20 February 2023, Volume 37 Issue 2

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  • Review
    Chenglong Ling, Xufeng Xiao, Faezeh Jalilian, Elham Abdollahi, Nafiseh Saghafi, Somayeh Moiendarbari, Sara Mirzaeian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 593-603. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.60
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    Severe coronavirus disease of 2019 (COVID-19) usually begins approximately one week after the onset of symptoms. Dyspnea is the most common symptom of severe disease and is often accompanied by hypoxemia. Progressive respiratory failure develops in many patients with severe COVID-19 after the onset of dyspnea and hypoxemia. These patients commonly meet the criteria for acute respiratory distress syndrome (ARDS), which is defined as the acute onset of bilateral infiltrates, severe hypoxemia, and lung edema. The majority of patients with severe COVID-19 showed some thromboembolic complications as well central or peripheral nervous system complications. Severe COVID-19 may also lead to acute cardiac, kidney, and liver injury, cardiac arrhythmias, coagulopathy, and shock. These organ failures may be associated with uncontrolled inflammation characterized by elevations in C-reactive protein and pro-inflammatory cytokines, including Interleukin-6, Interleukin-1, and tumor necrosis factor-α. This may associate with high fevers, thrombocytopenia, and exacerbating lung and cardiovascular complications. According to the American College of Obstetricians and Gynecologists (ACOG), the relative risk of COVID-19 infection is considerably lower relative to the risk of pandemic H1N1 (hemagglutinin type 1 and neuraminidase type 1) influenza infection in pregnant women. Less severe COVID-19 in pregnancy also was reported. Regulatory T cells (Tregs) are important in controlling adverse inflammatory reactions in severe COVID-19 making them effective cells for immunotherapy in severe COVID-19. Impairment in the number and/or function of Tregs was reported in severe COVID-19. Tregs are also part of the complex network of immune cells at the feto-maternal interface, and in peripheral blood that may have a critical role in facilitating implantation, placental development, and maintaining maternal tolerance. Pregnancy-induced Tregs are developed to control immune responses against paternal antigens. This review provides a new insight into whether the severity of COVID-19 could be influenced by the adoptive transfer of pregnancy-induced regulatory T cells in pregnant women.

  • Article
    Liang Li, Jie Luo, Weiliang Sun, Chenglong Han, Suyan Li, Hui Li, Li Wang, Zhengwen Cai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 605-616. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.61
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    Background: Matrine, the main active ingredient in the traditional Chinese medical herb Sophora flavescens, has promising antitumor properties on tumor cell lines. However, the underlying molecular mechanisms remain to be clarified. This study explored the underlying molecular events for the anticancer effect of matrine, a plant alkaloid, on colon cancer cells in vitro and in vivo from the perspective of the DNA damage response.

    Methods: Colon cancer RKO (human colon cancer cells) cells were grown and transfected with checkpoint kinase 1 (CHK1) cDNA or vector-only, and then treated with or without matrine (0, 2, 4, or 8 µM) for transwell and comet assays, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), western blot, immunofluorescence experiments, enzyme-linked immunosorbent assay (ELISA), and subcutaneous tumorigenesis experiments of nude mice.

    Results: Matrine dose-dependently inhibited the cell migration and invasion capacity as well as induced DNA damage in RKO cells in vitro. In addition, matrine dose-dependently upregulated the expression of DNA single- and double-strand break marker proteins (γH2AX (γH2A histone family member X) and cleaved PARP1 (poly (ADP-ribose) polymerase 1)), DNA damage marker proteins, and E-cadherin; However, it downregulated the expression of vimentin and CHK1. Furthermore, compared with the matrine plus vector control group, CHK1 overexpression induced the cell migration and invasion abilities of RKO cells. CHK1 overexpression also reduced E-cadherin expression but induced vimentin expression in RKO cells. CHK1 overexpression suppressed the expression of the DNA damage-related proteins (γH2AX, cleaved PARP1, and PARP1) and E-cadherin but increased the expression of vimentin in RKO cells. Moreover, matrine could reduce the release of interleukin (IL)-1β and IL-8 in vivo, which compose the DNA damage secretory program (DDSP). In the subcutaneous tumorigenesis experiment of nude mice, it was confirmed by immunohistochemistry that CHK1 expression decreased and γH2AX expression increased after matrine treatment.

    Conclusions: Matrine was able to inhibit activation of the DNA damage response kinase CHK1, thereby inhibiting the DNA damage response and epithelial-mesenchymal transition (EMT) in colon cancer cells.

  • Article
    Juan Ding, Tingting Sun, Juan Yao, Ni Zheng, Rong Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 617-628. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.62
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    Background: Currently, immunotherapy has shown significant clinical benefits in many cancers but is only beneficial in a subset of patients. With the purpose of ameliorating the diagnosis and treatment of lung cancer, we aimed to establish a prognostic signature of response to programmed cell death protein 1 (PD-1) immune checkpoint blockade (ICB) in lung cancer.

    Methods: Differentially expressed genes (DEGs) were identified and functional analysis performed. A prognostic signature was constructed and used to build a combined nomogram. In addition, the patients were categorized into high- and low-risk groups and the correlation with tumor immune microenvironment, drug sensitivity, and tumor mutation was analyzed.

    Results: A total of 449 DEGs were analyzed and found to be involved in cell adhesion, cytokine-cytokine receptor interaction, and antigen processing and presentation pathways. A 12-gene prognostic risk model was constructed, consisting of MTUS1, ID1, KYNU, HOXC5, COL4A2, BARX2, EPHA4, PADI4, CLEC7A, SPP1, PLIN2, and GFI1. A higher percentage of naïve B cells, memory B cells, and CD8 T cells were found in the low-risk group, while resting natural killer cells and neutrophils were found at a lower percentage (p < 0.05). The estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) and immune scores were found to be higher in the low-risk group than those in the high-risk group (p < 0.05). The half maximal inhibitory concentration (IC50) values of the six drugs, cisplatin, cyclopamine, docetaxel, doxorubicin, gemcitabine, and vinblastine, were found to be significantly higher in the low-risk group than in the high-risk group (p < 0.05). The tumor mutation burden was greater in the high-risk group compared to that in the low-risk group (p < 0.05).

    Conclusions: This immunotherapy-related 12-gene prognostic prediction signature could allow clinicians to predict the survival benefit of PD-1 ICB in patients with lung cancer, and these 12 genes could be used as potential markers for improving the response rate of PD-1 ICB in patients with lung cancer.

  • Article
    Zijing Wang, Yunfeng Zhen, Yong Tang, Guangyao Song, Huijuan Ma, Hang Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 629-636. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.63
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    Background: Animal studies have shown that maternal calorie restriction during pregnancy can increase the risk of adult obesity and metabolic disorders. Brown adipose tissue (BAT) is the main source of non-shivering thermogenesis and could be target to treat obesity. This study aimed to investigate whether maternal calorie restriction during pregnancy affect BAT development and thermogenic capacity in mouse offspring.

    Methods: Female Institute of Cancer Research (ICR) mice were fed a normal diet prior to gestation and were randomly assigned to either a normal calorie (NC) diet group or a 50% calorie restricted (CR) diet at 12.5 days of gestation, lasting until 18.5 days of gestation group. The offspring in the NC and CR groups were breast feeding for 3 weeks. After weaning, the mice were fed with high-fat diet (HFD) for four months. Then mice in the NC and CR groups were named the NCH (normal calorie with high-fat diet) and CRH (calorie restricted with high-fat diet) groups, respectively. Body weight (BW), thermogenesis-related gene expression, and protein expression of uncoupling protein 1 (Ucp1) were measured in interscapular BAT (iBAT).

    Results: The CRH group had a lower birth weight than the NCH group (p < 0.01). However, there was no significant weight difference between the two groups after weaning. There were no significant differences in total calorie intake and body weight between the NCH and CRH groups after four months of HFD (p > 0.05). mRNA expression of iBAT, Ucp1 and Adrb3 mRNA levels were significantly higher in the NCH group than those in CRH mice (p < 0.05). In addition, the mRNA levels of fatty acid oxidation-related genes (Pgc1α, Cpt1b, Cox8b, and Cox5b) were significantly higher in the NCH group than those in the CRH group (p < 0.05).

    Conclusions: Severe maternal calorie restriction during late gestation could adversely affect offspring iBAT development and thermogenic capacity when challenged with a HFD. This may be related to damaged fatty acid oxidation.

  • Article
    Wei Chen, Yu-nan Shan, Jing-wei Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 637-646. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.64
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    Background: USP9X (ubiquitin-specific protease 9X) is a substrate-specific deubiquitinating enzyme that regulates multiple components of diverse signaling pathways. The deregulation of USP9X is associated with various types of diseases. However, the role that USP9X plays in human pan-cancer remains largely unknown.

    Methods: A variety of bioinformatics methods were used to comprehensively analyze the expression level, survival relationship, mutation, protein phosphorylation, and immune infiltration of USP9X in various tumors from public databases.

    Results: USP9X was found to exhibit a dual role in different tumors. The expression of USP9X was high in tumors tissues of CHOL (cholangiocarcinoma), ESCA (esophageal carcinoma), HNSC (head and neck squamous cell carcinoma), and STAD (stomach adenocarcinoma), but low in tumors tissues of BLCA (bladder urothelial carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), PRAD (prostate adenocarcinoma), THCA (thyroid carcinoma), and UCEC (uterine corpus endometrial carcinoma). There is a differential association between the expression of USP9X and the prognosis of cancer patients. The level of phosphorylation was high or low at different sites in different tumors. Moreover, the expression of USP9X was associated with levels of immune infiltration of CAFs (cancer-associated fibroblast), B cells, neutrophil, CD8+ T cells, CD4+ T cells, Tregs, dendritic cells (DCs), as well as macrophages in most cancers. In particular, HNSC, HNSC-HPV (human papilloma virus)-, and PAAD (pancreatic adenocarcinoma) in CAFs and BLCA and THCA in neutrophils showed a significant positive correlation with USP9X expression in all algorithms.

    Conclusions: This is the first pan-cancer study on USP9X that summarizes the prognostic and immunological role of USP9X in different tumors.

  • Article
    Jili Wen, Pengwei Zhao, HuiJuan Ren, JunMin Wu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 647-655. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.65
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    Background: During sepsis, multiorgan failure often results as the body responds to infection. Lipopolysaccharides (LPS) are major players in the induction of sepsis. Because autophagy can protect against multiple organ dysfunction during sepsis, we explored LPS’s regulatory role in autophagy and its interaction with transforming growth factor (TGF)-β inhibited membrane associated protein (TIMAP), moesin, and the Wnt β-catenin signaling pathway in human pulmonary microvascular endothelial cells (HPMECs).

    Methods: Bioinformatics was used to screen for autophagy genes. HPMECs were selected for by determination of cell proliferation and LPS-induced autophagy. Enrichment of TIMAP and moesin was detected by chromatin immunoprecipitation (ChIP)-PCR (polymerase chain reaction).

    Results: LPS promoted autophagy in HPMECs, which resulted in the inhibition of TIMAP’s expression. Moesin expression was then activated by inhibited TIMAP in HPMECs treated with LPS. LPS promoted HPMECs’ autophagy by the suppression of the phosphatidylinositol-3-kinase (PI3K)/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) signaling pathway via inhibited-TIMAP-promoted-moesin expression.

    Conclusions: The LPS-TIMAP-moesin-PI3K/Akt/mTOR axis is involved in a protective capacity in the autophagy of HPMECs. Specifically, LPS prevented TIMAP’s expression, upregulated moesin’s expression, and inhibited the PI3K/Akt/mTOR signaling pathway.

  • Article
    Yanan Wang, Yue Sun, Jiahao Ma, Yifan Li, Dan Tian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 657-663. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.66
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    Background: Total hip arthroplasty (THA) is a common surgical procedure, performed on patients suffering from hip osteoarthrosis to ameliorate pain, and improve mobility and quality of life. Length of post-operative care and rehabilitation time before full recovery in the older population is a key concern in this surgical population. To improve these issues, we studied the effects of a novel combination of anesthetics on the anesthetic block effect, safety, and postoperative recovery time of old patients undergoing THA. We used increasing concentrations of ropivacaine (used for subarachnoid anesthesia) in combination with epidural hydromorphone.

    Methods: 90 old patients scheduled for THA were divided in three equal groups. A ropivacaine stock of 10 mg/mL was used for spinal anesthesia. Its final concentration for the three groups, A, B, and C was 0.33%, 0.4%, and 0.5%, respectively Hydromorphone (0.4 mg) was given through epidural catheter 30 min before the end of surgery.

    Results: Sensory block level at 5 min (T1) and 10 min (T2) in group C was higher than in group B followed by group A. Sensory block level was not different between the groups at 15 min (T3). Motor block score in group C was higher than in group B followed by group A. Incidences of hypotension, nausea, and vomiting were higher in group C compared to the other groups. Duration of sensory and motor blocks were longer in group C than in the other groups. The visual analog score at 12 h post-surgery in group A was higher than in group B followed by group C. Other rehabilitation parameters in group A were shorter than in group B followed by group C.

    Conclusions: Overall 0.4% ropivacaine hydrochloride 10 mg in combination with 0.4 mg hydromorphone led to quick rehabilitation with appreciable safety compared to the other combinations. Larger clinical studies are required to establish the efficacy of this novel anesthetic combination in THA.

  • Article
    Yanzhu Qin, Jing Peng, Jinfang Jiang, Shuaiji Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 665-672. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.67
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    Objectives: Acute radiation-induced skin reaction is a common complication related to nasopharyngeal carcinoma patients. The purpose of this study was to identify risk factors that help to predict the incidence of acute radiation-induced skin reaction and discriminate between moderate and severe acute radiation-induced skin reaction in nasopharyngeal carcinoma patients undergoing radiotherapy.

    Methods: This is a cross-sectional study including 110 patients with nasopharyngeal carcinoma. Patients were assessed for acute radiation-induced skin reactions by the Radiation Therapy Oncology Group criteria and the Radiotherapy-Induced Skin Reaction Assessment Scale during the final radiotherapy session. Demographic, clinical and blood test index data were collected before and during the radiotherapy. Risk factors associated with the development and severity of radiation-induced skin reaction were determined by univariate and multivariate binary logistic regression.

