20 January 2023, Volume 37 Issue 1

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  • Review
    Huile Li, Hongguan Zhang, Yanyou Cen, Yude Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 1-12. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.1
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    Objective: To investigate the efficacy of Songling Xuemaikang Capsule (SXC) on essential hypertension, as monitored on ambulatory basis.

    Methods: Relevant randomized controlled trials (RCTs) were obtained via a systematic search of several databases. The results were pooled with a randomized or a fixed-effect model, according to the heterogeneity. The Cochrane risk of bias assessment tool was used for quality assessment.

    Results: Thirteen RCTs with 1092 essential hypertension (EH) patients were included in the meta-analysis. Compared with Losartan, SXC was less effective at reducing 24-hour average systolic blood pressure (ASBP, weighted mean difference (WMD): 1.80 mmHg, p = 0.04). SXC combined with other anti-hypertensives significantly reduced ADBP (average diastolic BP) during the daytime (WMD: –1.24 mmHg, p < 0.0001) and systolic blood pressure variability (SBPV) during the nighttime (SMD: –0.58, p < 0.00001), compared to anti-hypertensives alone. Subgroup analyses showed that the combination of SXC and Amlodipine achieved significantly better control of 24-hour ASBP and ADBP (p < 0.05) compared to Amlodipine alone. The combination of SXC and an angiotensin converting enzyme inhibitor (ACEI) achieved significantly better control of 24-hour ASBP and ASBP during both the daytime and nighttime, compared to ACEI alone (p < 0.01).

    Conclusions: The combination of SXC and Amlodipine Besylate significantly reduced 24-hour ASBP and ADBP. Due to the modest quality of the RCTs included in this meta-analysis, more rigorously designed studies are needed.

  • Article
    Xiaoliang Yin, Dehai Lang, Jinlin Yan, Di Wang, Songjie Hu, Qiyang Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 13-24. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.2
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    Background: This study aimed to explore the molecular mechanism of Sushi repeat-containing protein X-linked 2 (SRPX2) overexpression in the growth of mouse vascular endothelial progenitor cells (EPCs).

    Methods: Lentiviral transfection was used to establish SRPX2 overexpression in the mouse EPC lines. Cell counting kit-8 (CCK8) and transwell assays were used to determine the role of SRPX2 overexpression in EPCs. Transcriptome sequencing of the SRPX2 overexpression (SRPX2 OE) and negative control (NC) groups was performed, followed by the screening of differentially expressed genes (DEGs). Protein-protein interaction (PPI) analysis was performed to screen potential hub genes. Furthermore, miRNAs and transcription factors (TFs) that regulated genes in the modules were predicted. The expression levels of genes were determined using real-time quantitative reverse transcription PCR (RT-qPCR).

    Results: SRPX2 overexpression promoted the proliferation and migration of EPCs. A total of 828 DEGs was identified. Five hub genes were screened using PPI analysis: Collagen type I alpha 2 chain (COL1A2), collagen type III alpha 1 chain (COL3A1), CX3-C motif chemokine receptor 1 (CX3CR1), insulin like growth factor binding protein 3 (IGFBP3), and sphingosine-1-phosphate receptor 3 (S1PR3). The RT-qPCR assay indicated that the expression levels of these genes were consistent with the results of the bioinformatics analysis. Moreover, miRNAs such as let-7e-5p, miR-29a-3p, and miR-29b-3p might be involved in the EPC proliferation.

    Conclusions: Our study suggested that SRPX2 overexpression could promote mouse EPC proliferation and migration, and the identified genes were considered as potential biomarkers for endothelial remodeling during angiogenesis.

  • Article
    Giovanni Barassi, Raffaello Pellegrino, Celeste Di Matteo, Loris Prosperi, Edoardo Di Simone, Celeste Marinucci, Noemi Pepe, Federico Papa, Marta Odorisio, Valentina Zincani, Ilaria Gabriella Micolucci, Alì Younes, Angelo Di Iorio
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 25-29. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.3
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    Background: The bioelectrical properties of human body tissues could represent an interesting means of interaction aimed at healing from musculoskeletal pathologies, through the use of different techniques, such as external Electrical Neuromodulation.

    Methods: The data of 10 patients suffering from Non-Specific Chronic Low Back Pain were considered. Patients were treated for 6 sessions on alternate days through Electrical Neuromodulation, applied to the skin of the areas where the local electrical conduction was most perturbed, measured through impedancemetry before and after each session. The temperature of the lumbar region was also measured, before and after each session, using thermal imaging. The level of perceived disability was assessed by administering the Oswestry Disability Index (in the first and last session) and the pressure-pain threshold was measured using an algometer on specific points of the body (in the first and last session).

    Results: Mixed results were observed, with some improvements in terms of the balance of the electrical activity measured through bioimpedancemetry on the various points of the body considered. Minimally positive results were observed with respect to thermographically measured lumbar temperature. Some positive results were observed also in terms of improvement of the disability induced by Non-Specific Chronic Low Back Pain and in terms of pressure-pain threshold in the areas of the body taken into consideration.

    Conclusions: The treatment approach observed was aimed at rebalancing the bioelectrical activity of the areas identified by the impedance analysis as sites of Key Myofascial Trigger Points, according to the logic of the method we define as the Bio-Physico-Metric Approach. The results obtained, albeit limited, would seem to encourage the application of this method and the carrying out of more extensive and prolonged studies to verify its efficacy in Non-Specific Chronic Low Back Pain and in other musculoskeletal pathologies.

  • Article
    Jia Hou, Ling Li, Xuetong Zhang, Yuan An, Liang Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 31-40. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.4
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    Background: This study aimed to assess the biological efficacy of phosphatase and tensin homolog-engineered bone marrow-derived mesenchymal stem cells (PTEN eBM-MSCs) in periodontitis treatment.

    Methods: Ligation was used to construct the experimental periodontitis model, and Sprague-Dawley rats were randomly divided into four groups (10 rats per group). Another 13 normal rats were used as controls. Micro-computer tomography (CT) was applied to measure the distance between the cemento-enamel junction (CEJ) and the palatal alveolar bone crest (ABC). Hematoxylin and eosin (HE) staining was used to observe the inflammatory infiltration and pathological morphology, and tartrate-resistant acid phosphatase (TRAP) staining evaluated the number of osteoclasts. Besides, enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of tumor necrosis factor (TNF)-α, interleukin-17, and interleukin-10.

    Results: Cell viability and the expressions of anti-alkaline phosphatase (ALP), anti-osteocalcin, and anti-Runt-related transcription factor 2 (RUNX2) in the PTEN eBM-MSC group was significantly increased (p < 0.05). Periodontal ligament fibers in the periodontitis group were disordered, and osteoclast number, CEJ-ABC distance, TNF-α and interleukin-17 contents were increased compared to control rats, while interleukin-10 levels were declined (p < 0.05). Compared with the periodontitis group, the other three groups showed improvement of periodontal tissue damage compare with the periodontitis group, also osteoclast number, CEJ-ABC distance, TNF-α and interleukin-17 levels were decreased, while interleukin-10 levels were increased (p < 0.05). The greatest therapeutic effect was seen in the periodontitis+PTEN eBM-MSC group.

    Conclusions: PTEN eBM-MSCs inhibited inflammation, osteoclast formation and alveolar bone resorption in rats with experimental periodontitis.

  • Article
    Lei Zhang, Jing Li, Daming Chen, Jiansheng Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 41-50. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.5
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    Background: Total peony glucoside (TGP), a traditional Chinese medicine, is used to regulate immune response and inflammation, and is often used to treat immunological diseases such as Sjogren’s syndrome and systemic lupus erythematosus. The purpose of this study was to investigate the efficacy of TGP in the treatment of immunocontact urticaria.

    Methods: The ICU mouse model was established and TGP was administered. The mice were then evaluated for frequency of scratching behavior and number of air masses, gastric motility, gastric emptying, intestinal transport, and colonic transport. Hematoxylin and eosin (HE) staining was used to detect the pathological changes of vascular endothelial tissues in mice. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of histamine, immunoglobulin E (IgE), interleukin-4 (IL-4), interferon-γ (IFN-γ), superoxide dismutase (SOD) and malondialdehyde (MDA) in the serum of the mice. Western blot was used to detect the expression level of c-Kit protein.

    Results: In contrast, the frequency of scratching behavior and the number of wheals were significantly increased in ICU mice and showed damage to vascular endothelial tissue. Serum histamine, IgE, IL-4, IFN-γ, MDA levels and c-Kit protein expression were significantly increased in ICU mice, and SOD levels, gastric motility, gastric emptying, and intestinal and colon transport abilities were decreased. In addition, TGP treatment significantly increased the expression levels of histamine, IgE, IL-4, IFN-γ, and c-Kit proteins in ICU mice and boosted their SOD levels, gastric motility, gastric emptying, intestinal and colonic transport functions in a dose-dependent manner.

    Conclusions: TGP treatment significantly improves gastric emptying and gastrointestinal transit in ICU mice. This study may offer new insights into ICU treatment.

  • Article
    Leying Zhang, Fang Wang, Haoliang Su
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 51-62. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.6
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    Background: Parkinson’s disease (PD) belongs to the chronic progressive disease of the nervous system and dopaminergic neuron defects is its major characteristic. Before research have indicated that the growth and survival of neurons were affected by the brain-derived neurotrophic factor (BDNF). Nonetheless, the function of BDNF and its regulatory mechanisms in the neuroinflammation of PD is not clear, further investigation is needed.

    Methods: Immunohistochemistry (IHC) assay were used to determine the levels of α-synuclein and tyrosine hydroxylase (TH)-positive neurons. Further, pole tests and accelerating rotarod tests were conducted to carry out the time-on-pole and time-on-rod behavioral measurements. Immunofluorescence staining assay was used to detect the expression of BDNF. Besides, RT-qPCR assays were used to measure the mRNA expression of XIST and miR-155-5p. And the luciferase reporter assays were used to examine the binding ability of XIST (or BDNF) and microRNA (miR)-155-5p. In addition, enzyme linked immunosorbent assays (ELISA) were implemented to verify the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6.

    Results: First, the PD mouse model were established successfully through MPTP injections. Results found that the BDNF showed low expression levels in the PD mice, but upregulated BDNF expression was relevant to the relieved PD progression. In regulatory mechanisms respect, it was exhibited that the XIST regulate BDNF by adsorbing miR-155-5p. The rescue assays were also conducted, results showed that the XIST/miR-155-5p/BDNF competing with endogenous (ce)RNA axis to influence PD progression, and XIST modulated miR-155-5p to regulate neuroinflammation through the BDNF/tropomyosin receptor kinase B (TrkB)/myeloid differentiation primary response 88 (MyD88) pathway. Moreover, ANA-12, a TrkB antagonist, was shown to reverse the influence of BDNF on PD progression.

    Conclusions: It is revealed that XIST adsorb miR-155-5p to regulate BDNF expression and reduce neuroinflammation in PD via acting as a ceRNA.

  • Article
    Jian Chen, Yaojun Yu, Liyi Li, Chengfang Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 63-73. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.7
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    Aim: To investigate the role of miR-212/Trim14 in the chemoresistance of gastric cancer cells.

