20 July 2023, Volume 37 Issue 7

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  • Review
    Uwe Wollina, Ayman Abdelmaksoud
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3417-3420. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.338
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    Guttate psoriasis (GP) is a clinical variant of psoriasis defined by morphology, triggers, and course. It is more common among children, adolescents, and young adults. Up to 70% of patients follow a chronic course, some with a switch to plaque psoriasis. Classic treatment for GP consists of topical corticosteroids, anthralin and vitamin-D analogues alone or in combination with ultraviolet B phototherapy. Small molecules and biologics have revolutionized the treatment of moderate to severe chronic plaque psoriasis. In this narrative review their potential in GP therapy is discussed and first clinical data are presented. Inhibition of the interleukin (IL)-23 pathway offers rapid clearance and durable remissions. Further trials are necessary. Possibly, the chronic course and switch to plaque psoriasis may be prevented by early use of IL-23 antagonists.

  • Review
    Marta Kamalska, Marek Karczewski, Evridiki Tsoureli Nikita, Sara Poggiali, Olga Olisova, Konstantin M Lomonosov, Torello Lotti
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3421-3430. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.339
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    Background: This review presents the mechanisms responsible for vitiligo and acknowledges the new agents of vitiligo, such as Janus kinase (JAK) inhibitors, Wingless and Int (Wnt) response inhibitors, microRNAs, rapamycin, and various cytokine-targeted treatments, which are currently being successfully studied and evaluated concerning their safety and efficacy.

    Methods: We searched for scientific work on vitiligo treatment and pathophysiology using PubMed, finding 92 relevant articles.

    Results: Vitiligo is a systemic disease, and accordingly systemic approach should always be considered in combination with local treatments. Nowadays, JAK inhibitors are the most promising vitiligo treatment, particularly when combined with phototherapy. Cytotoxic T lymphocytes (CD8+ T lymphocytes) and CD4+ T helper lymphocytes participate in developing vitiligo. Other relevant factors are endoplasmic reticulum (ER) stress and 78-kDa glucose-regulated protein (GRP78) activation, and adhesion deficit.

    Conclusions: Vitiligo is a chronic disease affecting not only one's appearance but also one's mental well-being. The treatment can be life-long; therefore, it should be effective and tolerable since compliance and, consequently, the quality of the outcomes rely on that. For these aspects of treatment to satisfy the recognition and understanding of numerous signalling pathways taking part in vitiligo pathogenesis is essential.

  • Systematic Review
    Matteo Conti, Maria Vadalà, Beniamino Palmieri, Sergio Rexhep Tari, Maria Stella Di Carmine, Felice Lorusso, Sergio Alexandre Gehrke, Francesco Inchingolo, Antonio Scarano
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3431-3454. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.340
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    Background: Outdated scientific literature claimed that bacteria was a cancerogenic agent. These studies were technically disfavored and the hypothesis of the role of bacteria in cancer was almost completely abandoned for many years. The aim of the present study was to investigate the role of microbiome in carcinogenesis and the potential role of engineered bacteria for the treatment of cancer.

    Materials and Methods: The literature review was performed on Pubmed/Medline, EMBASE, Google Scholar database in accordance to the PRISMA Guidelines. The screening, and eligibility session was performed to conduct the data synthesis of the included studies.

    Results: The screening process included a total of 415 papers, while 389 articles were considered for the eligibility session. A total of 334 scientific products were excluded and 55 articles were considered for the descriptive synthesis. Recent reports, however, have produced new results on the role of various microorganisms in tumors. Here, we reviewed the scientific literature on this issue in order to provide an updated organic framework on the topic.

    Conclusions: Although basic research studies investigated and confirmed the role of bacteria in cancer induction, maintenance and resistance to therapy, the more recent literature is oriented to modern diagnostic approaches from the basic scientific knowledge to the clinical practice. The approaches to biological and immunological onco-therapy, by natural or bioengineered bacteria, were also addressed.

  • Article
    Yunzhu Li, Lei Jiao, Chunping Shen, Shan Wang, Jieqiong Li, Lin Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3455-3461. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.341
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    Background: C19 is a C-terminal peptide derived from the Human chemokine-like factor (CKLF)1. It possesses the ability to trigger CC chemokine receptor (CCR)4 internalization and exhibits anti-inflammatory properties. We aim to investigate whether C19 can exert an inhibitory effect on the progression of inflammation in a murine model of T helper (Th)2-type allergic dermatitis, which is employed in studying human atopic dermatitis (AD).

    Methods: Type-2 T helper cell (Th2)-type allergic dermatitis was challenged on the back of female BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) for 5 weeks. The experimental groups were treated with an intraperitoneal injection of double distilled water (ddH2O), C19 (1 μg, 10 μg, and 100 μg), and hydrocortisone throughout the model establishment. Skin inflammation was scored, and serum and skin samples were collected after the experiment. Mast cells in the lesions were analyzed by toluidine blue staining. Expressions of serum immunoglobulin (Ig)E, skin interleukin (IL)-4, IL-17A, IL-25, and tumor necrosis factor (TNF)-α were determined and analyzed by Enzyme-Linked Immunosorbent Assay (ELISA).

    Results: The inflammation induced by DNFB in the mouse model was evident. C19 inhibited skin inflammation, skin thickening, and infiltration of mast cells into the dermis in BALB/c mice. The expressions of serum IgE, skin IL-4, IL-17A, IL-25, and TNF-α were reduced by intraperitoneal administration of C19 in high concentrations (10 μg and 100 μg). The expressions of serum IgE and skin IL-4 could also be reduced by a low concentration of C19 (1 μg).

    Conclusions: C19 mitigated skin inflammation and decreased the expressions of serum IgE, skin IL-4, IL-17A, IL-25, and TNF-α in a murine model of Th2-type allergic dermatitis. These findings propose that C19 could effectively treat human atopic dermatitis.

  • Article
    Hao Li, Yiwei Hu, Xidong Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3463-3468. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.342
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    Objective: To explore the curative effect of ifosfamide combined with MVAC (methotrexate, vincristine, adriamycin and cisplatin) to treat osteosarcoma.

    Methods: Data from patients with osteosarcoma admitted to the Second Hospital of Nanjing and the Fourth Hospital of Hebei Medical University from February 2020 to February 2021 were selected for a retrospective analysis. They were 1:1 divided in the experimental group (EG) and the control group (CG) according to the treatment method applied. The CG was given MVAC, and the EG received MVAC and ifosfamide. Short-term efficacy, inflammatory factors levels and the incidence of adverse reactions between the two groups was assessed.

    Results: Overall, 120 patients were included in the study. Treatment efficiency in the EG was higher than in the CG (p < 0.05). Tumor necrosis factor-α (TNF-α), c-reactive protein (CRP) and white blood cell (WBC) levels in the EG were overtly lower. Interleukin-10 (IL-10) level was significantly higher compared to the CG (all p < 0.001). Adverse reactions incidence in the EG was lower than in the CG (p < 0.05).

    Conclusions: Ifosfamide and MVAC combined to treat osteosarcoma show a good safety profile, with improved inflammatory factors levels.

  • Article
    Wei Lv, Qiu Meng, Rui Li, Jing Li, Na Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3469-3477. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.343
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    Background: The altered metabolism contributes to the metabolic reprogramming of tumor microenvironment, thus promoting the growth and proliferation of tumor cells. This study aimed to explore the mechanism of KIAA0101 in promoting the development of breast cancer (BC) through metabolic reprogramming.

    Methods: In this study, the expression of KIAA0101 in BC patients was measured using quantificational Real-time Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and Immunohistochemistry. The BC tumor mice model was constructed by subcutaneous injection of MDA-MB-231 cells and divided into the MDA-MB-231+si-NC (siRNA negative control) group and the MDA-MB-231+si-KIAA0101 group. The tumor volume of the BC mice model in the two groups was measured once a week to investigate the effect of KIAA0101 on tumor growth. The function of KIAA0101 and P53 on the migration and invasion of MDA-MB-231 cells in vitro was examined by Transwell assay. The glucose and lipid metabolism-related protein expressions in BC cells were measured by Western blot and qRT-PCR. Furthermore, the effects of glucose concentration and incubation time on the expression of KIAA0101 in BC cells were determined by qRT-PCR.

    Results: Both BC patients and mouse models exhibited overexpression of KIAA0101 (p < 0.05). This overexpression led to an increase in cell migration and invasion in vitro (p < 0.05). Conversely, P53 showed a contrasting trend to KIAA0101 in BC cells (p < 0.05). In addition, glucose incubation enhanced the expression of KIAA0101 in BC cells (p < 0.05), and the knockdown of KIAA0101 inhibited energy metabolism in BC cells (p < 0.05). The protein and mRNA expressions of the glucose transporter type 1 (GLUT1), pyruvate kinase M2 (PKM2), and hypoxia-inducible factor-1 (HIF-1) were decreased in KIAA0101-depleted cells (p < 0.05) but increased in P53-depleted cells (p < 0.05). Furthermore, si-KIAA0101 effectively inhibited the tumor volume and growth rate of BC mice model (p < 0.05).

    Conclusions: KIAA0101 regulates breast cancer progression through a mechanism involving metabolic reprogramming induced by P53.

  • Article
    Xi Yang, Ling Chen, Ke-Yuan Chen, Qiu-Ying Zou, Jiang-Bin Wu, Liang-Wan Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3479-3492. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.344
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    Background: One of the pathogeneses of aortic dissection (AD) is inflammation-induced collagen deposition and elastin degradation. The transplantation of adipose-derived mesenchymal stem cells (AMSCs) can prevent AD via the action of paracrine mechanisms. This study aims to investigate how microRNA-222 (miR-222) and exosomes from AMSCs influence the evolution of fibrosis and inflammation in AD.

    Methods: AMSC-exosomes were isolated and identified. Subsequently, they were traced in vitro using the PKH67 staining method. In vivo testing was conducted using an AD model induced by β-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II), and in vitro investigations were carried out utilizing aortic smooth muscle cells (SMCs). The miR-222 expression in AD patients, AD mice, and platelet-derived growth factor-BB (PDGF-BB)-treated SMCs after AMSC-exosome treatment was assessed by quantitative real-time PCR (qRT-PCR). A dual-luciferase reporter gene assay was used to determine the target relationship between miR-222 and G protein subunit alpha i3 (GNAI3). To better understand the role of inflammation and fibrosis throughout the course of AD, artificial activation and block experiments of miR-222 were carried out. The prevalence of AD, the survival rate, and histological stainings were utilized for evaluating the severity of AD between groups. Apart from proliferation, apoptosis and expression of inflammation factors were further evaluated using 5-Ethynyl-2'-Deoxyuridine (EdU), Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL), flow cytometry, qRT-PCR, and enzyme-linked immunosorbent assay (ELISA).

    Results: Exosomic-miR-222-mimic derived from AMSCs can be transferred into SMCs and decreased excessive proliferation and inflammation by targeting GNAI3-extracellular regulated protein kinases (ERK) signaling in vitro. Exosomic-miR-222 decreased a GNAI3 via direct binding to its 3'-untranslated region (3'-UTR). Meanwhile, in vivo testing showed that AMSC-derived exosomes can function in aortic tissues. Mice treated with exosomic-miR-222-mimic demonstrated a substantial decrease in the prevalence of AD and improved the level of fibrosis in the aorta, while its inhibition reversed this process.

    Conclusions: Exosomic-miR-222 functions as a regulator of AD progression and inflammation response by targeting the GNAI3-ERK signaling pathway. Exosomic-miR-222 may, therefore, have therapeutic value in lowering sudden unfavorable AD episodes.

  • Article
    Hongqin Xiang, Luling Qiu, Wenqian Meng, Liangying Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3493-3501. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.345
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    Objectives: Cervical cancer (CC) is a common gynecologic cancer. Paclitaxel (PTX) is a crucial component of CC chemotherapy, but drug resistance to PTX is a major challenge. Shikonin is known to have an inhibitory effect on various tumors. This study aimed to evaluate the effect of Shikonin on the epithelial-mesenchymal transition (EMT) of PTX-resistant CC cells.

    Methods: To investigate PTX-resistant CC cells, cells were treated with Shikonin at concentrations of 0, 10, 20, 30, and 40 μM. Cell viability was assessed using the 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and clone formation assays, and cell metastasis was evaluated using a Transwell® assay. Apoptosis was estimated by flow cytometry and the mRNA levels of HOX transcript antisense intergenic RNA (HOTAIR) in cells were measured through a quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The protein levels of E-cadherin, Vimentin, zinc finger E-box binding homeobox 1 (ZEB1), Bax, B-cell lymphoma-2 (Bcl-2), Caspase-3, cleaved-Caspase-3, c-Myc, Phosphorylated-Akt (p-Akt) and Akt were estimated by Western blot.