    Results: Acute radiation skin reactions were observed in 66 (60%) of the nasopharyngeal carcinoma radiotherapy patients and 14 (21.2%) of them were graded ≥2 skin reactions (moderate and severe acute skin reaction). Univariate analysis of risk factors (gender, age, smoking history, diabetes, the T helper/T suppressor lymphocyte (Th/Ts) ratio and red blood cell counts before radiation) for skin reactions revealed that age, smoking history, stage (I–III), induction chemotherapy, platelet counts, neutrophil ratio and albumin level in mid-radiotherapy were significantly associated with moderate and severe acute skin reaction. After a variable selection process with a logistic regression, Th/Ts ratio before radiotherapy remained significantly associated with acute skin reactions (OR (odds ratio) 2.29, 95% CI (confidence interval) 1.09–4.79, p < 0.05). Serum albumin level <35 g/L in mid-radiotherapy was a significant risk factor related to moderate to severe acute radiation skin damage (OR 6.61, 95% CI 1.31–33.43, p < 0.05).

    Conclusions: Based on the results of Th/Ts contributed to skin radiosensitivity and albumin level helped to predict the severity. To monitor T helper/T suppressor lymphocyte ratio before radiotherapy and albumin during mid-radiotherapy is a good strategy that may help decreasing the risk of acute radiation skin injury and severe acute radiation skin reactions for nasopharyngeal carcinoma patients who received radiotherapy.

  • Article
    Yu Shen, Xiaoxia Li, Luyi Zhang, Xin Wang, Yu Wang, Miaoqin Wu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 673-685. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.68
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    Purpose: To observe the therapeutic effect of pulsed ultraviolet A (UVA) radiation-mediated acceleration of scleral collagen crosslinking in a mouse model of myopia and clarify the regulatory mechanism of microRNA (miR) in the expression of proteins related to scleral remodelling.

    Methods: After isolating scleral fibroblasts (SFs) of lens-defocused myopic mice which underwent scleral collagen crosslinking with pulsed UVA, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and dual luciferase reporter assay were used to evaluate signal transduction pathways in miR-16-2-induced scleral collagen related proteins synthesis, and validate the targeting relationship of miR-16-2 and insulin-like growth factor-1 receptor (IGF1R).

    Results: The scleral crosslinking accelerated by pulsed UVA might play an active role in the expression of miR-16-2, which targeted downregulated of IGF1R, thereby decreasing the phosphorylated protein kinase B (p-AKT) and matrix metalloproteinase-2 (MMP2) levels and increasing the expression of tissue inhibitors of metalloproteinases-2 (TIMP2) and collagen 1A.

    Conclusions: Scleral collagen crosslinking accelerated by pulsed UVA radiation could prevent and control the progression of myopia by increasing miR-16-2 expression in a mouse model, inhibiting IGF1R expression and promoting the synthesis of scleral collagen.

  • Article
    Pu Li, Lu Li, Rui-Lin Chen, Tao Wu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 687-691. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.69
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    Objective: This study analyzes the failure of vancomycin blood trough concentration in critically ill patients and the influencing factors to provide a theoretical basis for its rational application.

    Methods: The data of 45 critically ill patients with infections induced by vancomycin treatment were retrospectively collected. Patients with a vancomycin blood trough concentration of <10 mg/L were assigned into the substandard group (n = 18), and those with a vancomycin blood trough concentration of ≥10 mg/L were assigned into the standard group (n = 27). Data such as age, gender, underlying diseases, treatment methods, albumin, creatinine, and glomerular filtration rate were analyzed, then multivariate analysis was performed using binary logistic regression.

    Results: The age, drug blood trough concentration, peak concentration, and blood creatinine concentration were significantly lower in the substandard group than in the standard group (p < 0.05), and the epidermal growth factor receptor (eGFR) level was significantly higher than in the standard group (p < 0.001). The rate of renal replacement therapy (RRT) was higher in the standard group than in the substandard group (p = 0.031). The factors with statistical differences between the two groups (age, blood drug peak concentration, eGFR, treatment methods, and continuous RRT) were used as the independent variables (X). Whether the blood concentration of vancomycin reached the standard was used as the dependent variable (Y). Binary multivariate logistic regression analysis was conducted. The results show that serum creatinine (p = 0.037, OR (odds ratio) = 1.248) and eGFR (p = 0.026, OR = 0.913) were independent influencing factors of vancomycin.

    Conclusions: The failure rate of vancomycin trough concentration in critically ill patients is higher. Serum creatinine and eGFR are independent associated factors for the substandard rate of vancomycin trough concentration.

  • Article
    Ying Deng, Xueguang Lin, Bo Chen, Jindong Tong, Weijun Shi, Bo Wang, Bo Yu, Jingdong Tang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 693-703. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.70
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    Aim: We aimed to characterize the profiles of long non-coding RNA (lncRNA) and mRNA associated with plaque instability in carotid artery stenosis (CAS).

    Methods: Three stable and three unstable plaque tissues were collected for RNA sequencing to filtrate differential expressed lncRNAs (DE-lncRNAs) and mRNAs (DE-mRNAs). Identified genes were then used for functional analyses, and six DE-lncRNAs as well as six inflammation-related DE-mRNAs were verified using RT-qPCR (reverse transcription quantitative polymerase chain reaction).

    Results: Using sequencing, we identified 920 DE-mRNAs (639 upregulated and 281 downregulated mRNAs) and 178 DE-lncRNAs (128 upregulated and 50 downregulated lncRNAs) in unstable plaques. According to functional analysis, these identified genes were obviously enriched in “signal transduction”, “phagocytosis”, “PI3K-Akt (phosphatidylinositol 3 kinase (PI3K)/protein kinaseB) signaling pathway”, “sphingolipid transporter activity”, “TNF (tumor necrosis factor) signaling pathway”, “ICAM-3 (intercellular adhesion molecule-3) receptor activity”, “Jak-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway”, “interleukin-6 receptor binding”, “Th17 (T helper cell 17) cell differentiation”, “HIF-1 (hypoxia-inducible factor-1) signaling pathway”, “Th1 (helper T lymphocyte 1) and Th2 (helper T lymphocyte 2) cell differentiation”, “NF-κB (nuclear factor kappa-B) signaling pathway”, and “sphingolipid signaling pathway”. Compared to stable plaque tissues, lncRNAs FAM30A, MIAT, and LUCAT1 were significantly upregulated in unstable plaque tissues (p < 0.05), whereas XIST (X inactive-specific transcript) and DLX6-AS1 were markedly downregulated (p < 0.05), based on RT-qPCR results. These findings corroborated expression patterns of lncRNA sequencing data. Compared with stable plaque tissues, expression of CCL19 (chemokine (C-C motif) ligand 19), IL6 (interleukin 6), CCL21 (chemokine (C-C motif) ligand 21), and IL18R1 (interleukin 18 receptor 1) was significantly upregulated, whereas SFRP5 (secreted frizzled related protein 5) was downregulated in unstable plaque tissues.

    Conclusions: DE-lncRNAs FAM30A, MIAT, LUCAT, XIST, and DLX6-AS1 may be potential targets for plaque instability, and the PI3K-Akt, Jak-STAT, NF-κB, TNF, and HIF-1 signaling pathways may have connection with plaque instability in patients with CAS.

  • Article
    Hongwei Zhang, Qintao Li, Ke Zhang, Ronghai Huang, Menglong Wang, Li Jiang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 705-710. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.71
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    Objective: To investigate the clinical effect of splenectomy combined with esophagogastric devascularization in patients with idiopathic non-cirrhotic portal hypertension (INCPH).

    Methods: A retrospective research method was used to analyze the clinical data of patients with INCPH hospitalized in the Ditan Hospital. The patients who had undergone splenectomy alone or splenectomy combined with esophagogastric devascularization (Hassab’s surgery) were placed into the intervention group (20 patients), and the others, who received conservative treatment (drugs, therapeutic endoscopy and transjugular intrahepatic portosystemic shunt (TIPS)), were placed into the control group (26 patients). The laboratory indicators of the two groups, including blood routine, liver function, and coagulation function before and two weeks after treatment, were compared; And the serum liver fibrosis indicators of the intervention group before and 6 months after surgery were compared. The portal vein pressure in the observation group was also compared before splenectomy, after splenectomy and after devascularization. The portal blood flow of the intervention group before and two weeks after surgery were compared.

    Results: There was no significant difference in baseline data between the observation group and the control group before treatment (p > 0.05). White blood cell (WBC) and platelet (PLT) levels of the intervention group had returned to normal two weeks after surgery, compared with the control group, the difference was statistically significant (p < 0.05). However, the comparison of the hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBil), prothrombin time (PT), and prothrombin time activity (PTA) after treatment showed no statistically significant differences (p > 0.05). Liver fibrosis indicators decreased after surgery compared with before surgery, and the difference was statistically significant (p < 0.05). The portal vein flow volume and flow velocity in the intervention group after surgery were lower than before, whereas the hepatic artery flow volume after surgery was higher than before surgery; The differences were statistically significant (p < 0.05). After treatment, the incidence of ascites (15.0%) and venous rebleeding (10%) in the observation group were lower than those in the control group, and the difference was statistically significant (p < 0.05). However, the rate of portal vein thrombosis (45.0%) was significantly higher than that in the control group. No hepatic encephalopathy or death occurred in either group of patients during the follow-up period.

    Conclusions: Splenectomy combined with esophagogastric devascularization has a hemostatic effect on patients with INCPH. It can significantly reduce portal venous pressure, ensure blood flow into the liver, and reduce liver fibrosis-related indicators. Therefore, it is a safe and reliable treatment for INCPH.

  • Article
    Xiangwei Xu, Ankang Li, Penghai Zhang, Yiyuan Xi, Meihong Zhou, Yinqiao Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 711-719. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.72
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    Purpose: Platinum drugs or other chemotherapies are still widely used in treating lung cancer, causing adverse effects on patients’ emotions and quality of life (QoL) the patients. Chemotherapeutic pharmaceutical care is necessary for patients with lung cancer to relieve side effects and enhance therapeutic efficacy. This study aimed to investigate the pharmaceutical care contribution to improvements in cancer-related fatigue (CRF), negative emotions, and QoL in lung cancer patients undergoing chemotherapy.

    Methods: Patients were divided into control and intervention groups. Patients in the control group received chemotherapy, whereas patients in the intervention group received pharmaceutical care combined with chemotherapy. CRF, negative emotions, and QoL were evaluated throughout the admission and the second and fourth chemotherapy cycles.

    Results: After two chemotherapy cycles, the intervention group had lower emotional, physical fatigue, and negative-emotion scores (p < 0.01) and higher QoL scores related to emotion, function, and additional lung cancer concerns (p < 0.01) than the control group. Similarly, after four cycles of chemotherapy, the intervention group had lower emotional, physical, cognitive fatigue, and negative emotion scores (p < 0.01) and a better total QoL score (p < 0.01) than the control group. In addition, the remission rate (RR) of patients after receiving pharmaceutical care was significantly increased compared to the group receiving chemotherapy alone (p < 0.05).

    Conclusions: Pharmaceutical care could significantly improve CRF, negative emotions, and QoL in lung cancer patients undergoing chemotherapy.

  • Article
    Min Cang, Xianqin Long, Feng Qiu, Xiaochen Zeng, Songtao Li, Guojin Xie
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 721-730. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.73
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    Background: Myocardial ischemia-reperfusion injury (MIRI) is usually accompanied by oxidative stress and inflammation, causing apoptosis. This study aimed to elucidate the regulatory function of microRNA (miRNA) on MIRI.

    Methods: Ferroptosis was evaluated using flow cytometry assay and DCFH-DA (2’,7’-dichlorodihydrofluorescein diacetate) method. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) assays were carried out to measure gene expressions. qRT-PCR was used to measure the expression of miR-27a-3p and Solute Carrier Family 7 Member 11 (SLC7A11). Dual-luciferase reporter assay was performed to determine the targeting relationship between miR-27a-3p and SLC7A11. Hemotoxylin and eosin (H&E) staining and terminal deoxynucleoitidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining assays were conducted to visualize myocardial tissue injury.

    Results: Myocardial ischemia-reperfusion promoted cell apoptosis. Ferroptosis enhanced cell apoptosis and increased intracellular reactive oxygen species (ROS) and iron accumulation. The expression of miR-27a-3p was abnormally elevated after MIRI modeling, and SLC7A11 was a direct target of miR-27a-3p. Thus, by targeting SLC7A11, miR-27a-3p was found to regulate SLC7A11 expression negatively.

    Conclusions: In conclusion, miR-27a-3p was responsible for myocardial reperfusion injury in rats through sponging SLC7A11 to promote ferroptosis in cardiomyocytes.

  • Article
    Yaning Gao, Jian Li, Liang Chen, Zhengjun Wen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 731-739. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.74
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    Aims: The aim of this study is to investigate the potential mechanisms of coronavirus disease (COVID-19) and asthma comorbidities.

    Methods: GSE147507 and GSE143303 datasets were obtained from the Gene Expression Omnibus (GEO) database, the differential expressed genes (DEGs) were identified, and the overlapping DEGs were obtained by determining the DEG intersection between the two datasets. A series of analyses of the shared DEGs were performed, including enrichment analysis, protein-protein interaction (PPI) network construction, construction of transcription factor (TF)/microRNA (miRNA)-gene interaction networks, drug-gene and disease-gene interactions, and receiver operating characteristic curve (ROC) analysis.

