSc after the second, fourth, and sixth chemotherapy courses, as well as at six months and one-year post-chemotherapy (all p < 0.05). Furthermore, both the motor conduction velocity (MCV) and sensory conduction velocity (SCV) of the IG were significantly higher than the CG after the fourth course (p < 0.001). After the second, fourth, and sixth courses, NGF levels in the IG were higher than that in the CG (p < 0.05). R analysis demonstrated a negative correlation between NGF and TNSc after the second, fourth, and sixth courses (p < 0.001).

    Conclusions: NGF can serve as a valuable tool for early assessment of CIPN. Additionally, using a cold compress on extremities effectively decreases the incidence of CIPN and is worthy of further endorsement.

    Clinical Trial Registration: Chinese Clinical Trial Registry: ChiCTR2300074397.

  • Article
    Yuan Ma, Xiaoyi Zhao, Kefei Duan, Yuanjie Niu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4227-4239. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.414
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    Background: Prostate cancer (PCa) is a significant health concern, and novel therapeutic approaches are needed. Celastrol, a natural compound, has shown promising anticancer effects in various cancer types. However, its regulatory effects on prostate cancer cells and the underlying molecular mechanisms remain unclear. This study aims to understand the regulatory effect of celastrol on the proliferation and apoptosis of prostate cancer cells.

    Methods: In this study, a nude mouse tumorigenesis model was established by subcutaneously implanting human prostate cancer cell suspension. Celastrol low (0.25 mg/kg), medium (1 mg/kg) and high (4 mg/kg) dose groups were administered by gavage once every three days. The tumor growth trend and tumor inhibition rate were detected. The 5-ethynyl-2'-deoxyuridine (EdU) staining was used to detect cell proliferation after treatment with different concentrations of celastrol. qPCR, western blot and co-precipitation experiments were used to explore the molecular mechanism of celastrol on the proliferation and apoptosis of prostate cancer cells.

    Results: Celastrol medium and high dose groups can effectively inhibit tumor proliferation in nude mice. As the dose increased, the anti-tumor effect increased. The expression of Ki67 and B-cell lymphoma/leukemia-2 (BCL-2) gene in prostate cancer cells can be significantly reduced by celastrol (p < 0.001), and the expression level was decreased in a dose-dependent manner. Meanwhile, prostate cancer cell proliferation was inhibited (p < 0.001). Moreover, the intervention of celastrol inhibits the migration of prostate cancer cells and significantly up-regulates the expression of tumor protein p73 (TP73) (p < 0.001), and the celastrol high-dose group had the best effect. A co-precipitation test found that celastrol can bind to TP73 protein. Overexpression of TP73 reduces the proliferation of prostate cancer cells, while the opposite effect was found when silencing TP73 (p < 0.001).

    Conclusion: Celastrol inhibits the proliferation and migration of prostate cancer cells and promotes apoptosis by up-regulating the expression of the TP73 protein. This study provides a research basis for the treatment of prostate cancer and the application of celastrol.

  • Article
    HongLiang Wang, Shuai Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4241-4248. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.415
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    Background and Purpose: Secondary intracranial infection is a common complication of craniocerebral surgery. This study aims to explore changes in the protein level of cerebrospinal fluid pentraxin 3 (PTX3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor for advanced glycation end-products (RAGE) in patients with secondary intracranial infection, and to evaluate the value of PTX3, GM-CSF, and RAGE in assessing disease severity and prognosis.

    Methods: From January 2017 to October 2020, 69 patients with secondary intracranial infection after craniocerebral surgery were selected as the infection group, and 46 patients without secondary intracranial infection after craniocerebral surgery were taken as the control group. PTX3, GM-CSF, and RAGE in cerebrospinal fluid of patients were measured to compare disease severity and prognosis. Whether protein levels of PTX3, GM-CSF, and RAGE were correlated with disease severity and patients' prognosis was analyzed.

    Results: PTX3, GM-CSF, and RAGE levels increased with the severity of intracranial infection (p < 0.05) and showed a positive correlation with disease severity (p < 0.05). The area under the curve (AUC) of the combined detection of the three indexes to evaluate the severity of intracranial infection was greater than that of single detection (p < 0.05). PTX3, GM-CSF, and RAGE levels were higher in patients with poor prognosis (p < 0.05), and combined detection of PTX3, GM-CSF, and RAGE was more effective to predict the prognosis of patients (p < 0.05).

    Conclusion: Protein levels of PTX3, GM-CSF, and RAGE in cerebrospinal fluid are elevated in patients with secondary intracranial infection and are associated with the disease severity. The three indexes have prognostic evaluation values for patients with secondary intracranial infection.

  • Article
    Yike Wang, Saisa Zhu, Deqin Chen, Jingpei Long
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4249-4259. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.416
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    Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Tubulin beta class I gene (TUBB) is highly expressed in breast cancer, but its specific role has yet to be identified. Our study thus aims to investigate the effect of TUBB on TNBC from the molecular perspective.

    Methods: Biological information analysis was carried out to identify our specific study topics. TNBC cells (MDA-MB-231 and BT549) were transfected with short hairpin RNA targeting TUBB (shRNA-TUBB) or negative control-shRNA (shRNA-NC). TUBB expression in TNBC cells was studied by reverse-transcription quantitative polymerase chain reaction. Cell apoptosis, proliferation and migration were assessed through flow cytometry, colony formation assay, 5-Ethynyl-2'-Deoxyuridine (EdU) assay, and wound healing assay, respectively. Quantification of apoptosis- and epithelial-mesenchymal transition (EMT)-related genes was analyzed by western blot.

    Results: TUBB was upregulated in TNBC tissues (p < 0.05). Downregulation of TUBB facilitated the apoptosis but inhibited the colony formation ability, proliferation and migration of TNBC cells (p < 0.01). Expressions of apoptosis-related proteins and EMT-related proteins was variable in TNBC cells under inducement of TUBB downregulation (p < 0.01).

    Conclusion: Downregulating TUBB can dampen proliferation, migration and EMT, while facilitating apoptosis of TNBC cells, which might provide new insight for treating TNBC by targeting TUBB.

  • Article
    Hao Zhang, Yongqian Bian, Congying Zhao, Yan Wang, Rong Huang, Bin Lin, Danying Qin, Wei Xiong, Jing Li, Xueyong Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4261-4270. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.417
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    Background: Keloids and hypertrophic scars are pathological scars that result from aberrant wound healing. The etiology of pathological scar formation remains elusive, but it causes great physical and psychological pain to patients. This study aimed to determine bacterial colonization in keloids and hypertrophic scars and further investigate the pathogenesis of their formation.