    Results: Shikonin was found to reduce the multiplication and metastasis of PTX-resistant CC cells while increasing cell apoptosis (p < 0.05). Additionally, Shikonin treatment led to a reduction in the HOTAIR mRNA levels in cells (p < 0.05). Shikonin was also found to increase the levels of E-cadherin, Bax and cleaved-Caspase-3/Caspase-3, while reducing the protein levels of Vimentin, Bcl-2, c-Myc and p-Akt (p < 0.05). Finally, it was found that HOTAIR inhibition played a role in the effects of Shikonin on the viability and metastasis of PTX-resistant CC cells (p < 0.05).

    Conclusions: Overall, Shikonin has been found to have several effects on cancer cells, including reducing the multiplication and metastasis of PTX-resistant CC cells and stimulating apoptosis. These effects may be related to the inhibition of HOTAIR and modulation of the Akt signal pathway.

  • Article
    Xiumei Feng, Qingchun Zhang, Qianjin Xu, Meiqin Shao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3503-3514. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.346
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    Background: Cervical cancer (CC) is a common gynecologic malignancy worldwide with high morbidity and mortality. MiR-202 was recently discovered to be a suppressor miRNA in many tumors, including CC. GLI family zinc finger 2 (GLI2) is a member of the Gli family, which binds DNA through zinc finger motifs. This study investigated the effects of miR-202 and GLI2 on cell metastasis and epithelial-mesenchymal transition (EMT) in CC.

    Material and Methods: The miRNA expression and clinical information in patients with CC were obtained from The Cancer Genome Atlas (TCGA) database. The connection between miR-202 or GLI2 and CC prognosis was analyzed by R packages, the correlation between miR-202 expression and GLI2 expression was determined. The expression of miR-202 messenger RNA (mRNA) in CC tissues and cells was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of GLI2 and EMT related marker proteins in CC cells was detected by western blotting. The migration and invasion abilities of CC cells were investigated by Transwell assay. The interaction between miR-202 and GLI2 in CC cells was verified by the dual luciferase reporter gene assay.

    Results: MiR-202 was lowly expressed while GLI2 mRNA and proteins were highly expressed in CC patients and cells compared with normal people and cells (p < 0.01). There were binding sites between miR-202 and GLI2 mRNA and the expression of miR-202 negatively correlated with the expression of GLI2 mRNA. The overexpression of miR-202 inhibited HeLa cell metastasis and EMT compared with the control group (p < 0.01), which could be reversed by binding with GLI2.

    Conclusions: MiR-202 overexpression inhibits CC cell metastasis and EMT by regulating GLI2 mRNA expression in CC. The miR-202/GLI2 axis provides new insights for the clinical treatment of CC.

  • Article
    Hui Wang, Weiqin Si, Leifen Shen, Jian Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3515-3521. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.347
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    Objective: This study aims to find the risk factors of gestational diabetes mellitus (GDM) and establish a prediction model.

    Methods: From August 2021 to December 2022, 210 pregnant women who registered in and provided information to the Huzhou Maternal and Child Health Care Hospital were enrolled and classified into the GDM group (n = 162) and the non-GDM group (n = 48). The clinical data of these pregnant women were collected. The biochemical biomarkers were also detected. The risk factors for GDM were determined using logistic regression analysis. The prediction model was established and evaluated using receiver operating characteristic curve (ROC) analysis.

    Results: There were more pregnant women with an education level above junior college in the non-GDM group than the GDM group (p < 0.05). The GDM group was significantly higher than non-GDM group in pre-pregnancy body mass index (BMI), family history of hypertension, increase of body mass during the first trimester, family history of diabetes, the positive rate of thyroid peroxidase antibody (TPOAb), history of macrosomia, history of GDM, history of polycystic ovary syndrome (PCOS), mean arterial blood pressure (MAP), as well as free thyroxine 3 (FT3), hemoglobin A1c (HbA1c), fasting serum insulin (FINS), triglyceride (TG) and hemoglobin (Hb) levels (p < 0.05). Logistic regression analysis demonstrated that the education level, pre-pregnancy BMI, family history of hypertension, family history of diabetes, history of macrosomia, history of GDM, TPOAb (+), and the levels of FT3, HbA1c, and Hb (p < 0.05) were the risk factors for GDM.

    Conclusions: Our findings indicated that the pre-pregnancy BMI, education level, family history of hypertension or diabetes, TPOAb (+), history of macrosomia or GDM, FT3, HbA1c, and Hb levels were associated with GDM, which may be helpful for predicting GDM.

  • Article
    Chunyan Wang, Lingye Fan, Jun Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3523-3528. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.348
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    Background and Objectives: Cervical cancer is the fourth most common cancer in women globally. The aim of this study was to compare lymphocyte subsets, inflammatory factor levels and postoperative infection between patients with cervical cancer at stage I and stage II.

    Methods: From January 2018 to January 2021, a total of 92 patients with cervical cancer (41 cases at stage I, 51 cases at stage II) were included in the study. The ratios of peripheral blood CD3+ T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, CD4+/CD8+ T lymphocyte, T Helper 17 Cell (Th17), regulator T cell (Treg), Th17/Treg, inflammatory factors including serum interleukin-2 (IL-2), IL-4, IL-13, IL-17, and interferon-γ (IFN-γ), and postoperative infection were compared between stage I and stage II patients.

    Results: The proportion of lymph node metastasis in stage I patients was lower than that in stage II patients (p < 0.05). The ratios of preoperative peripheral blood CD3+ T, CD4+ T, CD4+/CD8+ T were higher while Th17, Treg and Th17/Treg ratios in peripheral blood were lower in stage I patients compared to stage Ⅱ patients (all p < 0.001). Preoperative serum IL-2 and IFN-γ levels were higher, and serum IL-4, IL-17, and IL-23 levels were lower in stage I patients compared to stage II patients (all p < 0.001). In addition, the postoperative infection rates for stage I and stage II were 12.20% and 29.41%, respectively, (p = 0.047).

    Conclusions: Patients with cervical cancer at stage II have more severe immune dysfunction and inflammatory damage, higher postoperative infection rate, and more diverse infection sites compared to cervical cancer patients at stage I.

  • Article
    Tao Cheng, Xu-Yong Chen, Liu-Dan Wang, Wei Yuan, Xin-Pu Miao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3529-3540. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.349
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    Objective: Microbiota change has been recognized as an important player in the progression of inflammatory bowel diseases (IBDs). This study aims to evaluate the beneficial effect of rauvolfian pectic polysaccharide (PP) on mucosal inflammation and its impact on gut microbiota.

    Methods: Rauvolfian PP from Rauvolfia callus was prepared as intervention photochemical. Gut inflammation was induced by dextran sulfate sodium (DSS) in the mouse model and the beneficial effect of PP administration on colitis was evaluated. The microbiota composition in control group, DSS model group and DSS with PP treatment group was examined by integrative sequencing of 16S, 18S and internal transcribed spacer (ITS) targets using genomic DNA from the fecal samples.

    Results: We reported the beneficial effect of rauvolfian PP in alleviating the colitis and suppressing pyroptosis in intestinal mucosa of DSS-induced mouse model. Both colitis induction and PP administration significantly altered the composition of intestinal microbiota. DSS induced colitis decreased gut microbial diversity, and PP treatment further lower the diversity of gut microbiota. Interestingly, the abundance of Escherichia-Shigella and Citrobacter became increased after PP administration.

    Conclusions: Our data revealed the microbiota changes associated with the beneficial effect of rauvolfian PP in colitis model. The overall reduction of microbiota diversity and the increased abundance of specific microbial families may account for the beneficial effect of PP administration. Future work needs to focus on the elucidation of the mechanisms by which these microbial families may help alleviate the progression of IBD.

  • Article
    Hugang Jiang, Xinqiang Wang, Wenyan Lin, Kai Liu, Yingdong Li, Xinke Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3541-3552. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.350
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    Background: Myocardial fibrosis (MF) is a condition that plays a crucial role in heart failure (HF) development and death, and current drugs for its treatment are limited. Qishen Yixin Granule (QSYXG) is a Traditional Chinese Medicine (TCM) that has been shown to be effective in treating chronic HF, but its mechanism of action is not yet fully understood. This study aimed to reveal the molecular mechanisms and bioactive compounds of QSYXG treating MF using an integrated network pharmacology and pharmacological validation pathway.

    Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, drug-target database and GeneCard database were used to screen active ingredients, drug targets and MF genes. The clusterProfiler package in R programming language was employed for functional and pathway enrichment analyses. Experimental validation was completed using hematoxylin-eosin staining, Masson's trichrome staining, and immunohistochemistry in isoproterenol-induced MF rats. Western blot, phalloidin staining, and immunofluorescence staining were performed to elucidate the predicted mechanism on H9C2 cells.

    Results: In this study, 55 bioactive components and 59 putative targets were collected. Functional enrichment analysis revealed that responses to lipopolysaccharides, oxidative stress, and hypoxia constituted vital biological processes. Six targets, containing mitogen-activated protein kinase (MAPK) 14, prostaglandin-endoperoxide synthase 2 (PTGS2), serine/threonine kinase 1 (AKT1), MAPK8, Interleukin (IL)-6 and IL-1β, directly regulated these responses simultaneously. Five pathways were identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. QSYXG could downregulate the expression of PTGS2, MAPK14 and MAPK8 and upregulate the expression of AKT1 in the treatment of MF.

    Conclusions: This study revealed that QSYXG could alleviate MF based on multiple components, targets and pathways.

  • Article
    Xing Xu, Jia-zhi Yang, Hang Li, Luo-shai Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3553-3561. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.351
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    Objective: Cis-dichlorodiammine-platinum (CDDP) is an important drug in chemotherapy regimen for esophageal squamous cell carcinoma (ESCC). Unfortunately, CDDP, even at moderate doses, has toxic effects on normal cells and adverse effects in patients. Erythrocyte membrane protein band 4.1-like 3 (EPB41L3) acts as a cancer inhibitor in many cancers by promoting apoptosis and inhibiting tumor cell proliferation. Therefore, we investigated the potential synergistic anti-ESCC effect of EPB41L3 and CDDP for improving effectiveness of CDDP and lowering CDDP dosage.

    Methods: EPB41L3 expression in ESCC tissues and cells was examined using Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). ESCC cell models were treated with EPB41L3 transfection alone (EPB41L3 group), CDDP (2 μM) treatment alone (CDDP group), or combined EPB41L3 transfection and CDDP treatment (CDDP+EPB41L3 group), respectively. Cell Counting Kit-8 (CCK-8) was used to examine the cell proliferation in each group. The cell viability of each group was evaluated through cell colony assay. Cell apoptosis and cycles were evaluated using flow cytometry. Western blotting was performed to examine the levels of apoptosis-related proteins and cell cycle-related proteins in each group.

    Results: The expression level of EPB41L3 in ESCC tissues and cells was reduced, compared with control group. ESCC cell proliferation and cell viability in the CDDP+EPB41L3 group were lower as compared to those in EPB41L3 and CDDP groups. The CDDP+EPB41L3 group showed higher levels of apoptosis, Bax proteins and cleaved-Caspase3, whereas lower level of Bcl-2 protein was shown in ESCC cells, as compared to the other two groups respectively. The G2/M phase ratio and p21 protein levels of ESCC cells treated with both EPB41L3 and CDDP were increased as compared to those in the other two groups. In terms of G0/G1 phase ratio and cyclin-dependent kinases (CDK)1, CDK2 and Cyclin B protein levels, the CDDP+EPB41L3 group exhibited much lower levels than those in the other two groups.

    Conclusions: Overexpression of EPB41L3 increased the apoptosis-promoting effect of CDDP and its blocking effect on ESCC cells in the G2/M phase, by which the effect of CDDP on inhibiting ESCC cell proliferation and cell viability is improved. This study offers new perspectives on the clinical application of CDDP in the management of ESCC when combined with adjuvant therapy.

  • Article
    Ling Fan, Hui Zhang, Jisheng Li, Yuanyuan Mao, Chenxi Bao, Hongsheng Han, Pintong Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3563-3570. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.352
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    Objective: This study aims to explore the relationship between the contrast-enhanced ultrasound (CEUS) properties and biological prognostic factors of breast cancer.

    Methods: The study included 49 patients aged 29 to 84 (averaging 52.9 ± 13.2 years). Each patient diagnosed with primary breast cancer and presenting single lesions underwent surgical treatment in our hospital between July 2019 and December 2022. CEUS was conducted before surgery to capture the images of breast cancer. Following surgery, the expression levels of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 were determined using immunohistochemical analyses. The correlation with CEUS was then investigated using Spearman rank correlation and binary logistic regression statistical methods.