    Results: A total of 135 overlapping DEGs were obtained by determining the DEGs intersection between the GSE147507 and GSE143303 datasets. These overlapped DEGs were significantly enriched in the regulation of DNA-templated transcription, initiation, clathrin-sculpted gamma-aminobutyric acid transport vesicle, DNA binding, and eight KEGG (kyoto encyclopedia of genes and genomes) pathways. The PPI network revealed that HSPA8, SRSF1, NDUFAB1, PTEN, CCT8, HIST1H2BK, HIST2H2BE, DLAT, EIF3G, and WAC, with high scores, were the hub genes. In addition, 65 TFs (transcription factors) and 369 miRNAs targeted overlapping DEGs. Finally, these overlapped DEGs were also related to other diseases, such as hyperglycemia, metabolic acidosis, and lung neoplasm, and the top 10 drugs with the most significant potential included lanatoside C, digoxin, GW-8510, doxorubicin, daunorubicin, proscillaridin, anisomycin, helveticoside, ouabain, and bisacodyl. The ROC analysis results shown that these hub genes had good diagnostic performance.

    Conclusions: HSPA8, SRSF1, NDUFAB1, PTEN, CCT8, HIST1H2BK, HIST2H2BE, DLAT, EIF3G, WAC, FOXC1, GATA2, hsa-miR-93-5p, and hsa-miR-17-5p may play vital roles in COVID-19 (corona virus disease-2019)/asthma comorbidity. Lanatoside C, digoxin, GW-8510, doxorubicin, daunorubicin, proscillaridin, anisomycin, helveticoside, ouabain, and bisacodyl may serve as drug targets against COVID-19/asthma comorbidity.

  • Article
    Ning Ma, Weidong Wu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 741-752. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.75
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    Background: Shock is a complex physiological syndrome. Although the two most common types—septic shock and cardiogenic shock—have similar presentations, their etiologies differ. Therefore, this study was conducted to investigate the transcriptomic responses to septic shock and cardiogenic shock and the related molecular mechanisms.

    Methods: The GSE131411 (GEO Series) and GSE57065 microarray datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were identified by analysis of variance, and expression patterns at three time points were analyzed using Short Time-series Expression Miner. Functional enrichment analysis was conducted using the clusterProfiler package in R, and microRNA (miRNA)-messenger RNA (mRNA) interactions were predicted with the miRWalk v3.0 platform. Characteristic genes associated with septic shock were identified and confirmed using a support vector machine model.

    Results: In total, 28 genes were found to be differentially expressed in response to both septic shock and cardiogenic shock. These common differentially expressed genes were mainly enriched in the systemic lupus erythematosus pathway as well as in several biological processes (including the humoral immune response and phagocytosis). Furthermore, 467 interactions comprising 191 miRNAs and 150 mRNAs were established in the miRNA-mRNA network. The differentially expressed genes unique to the septic shock response were mainly enriched in the cytokine-cytokine receptor interaction and proteoglycans in cancer pathways as well as in the T-cell activation and leukocyte migration processes. AURKB (aurora kinase B), CEACAM6 (CEA cell adhesion molecule 6), AZU1 (azurocidin 1), DEFA4 (defensin alpha 4), CHI3L1 (chitinase 3 like 1), and FCER1A (Fc epsilon receptor 1a) were identified as characteristic septic shock-related genes, and the support vector machine model based on these six genes showed better predictive performance than that of previously identified genes associated with sepsis.

    Conclusions: The development of cardiogenic shock and septic shock involved changes in gene expression patterns. Several characteristic genes that distinguish septic shock were identified. This study provides a basis for distinguishing between cardiogenic shock and septic shock and is expected to improve diagnosis and guide treatment choices.

  • Article
    Yanli Yi, Yan Luo, Ruijing He, Haoyun Zhang, Zai Wang, Xianqiao Li, Jingchao Zhang, Zhiqiang Cui
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 753-761. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.76
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    Objective: To investigate the molecular mechanism of microRNA-425-5p promoting breast cancer cell proliferation, explore new targets of miR-425-5p in breast cancer, and provide new biomarkers and drug targets for clinical diagnosis and treatment.

    Methods: The miR-425-5p expression in BC (breast cancer) tissues and cells was assessed using the real-time quantitative polymerase chain reaction (RT-PCR) method. A miR-425-5p inhibitor or mimic was propagated into BC cells, and the cell proliferation was detected using cell counting kit-8 (CCK-8). The downstream target genes of miR-425-5p were predicted by using bioinformatics data resources and were subsequently verified via luciferase and western blotting assays.

    Results: The expression of miR-425-5p was higher in the BC tissues and cells than normal tissues (p < 0.01), while miR-425-5p silencing hindered the proliferation of BC cells (p < 0.05). And the expression of dihydropyrimidinase-like 2 (DPYSL2) RNA and protein levels were upregulated by miR-425-5p inhibitors (p < 0.01), while the miR-425-5p mimics reduced both the expression of DPYSL2 transcripts (p < 0.05) and the level of proteins (p < 0.01). Finally, the miR-425-5p connected to the three prime untranslated region of DPYSL2, suppressed the expression of DPYSL2 and promoted the growth of BC cells.

    Conclusions: These results indicated that miR-425-5p is a novel target in the treatment of BC and could provide new drug targets for clinical diagnosis and treatment.

  • Article
    Hong SHEN, Ning FAN, Ke MENG, Li-Ya WANG, Hai SUN, Dong-Hua LI, Qiao-Ying GAO, Shang-Wei WU, Yun-Feng CUI
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 763-771. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.77
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    Background: Comprehensive prescription of herbs (CPH) has been utilized for the clinical treatment of gallstone disease (GSD) in China. Our study attempted to observe how lipid-related genes interacted with other candidate gallstone genes after prolonged intake of a lithogenic diet (LD) and to assess the molecular mechanism through which CPH exerted biological effects on lipid-related genes in a mouse model of cholelithiasis.

    Methods: Gallstones were induced in susceptible C57BL/6J mice fed an LD. The mice were randomly assigned to five groups: (A) 0 weeks plus LD (0+LD), (B) 4+LD, (C) 8+LD, (D) LD+normal saline (NS), and (E) LD+CPH. Equal amounts of CPH or NS were administered by gavage with LD for 8 weeks consecutively. A qualitative analysis of gallstones, gallstone incidence, and the microstructure of liver tissue was performed. Bile lipids and the cholesterol saturation index (CSI) were measured. The expression of lipid-related genes was analyzed by real-time polymerase chain reaction (RT-PCR).

    Results: The gallstone incidence in the 8+LD and LD+NS groups was 100%. No gallstones, floccules, or crystals were evident in the 0+LD group. The gallstone rates in the 4+LD and LD+CPH groups were 50% and 40%, respectively, and the rates of floccules and crystals were 10% and 10%, respectively. The levels of bile total cholesterol (TC), phospholipids (PL), and total bile acid (TBA), as well as the CSI, in the 4+LD and 8+LD groups were significantly higher than those in the 0+LD group, whereas TBA tended to decrease in the 8+LD group. CPH decreased the levels of TC, PL, and CSI and increased TBA. RT-PCR demonstrated that the expression of adenosine triphosphate-binding cassette subfamily G members 5 and 8 (ABCG5, ABCG8), peroxisome proliferator activated receptor alpha (PPAR-α), liver X receptor (LXR), and adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) was significantly upregulated and that the expression of sterol regulatory element-binding protein 2 (SREBP2), cholesterol 7-α hydroxylase (CYP7A1), and oxysterol 7-α hydroxylase (CYP7B1) was notably suppressed between 0 and 8 weeks of LD administration. CPH treatment may relieve gallstone formation through the downregulation of ABCB4, PPAR-α, and LXR transcription.

    Conclusions: Abnormal expression of relevant lipid-related genes and dysfunction of lipid metabolism contributes to gallstone formation. CPH may exert cholagogic function and dissolve gallstones via the normalization of lipid compositions, the reversal of tissue lesions, and the reduction in ABCB4, PPAR-α, and LXR expression.

  • Article
    Jiaqian Xu, Wenqin Xu, Xinying Zhu, Yanhong Wu, Yunxing Gao, Fangliu Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 773-781. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.78
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    Purpose: Lentinan, a traditional Chinese herbal component that is isolated from shiitake mushrooms, shows prominent antitumor activity. This study aims to evaluate the treatment effects and possible mechanisms of Lentinan on mouse breast cancer.

    Methods: A 4T1 mouse breast cancer cells were subcutaneously injected into BALB/c mice to establish a breast cancer bearing mice model. Then mice were intragastrically administrated with Lentinan in varying doses at 100 mg/kg, 200 mg/kg, and 400 mg/kg, respectively, once a day for 14 days. After Lentinan treatment, the peripheral blood of the mice was obtained and subjected to ELISA (enzyme linked immunosorbent assay) to analyze the levels of serum IFN-γ (Interferon-γ), IL-4 (Interleukin-4) and IL-35 (Interleukin-35). The tumors, thymus, spleens, and lymph node tissues were concurrently collected from the mice to evaluate IL-35 expression and iTr35 (IL-35-producing regulatory T cells) subpopulation by qRT-PCR (reverse transcription quantitative real-time PCR), Western Blot, and Flow Cytometry.

    Results: Mice treated with Lentinan improved their quality of life, suppressed tumor progression, decreased the serum IL-35 level, the expressions of p35 and EBI3 (Epstein-Barr virus-induced gene 3) in lymph nodes and spleen tissues and reduced the percentages of CD4+ T cell (cluster of differentiation 4+ T cell) and iTr35 subpopulations in peripheral blood and spleens compared to the control mice. However, IFN-γ level increased, especially in the group at the 200 mg/kg dosage in the Lentinan treated mice compared to the control mice.

    Conclusions: Lentinan was shown as immunomodulator actor to improve antitumor activity by improving the IFN-γ, decreasing the IL-35 expression, and reducing the iTr35 cell subpopulation in the 4T1 breast cancer-bearing mice.

  • Article
    Wanting Wang, Zhaoqiang Feng, Jinghui Bai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 783-788. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.79
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    Background: At present, no research has systematically integrated existing data to assess the risks of cardiovascular toxicity caused by sunitinib. The goal of this study was to evaluate the risks of cardiovascular toxicity in patients with cancer who were taking sunitinib.

    Methods: Randomized controlled trials which used sunitinib to treat cancer patients and were published before 15 November 2021, were searched in Embase, Web of Science, and PubMed. Outcomes included cardiovascular toxicities such as hypertension, bleeding, and thromboembolism. Meta-analysis was performed using Stata (15.0, STATA Corp., College Station, TX, USA).

    Results: Eleven studies encompassing 5875 patients were included. Use of sunitinib was found to increase cardiovascular toxicity in patients, including all-grade hypertension (RR (relative risk) = 4.74, 95% CI 3.24–6.92), high-grade hypertension (RR = 4.13, 95% CI 2.95–5.76), and all-grade bleeding (RR = 3.16, 95% CI 2.38–4.20). However, sunitinib did not increase risks of all-grade thromboembolism in cancer patients compared to controls (RR = 1.45, 95% CI 0.44–4.79).

    Conclusions: This meta-analysis showed that use of sunitinib increases cardiovascular toxicity in patients with cancer. Doctors should understand these clinical risks and regularly perform cardiovascular monitoring.

  • Article
    Wang Tong, Junchao Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 789-798. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.80
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    Background: To analyze the pharmacological effects and molecular mechanisms of Qiju Decoction to treat acute lung injury (ALI) based on network pharmacology.

    Methods: The main chemical components of Qiju Decoction were collected from Traditional Chinese Medicine Systems Pharmacology Database. Analysis of the Platform, literature collection and screening of the active components and their targets were performed according to pharmacokinetics. Targets related to acute lung injury (ALI) were collected from Genecards, OMIM (Online Mendelian Inheritance in Man), DrugBank and TTD (Therapeutic Target Database). Network of protein-protein interactions were established using STRING database, the picture of the interconnection of Chinese medicine ingredients, targets and pathways was constructed using Cytoscape software. Metaspace database was used for Gene ontology (GO) analysis, and kyoto encyclopedia of genes and genomes (KEGG) analysis.

    Results: The core active ingredients of Qiju Decoction to treat acute lung injury were quercetin, kaempferol, Luteolin, Arachidonic acid, etc. The core targets of Qiju Decoction to treat ALI were ALB (Albumin), AKT1 (RAC-alpha serine/Threonine-protein kinase), TP53 (Cellular tumor antigen p53), TNF (Tumor necrosis factor), IL-6 (Interleukin-6), VEGFA (Vascular endothelial growth factor A), CASP3 (Caspase-3), EGFR (Epidermal growth factor receptor), IL-1β (Interleukin-1 beta), JUN (Transcription factor Jun), STAT3 (Signal transducer and activator of transcription 3), MAPK (Mitogen-activated protein kinase), etc. The biological pathways of Qiju Decoction to treat ALI are mainly PI3K-Akt (Phosphatidylinositol 3 kinase/Protein kinase B) signaling pathway, MAPK signaling pathway and TNF signaling pathway, which functions are mainly to regulate intracellular inflammatory response and oxidative stress response, etc.

    Conclusions: This study revealed the multi-component, multi-target, and multi-pathway mechanism of Qiju Decoction to treat acute lung injury. It provides the basis for the clinical development and utilization of Qiju Decoction.

  • Article
    Ping Gao, Xuguang Liu, Chen Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 799-806. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.81
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    Background: This study investigated the differences of the clinical treatment effect, prognosis, and immune functions of patients with aneurysmal subarachnoid hemorrhage (aSAH) between the treatment of intracranial clipping and interventional embolization.

    Methods: A total of 120 aSAH patients were recruited for this study. Participants were randomly allocated into the interventional embolization group (n = 60) and the intracranial clipping group (n = 60). The prognosis of patients was examined by Glasgow Outcome Scale (GOS). Serum immunoglobulin (Ig)G, IgA, and IgM levels were evaluated by immunoturbidometric method. The serum levels of C-reactive protein (CRP), cortisol (Cor), and interleukin-6 (IL-6) were quantified using enzyme-linked immunoassay (ELISA).

    Results: The rate of patients with a good prognosis was 28.3% in the interventional embolization group when compared to 18.3% in the intracranial clipping group. After treatment, the interventional embolization group had lower incidence of complications (p = 0.0006), longer hospital duration (p = 0.0032), and higher costs (p < 0.0001) than the intracranial clipping group. Meanwhile, serum levels of IL-6, cortisol, and CRP of the interventional embolization group were significantly lower than those in the intracranial clipping group 1-day and 3-day post-operation (all p < 0.05).