    Methods: 23 normal skin controls, 53 keloids and 35 hypertrophic scars (without any other previous treatments) were included in the study. After collecting the surgically removed samples, gram staining, immunofluorescence, immunohistochemical analysis, immunoelectron microscopy, microbiological culture and a 16S ribosome DNA real-time quantitative Polymerase Chain Reaction (16S rDNA RT-qPCR) were used to detect the presence of bacteria. PICRUSt2 tool and BugBase were used to map the 16S rDNA sequencing to the pathways, genes and phenotypic differences.

    Results: In normal skin tissues, the colonizing bacteria were only found in skin appendages, while extracellular and intracellular bacteria were widely distributed in keloids and hypertrophic scars, and intracellular bacteria mainly existed in the cytoplasm of macrophages and fibroblasts. A total of 2260 bacterial species were detected in keloids and hypertrophic scars, mainly concentrated in Clostridiales, Burkholderiales, Actinomycetales and Bacteroidales. The pathogenicity and athletic ability of colonizing bacteria were positively correlated with the degree of hyperplasia and invasions of scars.

    Conclusions: The difference in the species and number of colonizing bacteria in pathological scars may cause the heterogeneity of clinical manifestations, providing a new strategy for preventing and treating keloids and hypertrophic scars.

  • Article
    Tengjiao Ma, Ronghua Tang, Hongxia Fan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4271-4284. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.418
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    Background: Oral squamous cell carcinoma (OSCC) is a malignant tumor that poses a serious threat to patient's health and life. Despite extensive advances in the treatment of OSCC, the 5-year survival rate of OSCC remains dissatisfactory. SHC SH2 domain-binding protein 1 (SHCBP1) is involved in the development, metastasis and carcinogenesis of various types of cancers, but its specific role in OSCC is not well understood. This study aims to explore the role of SHCBP1 in OSCC.

    Methods: Gain-of-function and loss-of-function assays were conducted on the SCC-9 and CAL-27 cells to investigate the role of SHCBP1 in ferroptosis. This was achieved by overexpressing and downregulating the level of SHCBP1. Additionally, both cell lines were treated with erastin, ferrostatin-1, ZVAD-FMK and necrosulfonamide to further explore the role of SHCBP1 in ferroptosis. The direct role of growth differentiation factor 15 (GDF15) was also confirmed by overexpressing it in both cell lines. The expression of SHCBP1 was examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and Western blot. The effects of SHCBP1 on various cellular processes such as growth, invasion, mobility, epithelial-mesenchymal transition (EMT), and ferroptosis were investigated in SCC-9 and CAL-27 cells. This was done using cell counting kit-8 (CCK-8), colony formation assays, 5-ethynyl-2′-deoxyuridine (EdU) incorporation, Transwell® assays, and examination of the ferroptosis level. Additionally, a xenografted mouse model was constructed to conduct in vivo assays.

    Results: The expression of SHCBP1 was significantly increased in both OSCC tissues and cell lines (p < 0.01). Interfering with SHCBP1 suppressed the growth of OSCC (p < 0.05). Additionally, silencing SHCBP1 inhibited invasion, migration, and EMT, while enhancing ferroptosis in SCC-9 and CAL-27 cells, vice versa (p < 0.05). Besides, downregulation of SHCBP1 attenuated the expression of solute carrier family 7 member 11 (SLC7A11) and GDF15 (p < 0.05), which was reversed with the overexpression of GDF15 (p < 0.05). Moreover, the upregulation of GDF15 also reversed the effects of shSHCBP1 on proliferation, migration, invasion and ferroptosis in CAL-27 and SCC-9 cells (p < 0.05).

    Conclusions: Downregulation of SHCBP1 inhibits the progression and development of OSCC through GDF15 and enhances ferroptosis by repressing GDF15-mediated SLC7A11 in OSCC.

  • Article
    Xiaofang Pi, Mingliang Liu, Gaoli Zhu, Yan Zhang, Nana Liao, Tiantian Liu, Yeqing Chen, Yaoyao Lei, Hongyu Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4285-4292. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.419
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    Backgrounds: Liver fibrosis (LF) is the pathological basis of various chronic liver diseases. An in-depth understanding of the pathologic alterations leading to LF is of great significance for the future diagnosis and treatment of LF. The objective of this study was to investigate the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in LF and to provide a potential new target for diagnosis and treatment of LF.

    Methods: Twelve Specific Pathogen Free (SPF)-grade SD rats were randomized into four equal groups. One group was left untreated as the control group. The other three groups were subjected to LF modeling. LF was induced by intraperitoneal injection of a carbon tetrachloride/olive oil mixture twice weekly for 8 weeks. Three groups of LF model rats were then selected. One group was injected with lentiviral vector inhibiting PTGS2 expression (PTGS2 group), one group was injected with PTGS2 empty vector (blank group), and one group was injected with saline (model group). After 24 hours, the liver function of each group was measured, and the body weight and liver weight were obtained to calculate the liver index. Liver tissues were taken for hematoxylin-eosin (HE) staining and histopathologic examination, and the expressions of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), E-cadherin and N-cadherin were measured.

    Results: A large number of steatosis and inflammatory cell infiltration, interlobular connective tissue hyperplasia and fibrous septum formation were observed in the liver tissues of rats in the model and blank groups, which were significantly improved in the PTGS2 group. Alanine transaminase (ALT) in the PTGS2 group was significantly lower than in the model and blank groups, but significantly higher than in the control group (p < 0.05). There was no difference in liver index between the PTGS2 and control groups, both of which were lower than the model and blank groups (p < 0.05). TGF-β and α-SMA mRNAs were higher in the PTGS2 group than in the control group and lower than in the model and blank groups (p < 0.05). E-cadherin was decreased, while N-cadherin was increased (p < 0.05), in both the model and blank groups compared to the control and PTGS2 groups.

    Conclusion: Blocking PTGS2 expression ameliorated hepatic damage and reversed epithelial mesenchymal transition (EMT) in LF rats.

  • Article
    Xiaorui Dong, Xixi Chen, Mengling Xue, Yina Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4293-4302. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.420
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    Background: Evodiamine has been documented to suppress epithelial-mesenchymal transition (EMT), but its effects on adenomyosis are poorly understood. This study investigates evodiamine's potential effects and mechanisms in treating adenomyosis.

    Methods: The cohort comprised 90 women (34 healthy controls and 56 adenomyosis patients). The Jagged-1/Notch1/hairy expression levels and hairy and enhancer of split 1 (Hes1) signaling pathway in human endometrial tissues were assessed using western blot analysis. An adenomyosis mouse model was created using 1 mg/kg tamoxifen, followed by treatment with evodiamine and dual antiplatelet therapy (DAPT). Expression levels of alpha-smooth muscle actin (α-SMA), collagen I, neural cadherin (N-cadherin), epithelial cadherin (E-cadherin), Snail, and Vimentin were evaluated using western blot analysis. Immunohistochemistry was used to assess Jagged-1, Notch1, and Hes1 levels. Hematoxylin and eosin (H&E) staining evaluated the depth of endometrial infiltration into the myometrium, and Masson trichrome staining quantified collagen content.