    Results: A detailed analysis was conducted on the correlation between prognostic factor expressions of breast cancer and CEUS parameters of the lesions. The relationship between the enhancement degree, enhancement pattern, perfusion defects, enhancement scope variation, perforator vessels and the expression status of HER-2, Ki-67, ER, PR was thoroughly analyzed.

    Conclusions: A definite correlation exists between the CEUS findings and the prognostic biomarkers of breast cancer. This correlation offers a possibility for noninvasive preoperative evaluation in predicting breast cancer prognosis.

  • Article
    Lijuan Huang, Li Li, Yunzhi Pan, Qingyou Chen, Lijuan Zhu, Yinghui Qin, Tingting Qi, Xiaoqing Ma, Dongyang Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3571-3585. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.353
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    Purpose: This study aimed to verify the targeted inhibition effect of microRNA (miR)-210 on hypoxia inducible factor 1α (HIF-1α), and to explore the mechanism of HIF-1α/inducible nitric oxide synthase (iNOS) pathway in the inflammatory reaction after cerebral infarction.

    Methods: The mouse models of cerebral ischemia infarction and drug intervention were constructed, and the mice were grouped into the cerebral infarction + miR-210 antagomir group, cerebral infarction group, sham group, cerebral infarction + miR-210 agomir group, and cerebral infarction + 2-methoxyestradiol (2ME2) (HIF-1α inhibitor) group. The neurological functions were determined by water maze test and neurological impairment score, the percentage of cerebral infarction area was determined by triphenyltetrazolium chloride (TTC), and the levels of inflammatory factors (Tumour Necrosis Factor alpha (TNF-α) and interleukin 6 (IL-6)) in the serum of mice in each group were determined by the automatic biochemical analyzer. The oxygen-glucose deprivation/reoxygenation (OGD/R) model of brain neurons in mice was constructed, and the mice were grouped into OGD/R + miR-210 knockdown group, OGD/R group, normal group, and OGD/R + miR-210 over-expression group, and OGD/R + 2ME2 (HIF-1α inhibitor) group.

    Results: The water maze test and neurological impairment score showed that neurological abnormalities were observed in mice after cerebral infarction but were improved after over-expressing miR-210. The test results of TTC and the levels of TNF-α and IL-6 showed the inflammation in mice after cerebral infarction, which was alleviated after over-expressing miR-qu210 (the levels of IL-6 and TNF-α). The results of correlation analysis showed that the percentage of cerebral infarction area, the degree of neurological injury and the expressions of HIF-1α and iNOS in brain tissues were positively correlated with the degree of inflammatory injury, and miR-210 expression in brain tissues was negatively correlated with the degree of inflammatory injury. The results of luciferase reporter assay showed that miR-210 could target the regulation of HIF-1α. The results of real-time reverse transcription-polymerase chain reaction (qRT-PCR) showed that the expression of miR-210 was down-regulated after cerebral infarction. The results of Western blot showed that the expressions of HIF-1α and iNOS were up-regulated after cerebral infarction, and the overexpression of miR-210 could inhibit the expressions of HIF-1α and iNOS.

    Conclusions: The overexpression of miR-210 can weaken the inflammatory reaction of cerebral infarction in mice by inhibiting the HIF-1α/iNOS pathway and then improve the neural functions of mice.

  • Article
    Kai Liu, Huixiong Wang, Ming Hu, Han Yang, Dalin Li, Xiao Qin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3587-3594. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.354
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    Objective: Iliac vein compression syndrome (IVCS) encompasses a series of venous system diseases that stem from the compression of the left common iliac vein by the right iliac artery. This study aims to explore the efficacy and safety profile of endovascular interventional therapy in the treatment of IVCS complicated with acute deep venous thrombosis (DVT) of lower limbs.

    Methods: Participants were enrolled using a pre-designed inclusion criteria and randomly assigned into study group and control group using random serial numbers and the order of patient inclusion. Participants in the control group received anticoagulation and urokinase thrombolytic therapy whereas those in the study group were administered with endovascular interventional therapy. Following the treatments, the clinical efficacy, thrombus clearance rate, improvement rate of venous patency and detumescence rate of affected limbs were compared between the two groups. In addition, the occurrence of adverse reactions was recorded, while the factors influencing the degree of venous patency following treatment were analyzed.

    Results: The clinical efficacy of endovascular interventional therapy was 96.77%. The anticoagulation and urokinase thrombolytic therapy was 85.48%, so the efficacy was significantly higher in the study group compared with the control group (p < 0.05). In both the study group and the control group, the thrombus clearance rates for grade III were 83.87% and 62.90%, respectively. For grade II, the clearance rates were 14.52% and 20.97%, while for grade I, they were 1.61% and 16.13%, respectively. Moreover, the study group exhibited a venous patency improvement rate of 88.71%, whereas the control group had a rate of 69.35%. The removal rates of the thrombus in thigh and shank were 87.10% and 82.26% respectively for the study group, whereas the rates were 69.35% and 64.52%, respectively, in the control group. Moreover, there were significant differences between the two groups in terms of thrombus clearance rate, improvement rate of venous patency and detumescence rate of affected limbs (p < 0.05). The incidence of adverse reactions in the study group was 6.45%, which was significantly lower compared with that of the control group (20.97%, p < 0.05).

    Conclusions: Endovascular interventional therapy for IVCS with acute DVT of lower limbs is a safe and effective prevention modality. It significantly promotes thrombus clearance, improves venous patency and reduces swelling in the affected limbs.

  • Article
    Xu-qi Hu, Hui-gen Lu, Ye-feng Yu, Min-jie Hu, Xue-kang Pan, Bao Chen, Si-qi Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3595-3603. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.355
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    Objective: To explore the potential relationship between hyperuricemia (HUA) and intervertebral disk degeneration (IDD).

    Background: Lumbar disk herniation (LDH) has become an increasingly common disease in the modern era. Most studies suggest that intervertebral disc (IVD) degeneration (IDD) becomes the main cause factor of LDH. At present, the cause of HUA involving the IDD is not clear.

    Methods: The effect of uric acid at different concentrations (0, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 and 1200 μM) on the proliferation of human nucleus pulposus (NP) cells in culture was assessed by a Cell Counting Kit-8 (CCK-8) assay. The TdT-mediated dUTP nick end labeling (TUNEL) method was used to count apoptotic cells, and autophagy marker proteins were quantified to examine the impact of high-level uric acid at various concentrations (0, 100, 200, 400 μM) on NP cell autophagy. High levels of uric acid were studied for their potential impact on people who suffer from LDH.

    Results: Human NP cell viability was decreased, affected by an increase in uric acid concentration. TUNEL-positive cells in the NP cells were found to be significantly upregulated as a function of 400 μM uric acid (UA) concentration group (p < 0.01). Treatment with uric acid significantly suppressed type II collagen (COL2) messenger RNA (mRNA) expression (p < 0.001). The longer the incubation period, the less expression was seen. Both the microtubule-associated protein1 light chain3 (LC3)-II/LC3-I ratio, the Beclin1 and cleaved caspase-3 protein levels were significantly higher in uric acid-treated groups compared to the control group (p < 0.05), while the p62 protein levels were significantly lower in uric acid-treated groups compared to the control group (p < 0.001). The high levels of uric acid activated autophagy in the NP cells. Patients with LDH and HUA had significantly lower levels of COL2, aggrecan mRNA, and protein in their IVD tissues compared with those with normal uric acid levels (p < 0.05).

    Conclusions: High uric acid levels may reduce the extracellular matrix exression by lowering COL2, aggrecan mRNA, and protein levels, and may also activate autophagy in NP cells by increasing the levels of autophagy-related proteins. IVD tissue samples from IDD patients revealed significantly lower levels of COL2 and aggrecan in those with HUA compared to those without HUA.

  • Article
    Haoyong Zhang, Qian Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3605-3620. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.356
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    Background: Thyroid cancer (TC) is the commonest carcinoma of the endocrine system. Calcitriol (Cal) can regulate the proliferation and differentiation of TC. Therefore, we aim to explore whether cyclooxygenase 2 (COX2) and hippo signaling are correlated with Cal treatment for TC.

    Methods: Human TC cell lines were treated with different concentrations of Cal for 24 h and transfected with overexpression plasmids of COX2 and Yes-associated protein 1 (YAP1) by lipofection. The following assays, namely, cell counting kit-8, colony formation, Transwell, and anoikis assays, were adopted to determine TC cells' malignant phenotypes including viability, proliferation, migration/invasion, and anoikis. The expression location of YAP1 was detected by immunofluorescence staining. Quantitative real-time polymerase chain reaction or Western blot was used to quantify the messenger RNA (mRNA) or protein expression levels of examined genes in TC cells.

    Results: Cal inhibited viability, colony formation, migration, invasion and COX2 expression but promoted anoikis in TC cells. The translocation of YAP1 from the cytoplasm to the nucleus was blocked by Cal treatment. Meanwhile, Cal decreased the levels of B cell lymphoma-2 (Bcl-2), YAP1, transcriptional coactivator with postsynaptic density-95/discs large/zonula occludens-1-binding motif (TAZ), connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), SRY (Sex-Determining Region Y)-Box 9 (SOX9) and ankyrin repeat domain 1 (ANKRD1), but increased those of Bcl-2-associated X (Bax), phosphorylated (p)-large tumor suppressor kinase 1 (p-LATS1), p-macrophage stimulating 1/2 (MST1/2), and p-Yes-associated protein 1 (p-YAP1) in TC cells. However, overexpression of COX2 or YAP1 counteracted the effects of Cal on TC cells.

    Conclusions: Cal suppresses the proliferation and metastasis of TC cells by diminishing anoikis resistance via targeting COX2/YAP1 hippo signaling.

  • Article
    Chao Xiao, You Xiao, Xiaoyan Wang, Ge Xiao, Liao Pan, Zhenquan Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3621-3627. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.357
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    Objective: To explore the effects of Compound Qinbo Decoction (CQD) on the intestinal mucosa of ulcerative colitis (UC) through the Notch signaling pathway.

    Methods: The UC rat model, established using 2,4,6- Trinitrobenzene sulfonic acid (TNBS)/ethanol, was divided into the UC group, mesalazine (MS) group and CQD group. Normal rats were set as the normal group (n = 10). The pathological changes, messager RNA (mRNA) levels and protein expressions of Notch 1 and hairy and enhancer of split 1 (Hes1), epithelial cell proliferation in colon tissues were detected. Primary rat colon epithelial NCM460 cells were added with Tumor Necrosis Factor-α (TNF-α) to establish the UC model, then treated with different drug-contained serum. The cell proliferation and protein expressions of Notch 1 and Hes1 were measured.

    Results: In vivo, the UC rat model was established with obvious pathological changes in colon tissues, which were greatly relieved by MS or CQD. After MS or CQD treatment, mRNA and protein levels of Notch 1 and Hes1 in the UC rat model were increased (p < 0.05). The epithelial cell proliferation was listed from high to low: MS group, CQD group, normal group and UC group (p < 0.05). In vitro, UC in NCM460 cells was established with TNF-α of 50 ng/mL for 6 h, and the cell proliferation level was decreased, which was then increased with MS-containing serum or CQD-containing serum (p < 0.05). The protein expressions of Notch 1 and Hes1 were decreased with TNF-α treatment, which was increased with MS-containing serum or CQD-containing serum (p < 0.05). The effect of CQD-containing serum was suppressed by the Notch signaling pathway inhibitor (p < 0.05).

    Conclusions: CQD has a good therapeutic effect on the intestinal mucosa of UC through the Notch signaling pathway, and the underlying mechanism needs to be explored in the future.

  • Article
    Fatemeh Mollaamin, Majid Monajjemi, Samira Mohammadi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3629-3639. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.358
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    Background: By increasing Coronavirus disease pandemic, Artemisia annua and its phytocomponents with their biological activities containing anti-inflammatory, antibacterial and antioxidant have been investigated as the antivirus. The purpose of this research article is to measure physical and physicochemical properties of Artemisia annua and its component derivatives to approve the effectiveness of these compounds for fighting against the severe acute respiratory syndrome coronavirus 2 infection using carbon nanotube as nanocarrier through drug delivery method.

    Methods: The physical and physicochemical properties of dipole moment, thermochemistry of infrared spectroscopy, chemical shielding tensors of nuclear magnetic resonance, charge density, electrostatic potential and electron donating and electron accepting through frontier orbitals have been evaluated using density functional theory and m062x/cc-pvdz pseudo=Circular Error Probable (CEP) level toward drug delivery system.