    Conclusions: In conclusion, aSAH patients treated with interventional embolization had a lower incidence of complications, better prognosis, shorter hospital duration, and lower degree of stress response and immunosuppression than those treated with intracranial clipping.

  • Article
    Yong-Sheng Cao, Qi-Fei Deng, Ying Liu, Han Chu, Bo Peng, Xiang Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 807-813. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.82
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    Background: Cryptorchidism has gradually become one of the common congenital malformations of the urinary system. In this study, we explored the influence of vitamin D (VD) on testicular recovery after cryptorchidism and elucidated the underlying mechanism.

    Methods: The correlation between 25-(OH) (oxhydryl) VD levels and postoperative testicular volume in 30 children undergoing cryptorchidism surgery was analyzed retrospectively. Thirty 20-day-old cryptorchidism SD (Sprague-Dawley) rats were divided into cryptorchidism (group A, sacrificed when diagnosed), postoperative (group B, sacrificed 20 days after orchiopexy with normal feeding), and VD groups (group C, sacrificed after orchiopexy with VD feeding). Ten 20-day-old SD rats were used as the control group. The protein expression levels of Caspase-1, IL-1β (interleukin-1 beta), and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) were determined using western blotting, and cGAS and STING mRNA levels were determined using real-time PCR (polymerase chain reaction).

    Results: Testicular size after cryptorchidism positively correlated with body 25-(OH) VD levels. The weights of the testis and epididymis were the highest in group C. The expression levels of pyroptosis-related proteins (NLRP3, IL-1β, and caspase-1) in the testes were lower in group C than those in groups A and B. The expression levels of cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase), and STING (stimulator of interferon genes) in testicular tissues were the highest in group A and comparable in groups B and C.

    Conclusions: Cryptorchidism surgery combined with VD can promote rapid testicular recovery. VD supplementation reduces pyrogenesis, modulates the cGAS-STING signaling pathway, and promotes testicular recovery after cryptorchidism surgery.

  • Article
    Feng Xiao, Chuanli Liu, Junjie Wang, Yingnan Wei, Xinyu Wang, Yuemin Feng, Qiang Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 815-823. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.83
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    Background: High glutamate dehydrogenase (GLDH) levels are associated with hepatocellular carcinogenesis. This study investigated the value of preoperative serum GLDH levels in predicting postoperative recurrence in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).

    Methods: In total, 176 patients with HBV-related HCC who underwent hepatectomy were retrospectively evaluated. The optimal GLDH cut-off value to predict recurrence was determined using the receiver operating characteristic curve (ROC) model. The relationship between GLDH level and clinicopathological markers was investigated. Finally, risk variables for tumor recurrence were identified, and the value of GLDH level in predicting disease-free survival (DFS) of patients was evaluated.

    Results: The optimal cut-off value of GLDH level was 11.2 U/L (area under the curve, 0.676; 95% confidence interval, 0.597–0.754), which was used to divide patients into high (>11.2 U/L) and low (≤11.2 U/L) GLDH groups. High GLDH levels were associated with older age, multiple tumors, larger tumor diameter, higher alpha-fetoprotein (AFP) levels, vascular invasion, higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and advanced Barcelona Clinic Liver Cancer stage (all p < 0.05). High GLDH (>11.2 U/L) was an independent predictor of DFS (p < 0.001). Furthermore, the 1-, 2-, and 3-year DFS rates in patients with GLDH >11.2 U/L were significantly shorter than those in patients with GLDH ≤11.2 U/L (35.6%, 13.3%, and 10.0% vs. 74%, 56.5%, and 47.2%, p < 0.001). A sensitivity analysis of patients divided into high (>6.25 U/L) and low (≤6.25 U/L) GLDH groups according to the median GLDH value was also conducted, and the results were consistent with the main analyses.

    Conclusions: GLDH might be a potential recurrence predictor in HBV-related HCC patients undergoing hepatectomy.

  • Article
    Xin Xie, Ning Zhang, Hongchao He, Xiaojing Wang, Wenbin Rui, Danfeng Xu, Wei He, Yu Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 825-835. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.84
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    Background: Although discoidin domain receptor 1 (DDR1) can enhance cell invasion in bladder cancer by regulating the expression of epithelial-mesenchymal transition (EMT)-related molecules, the isoforms responsible for the phenomenon are still unknown. The purpose of our research was to identify the DDR1 isoform responsible for promoting bladder cancer progression, and potential mechanisms.

    Methods: The expression of DDR1a, DDR1b, COL4 (type IV collagen), MMP2 (matrix metalloproteinase-2), and EMT-related genes in bladder cancer cells or tissues was evaluated using western blotting, quantitative reverse transcription PCR (polymerase chain reaction), as well as immunohistochemistry. T24 cells (human bladder cancer cells) were transfected independently with DDR1 inhibitor, DDR1 overexpressed plasmid, and siRNA-ZEB1 (zinc-finger E-box binding homeobox 1). Then, the cell proliferation, as well as migration and invasion were examined by cell counting kit-8, and Transwell assays, respectively. Finally, an in vivo tumorigenic experiment was carried out to explore the actions of DDR1a in tumor invasion and metastasis.

    Results: In comparison with the SV-HUC-1 cells (human ureteral epithelial immortalized cells), DDR1a, COL4, vimentin, E-cadherin, and ZEB1 were overexpressed in T24 cells, while DDR1b expression was not significantly different between the two cell lines. Immunohistochemistry revealed that COL4 was significantly overexpressed in tumor tissues. In the background of DDR1 inhibition, the expression of COL4, MMP2, E-cadherin, Slug, and ZEB1 decreased significantly. DDR1a overexpression promoted bladder cancer cell proliferation. Meanwhile, ZEB1 silencing reversed the effect of DDR1a overexpression with respect to cell growth. The in vivo tumorigenic assay yielded results similar to those obtained in in vitro experiments.

    Conclusions: DDR1a promotes invasion and metastasis in bladder cancer via regulating the ZEB1/COL4 axis.

  • Article
    Zhaoyang Ruan, Zehai Xia, Qinxia Zhang, Zhangdan Huang, Qun Lv
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 837-844. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.85
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    Objective: This study aimed to evaluate the effect of continuous positive airway pressure (CPAP) effect on the cognitive function in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS).

    Methods: Twenty-four severe OSAHS patients diagnosed by polysomnography (PSG), and twenty-two healthy adults were included. OSAHS group underwent Epworth Sleepiness Scale (ESS), Montreal Cognitive Assessment (MoCA) score, and resting-state functional magnetic resonance imaging (rs-fMRI) scan before and after CPAP therapy. A statistical map of different brain regions of regional homogeneity (ReHo) was obtained by rs-fMRI images process with Matlab. Cognitive function brain areas in patients with OSAHS were assessed by evaluating changes of cognitive function and neurological function imaging to evaluate the clinical efficacy of CPAP.

    Results: Compared with the healthy control group, the apnea-hypopnea index (AHI), oxygen desaturation index (ODI) and ESS score were significantly increased, while the lowest oxygen saturation (LSaO2), mean oxygen saturation (MSaO2) and MoCA score were significantly decreased (p < 0.05) before treatment in OSAHS group. In OSAHS group, AHI, ODI and ESS scores after CPAP treatment were significantly lower than before treatment, while LSaO2, MSaO2 and MoCA scores were significantly higher than before treatment (p < 0.05). ESS scores in OSAHS group were significantly positively correlated with AHI (r = 0.687, p < 0.05) and ODI (r = 0.541, p < 0.05), and MoCA scores were significantly negatively correlated with AHI (r = –0.801, p < 0.05) and ODI (r = –0.783, p < 0.05). The ReHo values of the right angular gyrus, right precuneus, left parahippocampal gyrus, and left middle frontal gyrus were reduced in the OSAHS group at baseline compared to the healthy control group, while the ReHo values in the right posterior lobe of the cerebellum increased. The ReHo value of the right posterior cerebellar lobe in the OSAHS group and the healthy control group was positively related to the MoCA score (r = 0.324, p < 0.05). The ReHo value of the right precuneus before and after CPAP treatment in the OSAHS group was positively related to AHI (r = 0.478, p < 0.05) and negatively correlated to the MoCA score (r = 0.484, p < 0.05).

    Conclusions: Patients with severe OSAHS generally have cognitive dysfunction, and the structure and function of several brain regions have abnormal changes. After CPAP intervention for 3 months in patients with severe OSAHS, the neural activities of the left limbic lobe, right temporal lobe, posterior cingulate gyrus, and precuneus were increased. Changes in brain activity in these regions may be the neural functional basis for the emergence of cognitive function.

  • Article
    Xiali Yu, Xinwei Song, Zhenliang Fan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 845-853. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.86
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    Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular disease and tissue fibrosis in the skin and internal organs. Astragalus polysaccharide (APS) is an extract from dried stem of Astragalus membranaceus which can effectively delay SSc progression. The present study aimed to explore the role and mechanism of APS on SSc skin fibrosis.

    Methods: In vivo, bleomycin (BLM) was used to establish SSc skin fibrosis mice model. After that, the mice were intravenously injected with APS daily for 21 days. Hematoxylin-eosin (HE) staining and Masson staining were applied to detect the pathological changes in skin tissues. The hydroxyproline content of skin tissues was used to assess collagen deposition. In vitro, human foreskin fibroblast-1 (HFF-1) cells were stimulated by transforming growth factor-β1 (TGF-β1) to establish skin fibroblast fibrosis. HFF1 cells were treated with APS and transfected with micro RNA (miRNA)-30b mimic, inhibitor and short hairpin RNA against PTP4A1 (sh-PTP4A1). qRT-PCR (quantitative real-time polymerase chain reaction) and western blot were used to assess fibrosis-related markers expression. Dual luciferase reporter assay was carried out to explore the relationship between miR-30b and PTP4A1.

    Results: Our study found that in vivo, BLM induction increased skin thickness, inflammatory infiltration, and collagen accumulation, whereas APS intervention reversed BLM-induced SSc skin fibrosis and up-regulated miR-30b expression. In vitro, TGF-β1 intervention up-regulated fibrosis-related markers expression, which was reversed by APS. In addition, miR-30b inhibitor blocked APS effect on alleviating skin fibrosis. Therefore, we speculate that PTP4A1 is a potential target for the mechanism of miR-30b. Knockout of PTP4A1 eliminated the effect of miR-30b inhibitors on TGF-β1 and APS-induced HFF-1 cells.

    Conclusions: APS relieved SSc skin fibrosis by miR-30b upregulation targeting PTP4A1, which provides a novel insight to treat SSc.

  • Article
    Jinhua Xu, Jingjing Li, Guofeng Wu, Yajun Ren, Xue Wang, Qianyun Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 855-861. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.87
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    Background: We evaluated the effect of pemetrexed combined with cisplatin on the immune system of non-small cell lung cancer (NSCLC) patients.

    Methods: 376 NSCLC patients were divided into the pemetrexed plus cisplatin treatment group (PT group, n = 191) and the docetaxel plus cisplatin treatment group (DT group, n = 185). Patients in the PT group received 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin. Patients in the DT group received 75 mg/m2 docetaxel and 75 mg/m2 cisplatin.

    Results: Carbonic anhydrase IX (CA-IX) levels, osteopontin (OPN), interleukin-1β (IL-1β), IL-6, and C-reactive protein (CRP) was similar between groups. After treatment, the PT group had significantly higher interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) levels than the DT group. Treatment with pemetrexed plus cisplatin did not change CD4+ T cell or CD8+ T cell levels. Moreover, the PT group exhibited significantly lower neuron-specific enolase (NSE), carbohydrate antigen 199 (CA199), and carcinoembryonic antigen (CEA) levels.

    Conclusions: Pemetrexed plus cisplatin and docetaxel plus cisplatin showed equivalent therapeutic efficacy in NSCLC patients. Meanwhile, NSCLC patients treated with pemetrexed plus cisplatin showed higher IFN-γ and TNF-α levels, and lower levels of CD4+ T cells and tumor markers than those treated with docetaxel plus cisplatin.

  • Article
    Haruka Shimokado, Sayaka Ikejima, Mizuki Kanegae, Rin Imanishi, Kyohei Takata, Jun Nakata, Soyoko Morimoto, Sumiyuki Nishida, Fumihiro Fujiki, Hiroko Nakajima, Takayuki Ishida, Yoshihiro Oka, Haruo Sugiyama, Yusuke Oji
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 863-873. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.88
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    Background: Aging-related decline in the immune system is associated with cancer development. Anti-tumor immunity in healthy young adults needs to be elucidated as it is the starting point of the declining course. Here, we aimed to identify antitumor immune responses in healthy young adults.

    Methods: We analyzed the cellular and humoral immune responses to tumor-associated antigens (TAAs) in nine individuals aged 22–30 (average 23.9) years with HLA-A*24:02. The TAAs included Wilms’ tumor 1 (WT1), New York-esophageal cancer-1 (NY-ESO-1), eukaryotic elongation factor 2 (eEF2), and programmed death ligand 1 (PDL1). We examined TAA antigenic epitope-specific secretion of Th1 (T helper-1)-type cytokines, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and Th2-type cytokine interleukin 10 (IL-10) from peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunospot (ELISPOT) assay. Serum levels of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against these tumor-associated antigen (TAA) epitopes were examined using an enzyme-linked immunosorbent assay (ELISA).

    Results: The ELISPOT assay revealed that PBMCs from all nine individuals secreted Th1-type cytokines in response to stimulation with TAA antigenic epitopes, showing TAA-specific cellular immune responses. ELISA results revealed that eight of the nine individuals had IgM antibodies against multiple TAA epitopes. IgG antibodies were produced against multiple TAA epitopes in six individuals and against a single TAA epitope in two different individuals. Notably, different modes of cellular and humoral immune response were observed for each specific TAA epitope.

