20 October 2022, Volume 36 Issue 5

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  • Review
    Marcello Aragona, Katia Marabello, Carmen Mannucci, Ilaria Ammendolia, Fabrizio Calapai, Angela Alibrandi, Sabina Russo, Rossana Leanza, Caterina Musolino, Alessandro Allegra
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1201-1210. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.131
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    Background: Subjects affected by hematological malignancies may suffer relevant psychosocial alterations.

    Methods: Thirty-eight patients involved in a nine-weeks psychological support program were evaluated before and after the treatment using psychometric assessment scales and through the study of stress biological markers such as brain derived neurotrophic factor, cortisol and adrenocorticotropic homone (ACTH) levels, and pro-inflammatory cytokines. A control group consisting of hematological patients comparable to the study group but who were not subjected to psychological support was created for the evaluation of biological variables. In this group the biological markers were also studied with an interval of 9 weeks.

    Results: Participation in the psychological treatment was found to be correlated with reduction in self-reported anxiety and depression, and improvement of distress thermometer, impact of event scale, and needs evaluation. On the other hand, no change was evident about the quality of life and in mindfulness. Plasma levels of pro-inflammatory cytokines were increased after the retreat. In the control group we evidenced an increase of ACTH concentrations after nine weeks, testifying an increase in stress levels.

    Conclusions: The psychological health is proved as essential to preserve and enhance well-being in hematological patients. Therefore, the psychosocial area must be integrated in all regards in the context of ordinary care.

  • Article
    Jia-Wei GU, Run-Qi HONG, Yi ZHANG, Geng-Ming NIU, Zhi-Qing HU, Xiao-Tian ZHANG, Zhi-Peng CAO, Xi LI, Chong-Wei KE
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1211-1222. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.132
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    Background: Hepatocellular carcinoma (HCC) is an aggressive tumor. The discs large homolog 2 (DLG2) is expressed in some malignancies, and it may be related to tumor progression. However, its role in HCC has not been explored. The aim of this study was to explore the prognostic value and role of DLG2 in HCC.

    Methods: The data of mRNA (messenger ribonucleic acid) expression from Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases were used to evaluate DLG2 expression in HCC tissues. The DLG2 protein level was checked for using immunohistochemistry analysis of a tissue microarray. The univariate and multivariate Cox regression analyses and the Kaplan–Meier analysis were used to evaluated the correlation between DLG2 expression and overall survival (OS). Gene set enrichment analysis (GSEA) was performed to research potential pathway that DLG2 participates in. DLG2 overexpression and knockdown cells were constructed using HCCLM3 cell line transfected with DLG2 overexpression vector and HepG2 transfected with shDLG2 (short hairpin RNA targeting at DLG2), respectively.

    Results: DLG2 was significantly downregulated in HCC tissues. DLG2 expression was significantly associated with the pT (primary tumour) stage, tumor size, histological grade, and vessel invasion. More importantly, low DLG2 expression was significantly related to poor prognosis in advanced pStages (pathological stages), grade 3 HCC, alcoholic, and HBV (hepatitis B virus)-positive HCC patients. The MYC targets V2 (alias TCRGV9, T cell receptor gamma variable 9), E2F targets, and G2M (gap 2 phase and mitosis phase) checkpoint gene sets were differentially enriched in low DLG2 expression phenotype. DLG2 significantly correlated with MCM2 (minichromosome maintenance complex component 2), MCM5 (minichromosome maintenance complex component 5), MCM6 (minichromosome maintenance complex component 6), KPNA2 (karyopherin subunit alpha 2), CDK4 (cyclin-dependent kinase 4), H2AFZ (H2A histone family member Z), MAD2L1 (mitotic arrest deficient 2 like 1) and CDC20 (cell division cycle 20) in LIHC (liver hepatocellular carcinoma) patients. DLG2 silence and overexpression promoted and suppressed HCC proliferation, respectively.

    Conclusions: DLG2 might function as a biomarker of diagnosis and prognosis in HCC, and suppressed HCC cells proliferation.

  • Article
    Yuanxu Jiang, Zhewei Huang, Jing Xu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1223-1235. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.133
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    Background: Our previous studies have shown that Dexmedetomidine (Dex), an α2adrenergic receptor (α2AR) agonist, alleviates pulmonary edema in LPS-induced acute lung injury (ALI), but the mechanism is not clear. The aim of this study was to explore the underlying mechanisms by which Dex alleviates pulmonary edema.

    Methods: We established a rat model of acute lung injury (ALI) and alveolar epithelial cell injury induced by lipopolysaccharide (LPS) in A549 cells. Histology of the lungs was assayed with H&E staining, and the lung injury score was calculated. PaO2, PaO2/FiO2, the lung wet/dry (W/D) ratio and total protein in bronchoalveolar lavage fluid (BALF) and alveolar fluid clearance (AFC) were measured. The concentrations of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in serum and BALF and myeloperoxidase (MPO) activity in lung tissues and neutrophils in BALF were determined. The expression of α1Na,K-ATPase, β1Na,K-ATPase, phosphorylated phosphoinositide-3 kinase (p-PI3K) and phosphorylated protein kinase-B (p-Akt) in vivo and in vitro was analyzed.

    Results: Dex significantly alleviated the lung W/D ratio and total protein concentration in BALF and increased AFC, PaO2 and PaO2/FiO2. In addition, Dex reduced the concentrations of TNF-α, IL-β and IL-6 and decreased the MPO activity in lung tissues and the number of neutrophils in BALF. Dex also increased the expression of α1Na,K-ATPase, β1Na,K-ATPase, p-PI3K, and p-Akt in vivo and in vitro. However, these effects were partially reversed by the α2AR inhibitor yohimbine or the PI3K inhibitor LY294042.

    Conclusions: These results demonstrated that Dex attenuated pulmonary edema by stimulating AFC and reduced alveolar epithelial leakage by upregulating the expression of the Na,K-ATPase, and the mechanism is related to the α2AR/PI3K/Akt signaling pathway in LPS-induced ALI.

  • Article
    Chen Chen, Kaijing Wang, Chenglv Hong, Xiao Chen, Lu Lin, Xiangxiang Shi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1237-1245. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.134
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    Background: Emerging evidence indicates that the chemokine C-C motif ligand 20 (CCL20) promotes atherosclerosis via a chemo-attraction process. Statins improve atherosclerosis by inhibiting chemokine expression. Although the regulatory mechanisms of CCL20 have been investigated in other cells, they have not been clarified in macrophages. Moreover, the statin-induced regulation of CCL20 has not been studied previously. Therefore, this study explored the regulatory mechanism of CCL20 in oxidized low-density lipoprotein (oxLDL)-induced macrophages and the effect of statins on CCL20.

    Methods: CCL20 expression was tested after applying atorvastatin to interfere with oxLDL-induced macrophages, inhibiting nuclear factor-kappa B (NF-κB) activity in oxLDL-induced macrophages and the atorvastatin intervention model, and after transfecting a CCL20 overexpression plasmid into RAW 264.7 cells, after which NF-κB activity was also tested.

    Results: The results showed that atorvastatin downregulates CCL20 in oxLDL-induced macrophages, the NF-κB pathway participates in CCL20 regulation, and CCL20 overexpression in macrophages activates NF-κB.

    Conclusions: The results suggest that the NF-κB pathway is involved in regulating CCL20 expression in macrophages. Moreover, atorvastatin may regulate CCL20 to exert anti-inflammatory functions, indicating that the NF-κB/CCL20 signaling pathway represents a potential antiatherosclerosis target.

  • Article
    Heng-Mei Zhu, Na Liu, Liang Luo
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1247-1257. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.135
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    Background: Early tubular injury is the initiating factor of diabetic nephropathy. It is still unclear the effects of transfer RNA-derived small RNA (tsRNA) in the early tubular injury of diabetic nephropathy. This study was designed to investigate the effects and mechanisms of tsRNA in renal tubular injury caused by diabetes nephropathy.

    Methods: High-throughput RNA sequencing was applied to recognize differential tsRNAs of primary renal tubular epithelial cells, which were extracted from 12-week-old male db/m and db/db mice. The tsRNAs were further identified by quantitative real-time polymerase chain reaction (qRT-PCR). The target genes of tsRNAs were predicted using MiRanda. The Gene Ontology (GO) and Kyoto Encyclopedia of genes and genomes (KEGG) databases were used to explore the related physiological functions and signal pathways of target genes.

    Results: Seven tsRNAs with differential expression were identified, and the expression of six tsRNAs was verified to the same trend as high-throughput RNA sequencing by RT-qPCR. In comparison to db/m mice, the expression of 4 tsRNAs was up-regulated (tRF-51:72-chrM.Met-CAT, tRF-52:71-chrM.Arg-TCG, tRF-1:32-Val-CAC-4, tRF-+1:T17-Asn-GTT-3-9), and the expression of 3 tsRNAs was down-regulated (tRF-1:30-Gly-GCC-2-M3, tRF-57:76-Tyr-GTA-2-M2, tRF-+1:T16-Asp-GTC-1-6) in db/db mice. Furthermore, the target genes of tsRNAs were mainly linked to the toll-like receptor signaling pathway, circadian entrainment pathway, longevity regulating pathway, and hypoxia-inducible factor 1 (HIF-1) signaling pathway.

    Conclusions: The tsRNAs are involved in the pathology of renal tubular injury induced by diabetic nephropathy, and may be associated with some signaling pathway, including the HIF-1 signaling pathways, the longevity regulatory pathway, the circadian regulatory pathway and the toll-like receptor signaling pathway.

  • Article
    Xiaoyan Xie, Mu Xu, Hangjing Gao, Xianjing Chen, Liangzhi Cai
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1259-1267. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.136
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    Background: The purpose of this study was to identify how exosome-derived miR21 affected epithelial ovarian cancer (EOC) cells.

    Methods: miR21 expression was examined in isolated-exosomes of human normal ovarian epithelial cell line IOSE-80 and EOC cell line SKOV-3. The exosomes morphology was evaluated via a transmission electron microscopy. SKOV-3 cells were transfected with miR21 mimic or inhibitor, and then the transfected cell-secreted exosomes were co-cultured with untransfected cells. The quantitative real time-polymerase chain reaction (qRT-PCR) was used to analyze the miR21 expression in cells and exosomes derived from cells. The exosome-treated cells proliferation, apoptosis, migration and invasion were measured by performing methyl thiazolyl tetrazolium (MTT) assay, colony formation assay, flow cytometry, wound-healing assay, and transwell assay, respectively. The exosome molecular markers expression and epithelial-mesenchymal transition (EMT)-related proteins expression were examined via the Western blot analysis.

    Results: SKOV-3 cells had prominently significantly higher exosomal miR21 expression than IOSE-80 cells. Reduced exosomal miR21 expression led to a significant decrease in miR21 expression in exosome-treated SKOV-3 cells, while exosomal miR21 overexpression significantly increased miR21 expression. Overexpression of miR21 in exosomes significantly promoted ovarian cancer cell proliferation, suppressed cell apoptosis, facilitated the invasion and migration, and regulated the EMT-related protein expression, while down-regulated miR21 expression in exosomes showed significant counterproductive effects.

    Conclusions: This study found that EOC cell-derived exosomal miR21 could enhanced EOC cells proliferation, migration, and invasion while inhibiting apoptosis, suggesting that exosomal miR21 may be a tumor promotor for ovarian cancer.

  • Article
    Qinyan Shen, Liting Lv, Kangbin Wu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1269-1279. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.137
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    Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a dismal prognosis. 7-methylguanosine (m7G) methylation is a type of RNA modification closely correlated with tumour development.