    Results: The properties of monoterpenes and sesquiterpenes of Artemisia annua have been evaluated with the molecular weight of the principal phytochemicals and their tension for electron adsorption. The minimum Gibbs free energy consisting of –594.751 × 104, –500.891 × 104, and –455.161 × 104 (kcal·mol-1) for artemisinin, arteannuin B and artemisinic acid, respectively, versus dipole moment for three sesquiterpenes of Artemisia annua which can indicate the most stability of these structures as natural antiviral medications. In fact, the role of (5,5) armchair single-walled carbon nanotube as the electron acceptor and heterocyclic phytochemicals as the electron donor form the active site of “O–C”. In fact, it can be established how artemisinin, artemisinic acid, and arteannuin B extracts from Artemisia annua may act as the efficient antiviral of Coronavirus disease receptor.

    Conclusions: The results in this article have manifested that medicinal plants and phytocompounds can have a considerable function against coronavirus.

  • Article
    Yu lu Geng, Dian feng Liu, Hai Li, Xiao ping Zhu, Wen zhi Ren, Fu shi Quan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3641-3652. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.359
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    Background: Epilepsy is a neurological disorder attributed to transient and recurrent abnormal central nervous system (CNS) function due to the abnormal discharge of brain neurons. While many causes have already been recognized, some cannot be identified. Brain-derived neurotrophic factor (BDNF) plays a significant role in regulating the nervous system. The hippocampus, an area prone to epilepsy, has the greatest amounts of BDNF and its receptor's expression. Therefore, we used BDNF-tyrosine kinase receptor B (TrkB) signalling as the entry point to study the changes in the synaptic plasticity of hippocampal neurons in rats with kainic acid (KA)-induced epilepsy.

    Methods: Thirty healthy Specific Pathogen Free (SPF) Sprague Dawley (SD) rats were used to establish an epilepsy model by injecting KA into the lateral ventricle. The KA-only group of rats represented a model, while the KA+K252A group rats were treated with a specific blocker (K252A; 1 μL, 1 mM). Nissl staining was used to observe hippocampal tissue of all rats. Western blotting, immunohistochemical staining, and transmission electron microscopy (TEM) were applied to investigate the hippocampus and explore the potential relationship between BDNF-TrkB expression and the levels of the synaptic plasticity-associated proteins, microtubule-associated protein 2 (MAP-2), synaptophysin (SYP), and postsynaptic density-95 (PSD-95).

    Results: Histological observations of brain tissue sections and TEM showed that the CA3 region was damaged in KA-injected rats, demonstrating a substantial reduction in the numbers of pyramidal cells and dentate gyrus neurons. The KA-injected groups showed a significantly smaller number of synapses than the normal controls, with some association between BDNF-TrkB and synaptic plasticity observed. The BDNF-TrkB signalling pathway was blocked using the TrkB-specific blocker K252A. Subsequent examination confirmed its relationship with synaptic plasticity-related proteins. The synaptic plasticity-related proteins SYP, PSD-95, and MAP-2 were all decreased, and the decrease in MAP-2 expression was particularly significant.

    Conclusions: The BDNF-TrkB signaling pathway regulates synaptic plasticity in the hippocampus of epileptic rats by modulating the expression of synaptic proteins such as SYP, PSD-95, and MAP-2. In particular, MAP-2 appears to be strongly implicated, highlighting its potential as a novel therapeutic target for temporal lobe epilepsy.

  • Article
    Shuaishuai Zhang, Ling Tian, Yi Yang, Qiurong Zhao, Fei Han, Xiaohe Luo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3653-3663. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.360
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    Background: Acute myeloid leukemia (AML) exhibits a high rate of relapse and chemotherapy resistance and is considered as an aggressive cancer with high mortality. Hence, it is urgent to identify new therapeutic targets to develop personalized medicine for patients with AML. Zinc finger BED-type containing 3 (ZBED3) shows high expression in various solid tumors, and this protein is linked with poor prognosis. However, the role of ZBED3 in AML is unclear. The aim of the present study was to assess the role of ZBED3 in AML.

    Methods: ZBED3 expression pattern in AML was assessed using several online databases and the correlation between ZBED3 expression and clinical outcomes in AML patients was analyzed. Lentiviruses silencing and overexpressing ZBED3 gene were respectively transfected in KG1a and K562 cells. The expression of ZBED3 was analyzed by quantitative real-time PCR and western blotting. The effects of ZBED3 knockdown or overexpression on the viability, apoptosis and cytosine arabinoside (Ara-C) resistance of leukemia cells were evaluated by the Cell Counting Kit-8 (CCK-8), colony formation assay and flow cytometry, respectively. The interaction between ZBED3 protein and Axin1 was examined by Co-immunoprecipitation experiment. Finally, the expression levels of the Wnt/β-catenin pathway-related proteins, including nuclear β-catenin, cyclin D1 and matrix metalloproteinase 7 (MMP7), were analyzed by western blotting.

    Results: ZBED3 was upregulated in AML, and its expression was enhanced in the relapsed cases of AML as compared to that in the newly diagnosed ones (p < 0.05). Moreover, a high ZBED3 expression level was associated with poor prognosis of AML patients. ZBED3 knockdown significantly suppressed the proliferation of leukemia cells and promoted apoptosis, whereas ZBED3 overexpression led to the opposite effects. ZBED3 overexpression also enhanced the resistance of leukemia cells to Ara-C. ZBED3 directly interacted with the Axin1 protein and regulated nuclear β-catenin, cyclin D1 and MMP7 protein levels in leukemia cells.

    Conclusions: Our study showed that high ZBED3 expression level contributes to the proliferation and chemoresistance of leukemia cells and correlates with poor outcomes in AML patients. ZBED3 may play an important role in leukemogenesis via the Wnt/β-catenin pathway.

  • Article
    Deyu Kong, Jige Dong, Guobin Wang, Lihua Luo, Ning Lin, Qi Zhong, Ning Zhan, Erhao Ma, Xuezhu Bai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3665-3673. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.361
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    Background: Intervertebral disc degeneration (IDD) is the leading cause of low back pain. Nucleus pulposus cells (NPCs) play a key role in the production and maintenance of intervertebral disc stroma. This work probed into the role of long non-coding RNAs (lncRNAs) five prime to Xist (FTX) in NPCs and explored its effect on IDD.

    Methods: The intracellular localization of FTX was determined by fluorescence in situ hybridization (FISH) assay. NPCs were transfected with FTX overexpression plasmid, small interfering FTX (siFTX) and small interfering piezo-type mechanosensitive ion channel component 1 (siPIEZO1). FTX, PIEZO and transient receptor potential vanilloid 4 (TRPV4) expressions were detected through Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell viability, apoptosis and senescence were assessed by cell counting kit-8 (CCK-8), flow cytometry and β-galactosidase (β-gal) staining assays.

    Results: FTX was downregulated in IDD and localized in the nucleus of NPCs. FTX knockdown decreased cell viability and increased apoptosis rate, the proportion of β-gal positive cells and PIEZO1 expression in NPCs (p < 0.05), whereas FTX overexpression showed the opposite consequences (p < 0.05). Contrary to the functions of FTX knockdown, silencing PIEZO1 elevated cell viability whereas reduced apoptosis rate, the proportion of β-gal positive cells and TRPV4 level in NPCs (p < 0.05), which also reversed the effects of FTX knockdown on those aspects above (p < 0.05).

    Conclusions: FTX mitigates apoptosis and senescence in NPCs by suppressing PIEZO1 expression to alleviate IDD in vitro.

  • Article
    Tao Wang, Jingbin Zhao, Wei Yao, Jinxue Yang, Wentao Wei
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3675-3681. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.362
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    Background: Clinical evidence suggests that most thyroid diseases require surgical intervention for effective treatment. However, traditional open thyroid surgery often leads to conspicuous trauma, which can result in unacceptable aesthetic concerns for patients. As an alternative to traditional surgical methods, the transcervical approach significantly enhances the surgery process and improves patients' post-operative quality of life. This study aims to highlight the advantages of utilizing the transcervical approach for thyroid tumor surgical procedures.

    Methods: We analyzed clinical data from both surgical techniques and formulated a risk model for thyroid tumors. This model was developed using the least absolute shrinkage and selection operator (LASSO) and logistic regression analytical methods. We established a thyroid tumor-related nomogram and validated the model using Receiver Operating Characteristics (ROC) and calibration curves.

    Results: Our research compared two types of thyroid surgery: traditional and transcervical approaches. The traditional method works well for patients with larger tumors and usually involves less bleeding during the operation. On the other hand, the transcervical approach is quicker and leads to better outcomes after the surgery. Also, it achieves similar surgical results as the traditional method. To sum up, the transcervical approach is often better than traditional thyroid surgery.

    Conclusions: The model was validated using ROC and calibration curves, demonstrating a satisfactory level of discrimination and calibration. This validated model enables swift differentiation between the two types of surgeries. The findings indicate that the transcervical approach is more suitable than traditional surgical techniques for treating thyroid tumors.

  • Article
    Ximiao Ma, Xiaowu Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3683-3691. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.363
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    Background: Tetramethylpyrazine (TMP) is an effective treatment for pulmonary arterial hypertension (PAH), but it is unclear whether its mechanism is related to the regulation of endothelial progenitor cells (EPCs). In this study, we aimed to explore the effect and mechanism of TMP on EPCs.

    Methods: A rat model of PAH was established by intraperitoneally injecting monocrotaline in Sprague Dawley rats, followed by intraperitoneal injection with 100 mg/kg TMP. The effects of TMP on pulmonary pathological morphology were evaluated using hematoxylin-eosin staining. The hemodynamics and right ventricular hypertrophy index (RVHI) of PAH rats were evaluated. EPCs were isolated from healthy rats and identified by double positive staining with acetylated low-density lipoprotein (acLDL), Ulex europaeus agglutinin-1 (UEA-1), and flow cytometry assay. The expression of Nuclear factor erythroid 2-related factor 2 (NRF2) in lung tissue and EPCs was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). After NRF2-specific short hairpin RNA (shNRF2) transfection and/or TMP (50, 100, 200 μM) treatment on EPCs, the viability, proliferation, senescence, and protein expression levels of NRF2, p53 and p21 in EPCs were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), β-Galactosidase staining and Western blot assays.

    Results: TMP treatment improved the pathological condition of lung tissue, hemodynamic score and RVHI of PAH rats (p < 0.001). On the contrary, NRF2 silencing had negative effects on EPCs, including inhibition of viability and proliferation, promotion of senescence, and elevation of the protein levels of P53 and P21 in EPCs (p < 0.001). However, TMP treatment reversed the above effects of NRF2 silencing on EPCs (p < 0.01).

    Conclusions: TMP protects EPCs from senescence by activating the NRF2 pathway.

  • Article
    Yi Liu, Ke-ting Que, Peng-fei Yang, Jie Bai, Chan Qiu, Hui-hong Yu, Bo Ning, Song He, Liang Deng, Li Zhong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3693-3704. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.364
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    Objective: This study aims to explore the role of the triggering receptor expressed on myeloid cells 2 (TREM2) in liver fibrosis and the activation of hepatic stellate cells (HSCs).

    Methods: Tandem Mass Tag (TMT) proteomic analysis, immunohistochemical staining and immunofluorescence were conducted to examine the variations of TREM2 expression between healthy and fibrotic liver tissues. Sh-TREM2 adenovirus was delivered into the mouse portal vein, and a chronic liver fibrosis model was developed by injecting carbon tetrachloride (CCl4). The expression of TREM2 in liver tissues was evaluated using immunohistochemistry and immunofluorescence staining. Next, primary mouse HSCs were extracted, and the TREM2 expression in cells was knocked down by adenovirus. Primary HSCs were exposed to transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-BB (PDGF-BB), or epidermal growth factor (EGF) to observe the effects of cytokines on cells. The cells were incubated for 2 h in spleen tyrosine kinase (Syk) inhibitor R406 and serine/threonine-protein kinase (AKT) 1 inhibitor A-674563, and Western blot was used to detect the phosphorylation integrin αv (ITGAV) protein expression.

    Results: TREM2 expression was significantly increased in human liver fibrosis tissue. TREM2 knockdown markedly reduced liver fibrosis in the mouse fibrosis model. In addition, TREM2 knockdown affected the phagosome signal pathway. TREM2 knockdown failed to activate HSCs by cytokines, which could inhibit endocytosis and TGF-β signaling without impacting the TGF receptor. Interestingly, the integrin family (ITGAV, integrin αx (ITGAX) and integrin α4 (ITGA4)), especially ITGAV expression, decreased after the knockdown of TREM2. The overexpression or knockdown of TREM2 promoted or inhibited ITGAV and phosphorylation ITGAV protein expression, respectively. R406 treatment considerably reduced the phosphorylation ITGAV protein expression of HSCs compared to the control and A-674563 treatment groups.