    Conclusions: Healthy young adults exhibit cellular and humoral immune responses to multiple TAAs. These findings provide an essential piece for understanding antitumor immune surveillance in the context of immune aging.

  • Article
    Yun-nan Hu, Xiao-chai Lv, Xiao-dong Chen, Xing-feng Chen, Liang-wan Chen, Fan Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 875-884. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.89
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    Objective: Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) promote aortic dissection (AD). However, the mechanisms involved remain unclear. This study evaluated IL-1β and TNF-α effect on mitogen-activated protein kinase (MAPK) signaling and matrix metalloproteinase 9 (MMP-9) expression in dissected rat aorta receiving mechanical stretch.

    Methods: Rats were administered with β-aminopropionitrile to produce an AD model. Dissected aortas were mechanically stretched (3 g) and incubated with TNF-α, IL-1β, and inhibitors of the c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways (SB203580, U0126, and SP600125, respectively). IL-1β, TNF-α, ERK1/2, phospho-p38 (p-p38), p38, p-ERK1/2, JNK1, p-JNK1, and MMP-9 levels were assessed by immunohistochemical analysis and/or quantitative real-time polymerase chain reaction (qRT-PCR).

    Results: IL-1β, TNF-α, p-ERK1/2, p-p38, p-JNK1, and MMP-9 levels increased in the 3 g group relative to the 0 g group (p < 0.05) and were up-regulated by exogenous IL-1β and TNF-α in both the 0 and 3 g groups (p < 0.05). Treatment with p38/ERK1/2/JNK inhibitors remarkably down-regulated IL-1β, TNF-α, p-ERK1/2, p-p38, p-JNK1, and MMP-9 in the 3 g + IL-1β and 3 g + TNF-α groups (p < 0.05). IL-1β, TNF-α, p-ERK1/2, p-p38, p-JNK1, and MMP-9 levels were significantly lower in the 3 g + SB203580/SP600125/U0126 + IL-1β and 3 g + SB203580/SP600125/U0126 + TNF-α groups than the 3 g group (p < 0.05).

    Conclusions: Our data demonstrated that MMP-9 was up-regulated by IL-1β and TNF-α through ERK1/2/p38/JNK signaling in dissected rat aorta.

  • Article
    Suqin Zhang, Jianhua Zhou, Qiuyue Wang, Peitong Wen, Yingying Han, Qingxiang Hong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 885-895. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.90
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    Objective: Icariin (ICA) may have an antiaging effect. However, whether this applies to its hepatic cell remains unclear. The aim of this study was to explore the effect and mechanism of action of ICA on hepatic cell senescence.

    Methods: Serum exosomes isolated from patients with hepatitis B virus-induced liver cirrhosis were utilized to induce senescent phenotypes of human hepatic sinusoidal endothelial cells (HHSECs). ICA, microRNA-22-3p (miR-22-3p) inhibitor and mimic, and sirtuin 1 (SIRT1) overexpression were applied, to investigate the effect of ICA. Senescence-associated β-galactosidase (SA-β-gal) staining, flow cytometry, and quantitative real-time polymerase chain reaction and Western blot were employed to determine cellular senescence, cell cycle progression, and RNA and protein levels, respectively. A dual-luciferase reporter gene assay was performed to validate the binding between miR-22-3p and SIRT1.

    Results: Serum exosomes significantly promoted the senescent phenotypes of HHSECs, as revealed by the increased SA-β-gal positive cell number and cell cycle arrest at G1 phase. However, ICA significantly reversed these alterations, in a dose-dependent manner. miR-22-3p was shown to target SIRT1. miR-22-3p upregulation significantly promoted cell senescence and significantly downregulated SIRT1 levels, which could be duplicated by overexpressing SIRT1. Furthermore, the suppressive effect of ICA on cellular senescence and its promoting action on upregulating SIRT1 were significantly reversed by overexpressing miR-22-3p.

    Conclusions: ICA has an anti-aging effect on human hepatic sinusoidal endothelial cells, which is effected through miR-22-3p and its target SIRT1.

  • Article
    Zhengfang Xiong, Bing Li, Wenjuan Wang, Rui Wang, Ronghua Ma, Shengyan Jian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 897-904. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.91
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    Objectives: Most patients with polycystic ovary syndrome (PCOS) have glucose/lipid metabolism. Complement C1 tumor necrosis factor-related protein 1 (CTRP1) is an indicator of glucose/lipid metabolism in many diseases. However, the correlation between CTRP1 and PCOS is not clear.

    Method: This is a cross-sectional study. CTRP1 plasma concentration level in 210 PCOS and 316 non-PCOS patients undergoing in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) was assessed. Among PCOS patients 2 groups were formed depending on the presence of insulin resistance, the PCOS-IR (insulin resistance) (n = 84) and PCOS-NIR (non-IR) groups (n = 126). The inflammatory markers, antioxidant enzyme levels of follicular fluid and CTRP1 levels in PCOS group and non-PCOS group were compared. The levels of inflammation markers and antioxidant enzymes in follicular fluid and CTRP1 levels were compared between PCOS-IR group and PCOS-NIR group. Pearson correlation analysis was used to analyze the relationship between CTRP1 and glucose/lipid metabolism and gonadotropin dose in PCOS patients.

    Results: PCOS patients exhibited significantly higher plasma concentration of CTRP1 than non-PCOS patients (p < 0.001). Besides, the CTRP1 level was significantly elevated in PCOS-IR compared to PCOS-NIR group (p < 0.001). CTRP1 was strongly associated with markers of dyslipidemia and high gonadotropin dose (p < 0.05). In addition, CTRP1 expression level in the follicular fluid was higher in PCOS-IR sufferers and had a negative effect on inflammatory response, peroxidation, and antioxidant enzyme index.

    Conclusions: PCOS patients, especially PCOS-IR patients, show significantly CTRP1 up-regulation. CTRP1 may serve as a new marker for PCOS-IR patients. In addition, there is a correlation between the circulation of CTRP1 and glucose/lipid metabolic disorder in PCOS patients.

  • Article
    Jie Zha, ChangFang Wu, Zhen Gao, HongZhe Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 905-915. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.92
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    Objectives: Pulmonary arterial hypertension (PAH) is a disease characterized by the dysfunction of the lung endothelium and angiogenesis. In this study, we aimed to investigate the effects of granulocyte chemoattractant protein 2 (GCP-2) overexpression on adipose-derived stem cells (ADSCs) and the role of ADSCs overexpressing GCP-2 (ADSC-GCP-2) in PAH.

    Methods: ADSCs were obtained from the adipose tissues of rats and the expression of CD29 and CD45 surface antigens was detected by flow cytometry. The symptoms and tissue damage of PAH rats induced by monocrotaline were evaluated by observing the weight, heart rate, mean blood pressure (MBP) and hematoxylin-eosin (HE) staining. The mRNA and protein expression of genes were tested by Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Transwell® and tube formation assays were adopted to measure cell migration and tube formation capacity. Finally, the levels of vascular regulatory and inflammatory factors were measured by ELISA (Enzyme-Linked Immunosorbent Assay).

    Results: The improvement of cell migration ability, angiogenesis ability (upregulated VEGF (Vascular Endothelial Growth Factor)-A, FGF2 and TGF-β1), tube formation ability and decreased proinflammatory factors levels (downregulated IL (Interleukin) and TNF (Tumor Necrosis Factor)-α) in MBP induced by monocrotaline was significantly downregulated in the rats with ADSC-GCP-2 treatment compared with ADSC-vector, accompanied by improvement in pulmonary artery thickening and vascular remodeling (downregulated VEGF, HGF and α-actin). Moreover, ADSC-GCP-2 could also significantly reduce tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A, and IL-23 levels and increase IL-10 levels to alleviate inflammation in PAH rats (p < 0.01). In addition, ADSC-GCP-2 activated the apelin/APJ (Angiotensin Receptor-Like 1) and eNOS signaling pathways in PAH rats.

    Conclusions: ADSC-GCP-2 significantly alleviated PAH progression by regulating the apelin/APJ and eNOS signaling pathways. This study provides a potential therapeutic direction for treating PAH.

  • Article
    Xiang-yi Kong, Xue-song Yang, Guangyun Luo, Zhimin Wang, Shuangli Xia, Jing Mu, Fang Wang, Jian-zhou Ye
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 917-925. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.93
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    Objective: This study was carried out to examine the effect of electroacupuncture (EA) on wound healing and thrombosis in frostbite mice (Mus musculus). Furthermore, it preliminarily examined the molecular mechanism of its action.

    Methods: The mice were divided into Sham group, Frostbite group and Frostbite+EA group randomly. Frostbite mice received EA treatment (1 mA of intensity and 2 Hz of frequency) for 30 min once daily for 21 days. At three weeks, frostbite wound area was calculated. Mice histopathological changes were observed using hematoxylin-eosin (H&E) and Masson staining. The levels of thrombo-related factors, 6-keto-prostaglandin F1α (6-K-PGF1α) and thromboxane B2 (TXB2) levels were analyzed using enzymelinked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), interleukin (IL)-1β and tumor necrosis factor-(TNF-α) protein levels were determined using western blot.

    Results: Compared with frostbite rats, the average wound area of frostbite rats treated with EA was significantly reduced compared with frostbite rats (p < 0.05). Moreover, the mice skin tissue structure in frostbite+EA group was more complete and clearer, and showed higher levels of collagen than in frostbite group at three weeks after frostbite. In addition, NF-κB, IL-1β, TLR4, TNF-α protein levels in the skin tissue and the TXB2/6-K-PGF1α ratio in serum of frostbite rats significantly decreased after EA treatment (p < 0.05).

    Conclusions: EA can promote wound healing, inhibit thrombosis in frostbite mice, possibly via inhibiting the TLR4/NF-κB signaling pathway.

  • Article
    Chucheng Zhong, Xiaozhen Shen, Zhiyu Li, Xiaogang Zhao, Xueping Luo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 927-932. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.94
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    Objectives: To investigate microRNAs (miRNAs) gene polymorphisms and serum lipoprotein expression levels in patients with primary lung cancer metastasis, and to provide new ideas and basis for the diagnosis and treatment of primary lung cancer.

    Methods: From July 2016 to August 2018, 400 patients who were diagnosed with primary lung cancer were selected as the experimental group. Among them, 280 patients with bone metastasis were recorded as group A, including 200 male patients and 80 female patients, aged 28–85 years. The remaining 120 patients without bone metastasis were recorded as group B, including 90 males and 30 females, aged 29–88 years. For the clinical data characteristics of these patients, the plasma miRNAs were extracted and detected, and single nucleotide polymorphisms (SNPs) associated with miRNAs were selected and detected. The expression levels of serum lipoprotein in the plasma of the included patients were detected. Patients with bone metastasis underwent magnetic resonance imaging (MRI) examination based on artificial intelligence full convolutional neural network (CNN).

    Results: Statistically, there were no significant differences in the distribution of gender, smoking history, and drinking history among primary lung cancer patients with and without bone metastasis (p > 0.05). The expression levels of miR-145, miR-101, and miR-126 in primary lung cancer patients with bone metastasis were 1.22, 1.42, and 1.09, respectively. The expression levels of miR-145, miR-101, and miR-126 in primary lung cancer patients without bone metastasis were 0.83, 0.91, and 0.51, respectively. Therefore, the relative expression levels of 3 miRNAs in the plasma of patients in group A were increased (p < 0.05). Among the 8 ecological sites of the three miRNAs, there was a statistical difference in the genotype frequency distribution of rs353291 between the bone metastasis group and the non-metastatic group (χ2 = 4.676, p = 0.043). The expression levels of serum lipoprotein (a) in primary lung cancer patients with bone metastasis were raised compared with patients with non-bone metastasis.

    Conclusions: This study demonstrated that miRNAs gene polymorphisms and serum lipoprotein expression levels could provide new insights and a basis for the diagnosis and treatment of primary lung cancer.

  • Article
    Zi-jie Wei, Li-hua Luo, Shuo Hu, Lin Guo, Zi-you Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 933-941. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.95
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    Objective: To examine the effect and related mechanisms of KDM2B (lysine (K)-specific demethylase 2B) on myocardial ischemia-reperfusion injury.

    Methods: The oxygen glucose deprivation and reperfusion (OGD/R) model was created using H9c2 cells to induce myocardial ischemia-reperfusion injury. With help of flow cytometry, cell cycle and apoptosis were observed. Western blot and qRT-PCR (quantitative real-time polymerase chain reaction) were employed to examine the protein and mRNA (messenger ribonucleic acid) expression of KDM2B, TLR4 (toll-like receptor 4), P65, p-P65 and NLRP3 (NOD-like receptor thermal protein domain associated protein 3). Using enzyme-linked immunosorbent assay (ELISA), IL (interleukin)-1β and TNF-α (tumor necrosis factor-α) concentrations in cell supernatant were detected.

    Results: OGD/R increased the cell apoptosis, the proportion of S phase cells, and IL-1β and TNF-α concentrations in H9c2 cells. Knockdown of KDM2B promoted the apoptosis, proportion of cells in G0/G1 phase, and the IL-1β and TNF-α concentrations in OGD/R-treated H9c2 cells. Meanwhile, knockdown of KDM2B increased the TLR4, P65 and NLRP3 mRNA and protein expression, as well as the p-P65/P-65 ratio in OGD/R-treated H9c2 cells. However, over-expression of KDM2B exhibited the opposite effects on OGD/R treated H9c2 cells.

    Conclusions: KDM2B inhibits inflammation and apoptosis of H9c2 cells under hypoxia/reoxygenation via modulating the TLR4/NF-κB (nuclear factor-κB) p65 pathway.

  • Article
    Yuhong Zhao, Jianping Cao, Yan Lv, Dawei Cui, Jue Xie
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 943-950. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.96
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    Background: The roles of human platelet antigens (HPAs) in the occurrence and management of platelet transfusion refractoriness (PTR) are still unclear. It is helpful to investigate the local genetic polymorphisms of HPAs and to evaluate the method of antigen match-compatible platelet transfusion aiming to mitigate platelet transfusion refractoriness.