    Methods: In this study bioinformatic tools were used to identify three differentially expressed m7G-methylation related genes associated with the prognosis of TNBC using data from The Cancer Genome Atlas (TCGA) database. In addition, miRNAs associated with these genes were screened, and 8 prognostic miRNAs were identified via multivariate and univariate regression analyses. An 8-miRNA signature was established, and all patients with TNBC in the TCGA cohort were divided into the low- and high-risk groups.

    Results: Compared with the high-risk group, the low-risk group had substantially prolonged survival (p < 0.001). The areas under the receiver operating characteristic curve were 1, 0.965, and 0.931 for predicting at 1-, 2-, and 3-year survival, respectively. Furthermore, based on univariate and multivariate Cox regression analyses, the risk score was identified as an independent predictor of overall survival (hazard ratio: >1, p < 0.01). A nomogram was constructed based on clinical information (including age, distant metastasis, tumour size, and lymph node metastasis) and risk scores, which had a concordance index of 0.96 and exhibited a favourable discriminatory performance.

    Conclusions: Our nomogram can facilitate individualized prediction of prognosis and clinical decision-making. Additionally, genes and miRNAs associated with m7G methylation serve as useful prognostic markers or therapeutic targets for TNBC.

  • Article
    Muhammad Shahid, Muhammad Kashif, Komal Khan, Aziz Ur Rehman, Fozia Anjum, Mazhar Abbas, Samiah H. Al-Mijalli, Shaista Abbas, Abid H. Shahzad, Muhammad Riaz, Munawar Iqbal, Mahvish Fatima
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1281-1289. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.138
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    Background: Biofilms are the microbial population that causes recurring and chronic infections and are extremely resistant to available antibiotics and host immune systems. The current research aimed to evaluate the antibiofilm and anti-inflammatory potential of methanolic and aqueous extracts of Elettaria cardamomum and Cichorium intybus.

    Methods: Antibiofilm and antibacterial activities of both the plant extracts were evaluated against potential human pathogens i.e., Staphylococcus aureus, Pasteurella multocida and Escherichia coli. Moreover, in vitro antioxidant, thrombolytic, hemolytic, anti-inflammatory and antiarthritic activities were also performed.

    Results and Conclusions: Methanolic extract of E. cardamomum (MEE) showed highest antibacterial activities with MIC values of 0.53 mg/mL, 0.71 mg/mL and 0.60 mg/mL along with biofilm inhibition of 40.45%, 55.92%, 52.32% against E. coli, S. aureus and P. multocida. In vitro antioxidant activity results evidenced that both the methanolic extracts of E. cardamomum and C. intybus have a significant amount of Total Phenolic Contents (TPC) and Total Flavonoid Contents (TFC) with antioxidant potential. Methanolic extract of E. cardamomum (MEE) exhibited the highest 2,2-diphenylpicrylhydrazyl (DPPH) inhibition and reducing power capability with half maximal inhibitory concentration (IC50) values of 8.65 and 41.87%, respectively. Further, aqueous and methanolic extracts of both plants showed the least cytotoxicity towards human red blood cells (RBCs). Similarly, methanolic extract of E. cardamomum exhibited highest anti-inflammatory and anti-arthritic potential with 81.65%, 89.09% and 90.65% denaturation of protein, anti-proteinase activity and membrane stabilization against standard Diclofenac sodium, respectively.

  • Article
    Piwei Huang, Minghui Wei, Shufan Ji, Maolin He
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1291-1298. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.139
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    Background: Ribosomal protein L34 (RPL34) is a member of the L34E ribosomal protein family containing zinc finger domains. This protein plays a key role in regulating the apoptosis, cell cycle progression and proliferation of various cancers including osteosarcoma (OS). Based on the analysis of the University of California Santa Cruz (UCSC) database, it was found that c-Myc may play an important role in regulating the expression of RPL34.

    Methods: In this study, we explored the mechanism by which c-Myc regulates RPL34 expression. The expression levels of c-Myc and RPL34 were measured by qRT-PCR and Western blot. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to analyse the binding site of c-Myc and RPL34.

    Results: The results showed that c-Myc may bind to the E-box region in the RPL34 promoter to regulate RPL34 expression. The results indicated that c-Myc regulates OS cell proliferation through RPL34. This research may provide new ideas for targeted therapy of OS.

    Conclusions: c-Myc regulates osteosarcoma cell proliferation through RPL34.

  • Article
    Chenyu Jiang, Jiangmin Liang, Yiwan Wang, Chaohui Wang, Shenyu Wei, Junjie Ni, Yaojian Shao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1299-1310. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.140
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    Background: Hepatocellular carcinoma is a kind of cancer that begins in the liver and has a high recurrence and death rate. It has been shown that hepatocellular carcinoma patients who get treatment with novel immunotherapy that targets the tumor microenvironment have better survival rates than those who do not. However, not all patients with Hepatocellular Carcinoma respond well to immunotherapy due to a lack of knowledge about the tumor microenvironment.

    Methods: Hepatocellular carcinoma patients with infiltrated immune cells had a better prognosis, as determined by MCP-counter algorithms. To further understand the role of T cell markers in hepatocellular cancer, researchers sequenced the RNA of individual cells (GSE146115). T cell marker genes (TCMS) were constructed and validated using data from GSE10141, GSE14520, and The Cancer Genome Atlas-liver hepatocellular carcinoma.

    Results: Those with hepatocellular carcinoma who had T cells infiltrating their tumors had a better chance of surviving the disease, as shown by the survival study. The genes Helicase With Zinc Finger (HELZ), Granzyme A (GZMA), Solute Carrier Family 2 Member 2 (SLC2A2), and Janus Kinase 3 (JAK3) are four T cell marker genes accounted for in the TCMS model. Patients with hepatocellular carcinoma may be divided into high- and low-risk categories based on their TCMS scores. In a multivariate analysis of data from The Cancer Genome Atlas validation cohort, the TCMS risk score remained a significant determinant in overall survival. High levels of CD8+ T cell, and CD4+ T cell infiltration were also substantially linked with elevated expression of HELZ, GZMA, and JAK3.

    Conclusions: Successfully constructing the T cell marker genes profile with strong predictive function, we also presented a unique perspective on T cell infiltration in the tumor microenvironment, which may give guidelines for clinical application in Hepatocellular carcinoma immunotherapy.

  • Article
    Marotta Francesco, Zerbinati Nicola, Lorenzetti Aldo, Ayala Antonio, Barbagallo Mario, Munoz Mario, Rasulova Saida, Osato Maki
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1311-1319. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.141
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    Background: A specific fermented papaya preparation (ORI-FPP®), has been well established with non clinical and clinical validation in modulating redox and immune systems as well as mitochondrial efficiency. In addition, recent data from the Italian NIH (National Institute of Health) have shown that this compound was able to increase telomeres length and telomerase activity in an aged mouse model.

    Objective: The purpose of the study was to test the clinical effect of ORI-FPP® in healthy middle-aged/elderly subjects in terms of telomere dynamics and aging-related miRNAs (micro ribonucleic acids), as compared to an antioxidant formulation.

    Materials: The study population comprised 107 healthy non smoker middle-aged/elderly subjects (58 women and 49 men, mean age 56.6 ± 13.8 years, age range 44–74 years) free from medications and with a mean body mass index (BMI) of 24.7 ± 2.6. Subjects were double-blinded and randomly allocated to 2 groups: (A) ORI-FPP® 4.5 g plus 1 cp of cellulose and (B) flavoured sugar 4.5 g plus 1 cp containing a mix of antioxidants. Leucocyte telomere length (TL), gene expression related to telomere maintenance genes (TERT (telomerase reverse transcriptase) and Wrap53) and telomerase activity (TRAP) were assessed by quantitative reverse transcriptase-polymerase chain reaction after both nutraceutical interventions. This was also associated with gene expression evaluation of: SOD (superoxide dismutase), CAT (catalase), GPx1 (glutathione peroxidase-1) and hOGG1 (human 8-oxoguanine DNA glycosylase 1) as well as miRNA-146a and miRNA-181a. Dietary and psychological (10-item Cohen Perceived Stress Scale) questionnaires were administered at the start and throughout the two-year study.

    Results: TL was unaffected by treatments but a significant TL increase was observed at the end of the study in the 60–74 years old group treated with FPP®. Gene expression of TERT and WRAP53 showed a significant upregulation (168% and 57%, respectively) in group A as compared with group B starting from the 6th month observation (p < 0.01 vs group B), together with TRAP (p < 0.05 vs group B). CAT, SOD1 and GPx1 were comparably upregulated by both treatments. However, only FPP® upregulated hOGG1, miRNA-146a and miRNA-181a. TERT and WRAP53 gene expressions were significantly correlated to GPx, hOGG1, miRNA-146a and miRNA-181a gene expression.

    Conclusions: These data suggest that ORI-FPP®, unlike the antioxidant control formulation, could significantly benefit TL dynamics. This phenomenon seemed correlated to a concomitant antioxidant and, namely, DNA (deoxyribonucleic acid)-protecting genes upregulation and aging-related miRNAs.

  • Article
    Junjun Cha, Shipan Li, Jidong Sui
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1321-1329. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.142
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    Objective: To evaluate the correlation between the lymphocyte-to-monocyte ratio (LMR) and overall survival (OS) in patients with osteosarcoma.

    Methods: Eligible articles were selected from PubMed, Embase, the Cochrane Library, Web of Science, Wanfang Data, China National Knowledge Infrastructure, and the China Science and Technology journal databases from inception to September 8, 2022. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the correlation between LMR and OS in osteosarcoma. Subgroup, sensitivity, and publication bias analyses were performed.

    Results: Seven studies involving 1013 patients were extracted. LMR and OS of osteosarcoma showed a significant negative correlation (HR = 0.55; 95% CI: 0.44 to 0.69; p < 0.001). Subgroup analyses showed that the results of the following groups were consistent with the merged meta-analysis results: China, Turkey, with or without a multivariate analysis, high or moderate quality assessment, male sex ≥50% or <50%, follow-up time ≤24 or <24 months, surgery, and surgery or chemotherapy (all p for subgroup effects <0.05). The sensitivity analysis showed that the combined results were stable. No significant publication bias was observed in the included studies.

    Conclusions: Our results indicated that increased LMR was significantly associated with decreased OS in patients with osteosarcoma. These findings may contribute to the prognostic evaluation and development of immunotherapy strategies for osteosarcoma.

  • Article
    Ying Yang, Dapeng Li, Meng Shen, Yan Wu, Caihua Xu, Mengyao Wu, Kai Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1331-1340. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.143
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    Background: Advanced gastric cancer (AGC) patients may benefit from programmed cell death protein 1 (PD-1) inhibitors, but this is not the case for everyone. Some patients need a predicting model to assess immunotherapy efficacy.

    Methods: This is a retrospective study that analyzes 12 biomarkers of 70 AGC patients receiving PD-1 inhibitors in combination with taxane-based chemotherapy to construct a prognostic index (PI) equation to assess the associations between biomarkers and outcomes alongside with the value of the prognostic risk prediction model in patient prognostication. The biomarkers are carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), CA153, CA199, high-sensitivity C-reactive protein (hs-CRP), eosinophils, neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), albumin/globulin (A/G) ratio, prognostic nutritional index (PNI), lactate dehydrogenase (LDH), creatine kinase (CK).

    Results: Baseline low CA153 and NLR as well as high BMI and CK, together with critical eosinophilic rise of 0.01 × 109/L and an early expansion in BMI after 2 rounds of therapy might be valuable prognostic biomarkers of PFS in AGC patients. The PI equation is ∑βixi = 0.778 X1 + 0.726 X2 – 0.717 X3 – 0.682 X4, where X1 represents baseline CA153, and the value is 1 for CA153 ≥13.35 U/mL and 0 for CA153 <13.35 U/mL; X2 represents baseline NLR and is 1 for NLR ≥3.08 and 0 for NLR <3.08; X3 represents baseline BMI and is 1 for BMI ≥21.3 kg/m2 and 0 for BMI <21.3 kg/m2; X4 represents baseline CK and is 1 for CK ≥60.3 U/L and 0 for CK <60.3 U/L. The difference in survival rate between two prognostic risk groups based on the PI was significant (p < 0.001).