    Conclusions: TREM2 phosphorylated ITGAV via Syk, which boosted the endocytosis of cytokines to aggravate liver fibrosis.

  • Article
    Min Zhang, Ruqin Chen, Haimei Fan, Yanqing Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3705-3714. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.365
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    Background: Polycystic ovary syndrome (PCOS) is a widespread complex endocrine and metabolic disease. Genistein has been found to play a vital role in multiple human diseases. This study aims to investigate the effects of genistein on the development of PCOS and further explore the underlying molecular mechanisms.

    Methods: A PCOS mouse model was established through treating C57BL/6 mice with dehydroepiandrosterone (DHEA). The mice were divided into Control group (n = 6), PCOS group (n = 6), PCOS+Genistein (5, 10, or 20 mg/kg; n = 6/each group) groups to evaluate the effects of genistein on PCOS development. Later, PCOS+Genistein+Ad-NC group (n = 6) and PCOS+Genistein+Adenovirus-serum amyloid A1 (Ad-SAA1) group (n = 6) were designed to explore the potential mechanism of genistein in PCOS. Tumor necrosis factor-α (TNF-α)-induced human granulosa-like tumor (KGN) cells were utilized to establish an in vitro PCOS cell model. In in vitro experiments, there were multiple groups, including Control group (n = 3), TNF-α group (n = 3), Genistein group (n = 3), TNF-α+si-NC (n = 3), TNF-α+si-SAA1 (n = 3), TNF-α+Genistein (n = 3), TNF-α+Genistein+pcDNA (n = 3), and TNF-α+Genistein+SAA1 (n = 3). The in vitro experiments were performed to investigate the effects of genistein on KGN cells and the underlying mechanisms. Hematoxylin and Eosin (HE) staining was applied to ovarian tissue for observing ovarian morphology in mice. The levels of luteinizing hormone (LH), estradiol (E2), follicle stimulating hormone (FSH), DHEA, testosterone, interleukin-1β (IL-1β) and interleukin-6 (IL-6), and glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) were evaluated using the matched enzyme-linked immunosorbent assay (ELISA) kits, respectively. The relative level of (SAA1) in KGN cells and mouse ovarian tissues was measured by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot was conducted to detect the protein expression of SAA1 and nuclear factor kappa B (NF-κB) signaling-related proteins.

    Results: DHEA reduced corpus luteum and elevated cystic follicles in PCOS ovarian tissues (p < 0.05). Genistein dramatically attenuated the pathological changes in ovarian tissues and influenced the serum levels of LH, FSH and E2 (p < 0.05). Moreover, SAA1 was upregulated in TNF-α-treated KGN cells and PCOS mouse tissues (p < 0.05). SAA1 knockdown alleviated TNF-α-induced oxidative stress and inflammation in KGN cells (p < 0.05). Genistein downregulated SAA1 expression in TNF-α-treated KGN cells (p < 0.05), and the improvement effects of genistein on oxidative stress and inflammation were blocked by SAA1 overexpression in TNF-α-treated KGN cells and DHEA-induced PCOS mice (p < 0.05).

    Conclusions: Our findings indicated that genistein targeted SAA1 to alleviate the development of PCOS by repressing the activation of the NF-κB signaling pathway.

  • Article
    Mengyao Wang, Weini Zhou, Mei Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3715-3727. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.366
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    Background: Diabetic retinopathy (DR) is a commonly encountered microvascular complication in diabetic patients. It is a serious public health issue because it threatens human vision. To delve deeper into the molecular regulation mechanisms underlying DR, the present study screened differentially expressed genes (DEGs) in DR using a bioinformatic approach, and then investigated the regulatory effects on DR of candidate genes in cultured retinal epithelial cells and DR model mice.

    Methods: We first searched the Gene Expression Omnibus (GEO) database using diabetic retinopathy as the keyword and selected the GSE102485 data set for analysis. In retinal pigment epithelial (RPE) cells, lentiviruses were employed to overexpress and interfere with the gene NEUROD1. Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability. DR mice were injected with overexpressed lentivirus and interfering lentivirus of NEUROD1. Finally, NEUROD1 was overexpressed and interfered with vascular endothelial cells (VECs) cultured in vitro. Quantitative polymerase chain reaction (qPCR) and western blot were applied to test the expressions of BCL2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK), B-cell lymphoma 2 (BCL-2), Transforming growth factor beta (TGF-β), Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), and Interleukin 6 (IL-6). An immunofluorescence assay was applied to test NEUROD1 protein expression levels and cell apoptosis. Hematoxylin and eosin (HE) staining was applied to detect the condition of the retina in DR mice. An enzyme linked immunosorbent assay (ELISA) was used to detect the expressions of TNF-α, IL-1β, IL-6 and TGF-β in mouse serum.

    Results: The analysis revealed that the NEUROD1 gene was highly expressed in the DR group. When NEUROD1 was overexpressed, RPE cell viability was markedly reduced (p < 0.01) and apoptosis of RPE cells was increased. In contrast, after interference with NEUROD1, the viability of RPE cells was substantially increased (p < 0.05) and RPE cell apoptosis was decreased. After overexpression of NEUROD1, the expressions of BAX, BAK, TNF-α, IL-1β, and IL-6 increased markedly, whereas the expressions of the anti-apoptotic proteins BCL-2 and TGF-β decreased greatly. After overexpression of NEUROD1, the levels of blood glucose, total cholesterol, and triglyceride of mice were further increased. Interference of NEUROD1 aggravated the morphology of retinal blood vessels and the infiltration of inflammatory cells. Interference of NEUROD1 impaired the ability of VECs to adhere to the wall, causing cell aggregation and floating, thereby affecting cell viability. In the control group and the NEUROD1 overexpression group, VECs could grow and adhere to the wall and form primary blood vessels.

    Conclusions: The current study demonstrated that NEUROD1 inhibited the proliferation of RPE cells, promoted apoptosis and inflammation in RPE cells, promoted blood vessel formation, and exacerbated the development of DR. This research may establish a foundation for diagnosing and treating DR in a clinical setting.

  • Article
    Detao Tao, Jiaying Wang, Rui Yu, Chao Deng, Jingping Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3729-3737. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.367
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    Background: Understanding the mechanisms underlying chemoresistance is crucial for improving the outcomes of chemotherapy. Nuclear factor κB (NF-κB) signaling can be triggered by a variety of chemotherapeutic drugs and may be involved in the development of tumour resistance. However, its role in oral squamous cell carcinoma (OSCC) resistance to cisplatin (DDP) remains unclear. Here, we sought to investigate it.

    Methods: OSCC cells were divided into DDP and DDP+pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) groups, and their survival rates as well as the IC50 of DDP were examined after the 5-diphenyltetrazolium bromide solution (MTT) assay. The messenger RNA (mRNA) and protein levels of NF-κB, P-glycoprotein (P-gp), cleaved caspase-3, and B-cell lymphoma/leukaemia-2 (Bcl2) were analysed by reverse transcriptase–polymerase chain reaction (RT-PCR) and western blotting, respectively.

    Results: The survival rate of OSCC cells and the IC50 of DDP in the DDP+PDTC group were lower than those in the DDP group. Low-dose DDP activated the NF-κB pathway and increased Bcl2 expression in a time-dependent manner, whereas P-gp expression showed no significant changes. PDTC inhibited DDP-induced activation of the NF-κB pathway by upregulating recombinant inhibitory subunit of I Kappa B Alpha (IκBα) expression, which suppressed the expression of the target gene P-gp, resulting in reduced Bcl2 levels and increased caspase-3 activation, ultimately enhancing the sensitivity of OSCC cells to DDP.

    Conclusion: Low-dose DDP activates NF-κB signalling in OSCC cells, upregulating Bcl2 expression and leading to drug resistance. In contrast, PDTC inhibits NF-κB, which downregulates Bcl2 and P-gp expression and activates caspase-3, enhancing OSCC cell sensitivity to DDP. Our findings suggest that NF-κB signalling plays an important role in the resistance to chemotherapeutic drugs.

  • Article
    Fangxian Chai, Yiming Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3739-3750. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.368
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    Objective: Sirtuin (Sirt), an NAD+-dependent deacetylase, is known for its regulatory role in cellular metabolism, aging, and disease. Evidence suggests that Sirt1 is linked to the pathogenesis of Alzheimer's disease (AD). This study aims to elucidate how Sirt1 regulates p53, focusing on the AD cell model's inflammatory response and oxidative stress.

    Methods: Cell experiments were divided into three groups: the Control group, the Model group, and the Resveratrol group. The Control group underwent regular media changes, while the Model group was exposed to a mixture of Amyloid-beta (Aβ) oligomers (0.55 μM) and IBO (0.6 μM) for 48 hours to create an AD model. The Resveratrol group was treated similarly to the Model group but was exposed to 10 μM resveratrol for 24 hours before assessment. Through immunoprecipitation, proteomic analysis, and Venn analysis, Sirt1's acetylation substrate was identified as p53. An AD cell model was established using BV2 microglial cells, and the effects of Sirt1 on oxidative stress and inflammation, mediated by p53 regulation, were determined using immunofluorescence, Enzyme-linked immunosorbent assay (ELISA), Western Blot (WB), and qPCR technologies.

    Results: This study identifies p53 as a substrate for Sirt1 acetylation, corroborated through immunoprecipitation experiments and proteomic analysis. In microglial cells, the activation level in the Model group was significantly higher than in the Control and Resveratrol groups (p < 0.01). ELISA results revealed a significant increase in the expression levels of various substances in the AD Model group compared to the Control group, with a notable decrease in superoxide dismutase (SOD) expression (p < 0.01). However, these were improved in the Resveratrol group. The analysis of WB and qPCR indicated that Sirt1 decreased significantly in the Model group, while E74-like factor 1 (Elf-1), Nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3), Acetylated p53 (acetyl-p53) and other indicators increased significantly (p < 0.01). Compared with the Model group, Sirt1 in the Resveratrol group increased significantly (p < 0.01), and the indicators such as Elf-1, NLRP3 decreased. There was no significant difference in the mRNA transcription level of p53 among the Control group, Model group and Resveratrol group (p > 0.05).

    Conclusions: The results of this study suggest that Sirt1 may affect the inflammatory response and oxidative stress in AD cell models by regulating p53.

  • Article
    Yan Shen, Zhiling Luo, Deling Zhong, Jun Zhang, Jiang Wang, Tao Guo, Guimin Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3751-3760. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.369
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    Background: Cardiac shock wave therapy (CSWT) can inhibit cardiomyocyte apoptosis via several unknown mechanisms. The mitogen-activated protein kinase (MAPK) signaling pathway plays a pivotal role in cardiac and myocardial function by regulating tissue fibrosis and apoptosis. In this study we investigated the potential effects of CSWT on MAPK signaling pathway in the rat model of myocardial infarction (MI).

    Material and Methods: A total of 32 male Sprague-Dawley (SD) rats were enrolled in this study and MI was induced through coronary artery ligation surgery. In the model group, CSWT was performed in the presence or absence of MAPK inhibitor/activator for 4 weeks, and the therapeutic effect was compared with the model group and control groups. Hematoxylin and eosin (H&E) and Masson's trichrome staining were used for histological evaluation. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used for protein and mRNA expression analysis. Echocardiography was used for cardiac function assessment.

    Results: H&E staining and Masson staining revealed that MI induction in the model group caused the disruption of myocardial tissues in the infarcted myocardium, and increased the area of collagen staining area (p < 0.05). After CSWT intervention, the damages in the myocardial tissues were ameliorated in the MI model group and the collagen area was considerably reduced (p < 0.05). Protein p38, Extracellular signal-regulated kinase 1 (Erk1) and Erk2 levels were upregulated upon the induction of MI in the model group, CSWT intervention suppressed their overexpression (p < 0.05). The application of MAPK activator abrogated the effect of CSWT intervention in the MI model group (p < 0.05). In the MI model group, the administration of MAPK inhibitor showed similar protective effects as CSWT intervention (p < 0.05).

    Conclusions: CSWT can promote cardiac function and reduce myocardial fibrosis in the rat model of MI by regulating MAPK signaling pathway.

  • Article
    Lin Shen, Jun Hao, Yun-tao Li, Xian-tie Zeng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3761-3772. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.370
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    Background: This study aimed to evaluate the efficacy of the water extract of Psychotria serpens Linn (PSL) based on a rat model of post-traumatic ankle arthritis (PTAA) and tumor necrosis factor alpha (TNF-α)-induced apoptosis in chondrocytes, and to explore the related therapeutic mechanism based on nuclear factor-kappaB (NF-κB)/p38 mitogen-activated protein kinase (p38-MAPK) pathway.