    Methods: Polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) was used to perform genotyping of the HPA 1–6, 15 systems in 400 platelet donors and 60 patients with positive platelet antibody screening results, and to analyze the effect of matched platelet transfusion in those patients.

    Results: In the HPA 1–6, 15 systems, allele “b” of HPA-3 was found to have the highest frequency of 0.51, and HPA-15 has the highest heterozygosity of 0.33. The rest HPA systems were dominated by “aa” homozygotes with over 90% genotype frequencies. The results of corrected count increment (CCI) in the antigen match-compatible transfusion group were significantly better than those in the random donor transfusion group (p < 0.05). Inside the match-compatible transfusion group, there was a difference between the cross-match-compatible transfusion group and the gene-match-compatible transfusion group, but no statistical significance (p > 0.1).

    Conclusions: The prevalence of HPAs in the local population is crucial in the understanding and management of platelet-related clinical disorders. According to the devised matching rules, a local database of platelet genes should be established to provide compatible platelet products to the alloimmunized patients. The safety and efficacy of platelet transfusion are expected to be improved, and in-depth research into blood transfusion can be advanced.

  • Article
    Lei Zeng, Kexiang Zhou, Hong Yang, Peng Guo, Yumin Zhu, Jun Ding, Ping Bie, Zhiqing Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 951-959. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.97
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    Background: Hepatocellular carcinoma (HCC) is a common and deadly malignancy with poor clinical outcomes. Aerobic glycolysis is a hallmark of metabolic reprogramming in HCC progression.

    Methods: Validation of TRIM28 (tripartite motif containing 28) expression was conducted by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry assay using clinical HCC samples. Function-based experiments were carried out using TRIM28 siRNA transfection in vitro, including cell counting kit-8 (CCK-8), ethynyl-2-deoxyuridine (EDU) staining and transwell assay. Pyruvate, lactate concentration and adenosine triphosphate (ATP) level were examined through the glucose, lactate, and ATP assay kits, respectively. TRIM28 and PFKFB3 (6-phosphofructo-2-kinase) expression and colocalization were determined by immunofluorescence. RNA pulldown experiment was applied to elucidate the underlying interaction between TRIM28 and PFKFB3. Overexpression of PFKFB3 significantly reversed the TRIM28-induced cell proliferation, migration and aerobic glycolysis.

    Results: TRIM28 was up-regulated in both HCC clinical samples and cell lines. Silencing of TRIM28 inhibited cell proliferation, migration and aerobic glycolysis levels in Huh-7 cells. Immunofluorescence and RNA pulldown assays confirmed the interaction between TRIM28 and PFKFB3. Moreover, it was observed that overexpressing PFKFB3 could rescue the inhibitory impacts of TRIM28 siRNA on cell proliferation, migration and aerobic glycolysis.

    Conclusions: Our findings suggest a preclinical proof of concept for TRIM28 as a potential therapeutic target in HCC.

  • Article
    Xiao-Fang YAN, Da-Wei LIU, Lin BAI, Shou-Hong YANG, Fa-Ming CHEN, Yan GAO
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 961-968. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.98
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    Background: Diagnosis of preterm infants with bronchopulmonary dysplasia (BPD) at an early stage may improve their quality of life. However, there is no proper diagnostic method. Therefore, a specific and objective marker is critically required. Here, we aim to evaluate the predictive characteristics of human epididymis protein 4 (HE4) and krebs von den lungen-6 (KL-6) as diagnostic biomarkers for preterm infants with BPD.

    Methods: A prospective cohort study was performed on 11 preterm infants with BPD and 21 preterm infants without BPD. Plasma levels of HE4 and KL-6 were measured and compared at 1, 14, and 28 days after birth. The correlation of HE4 and KL-6 with the clinical characteristics of preterm infants was also evaluated by Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic efficiency in identifying BPD.

    Results: Interestingly, plasma HE4 and KL-6 levels were significantly increased in preterm infants with BPD at 1, 14, and 28 days after birth, and these levels were significantly correlated with gestational age, the weight of preterm infants, Apgar score (1 min), Apgar score (5 min), and invasive ventilation. ROC curve analysis showed that HE4 or KL-6 was highly capable of differentiating preterm infants with BPD from preterm infants without BPD. Notably, the combination of HE4 and KL-6 showed higher discriminatory capacity than HE4 or KL-6 alone.

    Conclusions: Plasma HE4 and KL-6 levels could serve as potential biomarkers for predicting BPD, and the combination of HE4 and KL-6 could also function as an efficient diagnostic marker.

  • Article
    Qian Zhang, Jie Tan, E Huang, Xiaorong Deng, Min Du, Hongping Wan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 969-976. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.99
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    Objectives: To assess the safety and effectiveness of transcranial magnetic stimulation (TMS) in cognitive function intervention in elderly sufferers with Alzheimer’s disease (AD).

    Methods: A total of 120 subjects aged 61–87 years who suffered from AD were assigned to a control group (n = 60) and a test group (n = 60), which were given Memantine Hydrochloride Tablets intervention and 4-week TMS intervention base on Memantine Hydrochloride Tablets intervention. The cognitive functions, mental status and activities of daily living, serum brain-derived neurotrophic factor (BDNF) and β-amyloid 1-42 (Aβ1-42) levels were estimated, and the occurrence of untoward response was recorded.

    Results: After a 4-week intervention, it was showed a significant difference between the Memantine Hydrochloride Tablets intervention and the TMS + Memantine Hydrochloride Tablets intervention in Disease Assessment Scale-Cognitive Portion (ADAS-Cog) score and Montreal Cognitive Assessment (MoCA) score, as well as the Neuropsychiatric Inventory (NPI) score and the Alzheimer Disease Assessment Scale Activities of daily living (ADCS-ADL). In terms of serum BDNF, the Aβ1-42 levels were notably higher than the BDNF levels in the test group, whereas, in the control group, they were significantly lower. As for adverse reactions, chi-square test analyses corroborated no significant difference between the test group (5.00%) and the control group (8.33%).

    Conclusions: TMS linked with the pharmacological intervention was more favorable than the pharmacological intervention alone in improving cognitive function in elderly AD subjects, and it also reduced psycho-behavioral symptoms, improved daily living ability and had a higher safety profile.

  • Article
    Jinghua Ou, Yongxiu Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 977-986. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.100
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    Background and Objective: Ubiquitin-binding enzyme E2 (UBE2E2) is a member of the human ubiquitin-binding enzyme family that has previously been shown to be closely linked to the onset of a range of cancer types. The functional importance of UBE2E2 in ovarian cancer, however, has yet to be established. Accordingly, this study was developed to explore the role of UBE2E2 as a regulator of ovarian cancer cell malignancy.

    Methods: Gene Expression Omnibus (GEO) datasets were initially used to identify differentially expressed genes related to patient prognosis, revealing UBE2E2 as a hub gene in this cancer type. Immunohistochemical staining was used to compare UBE2E2 protein levels in ovarian cancer and control tissues, while the role of this protein as a regulator of malignant activity was tested through cell counting kit-8 (CCK-8) (CK001-01, sunview, Shenzhen, China), wound healing, and Transwell assays. In addition, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of markers related to the epithelial-mesenchymal transition (EMT) process.

    Results: Significant UBE2E2 protein and mRNA overexpression was evident in ovarian tumors, and higher UBE2E2 mRNA levels were associated with a worse ovarian cancer patient prognosis. Knocking down UBE2E2 in ovarian tumor cells was sufficient to inhibit their proliferation, migration, and invasivity. This UBE2E2 silencing additionally enhanced E-cadherin protein and mRNA expression while promoting significant Vimentin, Twist1, N-cadherin, and Zeb1 downregulation.

    Conclusions: UBE2E2 can promote ovarian cancer development and progression through mechanisms potentially linked to EMT induction. As such, UBE2E2 may represent a promising target for therapeutic intervention in patients diagnosed with this debilitating malignancy.

  • Article
    Denghai Wu, Binhua Jiang, Jianan Lian, Jian Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 987-995. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.101
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    Background and Purpose: To investigate the expression and biological functions of secreted protein acidic and rich in cysteine-like 1 (SPARCL1) in the tumor microenvironment of colorectal cancer liver metastases (CRCLM). More over the study aimed to provide a new molecular marker for targeted therapy.

    Methods: Thirty male C57BL6/J mice were randomly divided into the control group (n = 3), the CRCLM group (n = 7), the CRCLM+Lv-vector group (n = 5), the CRCLM+Lv-SPARCL1 group (n = 5), the CRCLM+Lv-vector shRNA group (n = 5), and the CRCLM+Lv-SPARCL1 shRNA group (n = 5). Mice liver tissues in each group was obtained. The histopathological changes and indexes were measured by hematoxylin and eosin (H&E) staining, Reverse transcription quantitative PCR (polymerase chain reaction) (RT-qPCR), western blot, Masson staining, Enzyme-linked immunosorbent assay (ELISA), and flow cytometry.

    Results: SPARCL1 mRNA and protein expression levels in the CRCLM group decreased compared to the control group (p < 0.05). Further SPARCL1 upregulation reduced the metastatic foci number, collagen area (%), expression of collagen I, collagen Ⅲ, α-SMA (sarcomeric actin), CCL20 (chemokine CC-motif ligand 20), CCR6 (CC chemokine receptor 6), N-cadherin, and vimentin, percentage of Th17 cells, and IL (interleukin)-1β, IL-17, and TNF (tumor necrosis factor)-α content (p < 0.05). However, E-cadherin expression and IL-6, IL-8, and IL-10 content increased (p < 0.05). In contrast, downregulating SPARCL1 reversed the above index trends.

    Conclusions: SPARCL1 effectively reduced liver metastasis, collagen deposition, and liver fibrosis. Furthermore, it activated CCL20/CCR6 axis to inhibit immune responses and epithelial-to-mesenchymal transition (EMT), thus providing an experimental basis for targeted therapy.

  • Article
    Fangting Li, Yangsheng Huang, Fang Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 997-1007. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.102
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    Background and Purpose: Periodontitis was a common inflammatory disease which can lead to bone loss caused by bacterial infection, with the necessity to use local or systemic medication. It has been reported that Liraglutide (Lira) was effective in the treatment of periodontitis. However, its mechanism remains unclear. This study aimed to investigate the dental protective effect and potential mechanisms of Liraglutide on periodontitis rats.

    Methods: Specific Pathogen Free (SPF)-grade Wistar rats were placed with silk ligatures at the maxillary first molars to induce periodontitis. Rats were administered with different doses of Liraglutide or same volumes of saline (controls group) to investigate whether Lira could alleviate the periodontitis. Meanwhile, adenovirus-encapsulated si-Nrf2 or empty plasmid si-NC (normal control) were administered to investigate whether the protective effect was through the Nrf2/HO-1 signaling pathway. Alveolar bone loss was examined by micro-CT (Computed Tomography). Periodontal tissue paraffin sections were prepared by hematoxylin and eosin (H&E) staining and immunohistochemistry, or tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts. Oxidative stress indicators were assessed by ELISA (Enzyme-Linked Immunosorbent Assay); GLP-1R and Nrf2 mRNA levels were examined by RT-qPCR (Real Time Quantitative PCR), while the expression level of GLP-1R, Nrf2, HO-1, NADH dehydrogenase, Quinone 1 (NQO1), and inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) were measured by western blot.

    Results: Compared with the control group, the expression level of GLP-1R mRNA TNF-α, IL-1β and IL-6, osteoclast number, and malondialdehyde (MDA) content were significantly higher in the periodontitis group (p < 0.05), whereas the level of glutathione peroxidase (GSH-Px), Nrf2, HO-1 and NQO1 were remarkably lower (p < 0.05). However, these changes could be reversed after the administration of Lira and showed a dose-dependent effect. Moreover, the levels of Nrf2 mRNA, HO-1, NQO1 and GSH-Px were higher in the periodontitis + Lira (H) + si-NC group (p < 0.05) when compared with the periodontitis + solvent + si-NC group, but the levels of MDA, TNF-α, IL-1β and IL-6 were lower (p < 0.05). However, the knockdown of Nrf2 could effectively reverse these changes.

    Conclusions: Lira could protect periodontal tissues by inhibiting alveolar bone resorption, inflammation and oxidative stress through activation of the Nrf2/HO-1 pathway, which may have therapeutical implications in clinical management of periodontitis.

  • Article
    Hao Sun, Yuan Zhang, Zhe Jiang, JiaEn Miao, KuiHao Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1009-1016. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.103
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    Background: Previous studies have indicated that telomere-binding proteins, like TPP1 (telomere protection protein 1) and POT1 (protection of telomeres 1) might be associated with the aggressive biological behavior and prognosis of hepatocellular carcinoma (HCC). This study assessed TPP1 and POT1 in patients with hepatitis, liver cirrhosis, and HCC, and then evaluated their diagnostic value to differentiate HCC from benign liver disease.

    Methods: Whole blood TPP1 and POT1 levels in healthy controls (n = 267), and patients with hepatitis B (n = 209), liver cirrhosis (n = 248), or HCC (n = 248) were measured by real-time reverse transcriptase-polymerase chain reaction and Western blotting. Receiver operating characteristic curve analysis evaluated the diagnostic value of TPP1 and POT1 in HCC.

    Results: TPP1 and POT1 levels in whole blood of HCC patients were higher than that those with benign liver disease (hepatitis B + liver cirrhosis) and healthy controls (p < 0.05). In addition, TPP1 and POT1 showed good diagnostic performance to distinguish HCC from healthy controls, with an area under the curve (AUC) of 0.86 for TPP1, a sensitivity of 81.63%, and a specificity of 86.50%. The AUC of POT1 was 0.87, the sensitivity was 81.79%, and the specificity was 87.20%. Moreover, the combined diagnosis effect was more accurate, the AUC of TPP1 + POT1 was 0.91, the sensitivity was 84.50%, and the specificity was 91.80%.

    Conclusions: TPP1 and POT1 are promising markers for distinguishing patients with HCC. HCC predictive accuracy could be improved significantly by the combination of TPP1 + POT1 with AFP (alpha-fetoprotein) or PIVKA-II (protein induced by vitamin K absence or antagonist-II).