    Results: The Jagged-1/Notch1/(hairy and enhancer of split 1) Hes1 pathway was found to be activated in the endometrial tissues of adenomyosis patients. In adenomyosis mice, evodiamine treatment led to the inhibition of the Jagged-1/Notch1/Hes1 pathway, along with observable morphological changes, such as reduced adenomyosis nodules with congestion. This improvement was significant compared to the control group (p < 0.05). Furthermore, evodiamine and DAPT treatments reduced endometrial infiltration into the myometrium and collagen deposition while suppressing the expression of α-SMA, collagen I, N-cadherin, Snail, and Vimentin, and upregulating E-cadherin expression. The inhibitory effect was significantly greater than that in the control group (p < 0.05).

    Conclusion: Evodiamine mitigated adenomyosis by regulating EMT through the inactivation of the Jagged-1/Notch1/Hes1 pathway. This finding suggests that evodiamine could be a potential treatment option for adenomyosis.

  • Article
    Yongliang Ma, Zongtao Ren, Shufei Wei, Pan Qi, Aili Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4303-4312. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.421
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    Background: Prostate cancer (PC) is common among the elderly and significantly impacts their quality of life. This study aims to explore the role of acetyl-CoA acetyltransferase 1 (ACAT1) in the cellular process of PC cells and the interplay of ACAT1 and the Wnt/β-catenin pathway.

    Methods: Initially, we assessed the expression level of ACAT1 in normal and PC cells using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. Subsequently, after transfection with ACAT1 overexpression plasmid or siACAT1, we conducted a series of functional assays, including cell counting kit-8 (CCK-8), Transwell and flow cytometry, to evaluate the biological behaviors of PC-3 cells. qRT-PCR and Western blot were selected to determine expressions of apoptosis-related proteins, Wnt/β-catenin and its downstream genes. Later, PC-3 cells received treatment with FH535 or LiCl and transfection with ACAT1 overexpression plasmid/siACAT1, after which the cell's biological behaviors were determined again.

    Results: ACAT1 was expressed more in PC cells than in RWPE-1 cells (p < 0.001). Overexpressed ACAT1 exerted the effects of potentiating cell proliferation, migration and invasion and suppressing cell apoptosis (p < 0.001). Also, under the inducement of overexpressed ACAT1, levels of B cell lymphoma-2 (Bcl-2) and Wnt/β-catenin signaling and its downstream genes were elevated, while those of Bcl-2-associated X protein (Bax) and cleaved caspase-3 were repressed (p < 0.001). However, ACAT1 knockdown produced inverse results (p < 0.001). FH535 treatment repressed ACAT1 overexpression-induced proliferation, migration and invasion, while LiCl treatment reversed the negative effects of ACAT1 silencing (p < 0.001).

    Conclusions: ACAT1 enhances the biological functions of PC cells by modulating the Wnt/β-catenin signaling pathway and its downstream genes.

  • Article
    Biling Fu, Shihai Zou, Junxiong Weng, Cuiyun Liu, Jihong Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4313-4322. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.422
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    Objective: The study aimed to explore the role and molecular mechanism of High Mobility Group B 1 (HMGB1) on inflammatory response of Peritoneal Mesothelial Cells (PMC) mediated by high concentration glucose environment.

    Methods: The human peritoneal mesothelial cell (HPMC) line Human PMC strains (HMrSV5) was used as a research object and cultured in vitro. Enzyme-linked immuno sorbent assay (ELISA), immunofluorescence, and real-time polymerase chain reaction (PCR) were performed after grouping, and small interfering RNA (siRNA) gene silencing technique was used to analyze the effect of HGMB1 expression inhibition on the release of inflammatory factors in a high glucose environment. Finally, the effects of HMGB1 on monocyte chemoattractant protein 1 (MCP-1) and Interleukin-8 (IL-8) expression were investigated using inhibitors of key factors of the mitogen-activated protein kinase (MAPK) pathway.

    Results: The content of HMGB1 in the supernatant of group A was significantly higher than that in group B and group C (p < 0.05), suggesting that high glucose can promote the transfer of HMGB1 from intracellular to extracellular space in PMC. With the increase of glucose concentration and incubation time, the expression of extracellular HMGB1 significantly increased. After silencing HMGB1 expression, the content of inflammatory factors in PMC significantly decreased.

    Conclusions: HMGB1 can directly promote the release of inflammatory factors, especially inflammation factor MCP-1. And the path of inflammatory mechanism of HMGB1 was the HMGB1-MAPK signaling pathway.

  • Article
    Yuxuan Yong, Qinfen Wu, Xinling Meng, Ranran Lu, Huan Xia, Feifei Pei, Xinling Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4323-4333. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.423
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    Objective: Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is the main kinase which phosphorylates the residues of alpha-synuclein (α-syn). It has been reported that Single Nucleotide Polymorphisms (SNPs) distribution of the DYRK1A gene is associated with the risk of Parkinson's disease (PD) in different races. However, it is still unclear how α-syn phosphorylation modifications mediated by the DYRK1A gene and its mutations affect the progression of PD. The goal of this study is to uncover the molecular mechanisms involved in α-syn phosphorylation mediated by DYRK1A in dopaminergic (DA) neuronal apoptosis.

    Methods: SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+) to establish PD model. Negative control small interfering RNA (siRNA) and DYRK1A siRNA reagents were administered to establish negative control (NC) siRNA and DYRK1A siRNA groups. Empty vector and lentivirus plasmids were employed to construct the Vector and DYRK1A overexpression (OE) groups. Cell apoptosis was then assessed via western blotting and flow cytometry. Western blotting was used to determine the α-syn phosphorylation and the related protein expression of the Akt (Akt kinase)/GSK3β (glycogen synthase kinase 3 beta)/NF-κB (nuclear factor kappa B)/Cyclin D1 pathway. Co-immunoprecipitation and western blotting were employed to investigate the interaction between α-syn and GSK3β. Upstream and downstream relative gene expressions in the Akt/GSK3β pathway, including PI3K (phosphatidylinositol 3-kinase), mTOR (mechanistic target of rapamycin kinase), c-Myc (Myc proto-oncogene), and HIF1α (hypoxia inducible factor 1 subunit alpha), were detected by quantitative Polymerase Chain Reaction (qPCR) analysis.