    Conclusions: The PI shown in this study can forecast the prognosis of AGC patients using immunotherapy. Additionally, the PI can be used to guide the follow-up treatment and provide reference for the formulation of more acceptable therapeutic regimes.

  • Article
    Xuyu Bian, Jiajia Wang, Wei Chen, Mengdan Xu, Caihua Xu, Mengyao Wu, Min Tao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1341-1348. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.144
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    Background: Programmed death ligand-1 (PD-L1) status in tumor pathology is a key factor that predicts the response to immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients. Given that not every patient has access to the PD-L1 level test, it is imperative to identify peripheral blood indicators that are correlated with PD-L1.

    Methods: The discovery cohort comprised 198 patients diagnosed with adenocarcinoma NSCLC. A retrospective analysis was conducted to investigate the value of systemic inflammation and tumor proliferation markers at baseline to reflect the level of PD-L1 expression, and the correlations between these baseline biomarkers and treatment outcomes were assessed.

    Results: PD-L1 ≥50% was significantly correlated with worse overall survival (OS) in advanced adenocarcinoma NSCLC patients not receiving immunotherapy (p = 0.044). Nonetheless, PD-L1 was not a statistically significant prognostic indicator in patients treated with immunotherapy. C-reactive protein (CRP) levels were correlated with PD-L1 expression (r = 0.226, p = 0.001), while pretreatment CRP ≥5.78 mg/L emerged as an independent predictor of poor OS (HR = 1.65, 95% CI: 1.096–2.489, p = 0.017). Moreover, Ki-67 expression level was significantly correlated with PD-L1 level (r = 0.383, p < 0.0001), and Ki-67 ≥30% was validated as a predictor of an elevated progression risk (HR = 1.81, 95% CI: 1.200–2.720, p = 0.005). Interestingly, pretreatment CRP levels were also weakly correlated with Ki-67 expression level in the whole cohort (r = 0.174, p = 0.014).

    Conclusions: CRP and Ki-67 expression are strong indicators for PD-L1 expression and offer potential predictive value for the survival of adenocarcinoma NSCLC patients.

  • Article
    Lili Jiang, Zhe Peng, Yuhui Deng, Peiyu Chen, Bingwei Yu, Miaosen Guo, Jinping Huang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1349-1358. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.145
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    Background: Neuropathic pain (NP) is a chronic disease; Patients with NP most commonly seek treatment for primary or secondary injury of the peripheral or central nervous system. The complex pathophysiology of NP is not yet fully elucidated, which contributes to underassessment and undertreatment.

    Methods: To analyse and study molecular relationships in the spinal cord in peripheral nerve induced neuropathic pain, we used SNI-induced neuropathic pain and Ribonucleic Acid (RNA) sequencing to analyse differ entially expressed genes (DEGs). We established an SNI (shared nerve injury) model and used third-generation transcriptome sequencing technology to analyse messenger Ribonucleic Acid (mRNA) expression in mouse SDH (spinal dorsal horn) tissue and obtained 325 differentially expressed genes. The differentially expressed genes were further analysed by bioinformatics analysis. A protein-protein interaction (PPI) network was constructed based on the STRING database, and Cytoscape software was used for visualization. We used the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for DEGs to perform a Gene Ontology (GO) analysis. Real-time PCR (Polymerase Chain Reaction) was performed to verify the results.

    Results: Atf3, Sprr1a, Anxa10, Ccl7, Ccl2, Lck, and Timp1 as well as the NF-κB TNF (Tumor Necrosis Factor) and MAPK (mitogen-activated protein kinase) signalling pathways, were implicated in SNI-induced neuropathicpain.

    Conclusions: These findings further deepen the understanding of NP mechanisms and therapeutic targets.

  • Article
    Ying Zhang, Weimin Jiang, Qinglong Yang, Xiao Yu, Chen Cui, Xiangyang He
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1359-1367. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.146
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    Objective: To understand the relationship between changes of dominant intestinal flora and the occurrence of colorectal cancer (CRC) by analyzing the stool in normal people and CRC patients, and microbial diversity of cancerous tissues and para-cancerous tissues in patients with CRC.

    Methods: Stool samples from 44 patients with CRC and 51 healthy adults were collected. The bacteria 16s rDNA were amplified by polymerase chain reaction. The variable regions of 16s rDNA V3–V5 were sequenced. Diversity calculation was performed on the species information to compare the differences of species information among different samples.

    Results: Chao1 and Shannon index of stool in normal people were lower than those of CRC patients. Firmicutes, Fusobacteria, Synergistetes, Clostridia, Fusobacteriia, Erysipelotrichia, Lachnospiraceae, Ruminococcaceae, Lachnoclostridium, Escherichia and Faecalibaculum in stool sample of CRC patients were higher, while Bacteroidetes, Bacteroidia, Bacteroidaceae, Bacteroides, and Parabacteroides were lower than healthy people. No significant difference in Chao1 or Shannon index between cancerous tissues and para-cancerous tissues in CRC patients. Flavobacteriia, Flavobacteriaceae, Nevskia, Chryseobacterium, and Anaerofustis was lower, yet Xanthomonaaceae was higher in CRC tissues than that of para-cancerous tissues.

    Conclusions: The complexity of stool in CRC patients is relatively high. There are abundant differences in phyla, class, family, and genus, with no significant difference in microbial diversity between CRC tissues and para-cancerous tissues, except for only a few species.

  • Article
    Yahong Xue, Fei Liu, Shaohua Huangfu, Yunlin Jiang, Xiaofeng Wang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1369-1378. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.147
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    Background: Electroacupuncture (EA) treatment can alleviate chronic neuropathic pain, like visceral pain, but the underlying mechanism remains unclear.

    Methods: Herein, rats were intracolonically injected with capsaicin to create a visceral (rectal) pain model. Then rats were treated with EA. The number of visceral pain-related behaviors, along with the mechanical pain thresholds of the rats’ tail, metapedes and abdomen, were recorded. Meanwhile, the pathology of rectal tissue was observed by hematoxylin-eosin staining. The expressions of inflammatory factors (interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF-α)) and glial fibrillary acidic protein (GFAP) in the rat spinal cord or serum were assessed using enzyme-linked immunosorbent assay or Western blot. Likewise, the expression level of oxycocin-42 (OX42), GFAP, transient receptor potential vanilloid 1 (TRPV1), P2X4 receptor (P2X4R) and mitogen-activated protein kinase (MAPK) pathway-related proteins were determined by immunofluorescence or Western blot in the rats’ spinal cord.

    Results: The increased visceral behavioral pain, mechanical pain threshold, secretion of inflammatory factors, edema of rectal mucosa and activation of spinal glial cells induced by capsaicin were all reversed by EA treatment. Additionally, the upregulation of TRPV1 and P2X4R as well as the activation of the MAPK pathway caused by capsaicin was offset by EA treatment.

    Conclusions: EA treatment ameliorates rats’ rectal visceral pain by repressing TRPV1 and P2X4R expression levels as well as blocking MAPK pathway.

  • Article
    Xingmei Huang, Lei Zhang, Hongxia Li, Lianhua Han, Xiaobin Yu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1379-1385. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.148
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    Background: Adverse cardiac remodelling is common after acute myocardial infarction (AMI), which is closely related to heart failure and poor prognosis. Understanding the mechanism and early prediction of adverse cardiac remodelling may be beneficial to AMI patients. This study examined the clinical role of micro ribonucleic acid 16 (microRNA-16, miR-16) in cardiac remodelling after AMI.

    Methods: The expression changes of miR-16 in response to AMI were determined in vitro, and the correlation between miR-16 expression levels and clinical features was analysed. The receiver operating curve (ROC) of miR-16, cardiac troponin I (cTnI), and N-terminal pro-B-type natriuretic peptide (N-pro BNP) were plotted to predict their association with cardiac remodelling.

    Results: The expression level of miR-16 was significantly upregulated in response to AMI in vitro. The expression of miR-16 was positively correlated with N-pro BNP, left atrial diameter (LAD), interventricular septal thickness at diastole (IVSd), left ventricular posterior wall (LVPW) at the end of diastole, and left ventricular end-diastolic dimension (LVEDD), and negatively correlated with ejection fraction (EF). The areas under the ROC curve (AUC) of miR-16, troponin, and N-pro BNP in predicting cardiac remodelling were 0.81 (p < 0.001), 0.63 (p < 0.05), and 0.87 (p < 0.001), respectively.

    Conclusions: The results suggested that the miR-16 upregulation in AMI patients was a part of cardiac remodelling mechanism.

  • Article
    Zhucheng Yin, Hongli Xu, Yanli Nie, Ping Lu, Yifei Ma, Xin Liang, Lingyi Xiong, Xiangchen Zhang, Shaozhong Wei, Xinjun Liang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1387-1396. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.149
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    Background: Non-small cell lung cancer (NSCLC) is the most frequent cause of malignancy-associated mortality worldwide. Ferroptosis is involved in tumorigenesis and metastasis of various cancers. Research showed that microRNA-144-3p (miR-144-3p) has regulatory impacts in NSCLC. However, the mechanism of this regulation is still unknown.

    Methods: Realtime quantitative polymerase chain reaction (RT-PCR) was applied to examine the level of miR-144-3p in NSCLC cells. MiR-144-3p overexpression plasmid was designed and constructed. Cell Counting Kit-8 (CCK-8) was conducted to assess the cell cytotoxicity. The malondialdehyde (MDA), reactive oxygen species (ROS), extracellular iron contents and glutathione (GSH) levels were estimated through enzyme-linked immunosorbent assay (ELISA) and flow cytometry. RNA (ribonucleic acid) pulldown and luciferase reporter assays were applied to assess the interaction between miR-144-3p and solute carrier family 7 member 11 (SLC7A11).

    Results: The study showed down-regulation of miR-144-3p in NSCLC clinical tissues and cells. MiR-144-3p overexpression significantly enhanced cytotoxicity induced by Erastin in NCI-H23 and NCI-H1650 cells. Further studies demonstrated that miR-144-3p overexpression accelerated the MDA, ROS and extracellular iron contents while inhibited GSH level in NCI-H23 cells treated with Erastin. Moreover, the luciferase reporter and RNA pulldown assay unveiled that SLC7A11 was a downstream target of miR-144-3p. Overexpression of SLC7A11 effectively reversed lipid peroxidation and cell cytotoxicity induced by miR-144-3p overexpression.

    Conclusions: To summarize, this study provided evidences on the functions and mechanism of ferroptosis activated by miR-144-3p and revealed that miR-144-3p might be a novel potential application for NSCLC patients.

  • Article
    Congying Zhu, Lingyang Chen, Nanjin Chen, Yongqing Ye, Danjiang Lin
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1397-1407. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.150
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    Background: Postoperative cognitive dysfunction (POCD) is an adverse event in cognitive behavior after surgery and anesthesia. Dexmedetomidine (Dex) is a central sympathetic drug that can alleviate the process of POCD by reducing the inflammatory response. However, the underlying mechanism of Dex on POCD need be further clarification.