    Methods: Both the SGC7901-MDR (drug-resistant gastric cancer cells) and SGC7901 (drug-sensitive gastric cancer cells) cells was used. Cell viability was measured using cell counting kit-8 (CCK-8). Quantitative Real-time PCR (QRT-PCR) and Western blot were used to detect the expression levels of miR-212 and Trim14 in GC tissues and cells. The targeting relationship between miR-216a-5p and HMGB1 was verified through bioinformatics website prediction and double luciferase reporter gene experiment. Apoptosis was detected by flow cytometry. Finally, the migration and invasion abilities of the cells were tested by transwell and wound scoring experiments.

    Results: The miR-212 overexpression increased the chemosensitivity of SGC7901-MDR cells to 5-FU, cisplatin, and docetaxel, and decreased chemical resistance SGC7901-MDR cells to chemotherapy drugs. Trim14 is the target gene of miR-212, and in vitro experiments showed that overexpression of miR-212 promoted apoptosis of GC cells and inhibited the migration and invasion of SGC7901-MDR cells. Up-regulation of Trim14 promoted the reversal of the above effects.

    Conclusions: Our results indicated that miR-212 overexpression reversed multidrug resistance in GC cells by promoting apoptosis and targeting Trim14.

  • Article
    Yongjun Zhu, Bingbing Zou, Mingyi Wu, Jing He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 75-88. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.8
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    Objective: The Notch signaling pathway plays a key role in the tumor microenvironment. Activation of the Notch signaling pathway promotes the progression of gastric cancer. However, the role of Notch pathway genes in the immune microenvironment and the prognosis of gastric cancer remains unclear. This study aimed to investigate the effect of Notch pathway genes on clinical survival and the immune microenvironment in gastric cancer.

    Methods: The Cancer Genome Atlas stomach adenocarcinoma and GSE84437 datasets were downloaded. Notch pathway genes were extracted from the databases, and their expression levels between gastric cancer and normal groups were compared. Using univariate and multivariate Cox regression analyses, a risk score model was constructed, and the samples were divided into high- and low-risk groups. A nomogram model was constructed. The mutation frequency, immune cell infiltration, drug sensitivity, and response to immune checkpoint blockade were compared between the different risk groups.

    Results: Six Notch signaling pathway genes (HEYL, DTX3L, ST3GAL6, FZD7, NOTCH3, and NOTCH4) were selected to construct a risk score model. The overall survival in the low-risk group was better than that in the high-risk group. A nomogram constructed based on the American Joint Committee on Cancer stage and risk score could predict 1-, 3-, and 5-year survival rates. Additionally, the altered pathway, mutation pattern, immune microenvironment, drug sensitivity, and response to immune checkpoint blockade were significantly different between the two risk groups.

    Conclusions: The six-gene signature based on the Notch signaling pathway allows the prediction of the prognosis of gastric cancer patients and may prove useful for guiding gastric cancer therapeutic strategies.

  • Article
    Liping Feng, Xianghui Liao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 89-100. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.9
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    Aims: Colon cancer (CRC) is one of the common malignant tumors of digestive tract, and the main purpose of this study is to study the effect of miR-193a-3p and its probable pathway in the regulating of bevacizumab resistance in CRC.

    Methods: A bevacizumab-resistant CRC xenograft mice model was established by injecting LoVo cells. The miR-193a-3p mRNA level was determined by RT-PCR (Reverse Transcription-Polymerase Chain Reaction). The CCK-8 (Cell Counting Kit-8) assay and colony formation assay were respectively used to estimate cell viability and proliferation. The wound healing and Transwell assay were used to measure the migration and invasion of cells, respectively. Epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin, and Vimentin), PTEN (Phosphatase and tensin homolog deleted on chromosome ten), p-AKT (protein kinase B), AKT, p-mTOR (p-mammalian/mechanistic target of rapamycin) and mTOR levels were detected using western blot (WB) assay. The targeting relationship between miR-193a-3p and PTEN was verified by bioinformatics prediction and double luciferase reporter gene experiment.

    Results: MiR-193a-3p has a high expression in bevacizumab-resistant LoVo-R, and SW480-R. Silencing of miR-193a-3p suppressed the proliferation, viability, migration, and invasion of LoVo-R and SW480-R cells. Moreover, silencing of miR-193a-3p decreased the expression level of EMT. The down-regulated expression of miR-193a-3p enhanced the PTEN expression, but decreased the expression levels of p-AKT/AKT and p-mTOR/mTOR.

    Conclusions: MiR-193a-3p enhances bevacizumab resistance of CRC through regulating the PTEN/AKT pathway.

  • Article
    Cheng Cai, Xia Zhang, Jianping Wang, Xihan Jin, Tianming Zhang, Zhihui Dai, Zhifeng Zhong, Hongqi Shi, Qingwen Liu, Jinlin Du
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 101-109. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.10
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    Objective: Preoperative chemoradiotherapy (CRT) is a standard option for patients with advanced rectal cancer (RC) located in the lower part of the rectum. Besides, some early stage RC patients may be over-treated, due to imprecise preoperative staging. The aim this study was to explore the value of hypoxia-inducible factor 1α (HIF-1α) as a predictor of benefit from preoperative CRT for locally advanced RC patients in terms of pathologic complete response (pCR) and clinical outcomes.

    Methods: Colonoscopic biopsy specimens from 114 RC patients were subjected to immunohistochemistry method for analysis of HIF-1α expression, followed by analyzing clinicopathological characteristics. Independent factors associated with pCR were analyzed using univariate and logistic multivariate regression. Cox proportional hazard models were utilized to analyze parameters independently related to overall survival (OS) and recurrence-free survival (RFS) of RC patients.

    Results: HIF-1α was observed to be highly expressed in 52.6% patients (60/114). Tumor size was significantly larger in the HIF-1α high expression group than in the low expression group (p = 0.027). The proportion of patients who achieved pCR in the high expression group, was significantly lower than the low expression group (p = 0.001). Besides, HIF-1α was identified as the only predictor of pCR in the multivariate regression analysis (p = 0.006). In terms of prognosis, the 3-year RFS rate and OS rate were significantly lower in the high-expression HIF-1α group than those in the low-expression HIF-1α group (p = 0.015 & p = 0.027). HIF-1α level was significantly related to RFS and OS based on univariate and multivariate analyses.

    Conclusions: HIF-1α expression is a potential predictor for pCR and an independent prognostic factor for RC patients with preoperative CRT.

  • Article
    Caixia Li, Bing Chen, Hai Yu, Yonggang Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 111-120. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.11
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    Background and Objective: DNM3OS (Dynamin 3 Opposite Strand/Antisense RNA) is a hepatocellular carcinoma (HCC)-related long noncoding RNA. We aim to investigate whether DNM3OS regulates the growth of HCC cells by the DNA methyltransferase 1 (DNMT1)/Forkhead box O3a (FOXO3a) pathway.

    Methods: LncRNAs related to liver cancer were identified by searching the LncRNADisease v2.0 database. DNM3OS and FOXO3a expression levels were detected through qRT-PCR in clinical specimens, as well as in THLE-2, SK-HeP1, and Huh-7 cells. CHIP (Chromatin Immunoprecipitation) and RIP (RNA immunoprecipitation) assays were used to detect the interaction of DNM3OS and methyltransferase. A tumor formation experiment was used to detect growth of HCC cells into a tumor in nude mice.

    Results: In liver cancer patients, DNM3OS was highly expressed whilst the expression of FOXO3a was low. DNM3OS promoted the methylation in the FOXO3a promoter region and inhibited the transcription of FOXO3a.

    Conclusions: The lncRNA DNM3OS works as an oncogene that encourages liver cancer progression by promoting methylation of the FOXO3a promoter via DNMT1. Our research provides new clues for clarifying the molecular mechanisms underlying HCC.

  • Article
    Jing Su, Qing Zhong, Jijin Qi, Xue Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 121-128. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.12
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    Background: Essential hypertension as a refractory disease that is considered a major health problem. Proliferation of vascular smooth muscle cell (VSMC) is a key pathological aspect of hypertension. MicroRNAs are small noncoding RNA that modulate gene expression via binding different target genes. The aim of this study was to investigate whether certain miRNAs affect vascular remodeling in hypertension and explore the mechanism of their effect.

    Methods: We conducted experiments using Wistar-Kyoto rats and Spontaneous Hypertension Rat. Cell-counting-kit-8 and 5-ethynyl-2’-deoxyuridine assays were used to detect cell viability and proliferation. Gene and protein expression were measured using quantitative real time polymerase chain reaction and western blot. Additionally, the target binding was confirmed through luciferase reporter assay. Hematoxylin-eosin staining was used to assess vascular remodeling.

    Results: The expression levels of miR-128-3p were significantly reduced in Spontaneous Hypertension Rat aorta and vascular smooth muscle cells compared with Wistar-Kyoto. Overexpression of miR-128-3p arrested the function of proliferation in the VSMCs. Kruppel like factor 4 was shown to represent a candidate gene for miR-128-3p, and knockdown of kruppel like factor 4 significantly suppressed the proliferation. Upregulation of miR-128-3p in Spontaneous Hypertension Rat was shown to attenuate vascular remodeling and hypertension.

    Conclusions: miR-128-3p inhibited Spontaneous Hypertension Rat-vascular smooth muscle cells via targeting kruppel like factor 4.

  • Article
    Jia Wang, Dan Li, Huifang Zhang, Junfeng Li, Wenhong Liu, Su Mao, Qinfei Li, Jiang Qian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 129-139. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.13
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    Objectives: This study investigates how Dexmedetomidine (Dex) impacts liver regeneration after partial hepatectomy (Hep) for cirrhosis.

    Methods: Cirrhosis was induced in mice via intraperitoneal injection with CCl4. Eight weeks after cirrhosis induction, intraperitoneal injection with Dex was initiated, 30 min before 50% partial Hep. The plasma levels of Bilirubin, alanine transaminase (ALT) and aspartate transaminase (AST) were measured by an automatic biochemical analyzer. The survival rate of cirrhotic mice was presented using Kaplan–Meier’s curve. Histopathological changes in the liver were examined by hematoxylin-eosin staining. Primary hepatocytes were isolated from the livers of cirrhotic mice with Dex treatment and Hep, and verified by Periodic Acid-Schiff staining. Primary hepatocyte proliferation was evaluated by CCK-8, colony formation, and immunofluorescence assays. The levels of IL-6, VEGF, STAT3, TLR4, TNF-α, NF-κB, CyclinD1, and Bcl-2 in the liver or the primary hepatocytes were analyzed by Western blot.

    Results: Dex reversed the effects of Hep on increasing levels of Bilirubin, ALT and AST, decreasing mouse weight, liver weight, the ratios of liver weight to mouse weight and survival rate, and aggravating cirrhosis and liver histopathological abnormalities in cirrhotic livers. Meanwhile, Dex further potentiated the effects of Hep on promoting hepatocyte proliferation, and the expression of IL-6, VEGF, STAT3, TLR4, NF-κB, CyclinD1 and Bcl-2 in cirrhotic livers. Primary hepatocytes were successfully isolated and characterized. TAK-242 (TLR4 inhibitor) inhibited the proliferation of these isolated hepatocytes and the expression of IL-6, TNF-α, TLR4 and NF-κB.

    Conclusions: Dex facilitates liver regeneration in cirrhotic mice after Hep probably via activating the TLR4/NF-κB/IL-6 pathway.