    Results: We found that DYRK1A knockdown resulted in lower phosphorylated-alpha-synuclein (P-α-syn, Ser129) levels (p < 0.01), whereas DYRK1A overexpression heightened levels of P-α-syn (p < 0.01). Furthermore, DYRK1A interacts with α-syn and GSK3β. DYRK1A knockdown resulted in activation of the Akt/GSK3β/NF-κB pathway to promote DA neuronal apoptosis. Finally, DYRK1A knockdown increased the messenger RNA (mRNA) levels of PI3K, mTOR, c-Myc, and HIF1α (p < 0.01), which are involved in the Akt/GSK3β/NF-κB signaling pathway.

    Conclusions: These findings demonstrate that DYRK1A is responsible for α-syn phosphorylation and regulates activation of the PI3K/Akt/GSK3β pathway in DA neuronal apoptosis.

  • Article
    Jie Gao, Lianheng Xia, Zhen Jia, Jiayuan Zhang, Meiyu Song, Wukun Ding, Linggen Li, Xuewei Liang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4335-4343. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.424
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    Background: Chitosan has the advantage of improving inflammatory response. However, the molecular mechanism by which chitosan derivatives promote macrophage proliferation is not fully illuminated. Here, we focused on the Caveolin 1 (CAV1)/Wnt family member (Wnt) regulatory axis to study the effect of chitosan on wound healing of diabetic skin ulcer.

    Methods: We prepared Sprague Dawley (SD) rat models of diabetic (DM), DM with chronic refractory wound (CW), and CW with chitosan treatment (CTS). Flow cytometric assay was used to isolate macrophage from epidermis of skin tissues with chronic wound. RNA sequencing was used to study the transcriptome of M0 and M2 macrophages. Immunoprecipitation and western blot were used to study Wnt/β-catenin signaling pathway and the target gene Caveolin 1 (Cav1) of M0 macrophages. Molecular docking was used to mimic the protein-protein interaction between CAV1 and β-catenin.

    Results: We observed that chitosan was capable of facilitating the differentiation process of M0 to M2 macrophage in wound area. Total 734 differentially expressed genes (318 elevated and 416 reduced) were found compared between CTS and CW. Cav1 was significantly up-regulated in chitosan treated M0 macrophages. Furthermore, we noticed that the delivery of chitosan particle containing with Cav1 shRNA could enhance the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and the followed activity of canonical Wnt pathway in M0 macrophages in vivo. Both C-terminus of CAV1 and GSK3β shown by protein docking remodeling indicated the interaction of these two proteins.

    Conclusions: Current study determines that chitosan promotes the expression of Cav1, and enhances the activity of GSK3β function through canonical Wnt/β-catenin signaling pathway.

  • Article
    Wafaa LOUNIS, Khadidja KESSAS, Zehor CHOUARI, Imene BENYETTOU, Abdenour BOUMECHHOUR, Faiza CHAIB, Seghir Hadjadj AOUL, Gerard LIZARD, Omar KHAROUBI
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4345-4359. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.425
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    Background: This study aims to examine the potential neuroprotective effects of flaxseed oil (FSO) on the brain activity of rat pups sired by females intoxicated with aluminum (Al). The brain is known to be particularly vulnerable to the deleterious effects of aluminum, which promotes oxidative stress and neuroinflammation. FSO is a rich source of omega-3 (ω-3) fatty acids (FA), essential components of neuronal membranes and neurotransmission.

    Methods: After collecting 36 offspring aged three weeks from a control group and an intoxicated female group that received an intraperitoneal injection of aluminum chloride (AlCl3) (75 mg/kg body weight, twice a week) in the morning for 30 days. Six subgroups of pup rats for each group (n = 6) were used, with control groups having free access to food and water and two experimental groups receiving low and high doses of FSO administered by gavage (0.5 and 2 mL/kg b.wt.). An intoxicated group was also tested with rats receiving low and high FSO concentrations and free access to water. The study appears to focus on the effect of omega-3 in the FSO on the brain's development of young rats a neurobehavioral study was carried out, followed by estimation of prooxidant parameters and neurotransmitter activity of the brain, and a lipid composition was carried out on the brain membrane by gas chromatography-mass spectrometry (GC-MS) analysis.

    Results: The FA profile of FSO revealed domination by ω-3 type (86.9%). The 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging capability was found at half maximal inhibitory concentration (IC50) values of 18.12 g/mL. Neurobehavioral experiments showed significant hyperactivity and memory loss in intoxicated young rats, with decreased levels of lipid peroxidation (LPO) and nitric oxide (NO) and a significant increase in acetylcholinesterase (AChE) activity in the brain. However, ameliorative results were found in both concentrations of FSO administration when compared with intoxicated groups. GC-MS analysis of the brain membrane FA profile revealed the presence of elaidic acid in both the AL and AL+FSO. Neurobehavioral experiments showed significant hyperactivity and memory loss in intoxicated young rats, with decreased levels of lipid peroxidation (LPO) and nitric oxide (NO) and a significant increase in acetylcholinesterase (AChE) activity in the brain. However, ameliorative results were found in both concentrations of FSO administration when compared with intoxicated groups. GC-MS analysis of the brain membrane FA profile revealed the presence of elaidic acid in both the AL and AL+FSO” groups. In contrast, only the AL+FSO' group had eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) areas.

    Conclusions: Our results suggest that FSO supplementation at low concentrations has neuroprotective effects on developing rat brains, correcting and ameliorating the abnormalities brought on by embryo/fetal aluminum chloride toxicity.

  • Article
    Jia Liu, XunYuan Tuo, Lin Zhang, JinWei Yang, Yan Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4361-4366. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.426
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    Objective: To investigate the effects of levothyroxine (LT4) replacement therapy on pregnancy outcomes and offspring development in pregnant women with subclinical hypothyroidism (SCH).

    Methods: This prospective randomized study included 128 pregnant patients with SCH who underwent assisted conception at our hospital. Patients were randomly allocated via a random number table to either the intervention group (n = 64, basic treatment plus LT4 replacement therapy) or control group (n = 64, basic treatment only). Thyroid function hormone index scores, pregnancy outcomes, and growth and development of newborns were compared between the two groups. This study complied with all relevant clinical trial safety and medical ethics guidelines.

    Results: In early pregnancy, there were no statistically significant differences in serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), serum free thyroxine (FT4), and total triiodothyronine (TT3) levels between the intervention and control groups (p > 0.05). In mid- and late pregnancy, the serum TSH levels of pregnant women in both groups were significantly lower than those during early pregnancy; however, the intervention group exhibited a significantly greater decrease compared to the control group (p < 0.05). While FT3 and FT4 levels were not significantly different between the two groups during mid- and late pregnancy (p > 0.05), TT3 levels were significantly higher in the intervention group in mid-trimester (p < 0.05). Offspring weight was significantly greater than that in the control group at 1 and 7 months after birth (p < 0.05), while offspring length was significantly greater in the intervention group at birth and 1 month after birth (p < 0.05). The rate of adverse pregnancy outcomes was significantly lower in the intervention group (18.75%) compared to the control group (34.38%) (p < 0.05). The intellectual and motor development scores of infants at 12 months after birth were significantly higher in the intervention group than those in the control group (p < 0.05).