    Methods: The left liver lobules of POCD rats were surgically removed to establish a model group. The Morris water maze test was used to assess the behavior of healthy Sprague Dawley (SD) rats (male, 7–8 months old) and evaluate their cognitive abilities. All the rats were anesthetized and treated with an intraperitoneal injection of 2 mL of normal saline 30 minutes before operation and 2% pentobarbital sodium during the operation. Hematoxylin-eosin staining, TUNEL (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) staining and immunofluorescence staining were used to assess changes in hippocampal tissue structure, cell apoptosis, microglial cell production and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) expression levels, respectively. Western blot analysis of hippocampal tissue protein was used to determine the expression of NLRP3 inflammasome protein and mitophagy-related protein. An ELISA (enzyme linked immunosorbent assay) assay was used to assess changes on inflammatory factors in peripheral blood. Finally, reactive oxygen species and MDA kits were used to assess oxidative stress levels in the hippocampus.

    Results: It was found that Dex significantly ameliorated spatial learning and reference memory in POCD rats, attenuated neuronal injury and apoptosis in the hippocampus, and inhibited the production of microglial cells and the activity of the NLRP3 inflammasome. This process depends on PINK1 (PTEN induced putative kinase 1)/Parkin-mediated enhancement of mitophagy and a reduction of mitochondrial oxidative stress.

    Conclusions: Dex may promote mitochondrial autophagy by enhancing the expression of mitophagy-related protein. Dex inhibited the generation of reactive oxygen species (ROS) and the activation of the NLRP3 inflammasome what significantly amelio-rating postoperative cognitive dysfunction.

  • Article
    Jiahua Zhang, Ziman Fu, Weiwei Jiang, Yingying Zhang, Yiting Wang, Chunjian Shan
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1409-1418. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.151
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    Background: Breast milk jaundice (BMJ) is prevalent in breastfed newborns. Regarding the relationship between breastfeeding and BMJ, researchers have focused on certain components in breast milk. Peptides, low-molecular-weight fractions of proteins, have been identified more than 300 in breast milk. Many of these peptides are bioactive substances involved in regulating physiological and pathological processes. In the present study, we aim to further characterize the peptidome of BMJ and healthy neonates by LC-MS/MS (Liquid chromatography tandem mass spectrometry) analysis and attempt to quantify whether there are differences in breast milk peptide expression between the two groups of neonates to provide a basis for investigating the pathogenesis of BMJ.

    Methods: Six mother-and-child dyads were recruited into our study. Three newborns were diagnosed with BMJ, and the remaining were healthy. LC-MS/MS analysis was adopted to access the breast milk peptide profile. Gene Ontology (GO) analysis was applied to predict possible functions of the differentially expressed peptides.

    Results: After removing the interference of other macromolecular proteins, 245 peptides were identified, with 30 differentially expressed peptides, including 11 upregulated and 19 downregulated peptides. GO analysis demonstrated that the possible functions of the differentially expressed peptides were closely relevant to BMJ pathogenesis.

    Conclusions: This study implied that changes in the breast milk peptide profile may be related to BMJ development, which may offer new insight for exploring the formation of BMJ.

  • Article
    Kaibo ZHANG, Feng LIANG, Majjid A QARIA, Haihe WANG, Monan LIN, Fengmin ZHANG
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1419-1426. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.152
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    Background: The joint erosion occurs due to the classically activated macrophages (M1) that mainly secrete pro-inflammatory cytokines. Existing research results show the significant efficacy of LED (light emitting diode) in promoting cell proliferation, relieving oxidative stress, and inhibiting inflammatory factors in macrophage-like cells.

    Methods: In this study, we performed transcriptomic analysis of the control group (Lipopolysaccharide (LPS)-treated M0 cell and M1 cell) and the experimental group, to find the role of 630 nm red LED irradiation on macrophages and their inflammatory response. To investigate the molecular mechanisms that underline the LED light radiation efficacy in the treatment of hyperimmune response of macrophages, we employed efficient molecular techniques such as western blot and qRT-PCR (Real-Time Quantitative Reverse Transcription PCR) analysis.

    Results: These results showed that the 630 nm red LED irradiation, reduced the inflammatory response in macrophage-like cells after inducing the inflammatory response with LPS by suppressing TNF-α (Tumor necrosis factor α), IL-1β (interleukin-1 β), IL-6 (Interleukin-6) and CCL8 (Chemokine (C-C motif) ligand 8). The 630 nm red LED irradiation reduced the expression of NF-κB (nuclear factor kappa B) p65 protein and reduced the cell stress of macrophage-like cells after treatment with LPS. Moreover, 630 nm red LED light suppressed the illicit of PLEKHG5 (Pleckstrin Homology and Rho GEF Domain Containing G5) in macrophage-like cells induced by LPS treatment and subsequently, the activation of the RhoA exchange factor and NF-κB signaling pathway.

    Conclusions: This study demonstrated that red LED may inhibit the hyperimmune response in macrophages via inhibiting the RhoA signaling pathway via PLEKHG5 and subsequently suppresses the illicit of proinflammatory cytokines. These findings showed that red LED light irradiation could be used to alleviate the macrophage’s immune response in RA (rheumatoid arthritis) patients.

  • Article
    Xiao-Bo Mao, Bo Yue, Yu Han, Xiao-Dong Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1427-1437. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.153
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    Background: Cisplatin-induced cochlear damage causes permanent hearing loss, which can hamper social communication and daily lives. Upregulation of gene regenerating islet-derived protein 3-beta (Reg3b) is reported to have a protective role against damage to the organ of Corti and hearing loss. The aim of this study was to elucidate the role of Reg3β in cisplatin-induced cochlear damage, both in vitro and in vivo.

    Method: Sprague–Dawley rats were treated with an intraperitoneal injection of cisplatin (2 mg/kg a day), to generate a cochlear damage model. The hearing thresholds of these rats were measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests. The cochleae of these rats were harvested and cultured in vitro. Adeno-associated virus serotype 1 (AAV1) vectors were employed, to overexpress or knock down Reg3b in the organ of Corti both in vitro and in vivo. Changes in cochlear morphology were checked for, using hematoxylin and eosin staining and immunohistochemistry. A Terminal Deoxynucleotidyl Transferase Dutp Nick End Labeling (TUNEL) assay was performed, to evaluate hair cell apoptosis. The levels of apoptosis-related proteins were measured by western blotting.

    Results: In vitro, Reg3b overexpression reduced cisplatin-induced apoptosis, the level of cleaved caspase-3 and cleaved caspase-9, and the Bax/Bcl-2 ratio in cultured organs of Corti, whereas Reg3b knockdown elicited the opposite effects. In vivo, Reg3b over-expression protected rats from cisplatin-induced hearing damage, by reducing ABR threshold shifts and increasing the DPOAE amplitude, whereas Reg3b knockdown enhanced cisplatin-induced injury. Furthermore, Reg3b overexpression ameliorated the cisplatin-induced necroptotic changes and loss of spiral ganglion neurons in the organ of Corti, which was accompanied by a reduction in cleavage of caspase-3 and caspase-9 and the Bax/Bcl-2 ratio. In contrast, the level of apoptotic proteins was increased when Reg3b was inhibited.

    Conclusions: Reg3β can alleviate cisplatin-induced apoptosis in the organ of Corti both in vitro and in vivo. Targeting Reg3β may be a promising therapy for cisplatin-induced hearing loss.

  • Article
    Zhongying Ding, Yan Lu, Haiyan Zhang, Ke Hua, Guosong Shen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1439-1449. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.154
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    Background and Purpose: To study the pharmacodynamic effect and potential mechanism of Caulis Spatholobi on pregnancy-induced hypertension (PIH), providing an experimental basis for the clinical application of Caulis Spatholobi.

    Methods: Serum samples of 30 normal pregnant women and 30 PIH pregnant women were collected to detect hepcidin mRNA (messager ribonucleic acid) level and serum iron content. Then, a PIH mice model was established by the intraperitoneal injection of homocysteine, and different doses of Caulis Spatholobi alcohol extract were administered by gavage. The systolic blood pressure (SBP), angiotensin, vasodilation converting enzyme (VCE) and tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-10, reactive oxygen species (ROS), nitric oxide (NO) and endothelin (ET) levels and superoxide dismutase (SOD) activity were determined by the ELISA (enzyme-linked immunosorbent) assay. The hepcidin mRNA levels were measured through RT-qPCR (quantitative reverse transcription PCR) analysis. The divalent metal ion transporter 1 (DMT1) and ferroportin 1 (FPN1) expression were assessed by immunofluorescence analysis, and serum iron content was measured with the full-automatic deepening analyzer.

    Results: Compared with normal pregnant women, the level of hepcidin mRNA in PIH women increased significantly, but serum iron content decreased (p < 0.05). The optimal dosage of Caulis Spatholobi was 15 g/kg. Compared with the control group, SBP, angiotensin, VCE, urinary protein, hepcidin mRNA, TNF-α, IL-2, IL-6, ROS, and ET in the PIH group increased significantly, accompanied by a significant decrease in the levels of DMT1, FPN1, serum iron, IL-10, SOD, and NO (p < 0.05).

    Conclusions: Caulis Spatholobi improved the pathological symptoms of PIH mice by regulating the expression of hepcidin and iron homeostasis.

  • Article
    Jiye Liu, Can Xu, Jiahe Wang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1451-1465. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.155
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    Background: Single-stranded DNA-binding protein 1 (SSBP1) is pivotal to mitochondrial DNA (deoxyribonucleic acid) replication, reintegration, and reconstruction. However, precisely how SSBP1 contributes to lung adenocarcinoma (LUAD) remains unclear.

    Methods: In this bioinformatics study, raw datasets were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Genotype-Tissue Expression (GTEx) project. SSBP1 expression was investigated using TCGA, GEO, GTEx, cBioPortal, TIMER2.0, and Gene Expression Profiling Interactive Analysis databases. SSBP1 expression in clinical specimens was determined using fluorescence-based reverse-transcription quantitative polymerase chain reaction and immuno-histochemical experiment.

    Results: As LUAD progressed, SSBP1 was drastically upregulated and closely associated with disease progression. To assess the prognostic and diagnostic value of SSBP1, the Kaplan-Meier plot, Cox proportional hazard model, and receiver operating characteristic curve methods were employed. SSBP1 reliably and accurately predicted and diagnosed LUAD. SSBP1 overexpression correlated with poor overall survivability, as well as T, N, and pathological stages. Simultaneously, based on gene set enrichment analyses, SSBP1-related genes were closely related to the mitochondrial translation pathway. Furthermore, SSBP1 expression positively correlated with the infiltration degrees of aDC (activated dendritic cells), Th2 (T helper2 cells), and Tgd (gammadelta T cells); By contrast, negative correlations were observed with the infiltration degrees of CD56 bright cells, mastocytes, macrophages, iDC (interstitial dendritic cells), eosinophils, DC (dendritic cells), CD8 T cells, B cells, Tcm (central memory T cells), Tem (effective memory cells), TFH (T follicular helper cells), Th17 cells (T helper 17 cells), pDC (plasmacytoid dendritic cells), and NK cells (natural killer cells).

    Conclusions: In summary, SSBP1 may play a central role in mitochondrial translation and can be regarded as a molecular target for predicting LUAD prognosis.

  • Article
    Linxue Wang, Wei Luo
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1467-1477. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.156
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    Background: Tripterygium glycosides (TG) is a bioactive component of Tripterygium wilfordii. Protection against ischemia/reperfusion (I/R) injuries has been shown in animal models. However, the specific mechanism of TG in alleviating intestinal ischemia/reperfusion injury is still unclear.

    Methods: To assess the impact of TG on nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) levels was evaluated via the pathology, pro-inflammatory and oxidative stress level and enteric epithelial cell apoptosis in enteric I/R injured rats. We used western blot (WB) analysis, immunofluorescence staining and immunohistochemical staining. After this, a model of intestinal injury in vitro was established. IEC-6 cells were induced by hypoxia/reoxygenation (H/R). The silence of Nrf2 and HO-1 was assessed via small interfering ribonucleic acid (siRNA) (si-Nrf2). Cell viability, oxidative stress, pro-inflammatory levels, and cell apoptosis were utilized to investigate whether protection via TG depended on Nrf2/HO-1.