  • Article
    Shou-Yan TONG, Wen-Qiang ZHANG, Chen HU, Xing-Zi FENG, Yun JIN, Jun-Feng WANG, Lei HU, Yun WU, Zhi-Wei SUN, Xing-Yu LI
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1017-1028. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.104
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    Background: This study explored the mechanism underlying the regulation of the EZH2/miR-200b-3p/DNMT3A (enhancer of zeste homolog 2/micro ribonucleic acid-200b-3p/deoxyribonucleic acid methyltransferase 3 alpha) pathway by c-MYC in hepatocellular carcinoma (HCC).

    Methods: The mRNA (messenger ribonucleic acid) and protein expression of c-MYC, EZH2, and DNMT3A in HCC cell lines were examined using quantitative reverse transcription-quantitative polymerase chain reaction and Western blotting, respectively. The knockdowns of c-MYC, EZH2, or DNMT3A and DNMT3A overexpression were achieved through the transfection of corresponding small interfering RNAs and overexpression vectors, respectively. miR-200b-3p mimics or inhibitors were transfected into HCC cells for miR-200b-3p overexpression or knockdown. Colony formation and cell counting kit-8 assays were performed to measure cell proliferation viability, respectively. The apoptosis and invasion were examined using flow cytometry and Transwell invasion assay, respectively.

    Results: c-MYC silencing significantly upregulated miR-200b-3p expression, and EZH2 knockdown enhanced miR-200b-3p levels in HepG2 and SMMC-7721 cells. miR-200b-3p targeted DNMT3A and reduced DNMT3A mRNA level, whereas DNMT3A reduced miR-200b-3p levels through the promotion of miR-200b-3p promoter methylation. In HepG2 and SMMC-7721 cells, miR-200b-3p overexpression promoted apoptosis and inhibited invasion and proliferation.

    Conclusions: c-MYC regulates the EZH2/miR-200b-3p/DNMT3A pathway and affects the invasion and proliferation of HCC cells. miR-200b-3p and DNMT3A form a feedback loop to enhance miR-200b-3p inhibition and DNMT3A overexpression.

  • Article
    Xiaoyu Qian, Jian Tang, Yongquan Chu, Ziqiang Chen, Liang Chen, Chao Shen, Lin Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1029-1039. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.105
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    Background: The modification of 7-methylguanosine (m7G) is a type of tRNA modification closely associated with cancer. Nevertheless, the capacity of m7G-related genetic expression to prognose cancer outcomes remains elusive in thyroid cancer.

    Methods: Overall, among the 21 differentially expressed genes (DEGs) observed between thyroid cancer and nominal tissue, 4 were relevant to the overall survival (OS) (p < 0.05). A risk signature via least absolute shrinkage and selection operator (LASSO) Cox regressive analyses was developed in the The Cancer Genome Atlas (TCGA) cohort. In addition, reverse-transcription quantitative polymerase chain reaction (RT-qPCR) determined the mRNA expression of genes in the model, and the risk signature according to the genetic expression was validated. Finally, the functional enrichment method was used to investigate the underlying causal links.

    Results: A 4-gene signature (nudix hydrolase 16, NUDT16; Eukaryotic translation initiation factor 4E, EIF4E; Gem nuclear organelle associated protein 5, GEMIN5; Decapping mRNA 2, DCP2) showed powerful prediction ability in both TCGA and validation cohorts. The median risk score of the 4-gene signature was considered to classify patients into riskhigh group and risklow group. Sufferers in risklow group had a higher OS relative to riskhigh group (p < 0.01). According to Cox regression analysis, risk score could independently predict thyroid cancer patients’ OS. The receiver operating characteristic (ROC) method assisted in verifying the predictive ability of the genetic signature. Subsequently, we discovered that the 4 genes exhibited aberrant expression between thyroid cancer and healthy specimens. Function analyses revealed that both groups showed diverse immune status.

    Conclusions: The predictive ability of the 4-gene signature was proven. Overall, m7G-associated genes are valid to prognosis thyroid cancer outcomes and can be an underlying treatment target.

  • Article
    Lin Zhao, Mingchao Shang, Xiaofang Hu, Jun Li, Jun Tian, Lianjie Li, Bangqing Yuan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1041-1049. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.106
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    Objectives: Long non-coding RNAs (lncRNA) fulfill vital functions in glioma (GL) advancement. This work attempted to study the role and mechanism of LINC01578 in glioma.

    Methods: Cancerous and adjacent tissues were collected in pairs from 20 glioma patients who visited The 900th Hospital of Joint Logistic Support Force between February 2021 and June 2022. LINC01578 expression was quantified using Quantitative real-time Polymerase Chain Reaction (qRT-PCR). Additionally, GL U251 and U87 cells and human astrocytes SVGP12 were purchased to validate the expression profiling of LINC01578. Then, LINC01578 short hairpin RNA (sh-LINC01578), LINC01578 overexpression plasmid (oe-LINC01578), empty carrier for sh-LINC01578 (sh-NC) and empty carrier for oe-LINC01578 (oe-NC) were transfected into U251 and U87 cells, respectively. The untreated U251 and U87 cells were set as controls. Cell counting kit-8 (CCK-8), cell cloning, Transwell®, and cell scratch assays were employed to determine the impacts of LINC01578 on GL cell biological behavior, and Western blotting was adopted to measure apoptosis-related proteins proliferating cell nuclear antigen (PCNA), cleaved Caspase-3 (cl-Caspase-3) and epithelial-mesenchymal transition (EMT) marker proteins E-cadherin, N-cadherin and Snail.

    Results: LINC01578 presented a notably higher expression in GL tissues and cells than in adjacent counterparts and SVGP12 (p < 0.05). Enhanced capacities to proliferate, invade and migrate of U251 and U87 cells were observed following oe-LINC01578 transfection, accompanied by elevated PCNA and reduced cl-Caspase-3 levels at the protein level (p < 0.05); While sh-LINC01578 transfection led to weakened U251 and U87 viability and increased cl-Caspase-3 protein expression (p < 0.05). According to the quantification results of EMT marker proteins, oe-LINC01578 transfection promoted EMT in GL cells, while sh-LINC01578 transfection could not (p < 0.05).

    Conclusions: LINC01578 is kept at high levels in GL and can enhance EMT and the ability of GL cells to proliferate, invade, and migrate, thus participating in the development of GL.

  • Article
    Suhang Wang, Shuo Li, Jing Zhang, Nansheng Wan, Jie Cao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1051-1061. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.107
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    Objectives: Chronic obstructive pulmonary disease-obstructive sleep apnoea (COPD-OSA) syndrome is an overlapping respiratory disease characterised by hypoxia and inflammation. This study aimed to explore the degree of renal injury in COPD-OSA syndrome.

    Methods: The COPD-OSA rat model was established through exposure to cigarette smoke (CS) combined with chronic intermittent hypoxia (IH). Rats were randomly divided into six groups, including the normal control, CS, 5% IH, 10% IH, CS + 5%IH, and CS + 10% IH. Serum levels of creatinine (Cr), cystatin C (Cys-C), and blood urea nitrogen (Bun) were measured using an enzyme-linked immunosorbent assay. The histopathological injury was evaluated by haematoxylin-eosin staining and transmission electron microscopy. In renal tissues, apoptotic cells were detected by Terminal deoxynucleotidyl transferase-mediated dUTP in situ nick end labelling (TUNEL) staining, and the protein expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) was measured by western blot.

    Results: The serum level of Cys-C was increased by CS and IH. However, Cr and Bun levels were only significantly increased by 5% IH and CS, respectively. Histopathological injury in rats exposed to CS or IH mainly included tubular epithelial cell oedema, inflammatory cell infiltration, and collagen fibre deposition. Compared with the controls, CS and IH induced more TUNEL-positive cells, upregulated Bax, and downregulated Bcl-2 in renal tissues. In addition, IH had a stronger effect on inducing histopathological injury and apoptosis than CS. CS + IH had an additive effect on aggravating the renal injury in COPD-OSA rats.

    Conclusions: Renal injury was aggravated in COPD-OSA rats, mainly presenting as serum Cys-C elevation, tubular epithelial cell oedema, inflammatory cell infiltration, collagen fibre deposition, and cell apoptosis.

  • Article
    Xuezhang Chen, Xikang Chen, Zhixia Zhu, Yinsong Chen, Xiaoqi Pang, Xianxun Zhong, Shuang You, Yaoxu Chen, Huaqin Tian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1063-1073. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.108
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    Objective: This study aimed to identify a prognostic epithelial-mesenchymal transition (EMT)-correlated long noncoding RNA (lncRNA) signature in triple-negative breast cancer (TNBC).

    Methods: Gene expression data of TNBC were obtained from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) databases. EMT-related genes were searched using MSigDB. Differentially expressed (DE) EMT-related mRNAs and DE-lncRNAs were selected between tumor and normal samples, followed by correlation analysis to analyze EMT-correlated lncRNAs. Based on the EMT-correlated lncRNAs obtained, a risk score (RS) model was established, and the samples were divided into low- and high-risk groups based on the RS value. The prognosis, tumor microenvironment, and pathways were compared between the two groups. Four EMT-correlated lncRNAs (MIR22HG, HOXB-AS1, LINC00511, and AC097713.3) were screened to construct an RS model after multistep bioinformatics analyses. The samples in both datasets were divided into low- and high-risk groups. The overall survival of the samples in the low-risk group was significantly better than that in the high-risk group. Immune infiltration levels, expression of immune checkpoint genes, major histocompatibility complex (MHC), and costimulatory and coinhibitory molecule genes significantly differed between the two groups. Finally, a nomogram model significantly associated with the prognosis of patients with TNBC was constructed.

    Conclusions: Our study developed an EMT-related four-lncRNA signature that can predict the prognosis of TNBC and may serve as a treatment target for TNBC.

  • Article
    Liang Yang, Xinying Zhu, Wenjuan Zhao, Junmin Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1075-1080. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.109
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    Background: China has a high incidence of Helicobacter pylori (Hp)-positive peptic ulcers and triple therapy is widely used to eradicate Hp. However, the antibiotics and proton pump inhibitors used in the standard triple therapy can potentially disrupt the equilibrium of the intestinal flora, resulting in adverse reactions such as loss of appetite, abdominal pain, and diarrhea.

    Aim: To explore the effect of combined probiotics on the intestinal ecosystem during triple therapy.

    Methods: A total of 120 patients with a diagnosis of duodenal ulcer and confirmed Hp infection, admitted to the Third Hospital of Hebei Medical University between January 2018 and January 2019, were selected for a prospective randomized clinical study. They were divided into two groups. A joint group (n = 60) and a control group (n = 60) using a simple randomized method. The control group was treated with standard triple therapy, specifically a proton pump inhibitor + clarithromycin + amoxicillin, while the joint group received triple therapy plus Bacillus subtilis and Enterococcus faecium enteric-soluble capsules. Ulcer healing rate, clinical efficacy, Hp eradication rate, changes in the primary intestinal flora, and incidence of adverse reactions were compared between the two groups.

    Results: After treatment, there was no significant difference in the overall healing effect, clinical efficacy, and Hp-negative conversion rate between the two groups (p > 0.05). During treatment, the incidence of adverse reactions in the combined treatment group was 5.00% lower than 20.00% in the control group, and the difference was statistically significant (p < 0.05). After treatment, the numbers of Enterococcus and Enterobacter in the joint group were lower than those of the control group (p < 0.05), while the numbers of Lactobacillus, Bifidobacterium, Bacteroidetes, Clostridium, and total bacteria in the joint group were higher than those of the control group (p < 0.05).

    Conclusions: Combined probiotics used as an adjuvant to standard triple therapy have no beneficial or disadvantageous effects on ulcer healing and Hp eradication. But they can reduce adverse reactions for the duration of the treatment process and maintain the equilibrium of the intestinal flora.

  • Article
    Xuntao Deng, Danyi Zeng, Xuwei He, Ning Zhang, Qianwen Qiu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1081-1087. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.110
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    Background: This study aimed to investigate changes on inflammatory indexes in peripheral blood. Additionally, it evaluated the clinical value of lymphocyte subsets ratio for the prognosis of patients with sepsis on admission.

    Methods: A total of 147 patients with sepsis admitted to the Intensive Care Unit of Lishui People’s Hospital from June 2019 to June 2022 were selected. They were divided into ordinary sepsis group (N = 102) and septic shock group (N = 45). Healthy subjects from the health examination center of our hospital were selected as the control group (N = 80). Lymphocyte subsets in peripheral blood were determined by flow cytometry. Then they were divided into survival group (N = 105) and death group (N = 42) according to the 28-day survival result. Peripheral blood lymphocyte subsets were compared. Changes on peripheral blood inflammation indexes between admission and discharge were analyzed in the survival group with sepsis.

    Results: CD3+ cells (total T cells), CD3+CD8+ (suppressor T cells, Ts), CD3+CD4+ (helper T cells, Th), CD3-CD19+ (B cells), and CD3-CD16+/CD56+ (NK cells) in peripheral blood of patients with sepsis in ordinary sepsis group significantly decreased compared with healthy subjects (p < 0.05). There was no significant difference in NK (natural killer) cell percentage (NK %), Ts cell percentage (Ts %) and Th/Ts among ordinary sepsis group, septic shock group and healthy subjects (p > 0.05). T cells percentage (T %) and Th cells percentage (Th %) in septic shock group significantly decreased, and the percentage of B cells (B %) significantly increased compared with ordinary sepsis group (p < 0.05). CRP (C-reactive protein), PCT (procalcitonin) and Lac (lactic acid) in peripheral blood of the death group significantly increased, and the lymphocyte subsets T (Abs), Ts (Abs) and Th (Abs) significantly decreased compared with those in the survival group (p < 0.05). There was no significant difference in WBC (leukocyte, white blood cell), PLT (platelet) and NLR (neutrophil to lymphocyte ratio) between survival group and death group (p > 0.05).