    Conclusion: Basic treatment combined with LT4 replacement therapy can effectively improve thyroid hormone levels in pregnant women with SCH, promote early fetal and neonatal development, and reduce adverse pregnancy outcomes. Nevertheless, due to the single-center design of this study, as well as the limited sample size, further studies are required to confirm our results.

  • Article
    Ding Fu, Yajing Wang, Yunlong Zhao, Borui Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4367-4375. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.427
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    Background: The mechanical force signal transduction pathway and its regulation mechanism of orthodontic tooth movement and bone remodeling are the focus of orthodontic biomechanics and biology research. hydrogen sulfide (H2S) inhibits bone resorption and conducts an important role in osteogenesis and osteoblastogenesis in bone tissue. This study aims to investigate the effects of H2S and the Hippo-Yes-associated protein (YAP) pathway on autophagy of mouse periodontal ligament cells (mPDLCs) during orthodontic tooth movement.

    Methods: The orthodontic tooth movement model of C57BL6/J mice was established. Third to fifth-generation mPDLCs with good growth conditions were selected. They were divided into H2S alone groups (control (H2S = 0 mM), 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM); Apply tension group (control (Apply tension = 0 h), 1 h, 3 h, 6 h); Apply tension for 1 h + H2S (control, 0.01 mM, 0.05 mM, 0.1 mM; 0.5 mM); Apply tension for 3 h + H2S (control, 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM); Apply tension for 6 h + H2S (control, 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM). The morphology of mPDLCs was observed by immunofluorescence. Sodium hydrosulfide (NaHS) was used as the donor of exogenous H2S. The levels of bone plastic proteins, containing receptor activator of nuclear factor kappa-B ligand (RANKL) and Osteoprotegerin (OPG), autophagy-related proteins, containing Autophagy Related Protein 5 (Atg5), Autophagy Related Protein 7 (Atg7), and coiled-coil, myosin-like BCL2 interacting protein (Beclin-1), and the Hippo pathway protein (active-YAP) were assessed by western blot.

    Results: All experimental rats showed tooth movement, and the experimental modeling was successful. The level of RANKL increased and OPG declined after the application of tension and reached the most significant difference at 6 h of stress (p < 0.05). When the concentration of H2S was 0.5 mM, the increase of RANKL and the decrease of OPG were the most significant (p < 0.05), regardless of whether tension was applied or not. When tension was applied for 6 h and H2S was 0.5 mM, the level of active-YAP was significantly increased (p < 0.05). HY-101275, an inhibitor of the Hippo pathway, reversed the promoting effects of H2S and tension on bone remodeling and autophagy of mPDLCs (p < 0.05).

    Conclusions: Under the action of orthodontic force, H2S can increase the level of autophagy in mPDLCs. The Hippo-YAP signaling pathway is involved in the process of H2S-induced increase of mPDLCs autophagy.

  • Article
    Diandian Chen, Kezhi Shi, Yili Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4377-4385. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.428
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    Background: Emerging evidence has indicated that microRNAs (miRNAs) play a significant role in multiple biological processes, including controlling the cell cycle, apoptosis, autophagy, and metabolic reprogramming. Among them, microRNA (miRNA)-518a-3p has been revealed to display a notably key function during the development of many cancer types, including colorectal cancer, breast cancer, and squamous cell carcinoma. However, its functions and molecular mechanisms during hepatocellular carcinoma (HCC) progression remain unclear. In this study, we aim to elucidate the specific biological processes and mechanisms of miRNA-518a-3p affecting HCC, so as to provide reference for finding new therapeutic targets.

    Methods: Molecular and cell biology experiments were used to demonstrate the biological functions and molecular mechanisms of miRNA-518a-3p in HCC. Quantitative reverse transcription PCR (RT-qPCR) detected the miRNA-518a-3p expression level in HCC tumor tissues, and its related prognostic effects were also investigated. Furthermore, its functions during HCC progression were investigated by Cell Counting Kit-8 (CCK-8) experiment, transwell assay in two HCC cell lines. Moreover, its potential mechanisms were analyzed by bioinformatic analysis, RT-qPCR, western blotting, a luciferase reporter assay, and rescue experiments.

    Results: Downregulation of miRNA-518a-3p was found in HCC tumor tissues and correlated with an awful overall survival. Gain and loss of function analyses displayed miRNA-518a-3p repressed HCC cells proliferation, migration, and invasion. Bioinformatic analysis and luciferase reporter assays have shown that Zinc finger protein 281 (ZNF281), upregulated in HCC tumor tissues, was negatively regulated by miRNA-518a-3p. Moreover, rescue experiments demonstrated that the suppression of HCC progression by miRNA-518a-3p was mediated by ZNF281.

    Conclusions: Our study indicated that miRNA-518a-3p inhibited hepatocarcinogenesis by suppressing ZNF281 expression, indicating that miRNA-518a-3p is a promising therapeutic approach targeting the treatment of HCC.

  • Article
    Ai Yan, Jufang He, Yuntao Li, Xiaohu Nie, Bin Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4387-4394. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.429
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    Background: Subarachnoid hemorrhage (SAH) is a cerebrovascular illness with high mortality. Inflammation is considered as a potential pathogenic factor of SAH occurrence. Membrane-associated ring-CH type finger 1 (MARCH1) has been implicated to inhibit immune response based on ubiquitination activity, indicating the potential treatment for SAH. However, the role of MARCH1 in SAH remains unclear. We aimed to explore the role of MARCH1 in SAH.

    Methods: Enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in SAH patients and healthy donors. Oxyhemoglobin (OxyHb) was applied to PC12 cells to establish the SAH cell model. After OxyHb treatment, cell proliferation in PC12 cells was assessed using the cell counting kit-8 (CCK-8) kit. Lentiviruses were used to knock down or overexpress MARCH1 expression. Real-time PCR and western blot assays were used to detect the mRNA and protein expression levels of MARCH1.