    Results: The declined levels of Nrf2 and HO-1 induced via I/R detriment in enteric tissue was reversed via TG remedy was discovered. In the meantime, TG protected against enteric morphologic detriment, inflammatory reaction and oxidative stress, and cell apoptosis induced via I/R. Furthermore, transfection with si-Nrf2 memorably abolished the whole protection of TG on I/R-induced detriment.

    Conclusions: Hence, we concluded that through the Nrf2/HO-1 pathway, TG restrained enteric I/R detriment. Our study provides a new therapeutic drug for treating enteric I/R detriment.

  • Article
    Guangqing Fu, Wei Chen, Xiang Zeng, Xiaohui Luo
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1479-1487. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.157
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    Background: Several studies have shown that microRNAs (miRNAs), such as miR-17-5p, play critical roles in tumor cell radiosensitivity. However, its mechanism in radiosensitivity regulation in prostate cancer (PCa) is still unclear.

    Methods: PC3 cell lines were irradiated to screen out radiation-resistant PC3-R (Radioresistant PC3) cells. After irradiation at different doses, the expression levels of miR-17-5p and methyl CpG-binding protein 2 (MeCP2) in PC3 and PC3-R cells were detected by quantitative RT-PCR and Western blot analyses. MiR-17-5p mimic and MeCP2 plasmids and their negative control plasmids were constructed, and introduced into cells by liposome transfection. The colony survival and apoptosis rates of PC3-R cells were determined clonogenic survival assay and DAPI (4,6-diamino-2-phenyl indole) staining. Annexin V-PI (annexin V and Propidium lodide) staining and Western blot analysis were used to detect PC3-R cell apoptosis and expression of the apoptosis-related proteins Bax, Bcl-2 (B-cell CLL/lymphoma 2) and cleaved caspase3. Wounding healing and Matrigel transwell assays were performed the metastasis and invasion and EMT (Epithelial-Mesenchymal Transition) bio-marker protein expression was evaluated by Western blot analysis.

    Results: First, we assessed the radiation-resistant in PC3-R (Radioresistant PC3) cells from PC3 cell lines at different radiation doses. It was observed that miR-17-5p level was reduced and Methyl-CpG-binding protein 2 (MeCP2) level was enhanced in PC3-R cells. Then, it was identified that miR-17-5p enhance radiation resistance of PCa by targeting the 3′UTR (3′-Untranslated region) of MeCP2 and down-regulating MeCP2 level. Moreover, the clonogenic survival assay and DAPI (4,6-diamino-2-phenyl indole) staining suggested that over-expressed miR-17-5p impaired cell colony survival and promoted apoptosis of PC3-R cells. The annexin V-PI (annexin V and Propidium lodide) staining and Western blot assays verified that over-expressed miR-17-5p enhanced Bax, cleaved-caspase 3 level and restrained Bcl-2 (B-cell CLL/lymphoma 2) level. Over-expressed miR-17-5p reduced cell migration, invasion, and EMT (Epithelial-Mesenchymal Transition). Finally, MeCP2 counteracted the effects and functions of miR-17-5p overexpression.

    Conclusions: These findigns suggest that miR-17-5p has a regulatory effect on MeCP2, enhancing the radio-resistance of PCa cells by targeting MeCP2. Thus, miR-17-5p is implicated as a potential regulator of radiation resistance in PCa cells.

  • Article
    Qiaorui Yang, Zhenliang Fan
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1489-1499. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.158
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    Background: Er Chen decoction (ECD), a time-honored herbal mixture, has been broadly used in gynecological diseases, including polycystic ovary syndrome (PCOS). PCOS is a common reproductive disorder characterized by endocrine and metabolic dysfunction that has an increasing prevalence rate. However, the bioactive components in ECD and their underlying mechanisms for treating PCOS remain unknown. This study aimed to predict potential mechanisms of ECD in treating PCOS, through network pharmacology strategy.

    Methods: The bioactive compounds of ECD and therapeutic targets were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and potential targets of PCOS were acquired from Online Mendelian Inheritance in Man (OMIM) and Genecards database. Afterward, the ECD-Ingredient-PCOS-target regulation network, topology network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were performed to predict the core targets and pathways of ECD against PCOS.

    Results: A total of 156 potential targets were matched with 116 related bioactive ingredients and regulation network revealed their interactions. Network topology analysis showed the top 10 core proteins in ECD against PCOS to be TP53 (Tumor Protein P53), CUL3 (Cullin 3), YWHAZ (Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta), HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1), MCM2 (Minichromosome Maintenance Complex Component 2), NPM1 (Nucleophosmin 1), VCP (Valosin Containing Protein), CUL1 (Cullin 1), NTRK1 (Neurotrophic Receptor Tyrosine Kinase 1), COPS5 (COP9 Signalosome Subunit 5). GO analyses identified 1986 items of biological progress (BP), 58 items of cellular components (CC) and 186 items of molecular function (MF). KEGG functional enrichment analysis identified 167 signaling pathways, such as IL-17 (Interleukin-17) signaling pathway, TNF (Tumor Necrosis Factor) signaling pathway. ECD-gene-pathway network revealed that target genes MAPK1, CASP3, BAX, BCL2 and others were involved in numerous signaling pathways and every pathway was abundantly enriched by multiple genes.

    Conclusions: This preliminary study explored the potential mechanisms of ECD in treating PCOS, suggesting that the bioactive components of ECD, such as quercetin, kaempferol, naringenin and β-sitosterol, might treat PCOS by regulating IL-17, TNF and other signaling pathways as well as MAPK1, CASP3, BAX, BCL2 and other target genes. These results supplied novel comprehension of pharmacological mechanisms of ECD in treating PCOS in multiple dimensions.

  • Article
    Limiao Lin, Bihong Chen, Yanqing Li
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1501-1509. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.159
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    Background: Colorectal cancer (CRC) is a prevalent malignancy. Studies reported that microRNAs (miRNAs) are critical for CRC development. Thus, microRNA-199a-3p (miR-199a-3p)’s mechanism of action in CRC cells was investigated in this paper.

    Methods: In hypoxic CRC cells, the corresponding gene miR-199a-3p and its target genes were searched for by sequencing, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. CRC cell viability was detected via the Cell Counting Kit-8 (CCK-8) assay. CRC cell apoptosis was identified with a flow cytometry assay. Transwell assay was carried out to further assess CRC cells’ migrative and invasive abilities. Quantitative reverse transcription PCR (qRT-PCR) was employed to examine miR-199a-3p and fibronectin1 (FN1) mRNA expression. The proteins of FN1, E-cadherin, B-catenin, N-cadherin, and Vimentin were evaluated using western blot. The functional association of miR-199a-3p with its target genes was validated via luciferase reporter assay.

    Results: In hypoxia CRC cells, miR-199a-3p was significantly diminished. Overexpressed miR-199a-3p significantly inhibited HCT116 CRC cells’ proliferative, migrative, and invasive abilities and promote HCT116 apoptosis. Inhibiting miR-199a-3p reversed its effect. Additionally, overexpressed miR-199a-3p or FN1 knockdown significantly increased epithelial-mesenchymal transition (EMT) marker protein E-cadherin and B-catenin while decreasing EMT marker protein N-cadherin and Vimentin. FN1 overexpression reversed the effect.

    Conclusions: In CRC, miR-199a-3p is reduced, and it induces CRC cells’ proliferative, migrative, and invasive processes and suppresses their apoptosis via upregulation of FN1. The miR-199a-3p may function as a novel potential target for treating CRC.

  • Article
    Xue-Na Wu, Zhen-Dong Fu, Ying Cao, De-Sheng Cai, Jun-Lan Xu, Qi Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1511-1518. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.160
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    Background: Due to differences in the perineal and fetal conditions of pregnant women, there is no international standard or guideline on the reasonable use of episiotomy that aims to minimize its use.

    Objectives: This study aimed to investigate the factors affecting decision-making regarding episiotomy and to establish a logistic regression prediction model.

    Methods: A total of 224 women who underwent vaginal delivery at the Department of Gynecology and Obstetrics of the First Affiliated Hospital of Nanchang University from May to October of 2020 were selected as subjects for this study. Basing on the and analyzing the correlation between the clinical features and episiotomy with univariate analysis, eleven influencing factors related to episiotomy were identified in the literature; the midwives participating in this study received uniform training and collected data. The risk score prediction model was established using logistic regression analysis, and the predictive effect of the model was tested by plotting the receiver operating characteristic (ROC) curve.

    Results: The area under the ROC curve (AUC) of the model was 0.939; When the optimal cut-off value was 0.719, the sensitivity was 0.773 and the specificity was 0.946. The parameter with the lowest regression coefficient (perineal inflammation) was used as the reference, and the other regression coefficients were divided by this coefficient to obtain the final risk score model. The individual final risk score model = 1 × perineal inflammation + 10 × perineal edema + 17 × EFW (estimated fetal weight) + 8 × fetal biparietal diameter + 21 × maternal willingness + 12 × perineal length + 33 × perineal elasticity + 5 × perineal color + 11 × perineal injury + 27 × maternal compliance + 11 × amniotic fluid properties. When an individual’s final risk score was <232.5, natural delivery without episiotomy was relatively safe and effective. External 281 subjects participated in restrictive episiotomy to verify the the accuracy of the constructed the risk score prediction model. The accuracy of the constructed the risk prediction model in the first stage and the second stage of research was 80.80% and 82.56% respectively.

    Conclusions: The application of this model in the second stage of labor can provide an objective reference for clinical midwives to use for episiotomy decision-making.

  • Article
    Zhiyuan Zhang, Zhongbao Ruan, Guixian Song, Ruzhu Wang, Chunfang Hu, Li Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1519-1526. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.161
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    Purpose: The aim of this study was to examine therapeutic effects of Danhong injection (DHI) on coronary heart disease (CHD) and determine the mechanism of these effects.

    Methods: A total of 20 Sprague-Dawley (SD) provide in full on first mention rats divided into control, CHD, DHI-0.5 mL/kg and DHI-2 mL/kg groups with, 5 rats in each group the minimum number to carry out statistical tests is 6, the authors are advised to add more rats to each group. CHD were effected by injecting pituitrin (30 U/kg) for three consecutive days, and CHD rats were injected with 0.5 mL/kg or 2 mL/kg DHI daily. After 4-week treatment, echocardiography was performed to observe the left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic dimension (LVESD) in rats. The serum of rats was collected for measuring the levels of lipid metabolism-related indicators oxidation-related factors, myocardial injury markers and endothelial function-related indicators. Additionally, the expression of mitogen-activated protein kinase (MAPK) pathway-related proteins in the heart tissues was revealed by western blot.

    Results: There was a significant drop in LVESD and LVEDD and a significant rise in LVEF after DHI intervention for CHD rats. Besides, DHI also significantly reduced the serum level of Triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), up-regulated high-density lipoprotein cholesterol (HDL-C), and lowered the level of creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), malondialdehyde (MDA), and endothelin-1 (ET-1), and up-regulated glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) activity and the level of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) in CHD rats. Moreover, DHI significantly reduced phosphorylated-protein 38 (p-p38) and phosphorylated-c-Jun N-terminal kinase (p-JNK) protein level and inhibited the activity of MAPK pathway in the heart tissues of rats.

    Conclusions: DHI treatment showed efficacy in alleviating endothelial dysfunction and lipid peroxidation and this effect is probably achieved through MAPK pathway.

  • Article
    Hui Zhao, Peng Yan
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1527-1534. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.162
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    Aim: To study the effect and mechanisms of long intergenic non-protein coding RNA 265 (LINC00265) on osteoarthritis (OA) progression.