    Methods: After the PTAA rat model was successfully established, the rats were randomly divided into 4 groups (n = 4 per group): model group, ibuprofen group, PSL 5 g/kg group and PSL 20 g/kg group. X-ray imaging, hematoxylin and eosin (H&E) staining of ankle joints and modified safranin O-fast green staining and scoring of cartilage were carried out after the operation. Next, C28/I2 chondrocytes were cultured and divided into 5 groups: normal group, TNF-α group, TNF-α+4-Phenylbutyric acid (4-PBA) group (positive control), TNF-α+PSL group (300 μg/mL, 400 μg/mL, 500 μg/mL). The endoplasmic reticulum stress-related apoptosis of C28/I2 chondrocytes was induced by TNF-α. After the treatment of the chondrocytes with water extract of PSL, cell viability was measured by Cell Counting Kit-8 (CCK-8), apoptosis was detected by flow cytometry, and expression of NF-κB/p38-MAPK pathway was detected by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and western blotting.

    Results: In the in vivo experiments, compared with the model group, H&E staining of the rat's ankle joint, and modified safranin O-fast green staining and cartilage scoring (p < 0.05) all showed that PSL improved the PTAA healing in rats. In the in vitro experiments, compared with the TNF-α group, PSL significantly increased cell viability (p < 0.05) and proliferation (p < 0.05) and repressed apoptosis (p < 0.05) in TNF-α-treated chondrocytes and downregulated the expression of the NF-κB/p38-MAPK pathway (p < 0.05).

    Conclusions: PSL has a significant beneficial effect on traumatic ankle arthritis, the mechanism of which may be related to the repression of the NF-κB/p38-MAPK pathway.

  • Article
    Maandvi Sharma, Alok Shiomurti Tripathi, Tabinda Hasan, Mohammad Yasir, Kavitha Ganesh, Najwa Abdur Rashid, Himani Awasthi, Priya Pathak, Lucy Mohapatra, Rahul Kumar Maurya
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3773-3781. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.371
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    Background: Present investigation evaluates the neuroprotective effect of Trachyspermum ammi essential oil (TAEO) against monosodium glutamate induced excitotoxicity.

    Methods: Glutamate excitotoxicity was induced in rats by administrating monosodium glutamate [MSG; 2 g/kg body weight, intraperitoneally (i.p.)] for seven days and further animals were grouped into the following groups along with respective treatments: Group 1: Normal healthy control animals without any treatment; Group 2: MSG-2 g/kg, intraperitoneally (i.p.)+vehicle treated disease control animals; Group 3: MSG-2 g/kg, intraperitoneally (i.p.)+TAEO 250 mg/kg orally; Group 4: MSG-2 g/kg, intraperitoneally (i.p.)+500 mg/kg; Group 5: MSG-2 g/kg, intraperitoneally (i.p.)+D-cycloserine 10 mg/kg, i.p. Effect of TAEO was estimated on motor and cognitive function, oxidative stress parameters and Acetylcholinesterase (AChE) activity in the brain tissue of excitotoxicity rat model. Moreover β-Amyloid deposition on the brain tissue was estimated using Congo Red staining.

    Results: There was significant improvement in motor and cognitive function in TAEO group in comparison with the negative control group, which was observed to be reversed in TAEO+N-methyl-D-aspartate (NMDA) treated agonist. Treatment with TAEO ameliorates the altered parameters of oxidative stress and activity of AChE in the brain tissue of excitotoxicity rats. β-Amyloid deposition was observed to be reduced in TAEO treated group as compared with negative control group. However, this effect of TAEO was reversed in the brain tissue of TAEO+NMDA agonist treated group.

    Conclusions: Hence, the data of the present study suggested that the TAEO treatment improves the motor and cognitive function in MSG-induced excitotoxicity in rat model by reducing oxidative stress and formation of β-Amyloid plaque by targeting NMDA receptor.

  • Article
    Hua Yang, LiLi Ren, YaNing Wei, Qian Zhang, Yang Yang, Ye Ma, XueBin Bi, Lin Yang, Na Xiao, AiMing Zang, XiaoLi Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3783-3790. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.372
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    Background and Purpose: Mutations in the Breast cancer (BRCA) gene have been associated with a heightened risk of breast, ovarian, and various other types of cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors induce synthetic lethality in cancer cells that exhibit BRCA mutations. The focus of this study is to elucidate the connection between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA), p35 gene polymorphism and the prognosis of breast cancer patients following treatment with PARP inhibitors.

    Methods: Between February 2015 and April 2018, 158 breast cancer (BC) patients were enrolled in this study. We compared the polymorphisms of the PIK3CA and p35 genes in cancerous tissue and adjacent non-cancerous tissue, assessed the mRNA and protein expressions of PIK3CA and p35, and evaluated their diagnostic significance for BC. All patients received treatment with PARP inhibitors. Furthermore, we analyzed the correlation between PIK3CA and p35 gene polymorphisms and the clinical efficacy of the treatment. Patients were categorized into two cohorts according to their survival status three years after treatment: survival and the death groups. Subsequently, we examined the relationship between the polymorphisms of the PIK3CA and p35 genes and the patients' prognoses.

    Results: PIK3CA gene mutations and p35 gene CG/GG variants in cancer tissues were significantly higher than in adjacent tissues (p < 0.05). The simultaneous detection of PIK3CA and p35 expressions proved to have a larger Area Under the Curve (AUC), thus enhancing diagnostic accuracy for breast cancer, compared to individual detection (p < 0.05). A higher detection rate was observed for PIK3CA mutations and p35 CG/GG variants in non-remission cases versus those in remission (p < 0.05). Evaluating the effectiveness of PARP inhibitors via combined detection of PIK3CA and p35 expressions provided an increased AUC compared to the individual analysis (p < 0.05). The mortality and recurrence rates for PIK3CA gene mutations were significantly higher than the wild type (p < 0.05). However, no notable difference was found when comparing the mortality, recurrence rate, and distant metastasis rate of the p35 gene in both wild and mutated types (p < 0.05).

    Conclusions: The combined detection of PIK3CA and p35 expressions in BC tissues offers valuable diagnostic insight for BC and is an effective measure to evaluate the therapeutic efficacy of PARP inhibitors. Additionally, polymorphisms of the PIK3CA gene are associated with the prognosis of patients receiving PARP inhibitor treatment.

  • Article
    Yihua He, Shuting Wu, Jiazhi Zhi, Hailin Wei, Jianwei Chen, Junping Lin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3791-3802. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.373
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    Background: Abnormal levels of circular RNAs (circRNAs) induce tumorigenesis and metastasis in non-small cell lung cancer (NSCLC). Cancer cells-derived exosomes (exo), acting as carriers for intercellular communication, were involved in tumor progression by transporting specific circRNAs. Here, this study selected specific circRNA (hsa_circ_0005741) molecules by bioinformatics and was designed to clarify and explore the effect and mechanism of exosomal circ_0005741 on malignant behaviors of NSCLC cells.

    Methods: NSCLC (A549 and PG49) cells-derived exosomes (A549-exo, PG49-exo) purified from cell supernatants were characterized using western blot analysis, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The impact of exosomes on cell proliferation, metastasis was demonstrated by colony formation, wound healing, and transwell assays, respectively. Western blot analysis was also constructed to evidence the expression of Neural cadherin (N-cadherin), Epithelial cadherin (E-cadherin), and Yes-associated protein 1 (YAP1) after exosome treatment. Moreover, we carried out quantitative real-time PCR (RT-qPCR) to identify circ_0005741 expression in NSCLC and normal samples. Circ_0005741, miR-1251-5p, and YAP1 levels in exo-stimulated or unstimulated NSCLC cells were also measured by RT-qPCR. Binding relationships between miR-1251-5p and circ_0005741 or YAP1 were analyzed or pooled by online software, and then confirmed via dual luciferase reporter assay.

    Results: NSCLC cell-derived exosomes accelerated growth and metastasis of normal NSCLC cells. Importantly, exosome treatment induced cellular epithelial mesenchymal transition (EMT), as evidenced by down-regulated E-cadherin level (p < 0.001) and up-regulated N-cadherin level (p < 0.001). Circ_0005741 expression was elevated in NSCLC cell-derived exosomes (p < 0.001), tumor cells (p < 0.001) and cancer tissues (p < 0.001). Silencing of circ_0005741 demonstrated inhibitory effects on NSCLC cell biological behaviors. Mechanistically, circ_0005741 promoted YAP1-mediated cellular malignant evolution through sponging miR-1251-5p. Moreover, rescue experiments evidenced that miR-1251-5p and YAP1 were two essential participants in NSCLC, and co-culture of exosomes with NSCLC cells reversed the effects of circ_0005741 depletion.

    Conclusions: Our study indicated a previously unknown regulatory pathway, exosomes-delivered circ_0005741 accelerated the malignant evolution of NSCLC by miR-1251-5p/YAP1 axis.

  • Article
    Qiyi Hu, Zhu Wang, Yulin Lai, Qiong Deng, Jianwen Zhang, Hui Liang, Anyang Wei
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3803-3810. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.374
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    Background: Renal cell carcinoma (RCC) is a prevalent malignancy in humans of all ages worldwide. However, no identifiable risk factors have been identified in most patients, and the pathogenic mechanisms and molecular pathways of known risk factors remain unclear. Therefore, this study aimed to analyze the differentially expressed microRNAs (miRNAs) of RCC by bioinformatics and to explore their mechanism of action on RCC by in vitro experiments.

    Methods: ACHN and 786-O cells underwent transfection with the miR-19b-1 mimic, its inhibitor, and its negative controls. The miR-19b-1 expression level in the miRNA expression profile of RCC was analyzed using bioinformatics. The application of quantitative real-time polymerase chain reaction (qRT-PCR) was employed to examine the expression of miR-19b-1 and its transfection efficacy in RCC tissues and cells. The association between this RNA expression and survival prognosis in RCC patients was determined using the Kaplan-Meier survival curve. Transwell assay was employed to evaluate the effects of miR-19b-1 overexpression or knockout on the invasion and metastasis of ACHN and 786-O cells.

    Results: The expression level of miR-19b-1 was significantly elevated in RCC compared to controls (p < 0.05). The Kaplan-Meier survival curve analysis revealed that increased miR-19b-1 expression was associated with reduced overall survival in clear cell RCC (ccRCC) patients (Logrank p = 0.00047). Moreover, overexpression of this RNA promoted invasion and metastasis of ACHN and 786-O cells (p < 0.05).

    Conclusions: The significant upregulation of miR-19b-1 correlates strongly with poor prognosis in RCC patients and plays a crucial role in the invasion and metastasis of RCC. This suggests that miR-19b-1 may serve as a viable therapeutic target for RCC.

  • Article
    Muhammad Riaz, Mazhar Abbas, Sumaira Sharif, Aziz Ur Rehman, Qaisar Mahmood, Shaista Abbas, Abid H. Shahzad, Irum Javed, Fatima Yousaf, Ghulam Rasool, Aqsa Mumtaz
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3811-3818. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.375
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    Background: Mucuna pruriens (L.) is a tropical medicinal plant, used in folkloric medicine to treat various ailments. The current research was planned to study the antioxidant and hepatoprotective potential of Mucuna pruriens (M. pruriens) seeds methanolic extract using male albino rats.

    Methods: For the study, M. pruriens seeds methanolic extract was prepared, and antioxidant potential was determined. The methanolic extract of M. pruriens seeds was evaluated for antioxidant potential through different in vitro antioxidant assays. For hepatoprotective potential, the male albino rats were divided into six groups intoxicated with Carbon Tetrachloride (CCl4) except the normal control group rats. The rats in the test groups were treated by administering different dose concentrations of M. pruriens seeds extract. Liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) as well as serum proteins, were determined using kit methods. Oxidative stress markers such as total antioxidant status (TAS), total oxidant status (TOS), and malondialdehyde (MDA) were also determined.

    Results: Results showed the significant antioxidant potential of M. pruriens seeds methanolic extract. Significant (p < 0.05) improvements in ALT and AST activities were observed, while ALP activity showed no significant improvement in test group rats treated with M. Pruriens seeds methanolic extract compared to the intoxicated group rats. Significant (p < 0.05) variation in serum total protein, albumin and globulin level was noted in test groups rats treated with M. pruriens seeds extract. Significant (p < 0.05) increase in TAS, while at the same time, a decrease in TOS and lipid peroxidation in test group rats administered with varying doses of M. pruriens seeds methanolic extract compared to the toxic group rats verifies the antioxidant potential of this plant. The structure of hepatocytes was damaged in CCl4 intoxicated rats, with improved histological characteristics of liver tissue in positive control rats administered with Silymarin and in test group rats treated with M. pruriens seeds methanolic extract.