    Conclusions: Further sepsis diagnosis and treatment can be achieved by monitoring changes on lymphocyte subsets in peripheral blood, and inflammatory indexes. Changes on the level of this subsets had an impact on the prognosis and improve the survival rate of patients with sepsis.

  • Article
    Lang Lang, Angjin Yang, Langxi Lang, Yuanyuan Hu, Pan Xu, Lei Yu, Wenlan Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1089-1095. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.111
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    Background: Benzyl butyl phthalate (BBP) is an environmental endocrine disruptor, with an estrogen-like effect. To elucidate the toxicity mechanism of BBP on Sertoli cells, BBP and its metabolites monobutyl phthalate (MBuP), phthalic acid (PA), hippuric acid (HA) were selected for simultaneous study.

    Methods: The effects of BBP and its metabolites on Sertoli cells were observed by cytotoxicity assay (MTT assay) and cell cycle assay. The key proteins in Sertoli cells were detected by Western blot to find out the toxic mechanism of BBP.

    Results: The MTT assay results showed that BBP (10–5, 10–6, 10–7 mol/L) and HA (10–6 mol/L) significantly induced cell proliferation, while MBuP (10–4, 10–5 mol/L) and PA (10–4, 10–5 mol/L) significantly inhibited cell proliferation at 72 h. The results of cell cycle assay showed that both BBP and its metabolites significantly increased the proportion of G2 phase (Anaphase of DNA synthesis). The Western blot assay showed that estradiol (E2) significantly decreased the expression of vimentin and androgen binding protein (ABP), BBP significantly induced the expression of ABP and significantly decreased the expression of vimentin, MBuP and PA significantly reduced vimentin and ABP, HA significantly increased vimentin and ABP. BBP significantly promoted the expression of ABP similar to HA, and destroyed the cytoskeleton structure similar to MBuP and PA.

    Conclusions: This study revealed that the reproductive toxicity of BBP was directly related to its metabolites.

  • Article
    Qin Yang, Xiang-Cheng Shi, Li-Qin Zhai, Hong Bi, Jie Wang, Li-Zhu Yang, Chong-Xiao Qu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1097-1103. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.112
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    Background: Galectin-3 is the immunomarkers with strong specificity in the differential diagnosis of benign and malignant thyroid diseases. Galectin-3 could promote tumor progression through the Wnt pathway-mediated EMT. This study was aimed at investigating the effect of the interfering expression of the galectin-3 gene on the expression of transforming growth factor-β1 (TGF-β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) and epithelial-mesenchymal transition (EMT)-related pro-teins in papillary thyroid carcinoma (PTC).

    Methods: Fifty cases of PTC andbenign thyroid tissues resected in our hospital were collected and the expressions of galectin-3, TGF-β1, and Smad3 proteins were detected via immunohistochemistry. The designed and synthesized small molecule interfering RNA (galectin-3-siRNA) was transfected in a TPC-1 cell line using the Lipofectamine2000 method, while the detection of the expressions of galectin-3, TGF-β1, Smad3, vimentin, and E-cadherin were achieved using the western blot method.

    Results: Compared with in the benign thyroid tissues, the galectin-3 and TGF-β1 were increased in the PTC tissues, while the Smad3 was reduced, with the difference statistically significant (p < 0.05). The galectin-3 was positively correlated with the TGF-β1 (r = 0.298, p = 0.036) and negatively correlated with the Smad3 in the PTC (r = –0.342, p = 0.015). Interference with the galectin-3 gene expression can down-regulate the expression of TGF-β1 and vimentin proteins and up-regulate the expression of Smad3 and E-cadherin proteins in TPC-1 cells (p < 0.05).

    Conclusions: Interfering with the galectin-3 gene expression can reduce the migration and invasion capacity of the TPC-1. Galectin-3 could promote the incidence of the EMT in PTC through the TGF-β1/Smad3 signaling pathway.

  • Article
    Guoxin Qu, Jinchao Qiu, Chu Gao, Qingli Cai, Ling Zeng, Jin Deng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1105-1112. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.113
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    Background: Alveolar epithelial cells are cells lining along highly vascularized alveolar epithelial surface are capable of efficient gas exchange and host defense. Over the past decades, numerous methods have been developed to reliably isolate these delicate cells to study their functional, molecular, biological, and biochemical characteristics. However, methods for alveolar epithelial cells (AECs) purification with extremely reliable, reproducible, and efficient features are still needed.

    Methods: We developed an optimized protocol to isolate alveolar epithelial cells based on immunomagnetic enrichment. The protocol mainly includes two steps: (1) Immunocytes expressing Fc fragment receptor (FcR) depletion by rat immunoglobulin (IgG), panning to enrich for alveolar epithelial cells; (2) Immunomagnetic capture using magnetic-beads-conjugated monoclonal antibody against specific membrane markers T1α (Type 1 alpha, a specific AEC1s membrane protein) and epithelial cell adhesion molecule, EpCAM) to purify alveolar epithelial type I cells (ATIs), and alveolar epithelial type II cells (ATIIs). Subsequent observations of separated and cultured cells confirmed highly efficient isolation with common ATIs and ATIIs characteristics.

    Results: As for the cellular kinetics, there was a significant loss of ATIs at the third day after sepsis-induced acute lung injury (ALI), but the number of ATIIs did not significantly decrease at any point in time. Flow cytometry results showed that the percentage of ATIIs increased significantly 3 days after injury.

    Conclusions: ATIIs were damage-resistant during sepsis-induced ALI and they might be primary cells participating in sepsis-induced ALI and lung tissue repair.

  • Article
    Chunhui Zhang, Minjun Ma, Liqiong Zhou, Quan Cheng, Xinyu Fan, Xu Zha, Yuanping Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1113-1127. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.114
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    Background: Diabetic retinopathy (DR) is an extremely debilitating microvascular complication of diabetes mellitus (DM), and changes in the internal physiological microenvironment can shape the progression of this disease. At present, few metabonomics studies have systematically studied the small and medium molecular metabolite changes during DR progression.

    Methods: Peripheral blood samples from 91 patients with DR (41 patients with proliferative diabetic retinopathy (PDR) and 50 patients with non-proliferative diabetic retinopathy (NPDR)), 91 gender- and age-matched non-DR type 2 diabetes mellitus (T2DM) patients, and 91 healthy controls were analyzed by gas chromatography-time-of-flight mass spectrometry (GC-TOFMS). First, univariate and multivariate statistical analyses were used to identify metabolites with significant differences. Then, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to analyze the significantly affected metabolic pathways among the groups, and Spearman correlation analyses were used to study the correlation between these different metabolites and clinical parameters. Finally, candidate biomarkers related to the progression of T2DM and DR were selected by K-means and logistic regression analyses.

    Results: The metabolism of amino acids, glucose, and phosphatidylinositol was revealed to be significantly abnormal in T2DM and DR patients (NPDR and PDR). While potential diagnostic markers of T2DM and PDR were identified, further validation is needed to elucidate how these differential metabolites and related metabolic pathways influence disease progression.

    Conclusions: In this study, a metabolomics approach was utilized in an effort to detect specific biomarkers of T2DM in patients with or without DR while exploring the potentially pathogenic roles that these metabolites may play in DR progression.

  • Article
    Xing-Qiang Wang, Ying-Zi Sun, Yi-He Liu, Bing Wang, Jing-Xiao Zhang, Jin-Zhen Cai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1129-1135. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.115
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    Objective: To investigate the efficacy and safety of using regional citrate anticoagulation (RCA) in the molecular adsorbent recirculating system (MARS) therapy for patients with acute-on-chronic liver failure (ACLF) grade 3.

    Methods: Twenty patients with ACLF grade 3 who were waiting for liver transplantation at our center from July 2018 to June 2019 were selected as the research participants. Clinical data from all patients were collected prior to MARS therapy, and all patients were treated with RCA for eight hours. Arterial blood gas analysis, total serum calcium, ionic calcium, and ionic calcium after filtration were collected at 0, 2, 4, and 6 hours of treatment and at the end of treatment. After filtration, the blood calcium was maintained within the range of 0.2–0.4 mmol/L, and the quantities of 4% sodium citrate solution and 5% calcium chloride solution were adjusted based on the monitored results. Changes in observed indices before and after treatment were compared, and the service life of the tubes and any therapeutic complications were recorded.

    Results: The 20 study patients received a total of 27 MARS treatments. Following treatment, the liver and renal function indices of the patients improved significantly (p < 0.05), with no serious disturbance of electrolytes or acid-base imbalance. A calcium ratio greater than 2.5 was detected on 10 occasions during MARS therapy, and the calcium ratio significantly increased at 2 hours following the start of MARS therapy (p < 0.05). As the therapeutic duration was extended, the calcium ratio gradually decreased. Of the 27 MARS treatments administered, a pipeline blockage occurred twice, and there was one episode of a severe disturbance of electrolytes caused by citrate accumulation leading to withdrawal of treatment.

    Conclusions: Patients with ACLF grade 3 may be safely treated with RCA as an effective anticoagulation treatment during MARS therapy.

  • Article
    Tao Liang, Zheng-hao Dai, Hang Guo, Li-chang Zhong, Bin Zhang, Xiang Li, Wei-guo Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1137-1145. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.116
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    Background: Urethral stricture (US) is a common disease of the lower urinary tract in men caused by fibrosis. This study was designed to investigate the effect of adipose-derived stem cell (ADSC) exosomes (exos) and the possible mechanism on transforming growth factor β1 (TGF-β1)-induced urethral fibrosis in rats.

    Methods: ADSCs were isolated from adipose tissues from the inguinal region of three Sprague-Dawley (SD) rats and the expression of cell surface antigen markers CD90, CD105, and CD45 was detected by flow cytometry. Subsequently, ADSC-exos were isolated from third-passage ADSCs. The morphology, mean diameter, and expression of markers (CD63 and TSG101) of the ADSC-exos were observed by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting, respectively. After the construction of a rat model of urethral fibrosis (US) by the injection of 10 µg of TGF-β1, the effect of injecting ADSC-exos on urethral fibrosis was assessed. HE staining and Masson staining were used to observe the histopathological changes and degree of fibrosis in rat urethral tissues, respectively. The protein expression of Col III, α-SMA, fibronectin, TGF-β1, Smad3 (mothers against decapentaplegic homolog3), and p-Smad3 in urethral tissues was detected by western blotting.

    Results: After treatment of the US rat model with ADSC-exos, the mucosal injury of urethral tissues was ameliorated, the epithelium was well formed, and the degree of fibrosis was significantly reduced. Moreover, ADSC-exos significantly decreased the expression levels of fibrosis-related proteins (Col III, α-SMA, and fibronectin) and decreased the levels of TGF-β1, p-Smad3, and the p-Smad3/Smad3 ratio in the urethral tissues of US rats.

    Conclusions: ADSC-exos attenuate urethral fibrosis and inhibit the expression of fibrosis-related proteins in urethral tissues by inhibiting the TGF-β1/Smad3 signaling pathway in rats.

  • Article
    Yan Zhang, Xiangming Fang, Kui Tian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1147-1153. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.117
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    Objective: This study explored the role of the virulence factors found in different Helicobacter pylori (H. pylori) strains in the development of gastrointestinal diseases.

    Methods: A total of 501 patients diagnosed with gastrointestinal diseases at Wuhan Puren Hospital in the period from January 2020 to January 2022 were recruited. All patients underwent the urea breath test (UBT) and the H. pylori antibody test. Based on the detection of H. pylori virulence factors, the patients were classified into Type I (n = 296), Type II (n = 120) and Type III (n = 85) categories. Esophagogastric endoscopy (EGD) and colonoscopy were used to observe the lesions in the patients’ gastrointestinal tracts.

    Results: The proportion of peptic ulcer formation/bleeding in the Type I group was significantly higher than that in the Type II and Type III groups. Further, compared with the Type I and Type III groups, the incidence of gastritis in the Type II group was lower, while the incidence of reflux esophagitis was higher. There were significant differences in the histopathological changes of colon among the three groups (p < 0.05). Moreover, the Type I group had the highest incidence of adenoma/cancer and the lowest incidence inflammation and polyp.

    Conclusions: Type I patients have a higher probability of peptic ulcers, gastrointestinal bleeding, colon polyps, and cancer. The H. pylori virulence factors are associated with the occurrence and progression of gastrointestinal diseases. Overall, the results of this study may be of use in the clinical diagnosis and treatment of gastrointestinal diseases.

  • Article
    Enrico Cocchi, Giulia Squillacioti, Federica Ghelli, Claudio Plazzotta, Tiziana Musso, Luca Marozio, Valeria Bellisario, Roberto Bono
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(2): 1155-1161. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233702.118
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    Introduction: Oxidative stress (OS) can play a negative role in perinatal outcomes, but the underlying pathophysiology remains mostly unknown. This is a cross sectional study aiming to evaluate how the living environment, combined with some important maternal risk factors (i.e., smoke, overweight), could influence OS and inflammation markers during pregnancy and in newborns.

    Methods: Mothers and newborns were recruited at the Sant’Anna Gynecological Hospital (Turin, Italy). Environmental and lifestyle information was obtained through a standardized questionnaire (PRAMS). OS and inflammation markers (Isoprostane, IL (interleukin)-1, and IL-6) were analyzed in urine samples.

    Results: Overall, 126 mother-newborn couples were recruited. Oxidative stress and inflammation levels of mothers and infants have been shown to be significantly associated with each other (Spearman p < 0.01). Active and passive tobacco smoke during pregnancy (Spearman p < 0.01 and < 0.02, respectively), traffic exposure (Spearman p < 0.02), and higher BMI (body mass index) (Spearman p < 0.05) shown a positive role in this relationship.

    Conclusions: Our preliminary findings suggest that neonatal OS and inflammation are positively influenced by the three maternal risk factors analyzed: Tobacco smoke exposure, high urbanization levels, and high BMI. Further analysis are mandatory to better understand the biological mechanisms underlying such relationships. Nevertheless, correct management and monitoring of these factors must be considered by preventive Public Health strategies, to improve maternal and neonatal health and outcomes.