    Methods: Cartilage tissues from OA patients who received knee arthroplasty and from patients with traumatic amputees not suffering from OA or rheumatoid arthritis (normal) were collected and LINC00265 was evaluated by qRT-PCR (quantitative real-time polymerase chain reaction). In addition, CHON-001 cells were treated and classified into 4 groups: Control group, IL-1β (interleukin 1β) group (10 ng/mL), IL-1β + sh-NC group and IL-1β + sh-LINC00265 group. Subsequently, qRT-PCR was applied to determine LINC00265 expression, and extracellular matrix (ECM) degradation-related genes (ADAMTS-5, MMP3, COL2A1 and aggrecan). CCK-8 (cell counting kit-8) was used to study cell viability; ELISA (enzyme linked immunosorbent assay) was used to measure the levels of inflammatory cytokines IL-8 and IL-6, as well as tumor necrosis factor (TNF-α). Related kits were employed to identify reactive oxygen species (ROS) levels; Western blot was utilized for identifying MAPK/NF-κB (mitogen-activated protein kinase/nuclear factor kappa-B) pathway-related protein expression in cells.

    Results: LINC00265 was notably up-regulated in cartilage tissues of OA patients. The stimulation of IL-1β in chondrocytes could promote the expression of LINC00265 and inflammatory factors, the occurrence of ROS, and the degradation of ECM. However, the knockdown of LINC00265 reduced inflammation, cell proliferation and oxidative stress-related factor levels stimulated by IL-1β, and slowed down the progression of ECM degradation. In addition, the knockdown of LINC00265 suppressed the IL-1β-induced stimulation of the MAPK/NF-κB pathway.

    Conclusions: LINC00265 is a potential key signaling molecule for ECM degradation and IL-1β-stimulated chondrocyte inflammation.

  • Article
    Yuanwei Wang, Li Du, Xian Zhang, Ying Wang, Liwu Lu, Rui Wei, Benchi Xu, Xiaojie Hu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1535-1541. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.163
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    Background: This study investigated the correlation between the expression of asymmetric dimethylarginine (ADMA) in plasma and early neurological deterioration (END) as well as early recurrence of acute cerebral infarction (ACI).

    Methods: A total of 160 ACI cases were divided into the following five groups based on the occurrence of END and early recurrence: Group A (n = 48, had END at first admission), group B (n = 112, without END at first admission), group C (n = 32, with early recurrence 3 months after discharge), group D (n = 128, without early recurrence 3 months after discharge), group E (n = 17, patients in group A with early recurrence 3 months after discharge). Fifty healthy people during the same period were selected as controls. Participants’ blood glucose, blood pressure, hemoglobin and urine protein were measured biochemically, and ADMA levels in their plasma were measured by ELISA (enzyme linked immunosorbent assay). Further, the correlation of ADMA expression in the plasma of ACI patients with biochemical parameters, NIHSS (national institutes of health stroke scale) score, early recurrence and cerebral infarction area was performed using the Pearson’s method.

    Results: The results showed that compared with healthy people, the expression of ADMA was significantly higher in the blood of ACI patients and even higher in ACI patients with END. Logistic regression analysis indicated that ADMA level was a risk factor for END and early recurrence in ACI patients. Besides, ADMA levels were positively correlated with NIHSS score, early recurrence of ACI and cerebral infarction.

    Conclusions: These findings indicated ADMA as a potential diagnostic marker for END and early recurrence of ACI.

  • Article
    Yifen Shen, Ying Tang, Yongchun Gu, Chao Liu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1543-1554. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.164
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    Background: Wiskott-Aldrich syndrome verprolin-homologous (WAVE) 3 was shown to be an oncogene that is highly expressed in multiple tumors, and it had been reported to be involved in metastatic diseases. However, the expression profile of WAVE3 and its biological role in glioma remain unknown. The aim of the study was to uncover the effect of WAVE3 on glioma migration and metastatic disease.

    Methods: Four glioma cell lines and 90 human glioma samples were used for immunohistochemical and western blot assays in this study to evaluate the expression profile of WAVE3. The correlation between WAVE3 expression and clinicopathologic characteristics of patients with glioma and the function of WAVE3 played in regulating migration, invasion and epithelial to mesenchymal transition (EMT) in glioma cell lines were checked.

    Results: WAVE3 gene was significantly expressed in glioma tissues and four glioma cells, especially in high-grade glioma tissues and U87 cells. Patients with high WAVE3 expression exhibited shorter survival times than those with low WAVE3 expression, according to Kaplan–Meier analysis (p < 0.01). Silencing WAVE3 in U87 cells was found to prevent cell migration and invasion, whereas overexpressing WAVE3 in LN229 cells had the opposite effect. WAVE3 was shown to induce EMT and activate p38 mitogen-activated protein kinase (MAPK) signaling pathway.

    Conclusions: WAVE3 promotes glioma cells migration and invasion via EMT, and activation of MAPK/p38 signaling was involved in the underlying mechanism.

  • Article
    Pengcheng Zhang, Jie Zhou, Weiping Zhang, Kai Xu, Yongfu Zhu, Mingran Xie
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1555-1568. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.165
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    Objective: Necroptosis is closely related to tumor occurrence and metastasis, but the research on Lung Adenocarcinoma (LUAD) is unclear. We aimed to construct a model for LUAD patients’ prognosis prediction based on necroptosis-associated genes.

    Methods: We collected the Gene profiles of LUAD patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The identification of differentially expressed genes (DEGs) associated with necroptosis and the construction of the prognosis models were performed using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. The relationship between necroptosis pathways and LUAD was identified using the protein-protein interaction (PPI) network and functional enrichment analyses. Predictive and prognostic values of models were assessed using Cox proportional hazards regression. Finally, we used Quantitative verification of differential genes by Real Time Quantitative PCR (RT-qPCR) to verify the differential gene expression in A549 and normal cells.

    Results: We constructed a model including seven necroptosis-related genes (FADD, PLK1, PANX1, BIRC2, HSPA4, ID1, and HSP90AA1) for the prognosis and survival prediction of LUAD patients. Patients were stratified according to the risk score, and those with a high-risk score showed poorer outcomes when compared to low-risk patients. Functional enrichment analyses showed that the function of necroptosis in LUAD was mainly concentrated in cell mitosis, neurotransmitter transmission, and drug metabolism. Compared with other clinical factors, the prognosis model better predicted the prognosis (AUC (Area Under roc Curve) = 0.718). The model’s accuracy was confirmed in an independent verification set GSE (GEO (Gene Expression Omnibus) Series) 31210 (p < 0.0001). Finally, RT-qPCR confirmed the high expression of genes in the model in A549 cells, which was consistent with the trend of gene expression in the dataset.

    Conclusions: Our prognostic model can independently and accurately predict the prognosis of LUAD patients, which helps to clarify the link between necroptosis.

  • Article
    Rongmou Zhang, Peiwen Wang, Huafeng Zhuang, Haiming Yu, Hao Xu, Xuedong Yao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1569-1577. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.166
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    Objective: To explore the effect and mechanism of action of PIN1 (peptidylprolylcis/transisomerase, NIMA-interacting1) inhibitor juglone (Jug) on acute spinal cord injury (ASCI) in rats.

    Methods: After establishing an ASCI model in Sprague-Dawley (SD) rats, Jug was administered through intraperitoneal injection ASCI+Jug group of Jug for 4 weeks. The spinal cord glial cells were extracted and identified by immunocytofluorescence. Using hematoxylin-eosin (HE) staining, the structure of rat spinal cord was examined. Tarlov scores were used to measure lower limb function and Sirius red staining was used to observe the collagen distribution in rat spinal cord. The levels of Collagen I and Collagen III in spinal cord tissue and glial cells were measured using ELISA (Enzyme linked immunosorbent assay) and the levels of PIN1, P-LKB1/LKB1 (liver kinase B1) and P-P70S6K/P70S6K (P70 ribosomaiprotein S6 kinase) were measured using Western blotting.

    Results: Jug improved the morphology of spinal cord tissue, and attenuated the production of TGF-β1 (transforming growth factor beta 1) and collagen in SD rats after ASCI. Furthermore, Jug can reduce Collagen I and Collagen III levels, activate LKB1 and inhibit P70S6K whether in vivo or in vitro. After overexpression of PIN1 in vitro, TGF-β1-induced collagen I and III levels were further increased.

    Conclusions: PIN1 inhibitor Jug can improve spinal cord tissue morphology and reduce collagen production through the LKB1/P70S6K pathway.

  • Article
    Fang Chen, Taotao Hu, Dan Huang, Xiaoli Huang, Hongqing Liang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1579-1593. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.167
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    Background: Renal ischemia-reperfusion injury (IRI) is a critical part of acute kidney injury (AKI), which is accompanied with macrophage polarization. Roquin-1 (RC3H1)-depleted macrophages were demonstrated to aggravate hepatic IRI, but its role in AKI is still unclear. The aim of this study was to investigate the underlying mechanism of AKI mediated by RC3H1.

    Methods: A number of laboratory techniques were applied, including Enzyme linked immunosorbent assay (ELISA), flow cytometry and western blot.

    Results: After inducing AKI, macrophage M1/M2 ratio was significantly elevated and RC3H1 expression was significantly reduced. The promoter region of RC3H1 was found to be highly methylated after AKI, which was mainly modified by the methyl-transferase DNA (Cytosine-5)-Methyltransferase 3A (DNMT3a). DNMT3a was significantly upregulated in the AKI mice. Overexpression of RC3H1 suppressed the positive regulation of Jag1 (Jagged Canonical Notch Ligand 1)/Notch1 (Notch Receptor 1)/Hes1 (Hes Family BHLH Transcription Factor 1) signaling by AP2 Associated Kinase 1 (AAK1), thus relieving AKI.

    Conclusions: AKI-induced DNMT3a upregulation inhibited the expression of RC3H1 by hypermethylation. The low level of RC3H1 promoted AAK1 messenger ribonucleic acid (mRNA) accumulation, further activated Jag1/Notch1/Hes1 signaling to facilitate M1 polarization of macrophages and aggravated AKI.

  • Article
    Yong-bin Zhang, Yu-xuan Fang, Nan Xu, Long-long Tian, Tian-tian Dai, Xing-xing Min, Gui-yu Chen, Nian-xing Liu, Guo-qing Li
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1595-1603. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.168
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    Background: Osteoporosis (OP) is a systemic skeletal disease. Nowadays, still, there is a lack of effective biomarkers to estimate its treatment outcomes.

    Methods: The weighted gene co-expression network analysis (WGCNA) was used to build a weighted co-expression network to identify differentially expressed genes (DEGs). Then, least absolute shrinkage and selection operator (LASSO) logistic regression and Boruta package were used to determine the diagnostic indicators of OP. The single sample gene set enrichment analysis (ssGESA) was further performed to estimate the association between diagnostic indicators and infiltrating immune cells in OP. Biomarker-related pathway enrichment analysis was performed using Gene set variation analysis (GSVA).

    Results: Totally, 1073 genes and 17 modules were screened in this study. ProteinO-glucosyltransferase 1 (POGLUT1) and Src kinase-associated phosphoprotein 2 (SKAP2) were found to be diagnostic indicators for OP (area under curve (AUC)POGLUT 1 = 0.790, AUCSKAP2 = 0.540). POGLUT1 expression was related to OP phenotypes (bone mineral density (BMD) and menopausal, p < 0.05). In immune cell infiltration evaluation, POGLUT1 expression was significantly associated with infiltration of iDCs (immature dendritic cells, p = 0.027), Tfh (T Follicular helper cell, p = 0.001) and T cell co-inhibition (p = 0.002) in the OP. In addition, POGLUT1 was correlated with Interleukin 6 (IL6) , Janus kinase (JAK), transduction and activator of transcription 3 (STAT3) signaling, p53 pathway, Interleukin 2 (IL2) transduction and activator of transcription 5 (STAT5) signaling, bile acid metabolism and heme metabolism. Thus, it can be considered as marker for OP early identification and therapy.