    Conclusions: The study concluded that the methanolic extract of M. pruriens seeds possess antioxidant activities, ameliorating oxidative stress with potential therapeutic applications as a hepatoprotective agent in folkloric medicine.

  • Article
    Guohai Lu, Weiwei Zheng, Hao Wang, Xiaolin Li, Xing Yang, Yuefeng Hao, Qirong Dong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3819-3829. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.376
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    Background: Postmenopausal osteoporosis (PMOP) is a metabolic bone disease characterized by an increase in calcium absorption and bone mass due to a decrease in estrogen levels. This leads to frequent osteoporotic fracture among the elderly. The decreased osteogenic ability of bone marrow mesenchymal stromal cells (BMSCs) plays a key role in PMOP. The present study aimed to explore the underlying mechanism of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) on the osteogenic differentiation of BMSCs in PMOP rats.

    Methods: In this study, a PMOP model was established, and BMSCs were collected and cultured. The gene characteristics and expression patterns of PPWD1 were analyzed using a molecular database search. The expressions of PPWD1 were valued in different marrow mesenchymal stromal cells (MSCs) of PMOP. Furthermore, the function and mechanism of PPWD1 in BMSCs were furtherly explored both in vitro and in vivo.

    Results: We found that PPWD1 was significantly upregulated in BMSCs of PMOP, and it negatively regulated the osteogenic differentiation of BMSCs. In contrast, integrin/focal adhesion kinase (FAK) inhibition effectively suppressed the osteogenesis induced by PPWD1 knockdown both in vivo and in vitro. Moreover, our data demonstrated that lysine demethylase 4A (KDM4A) effectively enhances the transcription of PPWD1 by reducing the methylation of histone H3K9me (H3K9) at the PPWD1 promoter.

    Conclusions: The present study identified a new function of PPWD1 and shed new light on the molecular mechanism that underlies osteogenic differentiation of BMSCs in PMOP.

  • Article
    Jianmin Liu, Weibo Zhao, Junye Li, Beibei Jiao, Jianing He, Peijuan Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3831-3841. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.377
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    Background: The efficacy of Chinese herbal medicine on premature ovarian failure (POF) and possible targets of kaempferol (KAE) for treating POF are revealed. This study is designed to determine the efficacy of KAE, a major bioactive component of Tu Si Zi (Semen Cuscutae), on POF.

    Methods: Female C57BL/6 mice were divided into four groups and treated for 42 days as follows: control group (normal saline injection), KAE group (5 mg/kg/day KAE, tail vein injection), D-galactose (D-gal) group (200 mg/kg/day D-gal, subcutaneous injection for POF model), and D-gal + KAE group (both KAE and D-gal treatments). The number of ovarian follicles and the apoptosis of ovarian cells were assessed using Hematoxylin-Eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP Nick-End labeling (TUNEL) assay. Serum hormone levels were quantified using enzyme-linked immunosorbent assay (ELISA). The viability and apoptosis of D-gal-treated ovarian granulosa cells (OGCs) were detected using Cell Counting Kit-8 and flow cytometry assays. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used for gene expression quantification.

    Results: Tu Si Zi most probably regulated the genes related to the gamma-aminobutyric acid signaling pathway. D-gal treatment reduced body weight, the number of primordial, primary, secondary, and antral follicles, as well as the serum level of estradiol. It increased the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and promoted the apoptosis of ovarian cells (p < 0.001). These effects were reversed via KAE (p < 0.001). D-gal repressed the mRNA and protein levels of estrogen receptor 1 (ESR1) in mice and OGCs, which could be reversed by KAE treatment (p < 0.001). Additionally, the effects of KAE on the viability and apoptosis and the protein levels of apoptosis-and endoplasmic reticulum stress-regulated factors in D-gal-treated OGCs were reversed via silencing ESR1 (p < 0.001).

    Conclusions: KAE has been found to protect against ovarian injury and endoplasmic reticulum (ER) stress by promoting ESR1, suggesting that KAE holds great promise for the treatment of POF.

  • Article
    Xiaoqing Li, Xiaomin Xu, Wenhuan Wang, Congcong Sun, Hai Wang, Jiayong Zheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3843-3849. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.378
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    Background: Lymphocyte immunotherapy (LIT) is regarded as an efficacious treatment for unexplained recurrent spontaneous abortion (URSA), but its mechanism remains controversial. T cells play an important role in maternal-fetal immune regulation. Therefore, in this study we aimed to investigate the proportions of T helper (Th)1, Th2, Th17, and Treg cells, as well as the change in the Th1/Th2 and Th17/Treg balance in peripheral blood mononuclear cells (PBMCs) in patients with unexplained recurrent spontaneous abortion treated with lymphocyte immunotherapy and who had subsequent successful pregnancies.

    Methods: Flow cytometry was used to characterize the population and proportion of Th1/Th2 and Th17/Treg balance in 38 patients before and after immunotherapy.

    Results: The percentage of Th1 cells increased significantly after immunotherapy in patients with URSA (14.96 ± 6.57%), when compared to pretreatment (12.98 ± 7.13%) (p < 0.01), and patients with URSA and LIT and having successful pregnancies (before: 13 ± 7.52%, after: 15.25 ± 6.89%; p < 0.01), while the Th1/Th2 balance decreased significantly (8.37 ± 4.14), when compared to pretreatment (14.08 ± 12.04) (p < 0.05). Furthermore, the proportion of Th1 and Th2 cells was significantly higher in the successful pregnant group, whereas the Th17/Treg balance in patients with URSA did not exhibit significant changes between before LIT (0.39 ± 0.25) and after LIT (0.33 ± 0.23), but decreased significantly in successful pregnancy after LIT (0.29 ± 0.17), when compared to before LIT (0.38 ± 0.25).

    Conclusions: LIT may alter the Th1/Th2 and the Th17/Treg balance, ensuring successful pregnancy.

  • Article
    Yan Li, Shengping Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3851-3855. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.379
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    Objective: We aimed to explore the changes of β2-microglobulin (β2-MG) and urinary protein quantity (UPQ) in mercury poisoning-induced renal injury and their diagnostic significance.

    Methods: 25 inpatients with mercury poisoning admitted to our hospital from January 2019 to January 2022 were selected as the study group, and 25 healthy controls with no history of mercury exposure were enrolled as the control group. Urine β2-MG was detected by immunoturbidimetric method in midstream urine, UPQ was determined quantitatively by 24 h urine protein, and serum creatinine (Scr) and blood urea nitrogen (BUN) levels were detected by fasting venous blood in the morning. Then the receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of each index for renal injury caused by mercury poisoning.

    Results: The β2-MG and UPQ of the study group were (0.17 ± 0.12) mg/24 h and (0.14 ± 0.09) mg/24 h respectively, which were significantly higher than the average level of the control group (both p < 0.05). However, the mean levels of Scr and BUN in the study group were (63.64 ± 7.21) μmol/L and (5.08 ± 0.80) mmol/L, respectively, showing no statistical difference compared with the control group (both p > 0.05). The ROC results showed that the area under the curve (AUC) values of β2-MG and UPQ for the diagnosis of mercury poisoning-induced renal injury were 0.586 and 0.617, respectively, while the AUC value of the three combined diagnosis was 0.828, which was significantly higher than that of each parameter alone.

    Conclusions: Urine β2-MG and UPQ levels are significantly increased in patients with mercury poisoning. The efficacy of the combined three in diagnosing renal injury caused by mercury poisoning is encouraging, contributing immensely to the clinical diagnosis of renal injury caused by mercury poisoning.

  • Article
    Cheng Chang, Lili Zhang, Bin Fang, Yaoyao Miao, Zhenlin Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3857-3867. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.380
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    Background: Rutin has gained considerable attention in cancer research due to its potential anti-tumor effects. However, the low bioavailability of rutin effect its effectiveness in tumor treatment. Thus, the ion gel method synthesized the rutin-chitosan nanoconjugates in this study. Its anti-tumor effects were evaluated in a xenograft tumor in nude mice, and the underlying mechanisms were explored using transcriptome sequencing.

    Methods: In vitro release test of rutin was carried out using the drug release experiment. The anti-tumor effect of rutin-chitosan nanoconjugates was investigated using a xenograft mouse model. Further studies on rutin targets screened by the transcriptomic analysis were conducted.

    Results: It was proved that rutin-chitosan nanoconjugates had good drug loading, encapsulation rate, and slow-release effect. In vivo experiments showed that compared with free rutin, rutin-chitosan nanoconjugates compound had stronger anti-proliferation and pro-apoptotic effects on transplanted tumors of triple-negative breast cancer (TNBC) cells in nude mice. The sequencing, qRT-PCR and western blot results showed that the mRNA and protein levels of Rasgrp3, Flt4 and Vegfd were significantly decreased in the rutin-chitosan nanoconjugates group.

    Conclusions: Rutin-chitosan nanoconjugates may therefore serve as a new therapeutic agent for breast cancer treatment. This opens a new avenue for the development and use of anti-tumor drugs.

  • Article
    Min Hou, Long Cheng, Qing-mei Huang, Hong-mei Zhan, Ting-ting Jia, Jing Wen, Jing Lei, Ya-kun Zhang, Yan Gui
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3869-3877. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.381
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    Background: Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer. Due to the limited diagnosis and treatment for advanced ESCC, the mortality rate is high. Studies have shown that cystatin SN (CST1, cysteine proteinase inhibitor 1) plays an important role in the development of many cancers, but its role in ESCC remains unclear. The purpose of this study was to investigate the expression and clinical value of CST1 in ESCC, and the influence of CST1 on the development and drug resistance of ESCC.

    Methods: Cancer tissues (ESCC group) and adjacent normal esophageal epithelial tissues (normal group) was collected from patients with ESCC. Based on the sensitivity of patients to cisplatin (also known as DDP, cis-Diamminedichloroplatinum(II)), ESCC tissues were divided into the sensitive group and resistance group. Subsequently, the expression of CST1 in different tissue group was observed by quantitative real-time polymerase chain reaction (qRT-PCR). Cisplatin-resistant ESCC cells (EC9706/DDP cells) were established by continuous exposure to cisplatin in vitro. Next, knockdown (si-CST1) or over-expression (CST1) was carried out in EC9706/DDP cells. Besides, a mitophagy inhibitor (Mdivi-1) was employed to treat EC9706/DDP cells. Later, qRT-PCR was conducted to observe the efficiency of over-expression or knockdown of CST1. Colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were responsible to examining the proliferation ability of EC9706/DDP cells, and western blot to test the expression of mitophagy inhibitor-related proteins.

    Results: Compared to the normal group, CST1 expression was significantly up-regulated in ESCC tissues (p < 0.01). Also, the resistance group exhibited notably increased CST1 expression relative to that in the sensitive group (p < 0.01). MTT results indicated successful establishment of cisplatin-resistant EC9706 cells. Over-expression of CST1 not only remarkably up-regulated the proliferation ability and drug resistance in EC9706/DDP cells (p < 0.01), but also activated mitophagy (p < 0.01). However, knocking down CST1 showed the opposite result. In addition, over-expression of CST1 could reverse the effect of Mdivi-1.

    Conclusion: CST1 is significantly highly expressed in ESCC patients developing resistance to cisplatin. Additionally, CST1 can increase chemoresistance in EC9706 cells through inducing mitophagy.

  • Article
    Dong Tang, Yue Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3879-3888. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.382
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    Background: Glioma is a common and aggressive primary malignant brain tumor. However, the occurrence and development of glioma has not been well reported. Our study aims to detect the function and mechanism of steroid 5 alpha-reductase 3 (SRD5A3) in the proliferation and metabolism of glioma cells.

    Methods: SRD5A3 expression was estimated by bioinformatics analysis and western blot assay. Next, U118MG and LN229 cells were separated into si-control, si-SRD5A3-1 and si-SRD5A3-2 groups, respectively. Cell growth ability was determined by cell counting kit-8 and colony formation assays, whereas its mobility and cycle were measured by Transwell and western blot assays. The metabolism of glioma was determined by the corresponding enzyme-linked immuno sorbent assay kit and Seahorse machine. Subsequently, the transcriptional factor of SRD5A3 was predicted by University of California Santa Cruz (UCSC) and PROMO database and confirmed by dual luciferase assay and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) assay. The protein pattern of extracellular regulated protein kinase (ERK)/cAMP response element binding protein (CREB) pathway related molecules was examined by western blot.