  • Article
    Humaira Aziz, Javeria Malik, Shaaf Ahmad, Amna Zia Eusaph, Muhammad Amir Iqbal, Nabila Roohi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 141-150. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.14
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    Background: Endometriosis is histologically explained as the appearance of endometrial-like tissues or glands that lies on the outer side of uterine cavity. Endometriosis influence 10–15% of all women of fertile age. Considering the need of timely diagnosis of endometriosis, the present study aimed to discover new biomarkers for early diagnosis of this disease by using proteomics and mass spectrometry.

    Method: In this study, 250 females with endometriosis from Lady Willingdon Hospital Lahore, Pakistan in reproductive age of 16–45 years were registered. Out of these, 120 patients were of lower age group (16–30 Y) and 130 of higher age group (31–45 Y). Controls, n = 170 were involved in the study. After quantification of protein in blood samples, 2-dimensional gel electrophoresis was performed. After identification by LC-MS/MS (liquid chromatography-tandem mass spectrometry) and Mascot (version 2.3.02, Matrix Science Inc., Boston, MA, USA), Samespots software (4.5.1, TotalLab Ltd., New Castle, UK) was applied to calculate the volume and area covered by each protein. The data was analyzed statistically by using SPSS version 20.0 (IBM SPSS statistics, Chicago, IL, USA) and GraphPad Prism (5.0, GraphPad Software Inc., San Diego, CA, USA).

    Results: LC-MS/MS results were inspiring, indicating that significant up-regulation was showed by fibrinogen among lower and higher age groups of endometriosis patients when compared with healthy controls. The logistic regression showed odds ratio [OR] 4.70 [95% CI (confidence interval) 0.34–6.25] with p = 0.245 of fibrinogen. ROC (receiver operating characteristic) analysis showed AUC (area under the ROC curve) value of 0.917 (95% CI 0.825–1.00, p < 0.0001) with 82.40% sensitivity, 76.50% specificity.

    Conclusions: Hyperfibrinogenemia induced by endometriosis depicts risk of future complications. This study not only uncovered protein patterns specifically associated with the disease but also serves as a new test to non-invasively diagnose endometriosis at early stage.

  • Article
    Yang Liu, Xingjie Wu, Shan Jiang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 151-159. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.15
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    Background and Purpose: To investigate miR-141-3p’s role and regulatory mechanism in the pathogenesis of recurrent spontaneous abortion (RSA).

    Methods: MiR-141-3p and CD163 expressions in the decidual tissues of 30 RSA patients and 30 early pregnancy people were detected, and the relationship between miR-141-3p and CD163 were confirmed. Isolation and purification of the human decidual macrophages (DMs) was conducted, and the normal pregnancy mouse model and RSA mouse model were constructed. Besides, CD163 expressions, M2 DMs’ proportion, miR-141-3p levels, TNF-α, IL-6, and IL-8 levels were measured. Also CD163 relative optical density and the embryo absorption rate in the decidua tissue were calculated.

    Results: MiR-141-3p levels in RSA patients were significantly elevated compared to control people, while CD163 expressions were declined (p < 0.05). And CD163 was the target gene of miR-141-3p. miR-141-3p, IL-6, TNF-α, and IL-8 levels of human DMs in the miR-141-3p inhibitor + si-NC group were remarkably lower than the inhibitor NC + si-NC group, while CD163 expressions and M2 DMs’ proportion were increased (p < 0.05). Furthermore, the embryo absorption rate, miR-141-3p, IL-6, TNF-α, and IL-8 levels of the RSA group were elevated compared to control mice, while CD163 expressions and M2 DMs’ proportion were down-regulated (p < 0.05). After down-regulation of miR-141-3p, all indicators demonstrated the opposite trend. However, knocking down CD163 reversed the above trend.

    Conclusions: MiR-141-3p inhibited the polarization of M2 DMs and promoted the inflammation in the decidual tissue of RSA mice by targeting CD163.

  • Article
    Lingling Hong, Baoheng Xing, Yanping Xing, Xuezhen Wang, Yanyan Liu, Na Li, Dandan Shi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 161-167. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.16
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    Background: Interleukin-33 (IL-33) and its receptor, suppression of tumorigenicity 2 receptor (ST2), participate in the pathogenesis of preeclampsia (PE). This study investigated the significance of soluble ST2 (sST2) in the diagnosis of PE and its relationship with PE severity and maternal and neonatal complications.

    Methods: Participants included 36 patients with severe PE, 42 with mild PE, and 40 healthy pregnant women. The plasma level of sST2 was measured by the Presage ST2 Assay.

    Results: Patients with PE showed significantly higher sST2 level than healthy women. sST2 level was also significantly elevated in patients with severe PE compared to those with mild PE. The optimal cut-off value for sST2 to diagnose PE from healthy control was 40.95 ng/mL (AUC (area under the curve) 0.9253), and the optimal cut-off value for sST2 to diagnose severe PE from mild PE was 72.94 ng/mL (AUC 0.7963). Plasma sST2 level exhibited positive correlations with 24-h proteinuria, SBP (systolic blood pressure) and DBP (diastolic blood pressure) in patients with PE. PE patients with high sST2 level displayed significantly higher incidence rate of maternal and fetal complications than those with low sST2 level.

    Conclusions: In conclusion, this research illustrated that elevated level of plasma ST2 correlated with the severity of PE and the generation of maternal and fetal complications during PE pathogenesis. Meanwhile, sST2 was also identified to be a valuable diagnostic marker for PE.

  • Article
    Haiying Feng, Na Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 169-180. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.17
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    Background: Understanding the molecular differences between cold and hot tumors and selecting biomarkers associated with clear-cell renal carcinoma (ccRCC) may provide a reference for evaluating the efficiency of immunotherapy and the prognosis of ccRCC patients. The purpose of this study was to analyze cold-hot tumor typing in ccRCC.

    Methods: The Cancer Genome Atlas (TCGA) and European Bioinformatics Institute (EBI) ArrayExpress databases were used to download the mRNA expression data of ccRCC, and the cell infiltration proportion and tumor subtypes were evaluated using single sample Gene Set Enrichment Analysis (ssGSEA) and ConsensusClusterPlus, respectively. Subsequently, the immune scores classified all the ccRCC samples into “cold tumors” and “hot tumors”. Then, differentially expressed genes (DEGs) and checkpoint genes were analyzed in cold and hot tumor samples. Finally, a prognosis model was built using the optimized genes, and gene expression levels were validated using the E-MTAB-3267 dataset.

    Result: Patients with cold tumors have a better clinical prognosis than those with hot tumors. After comparison, 707 DEGs were identified between cold and hot tumor samples, and 10 immune checkpoint genes in hot tumors were found to be upregulated. Additionally, 10 optimized genes, PPARGC1A, SLC22A8, and IL20RB, were screened to build a risk score (RS) prognostic prediction model, and the expression tendencies of the 10 genes (except for DLX4) in TCGA were consistent with those in the E-MTAB-3267 dataset.

    Conclusions: The 10 important genes may be used as biomarkers for cold and hot tumors in ccRCC, and their related RS model could be used for risk assessment and prognosis prediction of ccRCC.

  • Article
    Lei Li, Lichun Guo, Guodong Cao, Xin Peng, Qinghong Cheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 181-190. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.18
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    Background: Existing studies have found that hydrogen sulfide (H2S) can alleviate heart damage caused by sepsis. The dynamic unbalance due to stress and inflammation in endoplasmic reticulum function will cause endoplasmic reticulum stress (ERS), which is related to sepsis. However, it remains unclear whether H2S reduces sepsis-induced heart damage by down-regulating cardiac ERS.

    Metheods: In this study, sepsis was induced in rats by cecal ligation and puncture (CLP). Cardiac enzymes were determined by biochemical analyzers. ELISA kits were used to detect inflammatory cytokine and histopathology and assess the histological characteristics of myocardial tissue. In addition, the myocardial injury was assessed by the TUNEL (TdT-mediated dUTP nick-end labeling) technique. The expression of the relative protein was tested by western blot.

    Results: Our study demonstrated attenuation of myocardial enzyme levels and inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels by H2S in rats with sepsis while that of interleukin-10 (IL-10) was increased. Histopathological examinations indicated that the use of H2S reduced myocardial tissue damage and myocardial apoptosis rate. Western blot analysis suggested significantly reduced expression of 78 kDa glucose-regulated protein (GRP78), C/EBP-homologous protein (CHOP), and cleaved caspase-12 by H2S, indicating inhibition of ERS. The expressions of proapoptotic factors Bax, cleaved caspase-3, the inflammatory factor, and nuclear factor kappa-B (NF-κB) were decreased by H2S. The expression of B-cell lymphoma-2 (Bcl-2) was increased by H2S, indicating alleviation of cardiomyocyte apoptosis and inflammation.

    Conclusions: Overall, our results suggest that alleviating sepsis-induced myocardial damage could be achieved by H2S via restraining ERS in rats.

  • Article
    Biaoliang Wu, Qingchen Wei, Guokang Lu, Tianqi Zhang, Mindeng Wang, Ying Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 191-196. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.19
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    Background: The association between sleep-wake cycles disorder and pineal gland lesions was rarely reported, while a growing number of literatures showed that patients have varying degrees of sleep rhythm disturbances. Individuals with these complications have to plan a life-long regimen to control their progressive illness. Effective assessment and treatment of the complication is urgently needed.

    Methods: 17 patients suffered from pineal lesions were distributed in two groups based on Glasgow Outcome Scale (GOS): Group 1: GOS <9 (N = 11); Group 2: GOS >9 (N = 6). Clinical data were collected 12 months after operation. The medical records were reviewed, the demographic information was extracted, and the clinical symptoms, cognitive level (coma, lethargy), hormonal results, and neurologic complications were recorded. Hydrocephalus was revealed in all patients by brain computed tomography (CT) scan.

    Results: The less measured values of hydrocephalus were observed in G2 patients under ventricular shunt treatment. Statistical analyses indicated that hydrocephalus was related to GOS and the score of the National Institutes of Health stroke scale (NIHSS) (p < 0.05). The mild fever (37.3–38.2 °C) was associated with pineal damage (p < 0.05).

    Conclusions: Patients’ recovery after pineal lesions surgery was affected by pineal damage or compression. Clinicians ought to pay attention to clinical profiles of these conditions and recommend ventricular shunt treatment accordingly.

  • Article
    Dongmei Hou, Qiang Ding, Ruiqi Li, Yuan Zhang, Fuming Zi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 197-206. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.20
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    Background: In order to find cost-effective drugs for synergistic therapy to improve the survival rate of acute myeloid leukemia (AML) patients. The aim of this study was to explore the action and mechanism of action of metformin in acute myeloid leukemia (AML), on the hope of finding cost-effective drugs for synergistic therapy to improve the survival of acute myeloid leukemia (AML) patients.

    Methods: Human AML cell lines (HL-60 (Human Promyelocytic Leukemia Cells), Kasumi-1, and KG-1 (Acute myeloid leukemia)) were treated with different concentrations of metformin from 0 to 40 mM. Cell viability was determined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay, and cell cycle was assessed using flow cytometry. Hoechst 33258 and Annexin V-FITC/PI (Annexin V Fluorescein Isothiocyanate/Propidium iodide) double labeling were used to evaluate apoptosis, and western blotting was used to determine the expression levels of proteins related to cell cycle arrest, apoptosis, and signaling pathways. The MTT assay was used to determine cell viability.