    Results: The levels of IL-1β and IL-18 were significantly higher in SAH patients compared to healthy donors (p < 0.001), with a notable upregulation observed in the advanced stages of SAH (p < 0.05 and p < 0.001). OxyHb enhanced IL-18 and IL-1β (p < 0.001) but decreased MARCH1 expression (p < 0.001) in a time-dependent manner in PC12 cells (p < 0.001). Besides, MARCH1 could inhibit SAH-induced inflammation and promote the proliferation of cells (p < 0.001). MARCH1 decreased the protein levels of NACHT (central nucleotide-binding and oligomerization), leucine-rich repeat (LRR), and Pyrin domain (PYD) containing proteins 5 (NLRP5) (p < 0.001) by promoting its ubiquitination. Furthermore, these effects could be reversed by the overexpression of NLRP5 in the SAH cell model (p < 0.001).

    Conclusions: Our study revealed that MARCH1 could inhibit the inflammation and promote cell proliferation in the SAH cell model by enhancing NLRP5 ubiquitination. MARCH1 and NLRP5 could be potential targets for the treatment of SAH. However, the in vivo experiment is needed to further verify this conclusion.

  • Article
    Lijun Xie, Wenxuan Sun, Mingtao Tan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4395-4401. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.430
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    Background: Characterized by large trauma, strong stress response, long operation time and postoperative pain in thoracic surgery, an efficient anesthesia during the surgery is very important to facilitate the operation.

    Methods: The clinical data of 130 patients who underwent thoracic surgery in Zibo Central Hospital from April 2020 to April 2022 were selected for a retrospective analysis. The patients were divided into the study group (STG, n = 62, etomidate combined with remifentanil) and the reference group (REG, n = 68, simple general anesthesia) according to different anesthesia schemes, the levels of inflammatory factors in the two groups were compared using enzyme-linked immunosorbent assay, and the immune function at different time was compared via a BD flow cytometer.

    Results: The STG had lower spontaneous breathing recovery time, smooth response time in speech and the time of completing action instruction, and reduced serum levels of inflammatory factors at T1, T2 and T3 than REG (p < 0.001). Serum levels of cluster of differentiation 3 (CD3+) at T1–T4, and CD4+, natural killer (NK) cells and CD4+/CD8+ at T2–T4 were higher in STG than in REG (p < 0.05). There was no difference in the total incidence of adverse postoperative reactions in the two groups (p > 0.05).

    Conclusion: The use of etomidate combined with remifentanil for anesthesia in patients undergoing thoracic surgery has an ideal anesthetic effect and less impact on the immune function of patients. Meanwhile, these patients have relatively mild inflammatory reactions, so the combination of etomidate and remifentanil has beneficial clinical application value.

  • Article
    Jiao-gui Xie, Ying Jiang, Yi-chao Wang, Li-feng He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4403-4411. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.431
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    Background: At present, sunitinib (ST) is the most frequently used targeted therapy drug for renal cell carcinoma (RCC). The objective of this study was to investigate whether dandelion root extract (DRE) could improve the curative effect of ST on RCC through in vitro experiments.

    Methods: First, 786-O human RCC cells were divided into Control, DRE, ST and DRE+ST groups. Next, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays were applied to test the proliferation and viability of 786-O cells, respectively. Cell apoptosis, reactive oxygen species (ROS) levels and changes in mitochondrial membrane potential were detected by flow cytometry. Western blot was used to evaluate protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, Caspase-9, apoptosis-inducing factor (AIF), cytochrome c (Cyt-c), cleaved-Caspase-9 and cleaved-poly ADP-ribose polymerase (PARP) in mitochondria. Besides, mitochondrial DNA (mtDNA) content and expression levels of peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α), mitochondrial transcription factor A (TFAM), dynamin-related protein 1 (DRP1), mitofusin 1/2 (MFN1/2) were measured by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR).

    Results: Compared with DRE alone or ST alone, DRE combined with ST significantly increased the toxicity of 786-O cells (p < 0.01), increased ROS accumulation (p < 0.01), promoted apoptosis (p < 0.01), up-regulated the expression level of mitochondrial apoptosis-related proteins (p < 0.01), decreased mitochondrial membrane potential (p < 0.01), and induced mitochondrial dysfunction in 786-O cells (p < 0.01).

    Conclusions: DRE may increase the toxicity of ST to RCC cells via inducing mitochondrial dysfunction and triggering apoptosis. Therefore, DRE combined with ST may be a potential treatment option for RCC.

  • Article
    Xiaodong Ni, Weiming Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4413-4418. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.432
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    Background: Short bowel syndrome (SBS) may result in nutrient malabsorption, intestinal dysfunction, and even complete intestinal failure, thereby compromising the quality of life and psychological status of patients. Animal models may help understand the mechanism involved in SBS, and improve its prognosis.

    Objective: To study changes in the behavioral pattern in a rat model of type III SBS, and it relationships with gut flora.

    Methods: A total of 20 male adult Sprague-Dawley (SD) rats, each weighing about 230 g, were randomly divided into an SBS group and a control group, with 10 rats in each group. Type III SBS model was established in the SBS group, while sham operation was adopted in the control group. All rats were kept for two weeks after surgery.

    Results: Massive small bowel resection resulted in significantly decreased weights of rats in SBS group, while control rats had marked increases in weight. Results of open-field test and sucrose preference test conducted two weeks postoperatively showed significantly lower sucrose preference index and lower frequency of horizontal and vertical movements in the SBS group (p < 0.05). The results of 16S ribosomal DNA (rDNA) sequencing in intestinal flora showed lower abundance of Firmicutes and Bacteroidetes and higher abundance of the Proteobacteria and Spirochaetes in the SBS group, although the differences were not statistically significant.

    Conclusions: Type III SBS rats exhibited significant depression/anxiety-like behavioral abnormalities at two postoperative weeks. This may be related to changes in intestinal flora after intestinal cut-off and anastomosis. However, there is need for further studies in this regard.

  • Article
    Ting Liu, Song Yang, Xin Wang, Yue Cao, Bing Tian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4419-4425. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.433
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    Objective: This study aims to study and evaluate the mechanism of adipose-derived stem cells-ductus arteriosus compound on the repair of facial nerve defects in rats.

    Methods: A total of 60 Sprague Dawley (SD) female rats (100–120 g), 5 weeks after birth, were randomly divided into 6 groups: Group A (arterial ductus group); Group B (arterial duct-autologous adipose-derived stem cells (ADSCs) group); Group C (artery-differentiated (d) ADSCs group); Group D (artery-stem cells (SCs) group); Group E (autologous nerve group); and Group F (sham-operated group) (n = 10/group). The rats in groups A and E were treated with decellularized arterial catheter combined with cell-free medium, autologous ADSCs, PKH26-labeled autologous dADSCs, autologous SCs, and bridging repair through autologous nerves, and the corresponding nerves of the rats in Group F were isolated and kept intact. The motor function of unilateral vibrissae, compound action potential of facial nerve buccal nerve muscle, and retrograde tracing of motoneuron nuclei of facial nerve buccal branch were compared among the groups.