    Results: SRD5A3 expression was significantly increased in glioma samples, p < 0.05. Functionally, U118MG and LN229 cells in si-SRD5A3-1 or si-SRD5A3-2 group revealed the obvious reduction in its growth, cycle, mobility and metabolism in contrast with those in the si-control group, p < 0.01. Moreover, transcriptional factor interferon regulatory factor 2 (IRF2) bound to SRD5A3 and affected its expression in glioma cells. Furthermore, si-SRD5A3 antagonized the function of IRF2 overexpression in modulating glioma cell proliferation, mobility, cycle and metabolism. The p-ERK and p-CREB levels were obviously increased after IRF2 upregulation, whereas the addition of si-SRD5A3 antagonized the effect of IRF2 overexpression on p-ERK and p-CREB levels, p < 0.01.

    Conclusions: In summary, the findings of in vitro studies insinuated that the administration of si-SRD5A3 suppressed the growth, mobility and metabolism of glioma cells, and SRD5A3 was transcriptionally regulated by IRF2.

  • Article
    Taishan Tang, Ye Xu, Lingling Tian, Lei Chen, Fande Kong, Changqing Zhu, Xiao Tan, Xiaona Zhao, Chengping Lu, Huixing Lin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3889-3895. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.383
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    Background: Brucella melitensis RM57, a mutant of B. melitensis M1981, is an effective vaccine candidate due to the reduced virulence. This study was aimed to explore the molecular mechanism of virulence reduction in Brucella melitensis RM57.

    Methods: The differentially expressed genes (DEGs) between samples from M1981 and RM57 were determined based on gene expression profiles and were used for protein subcellular localization (SCL) analysis. Then based on the SCL results, protein-protein interaction (PPI) network analysis was performed, followed by function enrichment analysis and gene-drug interaction prediction.

    Results: A total of 403 DEGs were identified between the RM57 and M1981 groups. Then, 58 proteins were predicted based on the NCBI protein database, including 3 membrane proteins (nuoK, exbD, and cydB), 31 cytoplasmic proteins, and 2 periplasmic proteins. A PPI network was constructed, which consisted of 27 nodes, such as rpoB, rpoA, rpsP, rpoC, RpsA and nuoK, and 146 interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the proteins in the PPI networks showed that they were mainly enriched pathways of ribosome, and RNA polymerase, and functions related to biosynthetic process and metabolic process. Mitoxantrone, adriamycin, and daunorubicin were predicted to be target drugs of RpsA.

    Conclusions: The membrane proteins of nuoK, exbD, and cydB, and cytoplasmic proteins, such as rpoB, rpoA and rpsP, may contribute to the virulence reduction of the RM57 strain. RpsA may induce an immune response against brucellosis infection through ribosome pathway. These proteins may be targets for novel vaccine development.

  • Article
    Yifan Li, Ru Yang, Hongxia Yan, Xiaoning Cheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3897-3902. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.384
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    Background: Hyperbilirubinemia is a commonly encountered condition during neonatal period. Accumulation of unconjugated bilirubin can cause jaundice, which affects the skin or other tissues in newborns. Furthermore, hyperbilirubinemia directly affects the energy metabolism and tissue structure of the brain. This cytotoxicity seriously threatens the safety of newborns.

    Aim: To investigate changes in transcutaneous bilirubin (TCB), transserum bilirubin (TSB), and magnetic resonance imaging (MRI) T1-weighted imaging (T1WI) mean signal of the pallidum in neonates with hyperbilirubinemia and the effect of intense light therapy.

    Methods: The study included newborns with hyperbilirubinemia treated at the No. 215 Hospital of Shaanxi Nuclear Industry from February 2019 to February 2021. All children received basic treatment combined with strong light therapy. Changes in TCB, serum TSB, MRI T1WI mean signal parameters of the pallidum, serum immunoglobulin, and neonatal behavioral neurological assessment scale (NBNA) scores before and after treatment were recorded, and the relationship between TCB, TSB, and MRI T1WI pallidum average signal parameters and NBNA score before treatment was examined.

    Results: A total of 100 neonates (54 males and 46 females) with hyperbilirubinemia were included. The gestational age was 37–40 (average: 38.5 ± 0.7) weeks, birth weight was 2964–3581 (average: 3298.4 ± 96.2) g, and the age was 7–26 (average: 14.8 ± 3.5) days. There were 38 cesarean sections and 62 vaginal deliveries. After intense light therapy, the average TCB values of the forehead, anterior chest, perineum, and three parts of children after treatment were significantly lower than those before treatment (p < 0.05). The serum TSB level after treatment was significantly lower than that before treatment (p < 0.05). The mean signal values of the left, right, and bilateral globus pallidus after treatment were significantly lower than those before treatment (p < 0.05). There was no significant difference between the signal difference of the left, right, and bilateral globus pallidus and frontal lobe after and before treatments (p > 0.05). There was a significant negative correlation between the TCB and TSB levels and NBNA scores, and a positive correlation was noted between the TCB and TSB levels and the average signal value of the bilateral globus pallidus (p < 0.05).

    Conclusions: The mean signal values of TCB, serum TSB, and MRI T1WI pallidum in children with hyperbilirubinemia that were significantly increased before treatment, significantly decreased after treatment. TCB and serum TSB are positively correlated with the mean signal value of MRI T1WI pallidum and the NBNA score, which can reflect the brain injury of children to a certain extent.

  • Article
    Shen-Shen Hao, Xiao-Peng Zhang, Sai-Ke Meng, Peng-Cheng Wang, Hong-Ke Li, Shuai Liu, Hong-Lei Chen, Zhi-Fang Zhang, Sheng-Li Dong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3903-3909. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.385
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    Background: Posterior lumbar interbody fusion (PLIF) is a common treatment for degenerative disorders of the lumbar region. The purpose of this research was to evaluate the effectiveness and safety of a single intravenous dosage of tranexamic acid (TXA) in patients with PLIF.

    Methods: We conducted a retrospective analysis of 61 patients with degenerative lumbar diseases treated with PLIF between January 2021 and November 2021. There were 40 patients in the observation group who received an intravenous unit dose of TXA (1 g/100 mL) after general anesthesia and 15 minutes before incision. The control group consisted of 21 patients who received 100 mL of normal saline. Details pertaining to the surgery time, intraoperative hemorrhage, postoperative drainage, blood transfusion rates, adverse events, and postoperative hospital stays of patients in the two groups were recorded. Additionally, the hemoglobin (Hb), platelet (PLT), activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), and D-dimer were recorded on the first and fourth days post-surgery.

    Results: All surgeries were completed successfully. The surgery time, intraoperative hemorrhage, postoperative drainage, and blood transfusion rates of patients in the observation group were significantly lower than those in the control group (p < 0.05). The D-dimer in the observation group was significantly lower than that in the control group on postoperative day 1 (p < 0.05), while there was no difference on postoperative day 4 (p > 0.05). There were no statistical differences in aPTT, PT, TT, Fg, Hb, PLT, or postoperative hospital stays between the two groups on postoperative day 1 and postoperative day 4 (p > 0.05).

    Conclusions: In this study, we found that an intravenous unit dose of TXA in PLIF did not affect blood coagulation function and was safe; it was effective in reducing perioperative hemorrhage and blood transfusion rates.

  • Article
    Xingshi Yuan, Kerong Wu, Zhi Li, Xiaodong Ling, Zhengliang Luo, Daijie Fu, Xiaoqi Zhang, Kun Chen, Xifu Shang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3911-3919. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.386
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    Background: Micheliolide (MCL) has ameliorating effects on tissue inflammation, but its potential therapeutic effect on osteoarthritis (OA) is unknown. The study aims to explore the pharmacological action and mechanism of MCL in the treatment of OA.

    Methods: Two models of OA were established and treated with MCL. Chondrocyte activity was evaluated by cell counting kit (CCK)-8 assay, while prostaglandin E2 (PGE2), nitric oxide (NO), and interleukin-1β (IL-1β) levels were measured using commercial kits. Mitogen activated protein kinase (MAPK) pathway-related proteins were evaluated by Western blotting, while key enzymes in cartilage degradation were analyzed by real-time quantitative polymerase chain reaction. Cartilage injury in OA mice was assessed by Saffranine O green staining, whereas pathological injury of brain, lung, kidney, and heart was determined by hematoxylin-eosin staining.

    Results: MCL suppressed the production of IL-1β-induced PGE2 and NO, cyclooxygenase 2, and inducible nitric oxide synthase in mouse chondrocytes. MCL also inhibited IL-1β-induced disintegrin and metalloproteinase with thrombospondin motif 4/5 mRNA and matrix metalloproteinases. MAPK pathway was inhibited by MCL. MCL effectively inhibited OA in mice.

    Conclusions: MCL inhibits IL-1β-stimulated chondrocyte inflammation by blocking the MAPK pathway. The application of MCL in the treatment of OA provides new data support.

  • Article
    Xuejiao Lv, Yanwei Du, Wenxi Tan, Shuang Fu, Lanying Yu, Xue Wang, Wenfeng Zhang, Yan Meng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3921-3928. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.387
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    Objective: Urea transporter-B (UT-B) shows high expression in the heart; However, its role in cardiac hypertrophy remains unknown. This study aimed to investigate the role and mechanism of action of UT-B in cardiac hypertrophy induced by pressure overload.

    Methods: 16-week-old UT-B knockout and wild-type mice were used in this study. A cardiac hypertrophy model was established by abdominal aorta banding. Echocardiography, histology, hematoxylin and eosin staining, and western blotting were conducted to evaluate cardiac function, morphology, nitric oxide (NO) synthesis, and oxidative stress. Proteasome activities were also examined using a fluorescent peptide substrate.

    Results: Systolic functional parameters [Ejection fraction (EF), Fractional shortening (FS)] and diastolic functional parameters [ratio of E peak to A peak (E/A)] did not change significantly in UT-B knockout mice compared with those in wild-type mice, but they were decreased significantly after abdominal aorta banding in UT-B knockout mice. Moreover, UT-B knockout mice showed increased heart volume and atrial natriuretic peptide (ANP) expression after abdominal aortic banding. Moreover, reactive oxygen species (ROS) and malondialdehyde levels were upregulated in UT-B knockout mice and were further increased after abdominal aorta banding, whereas the antioxidant enzyme activity was downregulated. In addition, nitric NO levels and endothelial nitric oxide synthase (eNOS) expression were downregulated in UT-B knockout mice and were further decreased after abdominal aorta banding.

    Conclusions: UT-B knockout enhances cardiac hypertrophy induced by abdominal aorta banding via upregulation of ROS levels and downregulation of NO levels in the heart tissue, suggesting that UT-B plays an important role in the maintenance of cardiac function.

  • Article
    Sarmistha Saha, Brigitta Buttari, Elisabetta Profumo, Luciano Saso
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(7): 3929-3940. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.388
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    Background: Polycrystalline aggregates formed in the urinary system leads to the production of reactive oxygen species (ROS), the development of oxidative stress, and renal injury.

    Aim: This study investigated the antioxidant activity of major bioactive components of Macrotyloma uniflorum (MU) such as Quercetin, Kaempferol and Sitosterol and its polyphenolic extract against the pro-oxidant effects triggered by sodium oxalate.

    Methods: We performed molecular docking and molecular dynamics simulations of major bioactive components with superoxide dismutase, catalase, glutathione reductase and glutathione-S-transferase, key enzymes of human antioxidant system. Thereafter, we performed in silico Absorption Distribution Metabolism Excretion-Toxicity (ADME-Tox) analysis to find drug-like molecules, absorption, distribution, metabolism and toxicity study. Then, by spectrophotometric analysis we determined the antioxidant potential of MU extract and of Quercetin, Kaempferol and Sitosterol against oxidative imbalance due to hyperoxaluria in the renal tissue of female Wistar rats002E.

    Results: Molecular dynamics simulations showed high binding interactions of Quercetin with superoxide dismutase (SOD) and glutathione-S-transferase (GST) enzymes. In silico ADME/Tox data analysis showed the polyphenolic components may interact with the antioxidants, thus complementing their antioxidant potency. In wet lab studies, the sodium oxalate treatment specifically induced a significant elevation of lipid peroxidation with a concurrent decrease in reduced glutathione content, superoxide dismutase and catalase activities in a dose-dependent manner in kidney tissue homogenates. The MU extract and the bioactive components Quercetin, Kaempferol and Sitosterol were able to counteract sodium oxalate-induced oxidative stress in a dose-dependent manner, with Quercetin resulting the most effective compound.

    Conclusions: Our in vitro results suggest MU as a possible source of bioactive components to counteract renal injury thus representing an add-on therapy approach in the hyperoxaluria-induced kidney stone formation.