    Results: Metformin at different concentrations could inhibit the proliferation of AML cells and primary cells. AML cells in G1 phase were significantly upregulated after metformin treatment. Hochest33258 staining and Annexin V-FITC/PI staining showed that metformin significantly induced apoptosis in AML cells. Western blot showed that metformin could activate caspase-3, caspase-9, poly ADP (Adenosine 5-diphosphoribose)-ribose polymerase 1 (PARP-1) and Bak, down-regulate the expression of myeloid cell leukemia-1 (Mcl-1), inhibite the expression of insulin-like growth factors 1R (IGF-1R) and phosphoinositide 3-kinase (PI3K), and ultimately inhibite the phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR).

    Conclusions: This study verified that metformin inhibits AML cell proliferation, induces apoptosis and G0/G1 cell cycle arrest by inhibiting the PI3K/AKT/mTOR pathway.

  • Article
    Shiping Wang, Ling Ye, Rui Wang, Wenqing Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 207-215. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.21
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    Background: Berberine (Ber) is effective in alleviating postoperative cognitive dysfunction in mice. However, the function of Ber on isoflurane-stimulated primary rat hippocampal neurons (RHN) is still unknown.

    Objective: To investigate the role of Ber in isoflurane-stimulated primary RHN.

    Methods: To reveal the toxicity of Ber (0, 2.5, 5, 10, 15, and 20 µM) on RHN cells, cell counting kit-8 (CCK-8) assay was conducted. Immunofluorescence was utilized to identify primary RHN cells. The role of Ber in apoptosis and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappa B (NF-κB) pathway-related markers in Iso (isoflurane)-stimulated RHN cells was assessed through enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription PCR (RT-qPCR), and Western blot. After the treatment using PI3K inhibitor wortmannin (Wor), apoptosis and PI3K/AKT/NF-κB pathway-related markers were tested again.

    Results: Ber (10, 15, and 20 µM) suppressed the viability of RHN cells. Neuron-specific nuclear protein (NeuN) was positive in primary RHN cells. Ber also blocked apoptosis, decreased tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and NF-κB family member REL-1A (P65) levels, and elevated PI3K and p-AKT levels in Iso-treated RHN cells, but these effects were counteracted by Wor.

    Conclusions: Ber mitigates neuroinflammation in Iso-mediated RHN cells via modulating the PI3K/AKT/NF-κB pathway. Ber might serve as a latent agent for postoperative cognitive dysfunction (POCD) therapy.

  • Article
    Ai-Ning Wu, Rong-Xin Yu, Li-Xue Liu, De-Bang Li, Ya Tuo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 217-222. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.22
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    Objective: The present study aims to explore (1) the changes in the expression of serum interleukin-2 (IL-2) and heme oxygenase-1 (HO-1) in patients with recurrent spontaneous abortion (RSA) and (2) the correlation between IL-2 and HO-1.

    Method: A total of 45 patients with RSA who (1) were admitted to the Obstetrics and Gynecology Department of the Affiliated Hospital of Inner Mongolia Medical University between June 2018 and December 2020 and (2) met the inclusion criteria were selected as the study subjects and assigned to the observation group. A total of 45 women with normal and early pregnancy were selected from the same hospital as the study subjects and assigned to the normal control group. The expression levels of serum IL-2 and HO-1 in the observation group (before and after successful fetal preservation treatment) and in the control group were detected using the enzyme-linked immunosorbent assay double antibody sandwich method and spectrophotometry. The correlation between the serum IL-2 and HO-1 expression levels in patients with RSA was analyzed.

    Results: The serum IL-2 expression level before treatment was significantly higher (p < 0.05) and the serum HO-1 expression level was significantly lower (p < 0.05) in the observation group than in the normal control group. In the observation group, the serum IL-2 expression level decreased (p < 0.05) and the HO-1 expression level increased (p < 0.05) after successful fetal preservation treatment. The results of Pearson’s linear correlation analysis showed that the serum IL-2 and HO-1 expression levels were significantly negatively correlated with RSA before and after treatment (r: –0.698 and –0.625, respectively; p < 0.05). The area under curve (AUC) of IL-2 and HO-1 in predicting RSA risk is 0.765 and 0.792 respectively.

    Conclusions: Serum IL-2 and HO-1 may be involved in maternal and fetal pregnancy immune response and placental nourishment; Furthermore, they are related with the occurrence and development of RSA. Therefore, maternal serum IL-2 and HO-1 expression levels could be served as potential markers for the clinical evaluation of RSA prevention and treatment.

  • Article
    Xiaoli Xu, Zehua Weng, Xiufang Yang, Juan Ni, Ming-min Ma, Ying-chun Huang, Xiao-ling Yin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 223-232. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.23
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    Background: Sepsis is an atypical systemic reaction to infection with high morbidity and mortality. Recently, an association between improved prognosis and obesity in sepsis has been reported; However, the results remain controversial. The objective of the present study was to investigate the association between body mass index (BMI) and sepsis mortality by performing a meta-analysis.

    Methods: Considering pre-established inclusion and exclusion criteria, eligible studies were retrieved from PubMed, Embase, and Web of Science. Cochran’s Q test and I2 test were used to evaluate the heterogeneity among studies for each outcome. Statistical analysis was conducted using Stata12.0 software (version 12 SE; Stata Corporation, College Station, TX, USA). Odds ratios (OR) and 95% confidence intervals (CI) were used as effect sizes to evaluate differences in hospital, intensive care unit (ICU), 30-day, 90-day, and 1-year mortality in underweight, overweight, and obese patients with sepsis when compared with those with normal-weight.

    Results: In patients with sepsis, underweight was associated with increased in-hospital, ICU, and 1-year mortality (all odds ratio [OR] >1, p < 0.05), whereas no significant association was detected with 30- and 90-day mortality (all OR >1, p > 0.05). The association between underweight and in-hospital mortality disappeared in the non-Asian (OR [95% CI] = 1.13 [0.90, 1.41], p = 0.310) and non-adjusted subgroups (OR [95% CI] = 1.19 [0.92, 1.53], p = 0.186). Overweight was associated with decreased ICU mortality, 30-day mortality, 90-day mortality, and 1-year mortality in patients with sepsis (all OR <1, p < 0.05), exhibiting no significant association with in-hospital mortality (OR [95% CI] = 0.89 [0.78, 1.01], p = 0.074). Obesity was associated with decreased in-hospital, ICU, 30-day, 90-day, and 1-year mortality in patients with sepsis (all OR <1, p < 0.05).

    Conclusions: The results of the present meta-analysis supported the view of the “obesity paradox”. An underweight BMI was associated with increased sepsis mortality, whereas overweight and obesity were associated with low mortality in sepsis. These findings suggest that the clinical management of sepsis should follow the principle of a personalized approach, and the impact of obesity on the pattern of infection, fluids, and antibiotic administration should be carefully considered.

  • Article
    Jinhui Shi, Xuesong Zhu, Huilin Yang, Weimin Jiang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 233-240. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.24
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    Background: This study compared the use of low-dose (0.5 mg/level) recombinant human bone morphogenetic protein-2 (rhBMP-2) and iliac crest autographs for anterior cervical discectomy and fusion (ACDF) and determined whether the incidence and severity of local complications were reduced with rhBMP-2.

    Methods: A total of 173 patients were enrolled in this retrospective study between June 2017 and March 2019. All patients who underwent primary one- or two-level ACDF procedures with either rhBMP-2 (the BMP group, n = 110) or iliac crest bone autografts (the IBG group, n = 63) were analyzed. The patients in both groups had comparable preoperative pain and disability. Follow-ups were conducted within 1 week after the operation and at 3, 6, 12, and 24 months postoperatively. The scores of the Neck Disability Index (NDI) and the Japanese Orthopedic Association (JOA) questionnaires were used to evaluate the clinical outcomes.

    Results: There was no significant difference in patient demographics between the BMP and IBG groups before the operation (p > 0.05), and there was no significant difference in the overall incidence of dysphagia between the two groups (p > 0.05). There was a significant difference in prevertebral soft tissue swelling (PSTS) at the C3 level between the two groups at all intervals (p < 0.01). There was a significant difference in PSTS at the C6 level within 1 week postoperatively (p < 0.01), while there was no difference at 3, 6, 12, and 24 months postoperatively (p > 0.05). Neither group had a case of pseudarthrosis. Finally, there was no significant difference in the NDI and JOA scores between the two groups (p > 0.05).

    Conclusions: Adverse events associated with low-dose rhBMP-2 for one- and two-level ACDF are rare. We recommend placing the rhBMP-2 carrier in the center of interbody fusion cage and bilaterally covering the carrier with excised local osteophytes.

  • Article
    Yunfeng Dai, Jiajia Ren, Huanbing Wei, Chunyao Cao, Xudong Zhang, Xuesong Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 241-247. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.25
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    Background: Diabetic nephropathy (DN) is a microvascular complication derived from diabetes mellitus (DM). The aim of this study was to explore the diagnostic value of retinol binding protein (RBP), transferrin (TRF) and osteopontin (OPN) to early detect nephropathy in T2DM (type 2 diabetes mellitus) patients.

    Methods: 90 T2DM patients were enrolled in the study and divided in three groups: Patients with normal albuminuria (ACR <30 mg/g creatinine), patients with micro-albuminuria (ACR = 30~300 mg/g creatinine) and patients with macro-albuminuria (ACR >300 mg/g creatinine). Thirty healthy people of the same socioeconomic status and age as the diabetic patients enrolled as controls. Glycosylated hemoglobin a1c (HbA1c), insulin, plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, cystatin C, creatinine, urea, TRF, RBP, glomerular filtration rate (GFR) and OPN were determined during the study.

    Results: Micro-albuminuria and macro-albuminuria DM groups showed higher levels of RBP, TRF and OPN compared to control and normal albuminuria DM groups (p < 0.05). The RBP, TRF and OPN of the micro-albuminuria group were 29.1 ng/mL, 97.8 ng/mL and 48.03 ng/mL, respectively, and the RBP, TRF and OPN of the macro-albuminuria group were 42 ng/mL, 142.3 ng/mL and 61.67 ng/mL, respectively. RBP, TRF and OPN were positively associated with the course of DM, diastolic and systolic blood pressure, HbA1c, glucose, triacylglycerol and ACR, HOMA-IR. However, they were negatively associated with GFR in the DM groups. Receiver operating characteristic (ROC) curve indicated that 94.5 ng/mL was the TRF optimal cutoff to differentiate DN and non-DN groups. TRF had a specificity of 75% and a sensitivity of 84%, AUC was 0.854. RBP cut-off was 26.5 ng/mL with a sensitivity of 86% and a specificity of 92%, AUC was 0.865. OPN cut-off was 37.3 ng/mL with a specificity of 81% and a sensitivity of 75%, AUC was 0.884. Creatinine cut-off was 37.5 mg/g with a sensitivity of 89% and a specificity of 72%, AUC was 0.840. RBP was more specific than OPN, TRF and ACR.

    Conclusions: Compared with OPN, TRF and ACR, RBP has higher specificity, so RBP marker can be a tool to track the development and progression of DN.