    Results: The animals in all groups survived after the operation without serious postoperative complications, and all facial wounds healed spontaneously without signs of discomfort. The arterial ducts of the rats in groups A and E were compatible with the host tissue, and some of the ducts were absorbed, but no neuroma formed or was significantly dislodged. After comparing the unilateral vibrissa motor function, regenerated buccal branch nerve muscle compound action potential, and retrograde tracing of the buccal branch motoneuron nuclei in each group, the recovery of Group E rats was the best, and the recovery of Group C was better than that of Group A, while the recovery of Group B was slightly inferior to groups D and E. Morphological analysis of the buccal branch of the regenerated facial nerve showed the highest density of myelinated nerve fibers in Group C and the longest diameter of myelinated nerve fibers and thickness of myelin sheath in Group E. The rats in Group A exhibited the highest parameters, and all parameters in Group F remained at normal levels.

    Conclusion: Adipose-derived stem cell-artery duct composite repair provides a new approach to the repair of peripheral facial nerve injury with a certain facilitative effect.

  • Article
    Ying Chen, Bo Chen, Haiwen Hou, Shanshan Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4427-4442. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.434
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    Background: Trimetazidine (TMZ) has been shown to have a protective effect against myocardial ischemia/reperfusion (I/R) injury (MIRI) by modulating the levels of microRNA (miRNA). The aim of this study was to investigate whether TMZ could prevent myocardial I/R injury by regulating miR-125b-5p.

    Methods: A cardiomyocyte injury model was established using hypoxia/reoxygenation (H/R) processing. Cellular function assays were used to determine the viability, apoptosis, miR-125b-5p expression, apoptosis- and autophagy-related protein levels as well as Adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1 (ULK1) pathway level in cardiomyocytes under H/R treatment or co-treatment of miR-125b-5p inhibitor and TMZ. A dual-luciferase reporter assay was used to verify the predicted targeting relationship between autophagy-related 4D (ATG4D) and miR-125b-5p. The possible involvement of target genes and the AMPK/mTOR/ULK1 pathway in miR-125b-5p-mediated effects was also analyzed.

    Results: H/R reduced miR-125b-5p messenger RNA (mRNA) expression and cell viability, while promoting the apoptosis and the protein levels of markers relevant to autophagy and apoptosis (p < 0.01). These effects of H/R were reversed by TMZ, while the reversing effect of TMZ was largely diminished by miR-125b-5p inhibitor (p < 0.01). The targeting relationship between miR-125b-5p and ATG4D has been confirmed. ATG4D overexpression or knockdown rescued the impact of miR-125b-5p mimic/inhibitor upon H/R-treated cells (p < 0.01). H/R facilitated phosphorylated (p)-AMPK and p-ULK1 protein levels yet reduced that of p-mTOR, and this effect was offset by miR-125b-5p mimic but was potentiated by the inhibitor (p < 0.01). The impacts of miR-125b-5p mimic or inhibitor upon the AMPK/mTOR/ULK1 pathway were reversed following the overexpression or knockdown of ATG4D, respectively (p < 0.01). Besides, the impacts of miR-125b-5p mimic or inhibitor upon H/R-treated cells were confirmed to be counteracted in the presence of AMPK/mTOR/ULK1 pathway agonist or inhibitor.

    Conclusions: Trimetazidine protects cardiomyocytes from H/R injury by modulating miR-125b-5p/ATG4D axis.

  • Article
    Pin Li, Shuang Zhang, Ningzi Zang, Chengjun Gong, Nan Li, Xiao Yang, Jing Lv, Tianshu Gao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4443-4457. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.435
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    Background: Autoimmune thyroid disease (AITD) is a prevalent autoimmune endocrine disease, affecting approximately 5% of the population. The literature related to AITD has been increasing annually. Therefore, we conducted a bibliometric analysis of this literature to gain an intuitive understanding of the research frontiers and development trends in this field.

    Methods: To investigate autoimmune thyroid disease literature published from December 1, 2007 to March 27, 2023, we retrieved data from the Web of Science Core Collection (WOSCC) database, limiting the search to English literature. We then used CiteSpace 6.2.R2 and VOSviewer 1.6.18 software to analyze annual publications, countries/regions, institutions, journals, authors, literature co-citation analysis, and collaborative network analysis of keywords in the AITD field.

    Results: The study collected 1095 articles from 72 countries, with the majority published by the United States and Italy. The number of publications related to autoimmune thyroid disease has been increasing annually, reaching its peak in 2020. The main research institutions are the University of Pisa, Harvard University, University of Messina, and UDICE-French Research Universities. The most frequently cited journals are “J CLIN ENDOCR METAB” (791 times) and “AIDS READ” (791 times), and the journal with the most published papers is “THYROID” (Q1, impact factor 6.506, published 38 papers, accounting for 16.17% of the total literature). These publications come from 479 authors, with Antonelli Alessandro, Fallahi Poupak, Ferrari Silvia Martina, Smith Terry J, and Benvenga Salvatore publishing the most papers. The co-occurrence of keywords indicates research hotspots. Early research directions focused on Graves' disease, autoimmune thyroid disease, Hashimoto's thyroiditis, and management. With the appearance of emerging vocabulary such as monoclonal antibody, selenium supplementation, orbital fibroblasts, and Teprotumumab, researchers became more interested in the pathogenesis, risk factors, and clinical treatment of AITD, and conducted deeper research.

    Conclusions: This study utilized data information mining and visualization software to analyze the current research status in the field of AITD. The study identified the hotspots of recent research and aimed to provide a theoretical basis for future research. The research findings can help researchers gain insight into the progress of AITD research and quickly determine new directions for future research.

  • Article
    Zhe Ji, Rui Guo, Zhigang Ma, Hongwei Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4459-4469. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.436
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    Background: Intervertebral disc degeneration-related disease (IVDD) involves the gradual deterioration of the structure and function of intervertebral discs. Understanding the pathogenesis of IVDD is crucial for developing effective prevention and treatment strategies. In recent years, the abnormal acceleration of apoptosis in nucleus pulposus cells (NPCs) has been identified as a major factor in the progression of IVDD. Reversing this pathological process is considered a potential breakthrough in the diagnosis and treatment of IVDD. Studies have indicated an association between hsa_circ_0008305 (circPTK2) and the Wingless/Integrated (WNT)/β-catenin pathway, which regulates cell growth. This suggests that circPTK2 may be linked to the progression of IVDD through its ability to modulate the biological behavior of NPCs. Our goal is to investigate how circPTK2 influences interleukin (IL)-1β-induced apoptosis of human nucleus pulposus cells (NPCs) through the WNT/β-catenin pathway, and to identify early biological markers for IVDD and provide clues for therapeutic targets.