    Conclusions: POGLUT1 may serve as potential diagnostic marker for OP. Compared with SKAP2, POGLUT1 showed a stronger relation with OP phenotypes what provided some insights into OP underlying mechanism.

  • Article
    Wei Wei, Wei Zou, Wei Han
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1605-1616. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.169
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    Background: Lupus nephritis (LN) is the predominant cause of death in systemic lupus erythematosus patients, for which current therapies are ineffective and often toxic. The aim of this study was to investigate the effect and related mechanisms of serine protease inhibitor B1 (Serpin B1) in LN.

    Methods: Kidney samples from LN and non-LN patients were observed pathologically and pro-inflammatory cytokines were detected in serum and urine using enzyme-linked immunosorbent assays. Subsequently, the expression of Serpin B1 was analyzed using bioinformatics analysis and further validated by western blotting. In vitro, the proliferation and apoptosis of simian virus 40-MES-13 (SV40) mouse glomerular mesangial cells and mitogen-activated protein kinase (MAPK) pathway activity were examined after the knockdown of Serpin B1. In vivo, the survival rate, inflammatory response, and histology of mice in each group were examined.

    Results: LN patients showed glomerular injury with high Serpin B1 expression (p < 0.001). Knockdown of Serpin B1 inhibited cell proliferation and extracellular regulated protein kinases activity, promoted c-Jun N-terminal kinase, P38 activity and accelerated apoptosis in lipopolysaccharide-induced SV40 cells (p < 0.001). In vivo, Serpin B1 overexpression significantly inhibited the expression of neutrophil extracellular traps, inflammatory factors, and monocyte chemoattractant protein-1. In addition, the glomerular injury was alleviated, Immunoglobin G deposition in the glomeruli was reduced.

    Conclusions: Overexpression of Serpin B1 can alleviate LN, and the MAPK pathway may play a key role in this process.

  • Article
    Zhiping Yuan, Lixia Zhang, Mingjie He, Huamei Lu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1617-1626. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.170
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    Background: Increasing evidence suggests that long non-coding RNAs (lncRNAs) play an important regulatory role in the physiopathology of tumors. Previous studies have shown that Tumor suppressor candidate 7 (TUSC7) is a suppressor lncRNA in a variety of tumors. However, the role of TUSC7 in gastric cancer (GC) remains unclear. The aim of this study is to evaluate the effect and mechanisms of TUSC7 on GC.

    Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of TUSC7, miR-130b-5p, and Protocadherin-9 (PCDH9) in GC tissues and cells. Western blot was used to detect protein expression levels of PCDH9. pcDNA3.1-TUSC7 (pc-TUSC7), miR-130b-5p mimics, miR-130b-5p inhibitors and pc-TUSC7 + si-PCDH9 were transfected to SGC-7901 cells using LipofectamineTM 2000. Cell proliferation and invasion were assessed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. Relationship of TUSC7 with miR-130b-5p or miR-130b-5p with PCDH9 were determined using Dual-luciferase reporter assays.

    Results: TUSC7 was down-regulated in GC tissues and cell lines. Over-expression of TUSC7 suppresses GC cell proliferation and invasion. The double luciferase reporter gene experiment showed that TUSC7 can target miR-130b-5p in GC and interact negatively with miR-130b-5p. It was observed that PCDH9 was a target gene of miR-130b-5p. In addition, rescue experiments have shown that TUSC7 can up-regulate PCDH9 to slow the progress of GC by targeting miR-130b-5p.

    Conclusions: TUSC7 inhibits the proliferation and invasion of GC cells through the miR-130b-5p/PCDH9 axis.

  • Article
    Tingyou Zhang, Xiaojuan Wang, Shanshan Deng, Lin Zhou, Xiaowen Sun, Ruizhan Tong, Lin Xu, Ran Li, Xiaorong Yang, Fang Chen, Ning Li
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1627-1636. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.171
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    Background: MicroRNA-301a (miR-301a) is related to tumor development, metastases, and poor prognosis in patients. Primary or acquired doxorubicin (DOX) resistance often leads to failure in breast cancer treatment. The aim of this study was to analyze the relationship between miR-301a and DOX resistance in breast cancer.

    Methods: Human breast cancer MCF-7 (human breast cancer cell line) cells stably overexpressing miR-301a were constructed by a lentivirus-mediated overexpression system. The expression of miR-301a in MCF-7 cells was detected by quantitative real-time PCR (qRT-PCR). The activity of MCF-7 cells was determined by CCK-8 (Cell Counting Kit-8) assay, and the apoptosis was analyzed by Western blotting and flow cytometry. Western blotting was used to examine the expression of phosphorylated p65 and IκB-α (inhibitor of NF-κB-α) protein. qRT-PCR and dual luciferase reporter assays were performed to verify whether miR-301a regulates NF-κB (nuclear factor kappa-B) and involves in DOX resistance in breast cancer.

    Results: DOX led to upregulation of miR-301a expression in MCF-7 cells, while miR-301a expression was significantly increased in miR-301a-overexpressed MCF-7 cells treated with DOX and dimethyl sulfoxide (DMSO). Overexpression of miR-301a impeded the inhibition of DOX on MCF-7 cell viability and promotion of apoptosis. MCF-7 cells treated with NF-κB inhibitor showed increased DOX resistance and decreased apoptosis levels upon miR-301a overexpression. Moreover, miR-301a overexpression increased phosphorylated IκB-α and p65 proteins. The mRNA (messenger RNA) level of IκB-α decreased after adding DOX.

    Conclusions: miR-301a/NF-κB pathway may be a novel target for enhancing DOX sensitivity in breast cancer patients.

  • Article
    Chenyuan Luo, Yuming Wei, Shuzhen Li, Chunjun Li, Honglai Zheng
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1637-1646. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.172
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    Background: Imperata cylindrica Beauv. var. major C. E. Hubb., a plant of Poaceae, is abundant in nature, and its rhizome has anti-inflammatory and anticancer activities.

    Aim: This study investigated the anti-inflammatory properties and signaling pathways of different solvent extracts from the rhizome of Imperata cylindrica (IMP) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages.

    Methods: Extracts with water, n-butanol, petroleum ether (PE), and ethyl acetate (EA) from the rhizome of IMP were incubated with LPS-stimulated RAW264.7 cells. CCK-8 (Cell Counting Kit-8) was used to perform in vitro cytotoxicity test to validate the concentration and reaction time of extracts. The experiment of scavenging superoxide anion free radical and DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical was applied to detect the antioxidant capacity and reducibility of different solvent extracts. RT-qPCR (real-time quantitative polymerase chain reaction) and ELISA (enzyme-linked immunosorbent assay) were applied to examine the impact of the drugs on LPS-induced IL-6 (Interleukin 6), IL-1β (Interleukin-1β), TNF-α (Tumour Necrosis Factor alpha), and iNOS (inducible nitric oxide synthase). The effectiveness of the extracts on the NF-κB (nuclear transcription factor-kappa B) and Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling pathways induced by LPS was measured using western blot.

    Results: The appropriate action time and concentration of different solvent extracts were determined by cytotoxicity test for subsequent experiments. The various extracts effectively scavenged DPPH free radicals and had good antioxidant capacity, while their performance in scavenging superoxide anion was non-specific. Different IMP rhizome constituents significantly diminished the synthesis of IL-6, IL-1β, TNF-α, and iNOS in RAW264.7 cells, dramatically impeded the phosphorylation of the LPS-induced NF-κB signaling pathway and notably increased Nrf2 expression.

    Conclusions: This study found that various solvent extracts from the rhizome of IMP possessed antioxidant capacity and antiinflammatory activity on LPS-induced RAW264.7 cells, which may be provoked by suppressing the NF-κB and activating the Nrf2. Therefore, the rhizome of IMP has the potential to develop new therapeutic agents for treating inflammatory diseases.

  • Article
    Xuewei Xing, Xuan Jin
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1647-1659. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.173
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    Background: Endometrial cancer (EC) is one of the most prevalent cancers of the female reproductive tract. Ferroptosis, a novel pattern of programmed cell death, is shown in many studies to be a key factor in the development of EC in close association with the tumour and immunotherapy. The aim of this study was to build suitable risk prognostic models for EC patients assessing ferroptosis- and immune-related differentially expressed genes.

    Methods: Inthe Cancer Genome Atlas (TCGA) dataset, differentially expressed ferroptosis-related genes (DEFRGs) in EC were identified. Cox regression, least absolute shrinkage and selection operator (LASSO) analyses were used to identify genes independently associated with the risk of suffering EC. After calculating risk scores using selected genes, patients were categorized in two groups depending on the median of the risk score, high- or low-risk group. Immune infiltrating cells, the tumour microenvironment, the tumour mutational burden and clinical were compared between groups. Clinical prognostic predictive models were built with the combination of patient’s clinical information and risk scores. The area under receiver operating characteristic (ROC) curves served as a measure of the models’ accuracy; Kaplan–Meier analysis was conducted to assess 3-, 5- and 7-year survival rate in both groups; And the clinical prognosis of patients was assessed by constructing nomograms.

    Results: Twelve DEFRGs associated with risk the risk of suffering EC (TRIB3, SLC2A1, CDKN2A, RRM2, ASNS, TSC22D3, AURKA, ATP6V1G2, HIG1, GPX4, TLR4 and SAT1) were identified and used to predict prognosis and survival of EC patients. Both groups showed significant differences in immune infiltrating cells (dendritic cells and CD4+ T cells), somatic mutation status and immune checkpoints (p < 0.05). The 1-, 3-, and 5-year survival rates of EC patients were found to be 3-year area under the curve [AUC (Area under the curve)] = 0.791; 5-year AUC = 0.795; And 7-year AUC = 0.783 by establishing a nomogram, respectively.

    Conclusions: We have created a ferroptosis-related risk model which is capable of effectively predicting the outcome of EC patients, including survival and response to immunotherapy. However, additional research is needed to clarify the underlying mechanisms of ferroptosis in EC.

  • Article
    Xingzhong Tian, Yuan Xue Yi, Jian Xu, Zeqin Luo, Na Xing, Zhengbing Wang, Sini Chen, Xin Ye, Youliang Shen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1661-1668. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.174
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    Objective: Cervical cancer is one of the most common malignant tumors affecting women. It is estimated that 99.6% of cervical cancer patients are caused by persistent infection with human papillomavirus (HPV). The aim of this study was to combine the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/associated proteins (Cas12a) detection system with colloidal gold rapid diagnosis technology to develop a new rapid diagnosis technology for HPV16 nucleic acid detection.

    Method: Based on the advantages of CRISPR-Cas12a and recombinase polymerase amplification (RPA) technology, this experiment intended to establish an innovative technology suitable for rapid clinical detection of the L1 gene for HPV16 and develop a rapid nucleic acid lysis solution. The RPA technology was developed through primer verification to synthesize a large number of templates for the Cas12a-crRNA cleavage system swiftly. RPA technology was combined with lateral flow test strips to complete the interpretation of the results. The lysate contained 1.5 M guanidine hydrochloride, 50 mM Tris (pH = 8.0), 100 nM NaCl, 5 mM Ethylene Diamine Tetraacetic Acid (EDTA), and 1% Tween-20.

    Result: In this study, according to the concentration of the template and the results of agarose gel electrophoresis without dragging phenomenon, a third solution was finally determined as the optimal cleavage scheme: 1.5 M guanidine hydrochloride, 50 mM Tris (pH = 8.0), 100 nM NaCl, 5 mM EDTA, 1% Tween-20. After optimization, the optimal concentration of the probe was finally determined as 0.02 µM.