  • Article
    Xinghe Liao, Tianzhen Jian, Zhe Zhang, Jing Zhang, Chenyue Zhang, Shiyu Jiang, Weiwei Zhao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 249-258. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.26
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    Background: The C-type lectin domain family 10 member A (CLEC10A), which is an affiliate of the C-type lectin receptors (CLRs), performs a crucial function in regulating adaptive and innate immunity and has demonstrated tremendous promise as a target for cancer immunotherapy. Nevertheless, there has been no functional study of CLEC10A in breast cancer (BRCA) prognosis risk, immunotherapy, or any other treatment.

    Methods: The Gene Expression Profiling Interactive Analysis (GEPIA) and the Tumor IMmune Estimation Resource (TIMER) were used to assess CLEC10A expression in BRCA and to look at immunohistochemistry in the Human Protein Atlas (HPA). PrognoScan, GEPIA, Oncolnc and Kaplan–Meier (KM) plotter were employed to assess the prognostic impact of CLEC10A on BRCA. TIMER, GEPIA 2021, and TISIDB were utilized to assess the impact of CLEC10A on the immune microenvironment and cBioPortal was used to assess the alteration of CLEC10A, both in BRCA.

    Results: We found that C-type lectin domain family 10 member A (CLEC10A) expression was reduced in BRCA and was associated with poorer survival. We found that CLEC10A was 0.8% genetically altered in BRCA, with profound deletion being the most common alteration. Furthermore, CLEC10A expression was shown to be strongly linked to a number of different tumor-infiltrating immune cells (TIICs), and we found that CLEC10 was closely related to PDCD1, CD244, CD27, CD48, HLA-DOA, HLA-DPA1, XCL2, CCL17, CXCR3 and CCR7 among others.

    Conclusions: CLEC10A expression has a high prognostic significance and may be a potential biomarker for immunotherapeutic approaches in BRCA.

  • Article
    Chunguang Li, Cheng Gong, Wenhao Chen, Daojiang Li, Youli Xie, Wenhui Tao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 259-270. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.27
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    Background: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Therefore, identifying prognostic biomarkers for GC is important to improve the clinical outcomes of patients.

    Methods: Univariate Cox survival analysis and random survival forest (RSF) were performed on all genes in The Cancer Genome Atlas (TCGA) cohort I (n = 261) to screen for survival-related seed genes. A forward selection algorithm was used to further determine prognosis-related genes using ribonucleic acid sequencing (RNA-seq) or clinically integrated RNA-seq data, followed by the construction of prognostic models. The concordance index (C-index) and Akaike information criterion (AIC) were calculated to identify the optimal model, the performance of which was further validated in TCGA cohort II (n = 109) and the Gene Expression Omnibus series 84437 (GSE84437) cohort (n = 431), and compared with five previous prediction models.

    Results: Four prognostic models were constructed using the machine learning method. Model 3, based on the RSF model and RNA-seq data, was identified as the optimal model (AIC = 1050.76, C-index = 0.74, p = 2.39 × 10−13). Compared with models 1, 2, and 4, model 3 showed the highest predictive accuracy in both the internal (C-index = 0.73, p = 1.48 × 10−2) and external (C-index = 0.62, p = 0.020) validation cohorts. Receiver operating characteristic curves also confirmed the robust ability of the nine-gene signature in model 3 to assess GC prognosis in both TCGA and GSE84437 cohorts, with all areas under curves over 0.65. Furthermore, the prognostic performance of model 3 outperformed that of the other five existing prediction models (C-index = 0.74, p = 2.39 × 10−13).

    Conclusions: We propose a nine-gene marker with high sensitivity and specificity as a powerful tool for predicting the prognosis of GC.

  • Article
    Nannan Wang, Rui He, Li Fan, Jinxia Fu, Xiaoqiong Li, Guiling Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 271-284. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.28
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    Objectives: This study aims to explore the molecular mechanisms of the protein subunit of complement I (C1q) tumor necrosis factor (TNF) related protein 1 (CTRP1) in the development of carotid plaque.

    Methods: An injury model and a CTRP1 over-expression model of high-glucose and high-lipid human umbilical vein endothelial cells (HUVECs) were constructed in vitro. The expression levels of inflammatory factors, tumor necrosis factor-α (TNF-α), human interleukin-1β (IL-1β) and interleukin-6 (IL-6), of all the groups, were detected by enzyme-linked immunosorbent assay (ELISA), and the gene expression levels of CTRP1, AMP-activated protein kinase (AMPK) and matrix metalloproteinase-9 (MMP-9) were detected by quantitative polymerase chain reaction (qPCR). The over-expressed CTRP1 with carotid plaque mouse model (CTRP1 + CAS) and carotid plaque mouse model (CAS) were established. The content of CTRP1 in serum and downstream AMPK, MMP-9, as well as inflammatory factors, were determined by ELISA. Mice in each group were biochemically examined for lipid indexes, including levels of triglycerides (TG), serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). CTRP1 knockout C57BL/6 mouse model was constructed. The levels of inflammatory factors, TNF-α, IL-1β and IL-6, in serum and the molecular levels of CTRP1/AMPK/MMP-9 in mice of each group were detected by ELISA. Biochemical assays were conducted to detect the blood lipid indexes of mice in each group, including the levels of TC, TG, LDL-C and HDL-C.

    Results: The results of ELISA on the in vitro and in vivo CAS models showed that in the serum of the model group, the expressions of TNF-α, IL-1β and IL-6 were up-regulated (*p < 0.05). The expression of CTRP1 was down-regulated (*p < 0.05), that of AMPK was also down-regulated (*p < 0.05) and that of MMP-9 was up-regulated (*p < 0.05) compared with the controls. The results of ELISA on the in vitro and in vivo CTRP1 + CAS models showed that compared with the ApoE knockout group, the levels of inflammatory factors (TNF-α, IL-1β and IL-6) in the CTRP1 + ApoE knockout group were significantly down-regulated (*p < 0.05).

    Conclusions: As an upstream molecule of a signaling pathway, CTRP1 can activate the AMPK signaling pathway, regulate the expressions of molecules such as AMPK and MMP-9, reduce the level of inflammatory factors (TNF-α, IL-1β and IL-6), drive the development of blood lipid indexes to the normal direction, and has a potential protective role in the occurrence and development of carotid plaque.

  • Article
    Chenchen Yang, Can Shi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 285-293. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.29
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    Objective: This meta-analysis aimed to study the correlation between four polymorphisms in the matrix metalloproteinase (MMP) gene and risk of cervical cancer.

    Methods: Eligible studies were retrieved from PubMed, Cochrane Library, and Embase. Case-control studies that focused on polymorphic loci rs1799750 in MMP-1, rs243865 in MMP-2, rs3025058 in MMP-3, and rs11568818 in MMP-7 were included in the meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the effects of interest. Quality assessment, heterogeneity analysis, publication bias evaluation, and sensitivity analyses were performed to confirm the reliability of this meta-analysis.

    Results: Nine studies with 3790 subjects were included. There was significant heterogeneity for rs11568818 GA vs. AA, rs3025058 5A6A vs. 6A6A, and all genetic models of rs243865. There were significant differences in rs11568818 G vs. A (OR [95% CI]: 1.3059 [1.1484; 1.4851], p value < 0.0001), GG vs. AA (OR [95% CI]: 1.6884 [1.2912; 2.2078], p value: 0.0001), GG vs. AA+GA (OR [95% CI]: 1.6884 [1.2912; 2.2078], p value: 0.0001), and GG+GA vs. AA genotype (OR [95% CI]: 1.3805 [1.1459; 1.6632], p value: 0.0007); And rs3025058 5A vs. 6A (OR [95% CI]: 1.2078 [1.0379; 1.4056], p value: 0.0147), 5A5A vs. 6A6A (OR [95% CI]: 1.4787 [1.0876; 2.0103], p value: 0.0126), and 5A5A+5A6A vs. 6A6A (OR [95% CI]: 1.2747 [1.0104; 1.6081], p value: 0.0406). There was no significant difference in any of the genetic models for rs1799750 and rs243865. No publication bias was observed in any of the genetic models.

    Conclusions: MMP-7 rs11568818 G/A and MMP-3 rs3025058 5A/6A were significantly associated with cervical cancer susceptibility.

  • Article
    Zhi-xiong Chen, Jin Li, Jing-kun Shang, Mao-cai Tang, Li-hui Chen, Yu-yu Lv, Shou-ru Zhang, Hao Sun
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 295-304. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.30
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    Background: Trastuzumab resistance poses a challenge to the treatment of patients with Human epidermal growth factor receptor-2 (HER2)-positive gastric cancer (GC). The aim of this study was to determine the function and possible mechanism of Regulator of G Protein Signaling 1 (RGS1) on trastuzumab resistance in GC.

    Methods: There were 20 cases each of tumor tissue (GC) and histologically normal paracancerous tissue (Adjacent) from GC patients. Trastuzumab-resistant human gastric cancer cells SNU216 cell line (SNU216-TR) was constructed by Etest, and then quantitative real-time polymerase chain reaction (qRT-PCR) was responsible for expression measurement of RGS1 in GC clinical tissues and different cells lines. The viability of cells treated with trastuzumab of 0, 1, 10, 100, and 200 µg/mL was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Transwell and scratch assays were performed to examine the cells migration and invasion abilities. Additionally, the expression of RGS1, Gαq, as well as related proteins of epithelial-mesenchymal transition (EMT) and MEK/ERK (mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase) pathway were estimated, using western blot.

    Results: RGS1 expression had a significant upregulation in GC tissues and trastuzumab-resistant GC tissues and cells (p < 0.05). Overexpression of RGS1 could enhance the resistance to trastuzumab, migration and invasion of SNU216-TR cells and promote EMT progression (p < 0.05). Moreover, overexpression of RGS1 could activate the MEK/ERK pathway in SNU216-TR cells, while knockdown of RGS1 significantly inhibited the pathway (p < 0.05). In addition, RGS1 significantlyup-regulated Gαq expression and activated the MEK/ERK signaling pathway (p < 0.05).

    Conclusions: RGS1 activated the MEK/ERK pathway by regulating Gαq signaling, thereby promoting trastuzumab resistance and malignant behaviors of GC cells SNU216.

  • Article
    Yu-Dong Zhang, Guo-Hua Wei, Xiao-Dong Zhang, Jun Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 305-319. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.31
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    Background: Long noncoding RNA hox transcript antisense intergenic RNA (HOTAIR) is an oncogene of non-small cell lung cancer (NSCLC), which shows the effect of enhancing cancer cell activity and inhibiting apoptosis. However, its specific regulatory mechanism is not clear. The aim of study was to clarify the role and downstream molecular signals of HOTAIR in the regulation of endoplasmic reticulum stress (ERS) and apoptosis in NSCLC cells.