    Methods: NPCs cells were cultured and treated with IL-1β to establish a model group of IVDD. Meanwhile, untreated NPC cells were established as a control group. Next, we performed qRT-PCR quantitative analysis on the expression of circPTK2 and WNT/β-catenin in the cells. In order to further study the role of circPTK2 in IVDD model cells, we performed interference experiments. We introduced the circPTK2 small interfering vector into IVDD model cells to form the si-circPTK2 panel. At the same time, we introduced the circPTK2-negative sequence as a control to form the si-NC group. To assess cell viability and apoptosis, we used Cell Counting Kit-8 (CCK-8) reagent and flow cytometry, respectively. In addition, we also used western blotting technology and Enzyme-Linked Immunosorbent Assay (ELISA) to measure the contents of IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) in the cell supernatant to evaluate the inflammatory response in the cells.

    Results: Both circPTK2 and WNT/β-catenin presented higher levels in the model group than in the control group (p < 0.05). Inhibiting circPTK2 caused enhanced proliferative capacity of IVDD model cells and a reduced apoptosis rate (p < 0.05). The apoptotic proteins (Bax and cleaved Caspase3) in the si-circPTK2 group were significantly higher than in the control group but lower than in the model and si-NC groups (p < 0.05), while the anti-apoptotic protein Bcl-1 was higher than in the model and si-NC groups (p < 0.05). The test results of inflammatory cytokines (ICs) identified lower pro-ICs (IL-6, IL-8 and TNF-α), but higher anti-IC (IL-10) in the si-circPTK2 group compared with the model and si-NC groups (p < 0.05). WNT/β-catenin suppression reverses the inhibitory effect of circPTK2 on apoptosis in nucleus pulposus cells (p < 0.05).

    Conclusion: circPTK2 is highly expressed in IVDD. After inhibiting circPTK2, the proliferation of NPCs is increased, and the apoptosis and inflammatory reactions are decreased, which may be realized through the WNT/β-catenin pathway.

  • Article
    Jie Zi, Fang Wang, Yunxia Wang, Zebin Liu, Guosheng Zhu, Liying Qiu, Henghua Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4471-4478. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.437
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    Objective: This study aimed to screen early diagnostic markers for chorioamnionitis (CAM) in preterm premature rupture of membranes (PPROM) patients based on the Toll-like receptor/C-type lectin domain family 4 member E/Nuclear Factor-kappa B (TLR/CLEC4E/NF-kB) pathway.

    Methods: 50 PPROM patients admitted to Shenzhen Futian District Maternity and Child Health Care Hospital from May 2020 to March 2021 were selected and divided into a Study Group and a Control Group. The Study Group had 27 patients with CAM and the Control Group had 23 patients without CAM. The peripheral blood of all pregnant women was collected, and the differentially expressed genes of the two groups were obtained by gene expression profile technology. GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were used to identify the signaling pathways related to differentially expressed genes.

    Results: Forty-four differentially expressed genes were detected by gene expression profile technology, including 40 upregulated genes and 4 downregulated genes. Among them, the genes related to the inflammatory response, including TLR-2, TLR-4, NF-kB, and CLEC4E, showed more expression changes. These genes are related to the TLR and NF-kB pathways in the immune response.

    Conclusion: Differentially expressed genes obtained by gene expression profile technology may become early diagnostic markers of CAM in PPROM patients, especially the TLR-2, TLR-4, NF-kB, and CLEC4E genes, which can be used to predict early CAM.

  • Article
    Xiaoxiao Ding, Chenan Guan, Xinhua Ding
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4479-4489. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.438
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    Background: There are currently no standard treatment regimens for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and only few treatment options are available. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) blockade is considered effective in the treatment of many malignancies, such as non-small cell lung cancer, melanoma and renal cancer. At present, most of the clinical studies on PD-1/PD-L1 blockade in DLBCL that have been published are in phases 1 and 2 trials; however, satisfactory therapeutic effects were not observed in these trials. The aim of this meta-analysis was to test the safety and efficacy of PD-1/PD-L1 blockade in R/R DLBCL.

    Methods: Original studies evaluating the effect of anti-PD-1/PD-L1 antibodies on R/R DLBCL were searched in PubMed, Cochrane Library, Web of Science and Medline databases from the establishment of the databases to January 2023. RevMan 5.20 statistical software was used for meta-analysis. The presence of publication bias was assessed using funnel plot. The efficacy and safety effects were combined by odds ratio (OR) with 95% confidence interval (CI).

    Results: A total of 49 papers were retrieved, while eight clinical studies were collected. The estimated effect of overall response rate (ORR) was [OR = 0.46, 95% CI (0.21, 1.01); p = 0.05], the estimated effect of complete response rate (CRR) was [OR = 0.23, 95% CI (0.12, 0.43); p < 0.001], while the estimated effect of progression-free survival (PFS) was [OR = 0.60, 95% CI (0.24, 1.51); p = 0.28]. The estimated effect of overall survival (OS) was [OR = 1.84, 95% CI (0.95, 358); p = 0.07]. In addition, the estimated effect of three levels of adverse events was [OR = 0.74, 95% CI (0.28, 1.96); p = 0.55].

    Conclusions: Anti-PD-1/PD-L1 antibodies may increase the ORR and CRR of patients with R/R DLBCL.

  • Article
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(8): 4491-4497. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233708.439
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    Background: Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis (MTB) that affects both humans and animals. It is one of the world's most widespread serious public health challenges. The present study aimed to check the prevalence of tuberculosis through GeneXpert and association with possible risk factors in suspected tuberculosis positive patients in district Narowal, Pakistan.

    Methods: A designed questionnaire was filled out to collect data from suspected patients including age, gender, area, marital status, diet, economic status, smoking status, home condition, education, and close contact with tuberculosis (TB) patients. A Lung function test was performed. Statistical analysis was done by applying a chi-square test in SPSS software (version 22) to evaluate the association between GeneXpert and acid-fast staining technique.

    Results: A total of 500 samples were collected and they were analyzed through auramine rhodamine staining to get efficient results samples were further analyzed to GeneXpert. Out of 500 samples, 195 samples were positive for staining and 282 were positive for GeneXpert from both male and female. The prevalence rate was recorded higher in age groups >50 while a lower prevalence rate was recorded in less than 40 age groups. Rifampicin (RIF) resistance was detected in 63 patients in which males showed high resistance to rifampicin with (52.4%) as compared to females with (47.6%) resistance.

    Conclusion: The actual prevalence of suspected tuberculosis cases is relatively high, and the GeneXpert MTB/RIF assay is superior to traditional acid fast staining in detecting the disease and identifying rifampicin-resistant patients at the same time, which is an important guideline for the diagnosis and treatment of the disease.