    Conclusions: The current study verified the rapid detetion capacity of CRISPR/Cas12a combined with RPA technology, hoping to provide a new technical method for HPV16 detection.

  • Article
    Yu Zhang, Zunqi Hu, Dejun Yang, Jiapeng Xu, Hongbing Fu, Xin Zhang, Ronglin Yan, Weijun Wang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1669-1678. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.175
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    Background: Stomach adenocarcinoma is a high risk cancer of the digestive system. Aspartoacylase (ASPA) has been indicated to involve in the progression of various cancers. We herein aimed to evaluate the role of ASPA in stomach adenocarcinoma patients.

    Methods: Stomach adenocarcinoma patient data was downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. DEseq2 and limma package of R- were used to run the differential expression analyses. Significance difference was determined by Wilcox method. Survival analyses was performed using Survival and survminer packages. CIBERSORT was used to assess the immune cell infiltration. Functional enrichment analyses were performed on the differentially expressed genes (DEGs) using clusterProfiler package of R.

    Results: In both databases, ASPA was significantly lower in stomach adenocarcinoma samples than in normal samples (p < 0.001). ASPA expression increased gradually with the grade of stomach adenocarcinoma. Patients with higher ASPA expression showed poorer overall survival compared to those patients with lower ASPA expression (p < 0.01). ASPA was an independent prognostic factor. Ten types of immune cells, such as T cells regulatory, showed significant differential infiltration between high and low ASPA expression stomach adenocarcinoma patients. In total 3192 DEGs were identified between high and low ASPA expression stomach adenocarcinoma patients, which were significantly enriched in 1362 gene ontology (GO) terms and 86 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.

    Conclusions: Lower ASPA expression is associated with the onset of stomach adenocarcinoma. High ASPA expressed stomach adenocarcinoma patients showed unfavorable overall survival. Our findings give new insights about the pathogenic and diagnostic role of ASPA in stomach adenocarcinoma.

  • Article
    Xin-yu Wang, Zhi-chao Mao, Yong-tang Zhao, Fang Liu, Hua-Min Zhao, Qin Qin, Qiong-yao Zou
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1679-1687. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.176
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    Purpose: The morbidity and mortality of gastric cancer (GC) remain high and are rising. Early diagnosis and treatment can lower mortality. However, early GC (EGC) is challenging to diagnose and often accompanied by lymphatic metastasis. Therefore, this study sought to find long non-coding RNAs (lncRNAs) that are diagnostic and associated with metastasis.

    Methods: Bioinformatics was employed to analyze the intersection of up-regulated lncRNAs in three Gene Expression Omnibus (GEO) datasets associated with GC. The long non-coding RNA LINC01094 (LINC01094) expression levels in GC tissues and adjacent tissues were determined by Quantitative real time polymerase chain reaction (qRT-PCR). GC patients was allocated to non-metastasis and metastasis groups, and their expression levels of LINC01094 were estimated. At the cellular level, LINC01094 expression levels in human GC cell lines (AGS and SNU-16) and human gastric epithelial cell line (GES-1) were also estimated with qRT-PCR. Subsequently, cell cloning, transwell and wound healing assays were used to determine the effect of knockdown or overexpression of LINC01094 on human gastric adenocarcinoma cell line (AGS) cell proliferation, migration and invasion. Western blot was used to measure the role of LINC01094 in epithelial-mesenchymal-transition (EMT)-related proteins and RhoA/Rho-associated coiled-coil kinase (ROCK) pathway.

    Results: Bioinformatics analysis revealed significantly high expression of LINC01094 in GC tissues. qRT-PCR results further confirmed that LINC01094 expression was significantly raised in GC tissues, GC metastasis group, and GC cell lines. Additionally, LINC01094 overexpression significantly encouraged AGS cells to proliferate, migrate and invade, lowered the E-cadherin expression and boosted the protein expressions of N-cadherin, Snail, RhoA and ROCK2. Knockdown of LINC01094, however, produced the opposite result to the LINC01094 overexpression.

    Conclusions: LINC01094 facilitates AGS cell proliferation, migration, invasion and EMT by activating RhoA/ROCK pathway. Therefore, LINC01094 has the potential to be an early diagnostic biomarker and therapeutic target for GC.

  • Article
    Ling Ge, Jing-Hao Qin, Shao-Bo Yu, Guo-Yong Yin
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1689-1694. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.177
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    Objective: To investigate the correlation between tumor necrosis factor-α receptor gene polymorphism and ankylosing spondylitis (AS) in Han population.

    Methods: This study matched 200 Han AS patients admitted to our hospital from March 2014 to March 2020 with 240 healthy controls during the same period. Ligase detection polymerase chain reaction (LDR-PCR) was used to detect TNFRSF1A gene+36A/G (rs767455) site and –383A/C (rs2234649) site, TNFRSF1B gene +196T/G (rs1061622) site single nucleotide polymorphism (SNP) in both groups of patients.

    Results: The distribution frequency of A allele and G allele at rs767455 of TNFRSF1A gene were different in the AS patients and healthy controls (p < 0.05). The GG genotype and the AA genotype were combined into a homozygous group, and the distribution frequencies of homozygous and heterozygous types between the two groups were statistically significant (p < 0.05). There was no significant difference in the SNPs at rs2234649 of the TNFRSF1A gene and rs1061622 of the TNFRSF1B gene between the AS group and the control group (p > 0.05).

    Conclusions: The distribution frequency of rs767455 heterozygous (AG) was statistically higher in the AS group, while there was no significant difference in genotype distribution of rsl061622 and rs2234649 between the two group. SNPs in the TNFRSF1A and TNFRSF1B genes were not associated with TNF-α antagonist effectiveness.

  • Article
    Xiaoping Dong, Xiaonan Liu, Cencen Wang, Zhen Bi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1695-1704. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.178
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    Background and Purpose: The aim of this study was to investigate the effects of berberine on sevoflurane-induced neurotoxicity and its mechanism of action.

    Methods: Ninety-seven-day-old Sprague Dawley (SD) rats had their primary hippocampal neuron cells anesthetized with 3% sevoflurane for 6 hours, to establish the sevoflurane-induced neurotoxicity model. They were split into two groups; One treated with 100 mg/kg berberine per day, and their neurons treated neurons with different concentrations of berberine and a control group, which was treated with normal saline. Afterwards, the changes of learning and memory ability, cell proliferation, apoptosis, reactive oxygen species (ROS), inflammatory cytokines, and expressions of nuclear factor NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) were measured.

    Results: Compared with the control group, the learning and memory ability of rats in the “3% sevoflurane for 6 hours” (Sev) group was significantly impaired, and the neurons in their hippocampus were atrophied and disordered. The apoptosis rate, ROS content, and inflammatory cytokines levels were significantly increased, and the expressions of Nrf2, HO-1, and NQO1 were significantly reduced (p < 0.05). Compared with the “3% sevoflurane for 6 hours and treated with normal saline per day” (Sev+NS) group, the learning and memory ability of rats in the “3% sevoflurane for 6 hours and treated with 100 mg/kg berberine per day” (Sev+Ber) group was significantly improved, with which cells arranged neatly, and the pyknosis was significantly improved. At the same time, the apoptotic rate, ROS content, and inflammatory cytokines levels were significantly decreased, while the expressions of Nrf2, HO-1, and NQO1 increased significantly (p < 0.05). Knocking down significantly Nrf2 attenuated the protective effect of berberine on hippocampal neuron cells.

    Conclusions: Berberine ameliorates sevoflurane-induced neurotoxicity, and its mechanism may be related to the Nrf2/HO-1 signaling pathway.

  • Article
    Yanneng Xu, Si Xie, Gang Yuan, Wei Hu, Xiangqiong Zhang, Bo Zheng, Jianming Luo, Xun Zhang, Shuhao Xu, Guangyan Si
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1705-1715. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.179
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    Introduction: Cholangiocarcinoma (CCA) accounts for 2% of all malignancies and it has shown an increased in recent years. Several studies have elucidated that long non-coding RNAs (lncRNAs) participate in processes associated with cancer development. LncRNA MNX1-AS1 (motor neuron and pancreas homeobox 1-antisense RNA1) has been identified as a malignant promoter in various cancers. Nevertheless, its biological role in CCA has not been explored yet. Thus, the aim of this study is to evaluate the underlying mechanism and functions of lncRNA MNX1-AS1 in CCA.

    Methods: By searching circlncRNAnet and The Cancer Genome Atlas (TCGA) database, we determined the expression of MNX1-AS1 and MNX1 (motor neuron and pancreas homeobox 1) in CCA tissue. Reverse-transcription and quantitative real-time PCR (RT-qPCR) detected gene expression. The underlying mechanism of MNX1-AS1 was assessed by luciferase reporter assay, ribonucleic acid (RNA) pull-down assay and RNA immunoprecipitation (RIP) assay.

    Results: MNX1-AS1 and MNX1 were overexpressed in CCA tissue and CCA cells. Their expression level was positively correlated to each other. Moreover, it was validated that MNX1-AS1 could positively regulate MNX1 messager ribonucleic acid (mRNA) expression and could bind to embryonic lethal, abnormal vision like RNA binding protein 1 (ELAVL1; Also known as HuR). Furthermore, HuR bound to MNX1 mRNA what promoted the mRNA stability of MNX1. Finally, rescue assays proved that the reduced CCA cell proliferation and migration induced by MNX1-AS1 deficiency could be reversed by MNX1 overexpression.

    Conclusions: Our work confirmed that MNX1-AS1 strengthened CCA cell malignant behaviors through HuR interaction what stabilized MNX1 expression.

  • Article
    Chong Fu, Wenjiao Cai, Yanping Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(5): 1717-1725. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223605.180
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    Background: Ulcerative colitis (UC) is a widely known form of inflammatory bowel disease (IBD), and its main symptoms include colonic and rectal inflammation. This research focused on the identification of key genes associated with UC ferroptosis and the development of novel biomarkers for the disease.

    Methods: Gene set variation analyses (GSVA) were used to calculate the enrichment score (ES) of the ferroptosis-related gene set in each sample in GSE38713 and GSE47908, respectively. Subsequently, to obtain key modules, the ES were used as traits for subsequent weighted gene co-expression network analysis (WGCNA), and finally, to obtain key genes, the genes in the two modules were intersected. Biomarker screening was performed by building a protein-protein interaction (PPI) network of key genes, where the top 20 hub genes were screened using the Cytoscape. In addition, the receiver operating characteristic (ROC) curve was drawn for the selected hub genes, and the top-ranked hub genes were screened out for the diagnosis of ulcerative colitis. To assess the diagnostic value, the validation dataset GSE87466 was applied to draw ROC curves for the candidate hub genes.

    Results: GSVA revealed that the ferroptosis gene set had a strong association with UC. WGCNA was used to obtain 2636 significant genes in GSE38713. WGCNA was used to obtain 3512 significant genes in GSE47908. Intersection analysis of the two yielded 604 intersection genes. In addition, in the protein-protein interaction (PPI) network, 20 hub genes of intersection genes were identified using the Cytoscape. Finally, receiver operating characteristic analysis of selected hub genes revealed that four genes were the potential ferroptosis-associated genes for UC.

    Conclusions: Four ferroptosis-associated potential hub genes (UTP6 (U3 small nucleolar RNA-associated protein 6), PRKACB (Protein kinase CAMP-Activated catalytic subunit beta), AATF (Anti-Apoptotic transcription factor), and NOC4L (Nucleolar complex associated 4 homolog)) were identified in the colonic mucosa. Our study could provide potential diagnostic candidate genes for UC.