    Methods: The interaction between HOTAIR and microRNA (miR)-137, heart development protein with EGF (epidermal growth factor) like domains 1 [(human)] (HEG1) and recombinant activating transcription factor 6 (ATF6) was verified using bioinformatics analysis, RNA pull down and immunocoprecipitation (IP) techniques. Real time-quantitative r polymerase chain reaction (RT-qPCR) and western blotting were used to verify the regulatory effects of HOTAIR and miR-137 on downstream proteins HEG1, ATF6, B-cell lymphoma-2 (Bcl-2), Caspase-8 and TNF-related apoptosis-inducing ligand (TRAIL). 3-(4,5)-Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and terminal deoxynucleotidyl transferase dUTP (2’-deoxyuridine 5’-triphosphate) nick end labeling (TUNEL) methods were used to detect the effects of HOTAIR and miR-137 on the proliferation and apoptosis of A549.

    Results: HOTAIR was highly expressed in NSCLC cell line (p < 0.001). Up-regulation of HOTAIR or down-regulation of miR-137 can significantly promote cell proliferation, inhibit cell apoptosis (upregulated Bcl-2, downregulated Caspase 8 and TRAIL (Tumor Necrosis Factor (TNF)-Related Apoptosis Inducing Ligand)), endoplasmic reticulum stress (downregulated ATF6) and HEG1 expression (p < 0.05). However, siHOTAIR (HOTAIR siRNA) or miR-137 mimic transfection showed an opposite role in A549 cells. HOTAIR was significantly enriched in the pull-down miR-137 and inhibited miR-137 expression (p < 0.05). HEG1 and ATF6 were co expressed in A549.

    Conclusions: The HOTAIR/miR-137 axis significantly inhibits cell apoptosis, endoplasmic reticulum stress and the expression of HEG1, and promotes cell proliferation, exerting a significant pro-cancer effect.

  • Article
    Wen-Chuan Zhao, Hong Chen, Chen-Ping Tang, Chuan-Du Tang, Lei Wu, Hao-Ran Kong, Jing-Yi Zhou, Yi-Xin Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 321-332. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.32
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    Introduction: This study aimed to observe the changes in miRNA and inflammatory mediators before and after high tibial osteotomy (HTO) and investigate the mechanism of HTO to relieve knee osteoarthritis.

    Material and Methods: Seventeen cases of patients with arthritis were collected. A synovitis cell model was established by challenging immortalized human synoviocytes (HSs) with lipopolysaccharide (LPS). The weight-bearing line ratio (WBL) values of patients with osteoarthritis before and after HTO surgery were collected. Lubricin, matrix metalloproteinase-1 (MMP-1), monocyte chemoattractant protein-1 (MCP-1) hyaluronic acid (HA), and the concentrations of proinflammatory factors IL (Interleukin)-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α) in the synovial fluid of patients with osteoarthritis before and after surgery were determined using enzyme linked immunosorbent assay (ELISA). miR-23a-3p and miR-30c-5p expression levels in the synovial fluid before and after surgery were measured using quantitative real-time PCR (qRT-PCR). Proliferative activity of HSs was assayed with cell counting kit-8 (CCK-8) proliferation experiment.

    Results: Proinflammatory cytokines IL-1β, IL-6, IL-8 and TNF-α levels were reduced in the synovial fluid after HTO surgery. Similarly, extracellular matrix proteins, including lubricin and MMP-1 were reduced. In contrast, increased HA, miR-23a-3p, and miR-30c-5p expression levels were observed after HTO surgery, which was accompanied by the recovery of joint function, as revealed by the increased WBL. In the cell model, LPS induction caused the decrease in miR-23a-3p and miR-30c-5p. MiR-23a-3p and miR-30c-5p upregulation rescued the LPS-induction damaging effect on HSs, including cell proliferation capacity and the inflammatory response.

    Conclusions: These results indicated that HTO ameliorates synovial inflammation and cartilage damage in patients with osteoarthritis. MiR-23a-3p and miR-30c-5p elevated levels may contribute to the beneficial effect of HTO treatment on osteoarthritis by attenuating inflammatory responses in knee joints.

  • Article
    Dongwei Qi, Xi Chen, Juan Gong, Yourang Jiang, Juan Long, Wei Xu, Xueyong Tang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 333-343. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.33
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    Background: Psoriasis vulgaris (PV) is one of the most common chronic inflammatory skin diseases, but its exact etiology and pathological mechanism are not fully understood. The regulation of tryptophan metabolism by gut microbiota-host co-metabolism has been confirmed to significantly affect the pathogenesis of various chronic inflammatory and autoimmune diseases. Tryptophan and its main metabolites are partly involved in the pathogenesis and progression of psoriasis, but its specific regulatory mechanism has not yet been clarified. The purpose of this study is to explore the changes in the intestinal flora and its metabolic characteristics in PV patients.

    Methods: 16S rRNA sequencing combined with metabolomics was used to explore changes in gut microbiota and its metabolic characteristics. Alpha, Beta diversity and LEfSe (Linear Discriminant Analysis Effect Size) analyses were used to analyze the changes in the intestinal flora and to screen biomarkers. PCA (Principal Component Analysis) and OPLS-DA (Orthogonal Partial Least Squares-Discriminant Analysis) methods were used to analyze the differences in metabolite composition. PICRUS (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) software was used to predict metabolic function.

    Results: The result revealed differences in the tract microbiota composition between normal and psoriasis patients, suggesting that microbial populations may mediate the development of psoriasis. Fecal metabolite profiles revealed distinct metabolites associated with the psoriasis samples group (PSG). These products of metabolism primarily participated in metabolic pathways including amino acid biosynthesis, carbohydrate degradation and glycolysis. There is a positive/negative correlation between these gut microbes and metabolites.

    Conclusions: The results suggest that the gut microbiota and its metabolites may play a crucial role in the development of PSG, which may provide a potential biomarker for the treatment of PSG.

  • Article
    Wenqiao Sun, Cuicui Chen, Shuhai Zhong, Huankun Liang, Guiling Guo, Laiqing Li, Licheng Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 345-351. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.34
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    Background: Clinically, the symptoms of hepatitis A virus (HAV) and hepatitis E virus (HEV) infection are similar, which can easily lead to misdiagnosis. This study was performed to establish a new detection assay to distinguish HAV and HEV infections using a time-resolved fluorescence immunoassay (TRFIA) via the detection of HAV-IgM and HEV-IgM antibodies in serum.

    Method: A capture TRFIA was established after optimization. Anti-IgM antibodies were immobilized on 96-well plates and used to capture all IgM (including HAV-IgM and HEV-IgM) antibodies, then they were banded together with HAV-specific antigen (HAVAg) and HEV-specific antigen (HEVAg) that labeled with europium (III) (Eu3+) and samarium (III) (Sm3+) respectively. Lastly, the fluorescence intensity was measured with time-resolved fluorometry.

    Results: For HAV-IgM, the sensitivity was 0.25 mIU/mL, while for HEV-IgM was 0.32 mIU/mL. In serum samples, the inter-assay and intra-assay CVs (Coefficient of Variations) were under 10% and had high specificity. HAV-IgM and HEV-IgM cut-off values were 0.36 mIU/mL and 0.57 mIU/mL, respectively.

    Conclusions: Both tests demonstrated detection effect of the TRFIA method we developed is on par with that of clinical ELISA (enzyme-linked immunosorbent assay) methods. TRFIA method is appropriate for qualitatively and quantitatively detecting HAV-IgM and HEV-IgM antibodies to discriminate between HAV and HEV infections.

  • Article
    Xuanping Zhou, Shu Yang, Shuolin Feng, Chilong Yuan, Hexin Zhang, Yuewen Peng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 353-366. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.35
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    Background: Despite the evidence showing deregulation of autophagy to play a part in the pathogeneis of rheumatoid arthritis (RA), its role in the etiology of RA remains largely unknown. The aim of this study was to identify novel differentially expressed autophagy-related genes (DEARGs) in RA and their role in its pathogenesis.

    Methods: DEARGs and central modules of RA were obtained, using weighted gene co-expression network analysis (WGCNA) from GSE55457 dataset of the Gene Expression Omnibus database. Enrichment analysis was used for the identification of potential functions and pathways of the hub modules. Hub genes were obtained via intersection of DEARGs and turquoise modules, and their expressions were verified using GSE55235 and GSE97779 datasets and quantitative real-time polymerase chain reaction (qRT-PCR). CIBERSORT was used to assess single cell infiltration of RA and to assess the relevance of hub genes to immune cells.

    Results: A total of 14 DEARGs were obtained. Enrichment analysis showed hub modules and genes to be associated with immune and inflammatory related pathways. CC chemokine receptor 2 (CCR2+) and Caspase-1 (CASP1) were identified as potential biomarkers of RA. Furthermore, immune cell infiltration analysis showed that CCR2+ and CASP1 to be associated with T cell CD8+ and activated NK cells, among others.

    Conclusions: CCR2+ and CASP1 may be involved in RA development, via immune homeostasis, and may serve as potential markers for RA diagnosis and treatment. These findings may provide therapeutic targets for immune-based therapies and expand the understanding of RA etiology.

  • Article
    Meng Dai, Ling Tian, Haojun Luo, Haoyang Cao, Sixiong Wang, Huiqing Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 367-375. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.36
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    Background: Information on the difference between left and right atrium in Atrial fibrillation (AF) is still lacking. In the present study, we aimed to identify differences in immune cell infiltration and differentially expressed genes (DEGs) between atrial tissue in patients with AF and sinus rhythm (SR), and to compare the differences between left and right atrial tissues in AF.

    Methods: The gene data of GSE79768 (Gene Expression Omnibus Series79768), GSE115574, and GSE128188 from the Gene Expression Omnibus (GEO) database were retrieved. After merging all data and adjusting batch effect, DEGs were identified. Single-Sample Gene Set Enrichment Analysis (ssGSEA), Functional enrichment analysis based on Gene Ontology (GO) resource, Kyoto Encyclopedia of Genes and Genomes (KEGG) resource, and ESTIMATE algorithm were carried out to analyze the difference between AF and SR.

    Results: In total, 105 atrial samples from 3 studies were included in the analysis. Compared with SR, AF tissue had more CD8+ T (cluster of differentiation 8+ T) cells (p = 0.039) and Th2 (T helper 2) cells (p = 0.016), and it had fewer Th17 cells (p = 0.008), Tgd (p < 0.001) and NK (natural killer) CD56dim cells (p = 0.047). The differences between the left and right atrium in AF and SR were also analyzed. In AF atrium tissue, a total of 87 DEGs (26 up-regulated, 61 down-regulated) were identified. The enrichment signaling pathways and biological functions of DEGs were predicted.

    Conclusions: The difference in infiltrating immune cells and DEGs between left and right atrium indicates that there are different mechanisms for development remodeling and inflammatory environment of AF within the left and right atrium.

  • Article
    Bingxuan Zheng, Yingcong Guo, Yuxi Qiao, Yang Li, Jin Zheng, Puxun Tian, Xiaoming Ding, Wujun Xue, Chenguang Ding
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 377-385. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.37
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    Background: Ferroptosis, a regulatory mode of cell death, has been extensively recognized as a crucial mechanism of ischemia/reperfusion (IR) that leads to acute kidney injury (AKI). However, the underlying mechanisms are not totally understood. This study aimed to explore the role of ferroptosis in IR-related acute kidney injury (AKI).

    Methods: Renal IR rat model and hypoxia/reoxygenation (HR)-induced HK-2 (human kidney 2) cell model were established. HK-2 cell viability was measured by CCK-8 (cell counting kit 8) assay. Ferroptosis activation was evaluated through Fe2+ and reactive oxygen species levels, and lipid peroxidization through glutathione level and malondialdehyde level. We used Western blot analysis to detect glutathione peroxidase 4 (GPX4) expression, and qRT-PCR (quantitative real-time polymerase chain reaction) to evaluate GPX4 mRNA and microRNA level. Luciferase reporter assay was applied to verify if miR-188-3p bound GPX4 directly.

    Results: Ferroptosis was observed in the renal tissue of IR rats. miR-188-3p expression correlated negatively with GPX4 expression in renal injury (R2 = 0.4477). miR-188-3p knockdown and GPX4 overexpression inhibited HR-induced cell injury and ferroptosis. We further found that miR-188-3p could directly bind to the 3′UTR (untranslated region) of GPX4 mRNA, thus negatively regulating GPX4 expression.

    Conclusions: We demonstrated that miR-188-3p promoted ferroptosis in IR-associated AKI through GPX4 downregulation.

  • Article
    Wei Zhou, NanXiong Wang, JinJun He, Jun Shen, PingYu Ge, ZhaoMei Deng, Yuan Huang, Feng Yu, Haibo Zhang, Wei Ding
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 387-397. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.38
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    Objective: Sodium tanshinone ⅡA sulfonate (STS) is recognized to be beneficial to oxidative stress (OS). However, it is unclear whether it protects erectile function by antioxidative stress and maintains the contractile phenotype of cavernosal smooth muscle cells (CCSMCs) in hyperlipidemia-induced erectile dysfunction (ED) rats. Therefore, this research aimed to assess the protective effect and the mechanism of STS on cavernous smooth muscle cells in hyperlipidemia-related ED.

    Methods: This study assessed erectile function using the intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The phenotypic and oxidative-related markers were determined using western blot and immunohistochemistry assays. Sprague-Dawley rats were grouped as a normal control (NC) and four hyperlipidemia groups, including hyperlipidemia rats (HR), hyperlipidemia with saline (HR+NS), hyperlipidemia with 300 mg/kg N-acetylcysteine (HR+NAC), and hyperlipidemia rats with 10 mg/kg sodium tanshinone ⅡA sulfonate (HR+STS). After 4 months, all rats were sacrificed for serum biochemistry, OS markers, and penile histologic examinations after ICP and MAP tests.

    Results: The ICP/MAP ratio was significantly higher in HR+STS and HR+NAC groups than in HR and HR+NS groups (p < 0.05). Compared to the other hyperlipidemia rats, STS treatment markedly increased the expression of phenotypic proteins alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain (SMMHC), calponin, and Myocardin and decreased the osteopontin (OPN) expression in the penis (p < 0.05). Furthermore, we demonstrated that STS increased SOD and GSH expression while reducing MDA expression in serum and corpus cavernosum tissues compared with the HR group.

    Conclusions: STS treatment protected the erectile function by reducing the OS and maintaining the contractile phenotype in the CCSMCs of the hyperlipidemia-induced ED rats.

  • Article
    Man-Man Zhang, Bao-Fang Zhang, Kai Zhong, Ying-Qian Kang, Rohitha Muthugala, Hui-Min Zhao, Cong Wang, Ming-Liang Cheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 399-411. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.39
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    Background: The aim of this study was to investigate the effectiveness of different antiviral treatments and the timing of the initiation of treatment in hepatitis B virus (HBV)-infected newborn mice.

    Methods: Newborn mice, infected with HBV after the failure of blocking maternal-fetal transmission, received an 8-week treatment with the following antiviral agents, either alone or in combination: Entecavir (ETV), ETV + pegylated interferon a-2b (PEG IFN-a2b), tenofovir disoproxil fumarate (TDF), TDF + PEG IFN-a2b, PEG IFN-a2b, or normal saline at 4, 8, or 12 weeks after birth. HBV DNA, HBV RNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) were examined before or after treatment.

    Results: The greatest rate of HBV DNA inhibition was achieved after an 8-week treatment with ETV + PEG IFN-a2b in the newborn mice with antiviral therapy initiated at 4 weeks of age (p < 0.05). Moreover, ETV, ETV + PEG IFN-a2b, TDF, or TDF + PEG IFN-a2b elicited a significantly greater inhibition of HBV DNA than PEG IFN-a2b at all treatment initiation timings (p < 0.05). There was no significant difference in the effects of HBV RNA and HBV DNA. Furthermore, antiviral therapy initiation at 4 weeks of age had significantly greater effects on HBsAg and HBeAg than when the therapy was initiated at 8 weeks of age for ETV + PEG IFN-a2b (p < 0.05). Alanine transaminase was significantly elevated after 8-week treatment with ETV + PEG IFN-a2b or TDF + PEG IFN-a2b in the newborn mice with treatment initiation at 12 weeks after birth, whereas the creatinine and phosphorus levels remained within the normal ranges at all treatment initiation timings (p < 0.05).

    Conclusions: ETV or TDF in combination with PEG IFN-a2b was significantly more effective than either drug alone in the treatment of HBV-infected newborn mice. Furthermore, 4 weeks of age was found to be the optimal timing to initiate antiviral therapy. Therefore, these findings may help to develop an optimal treatment to improve the care of patients infected with HBV as a consequence of the failure of blocking mother-to-baby/neonata transmission.

  • Article
    Xiaolu Shi, Xueping Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 413-421. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.40
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    Background: Sjogren’s syndrome (SS) is a common autoimmune disease, which mainly invades glands and belongs to global disease, seriously affecting the quality of life of patients. The purpose of this study is to observe the therapeutic effect of Jinxueyuan Granules (JXYG) on SS and the regulatory effect of JXYG on follicular helper T (Treg) cells/follicular regulatory T cell (Tfh/Tfr) immune balance through animal experimental research.

    Methods: Statistical method was used to analyze the changes in water intake of NOD (non obese diabetic) mice after JXYG treatment. Hematoxylin and eosin (H&E) staining was used to observe the pathological morphology of the submandibular gland of NOD mice. Flow cytometry was used to analyze the effect of JXYG on the changes of Tfh cells and Tfr cells in the peripheral blood of NOD mice. Immunohistochemistry was used to analyze the effects of blood source on the expressions of CD4 (cluster of differentiation 4), CXCR5 (C-X-C chemokine receptor type 5), FOXP3 (fork head box P3), Bcl-6 (B-cell lymphoma 6), and Blimp-1 (B lymphocyte-induced maturation protein-1) in NOD mice’s submandibular gland and western blot was applied to analyze the expression of Bcl-6, Blimp-1, STAT3 (signal transducer and activator of transcription 3), and p-STAT3 (phosphorylated-signal transducer and activator of transcription 3) in submandibular glands of NOD mice in each group.

    Results: The amount of drinking water and the degree of lymphocyte infiltration in the submandibular gland of NOD mice could be reduced after the intervention of JXYG, which was closer to the normal level, and the effect of the high-dose group was more significant than that of the low-dose group. JXYG could promote the decrease of Tfh/CD4+ T, Tfr/CD4+ T, and Tfh/Tfr ratio in the peripheral blood of NOD mice, but there is no significant difference. JXYG could remarkably reduce the expression levels of Bcl-6, Blimp1, CD4, and p-STAT3, and increase those of FOXP3 in the submandibular gland of NOD mice.

    Conclusions: The above results suggested that JXYG may play a regulatory role in Tfh/Tfr immune balance by regulating the above molecular pathways. This study investigated the possible mechanisms underlying the treatment of SS with JXYG from a cellular and molecular perspective, thereby elucidating the pathogenesis of SS and providing an evidence-based foundation for the clinical treatment of dryness syndrome with the use of Chinese herbal compounds.

  • Article
    Bayiercaicike, Mingxia Li, Le Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 423-431. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.41
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    Objective: To investigate the correlation between platelet-derived growth factor-BB (PDGF-BB) and hypoxia-inducible factor-1α (HIF-1α) in the proliferation of pulmonary artery smooth muscle cells (PASMCs) in neonatal rats with hypoxic pulmonary hypertension (HPH) and the effect of PDGF-BB on pulmonary vascular remodeling and right ventricular structure and function in this disease.

    Methods: Sixty-four neonatal rats were randomly divided into an HPH and control group. Based on the observation time points, each group was split into groups for days 3, 7, 14, and 21. The HPH model was established in the HPH group. After detecting right ventricular systolic pressure (RVSP) in the neonatal rats in each group at the corresponding observation time points, the rats were sacrificed to obtain heart and lung tissue samples. The pulmonary vascular remodeling indexes and right ventricular hypertrophy index (RVHI) were calculated. PDGF-BB, HIF-1α, and proliferating cell nuclear antigen (PCNA) expression levels in the lung tissue were evaluated.

    Results: (1) The RVSP in the HPH group was higher than that in the control group at each observation time point (p < 0.001). (2) The pulmonary vascular remodeling indexes in the neonatal rats in the HPH group after 7 days of hypoxia were higher than those in the control group (p < 0.05). With the prolongation of hypoxia, the pulmonary vascular remodeling indexes gradually increased. (3) After hypoxia for 7, 14, and 21 days, the RVHI of the neonatal rats in the HPH group was significantly higher than that of the control group at the same age (p < 0.001). (4) PDGF-BB, HIF-1α, and PCNA expression levels in the HPH group at each observation time point were higher than those in the control group (p < 0.05), gradually increasing with the prolongation of hypoxia.

    Conclusions: In HPH neonatal rats, PDGF-BB, HIF-1α, and PCNA expression levels and the number of PASMCs are increased, which leads to pulmonary vascular remodeling and increased pulmonary artery pressure.

  • Article
    Jingjing Zhang, Zhiming Xu, Hongying Dai, Changqing Jiang, Tingting Liu, Liying Huang, Hongyi Kang, Xiao Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 433-440. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.42
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    Objectives: To investigate the association of pentraxin 3 (PTX3) expression with the clinicopathological features of patients suffering from endometrial cancer (EC).

    Methods: A total of 150 patients diagnosed with EC were recruited in the Affiliated Hospital of Qingdao University from 2015 to 2019, and their EC and tumor-adjacent histologically normal tissues (normal) were collected. Then, quantitative reverse transcription PCR (RT-qPCR) and Western blot were employed for detecting the PTX3 expression levels and analyzing how PTX3 expression levels could affect the overall survival rate of EC patients. The Chi-square test was used for the correlation analysis of PTX3 expression levels and clinicopathological features, and the Cox regression analysis model was utilized for the risk factor prediction of poor prognosis in EC patients. HEC1B cell transfection was carried out with PTX3 siRNA, Vector, PTX3 and siRNA overexpression plasmids. Then, the proliferation, migration and invasion abilities of cells were detected using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), scratch, and transwell assays, respectively; And the matrix metalloproteinase (MMP)-2 and MMP-9 expression levels in the cells were checked through Western blot.

    Results: First, we discovered that PTX3 was highly expressed in the EC group and the high expression resulted in poor prognosis of patients. Moreover, the PTX3 expression level was also bound up with body mass index (BMI), lymph node metastasis, tumor size, FIGO (International Federation of Gynecology and Obstetrics) staging, and myometrial infiltration. Furthermore, the PTX3 expression level was also one of the independent risk factors in EC patients suffering from poor prognoses. When the expression of PTX3 was knocked down, the invasion, proliferation and migration abilities of HEC1B cells were notably down-regulated, as well as the MMP-2 and MMP-9 expression levels.

    Conclusions: Highly expressed PTX3 has a bearing on the poor prognosis and malignant behavior of EC cells.

  • Article
    Shajidan Abudureyimu, Chunhui He, Yunlin Song, Palida Abulaiti, Hui Li, Zhi Xing, Yu Wang, Halisha Aierken, Ying Gao, Hai Lin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 441-448. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.43
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    Background: ABCA1 (ATP-binding cassette transporter A1 gene) is a principal gene involved in the reverse cholesterol transport and HDL-C (high-density lipoprotein-cholesterol) formation, and ABCA1 polymorphism is related to the development of coronary artery disease (CAD). The objective of this study was to investigate genetic polymorphisms of the ABCA1 gene among Uyghur CAD patients in Xinjiang, China.

    Methods: The case-control study included 381 Uyghurs with CAD (258 males and 123 females) and 394 healthy Uyghurs (265 males and 129 females). The ABCA1 gene contains two single nucleotide polymorphisms (SNP) (rs2230806 and rs2230808) that were genotyped using SNP scan TM high-throughput genotyping technology.

    Results: Cases and controls were significantly different in rs2230806 allele distributions in the dominant model (GG vs. GA+AA) and additive model (AA+GG vs. GA) in Uyghur male subjects (p = 0.001 and p = 0.024, respectively). According to a univariate analysis, the GA genotype was correlated with a lessen risk of CAD (OR (odds ratio) = 0.543, 95% CI (confidence interval): 0.369–0.798; p = 0.002), as well as the AA genotype (OR = 0.536, 95% CI: 0.320–0.897; p = 0.018). After adjusting compounding factors such as TG (triglyceride), TC (total cholesterol), LP(a) (lipoprotein a), HDL-C, LDL-C (low-density lipoprotein cholesterol), diabetes, smoking, and hypertension, logistic regression analysis revealed that the AA genotype (OR = 0.570, 95% CI =0.328–0.991, p = 0.046) and GA genotype (OR = 0.484, 95% CI = 0.321–0.723, p = 0.001) of rs2230806 were still correlated with a reduced risk of CAD in Uyghur male subjects.

    Conclusions: A polymorphism in ABCA1 rs2230806 associated with the A allele in Uyghur men in Xinjiang, China, protects against the risk of CAD.

  • Article
    Bingping Wu, Zhimin Li, Hua Lin, Lan Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 449-453. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.44
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    Objective: To analyze the relationship between different types of polocyte with the perivitelline space and embryonic developmental potential after short-term insemination.

    Methods: Early cumulus cells removal around the oocyte after short-term insemination, and the number and morphology of polocytes in the perivitelline space were observed under microscope. Then the oocytes, according to the polocyte situation, were divided into 4 groups: 2 polar body (PB), 1 PB, crushed PB (C-PB) and multiple PB (M-PB). The fertilization rate, 2 pronucleus (PN) rate, ≥3 PN rate, cleavage rate, optimal embryo rate, blastocyst formation rate, and high quality blastocyst formation rate among the 4 groups were compared.

    Results: The fertilization rate and 2 PN rate of the 2 PB group were significantly higher than that of the 1 PB group and the C-PB group (p < 0.01). The ≥3 PN rate of the M-PB group was significantly higher than that of the other groups (p < 0.01). There was no significant difference in cleavage rate and high quality blastocyst formation rate among the four groups (p > 0.05), but the rate of optimal embryo, and blastocyst formation rate in the 2 PB group were higher than in the 1 PB group (p < 0.01).

    Conclusions: The embryonic developmental potential of the oocytes with 2 PB after 4–6 h insemination were superior. It is helpful to predict embryonic development through the observation of different types of polocyte in the perivitelline space after short-time insemination.

  • Article
    Jing-min Yu, Min-yi Yang, Xia Zhao, Jing-hui Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 455-462. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.45
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    Objective: The existing literature suggests that osteoglycin (OGN) expression may be closely related to tumor transformation and invasion and metastasis, but there is a lack of evidence for OGN involvement in invasion and metastasis in ovarian cancer. The aim of this study was to investigate the relationship between OGN expression levels and the extent of ovarian cancer growth and metastasis through in vitro and in vivo studies.

    Methods: Microarrays of tumor tissue from 122 patients with epithelial ovarian cancer were used to detect OGN expression. The pMSCV-OGN lentiviral vector and its negative control were transfected into SKOV3 cells and the transfection efficiency was detected using Western blotting. The effects of OGN overexpression on the migration and invasion of SKOV3 cells were examined using wound healing tests and Transwell® assays. Cell Counting Kit 8 (CCK8) assay was used to detect SKOV3 cell proliferation. In addition, a mouse model of lung metastasis of ovarian cancer was established by tail vein injection of SKOV3 cells overexpressing OGN to investigate the effect of overexpressing OGN on the growth and metastasis of ovarian cancer by calculating the survival time, tumor volume, and the number of lung surface metastases of mice.

    Results: Ovarian cancer patients with low OGN expression are more likely to metastasize. OGN does not affect cell proliferation, but overexpression of OGN significantly inhibits the migration and invasion of SKOV3 cells. Overexpression of OGN in combination with cisplatin therapy significantly prolonged survival and inhibited tumor growth in mice with lung metastases from ovarian cancer.

    Conclusions: Overexpression of OGN prolonged the survival of tumor-bearing mice by inhibiting invasion and metastasis of ovarian cancer cells. OGN may become an important potential target for the prediction and control of ovarian cancer metastasis.

  • Article
    Can Wang, Cheng-e Gao, Zheng-yi Luo, Chuan-qing Jing, Wei Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 463-476. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.46
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    Background: Idiopathic pulmonary fibrosis (IPF) is a lung condition marked by microscopic honeycombing, subepithelial fibroblastic foci, and subpleural fibrosis, which is typically deadly, irreversible, and progressive. Angiogenesis is crucial to the development of pulmonary fibrosis. Nevertheless, the underlying molecular events involved remain unclear. The aim of this study was to identify specific central gene expression in pulmonary fibrosis and its underlying mechanism of action.

    Methods: GSE53845 dataset of pulmonary fibrosis patients were obtained from Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) and conducted principal component analysis. Differentially expressed ARGs (DE-ARGs) were obtained, by cross-analysis of angiogenesis-related genes (ARGs) and DEGs, downloaded from GeneCards. DE-ARGs were enriched using the R package clusterProfiler. Geneset variation analysis (GSVA) and gene set enrichment analysis (GSEA) were employed, to analyse the characteristics of related common pathways and the biological processes of DE-ARGs. In addition, protein-protein interaction (PPI) molecular regulatory interaction networks were created and hub DE-ARGs were screened. The correlation between IPF and immune cell infiltration was checked for, using the CIBERSORT algorithm. Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR) was employed, to examine hub DE-ARG expression in IPF rat tissues.

    Results: A total of 117 DE-ARGs were obtained, and these genes were primarily involved in biological activities including leukocyte migration, cell chemotaxis, and angiogenesis. In addition, eight hub DE-ARGs were identified; CCR7, CD24, MDK, CXCL12, IL1R2, CXCL14, CCL19, and IL13RA2. Furthermore, miR-374a-5p was significantly associated with CD24, CXCL14, IL13RA2 and CXCL12 central genes. Immune infiltration analysis showed a significant rise in the number of infiltrating B cells and CD8+ T cells in patients with IPF.

    Conclusions: Hub DE-ARGs may contribute to the angiogenic process of pulmonary fibrosis, providing potential targets for treating IPF, which is influenced by changes in the abundance of immune cells.

  • Article
    Feifei Wang, Hongda Yu, Lei Wang, Xinping Qiu, Weiming Zhang, Qiuchen Huang, Yanping Bai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 477-487. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.47
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    Background: T helper 17 (Th17) cells play an important role in the pathogenesis of psoriasis. Th17 differentiation and function are modulated by stromal interaction molecule 1 and/or store operated Ca2+ entry (STIM1/SOCE) pathway. Liangxue Huoxue Formula (LXHXF) is an effective traditional Chinese herbal formula used to treat psoriasis. But the specific mechanism of action is unclear. Here, we established a psoriasis animal model to evaluate the therapeutic effects of LXHXF and how it may regulate Th17 cell differentiation through STIM1/SOCE pathway.

    Methods: A psoriasis animal model was established using BALB/c male mice induced by imiquimod. Then, A course of 8-day intervention was conducted with methotrexate, STIM1 inhibitors, and LXHXF (high dose, medium dose, and low dose) in different groups. Skin lesions were recorded at the end of the intervention for pathological evaluation. Immunohistochemical staining was conducted to assess the infiltration of Th17 cells. Moreover, we performed cytometric bead array (CBA) method and flow cytometry to determine serum inflammatory cytokines and the Th17 percentage in peripheral blood cells, respectively. STIM1/SOCE pathway-related mRNA expression in skin lesions was also evaluated.

    Results: The model group presented typical psoriasiform manifestations, and the infiltration of Th17 cells in skin lesions increased significantly, compared to the control group (p < 0.05). In addition, the percentage of Th17 cells in peripheral blood and the level of inflammatory factors in serum, including interferon γ (IFN-γ), interleukin 17A (IL-17A), interleukin 21 (IL-21), and interleukin 22 (IL-22), increased in the model group compared to the control group (p < 0.05). mRNA expression level of STIM1 and calcium release-activated calcium modulator 1 (Orai1) in skin lesions increased after modeling (p < 0.05). LXHXF, Methotrexate, and STIM1 inhibitors intervention contributed to the reversion of the model-induced abnormalities to a certain extent (p < 0.05). LXHXF therapeutic effect suggested a dose-dependent effect.

    Conclusions: LXHXF may significantly improve the psoriasiform skin lesions in mice by imiquimod what improved Th17 infiltration and expression, inhibited inflammatory factors (IFN-γ, IL-17A, IL-21, and IL-22), and decreased Th17 percentage in peripheral blood. The mechanism may provide insights into the potential therapeutic strategy based on the STIM1/SOCE pathway.

  • Article
    Wei Zhang, Mingliang Xiang, Tinghong Wang, Jianlin Ke, Xiaodong Deng, Ying Ma, Yun Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 489-497. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.48
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    Objective: Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) had emerged as useful inflammatory biomarkers in multiple diseases. The study aimed to explore the possible relationships between NLR, PLR, MLR and methylamphetamine dependence, and explore their potential wider use in clinical research.

    Methods: 632 methylamphetamine-dependent patients and 325 controls were enrolled. The demographics, complication of dependence, and hematologic parameters were compared. The NLR, PLR, and MLR were estimated and compared between the two groups.

    Result: The count of white blood cell (WBC), neutrophil, monocyte, NLR, MLR, and PLR were significantly higher and the lymphocyte count was significantly lower in methylamphetamine-dependent patients than controls (p < 0.05). Multivariate analysis showed that the NLR, MLR, monocyte, and platelet were screened as useful biomarkers to evaluate the inflammatory states of methylamphetamine dependence, respectively (NLR: OR (odds ratio) = 71.72, 95% CI (confidence interval) [27.63–186.19], p < 0.001. MLR: OR = 6.34, 95% CI [3.27–12.27], p < 0.001. Monocyte: OR = 26.34, 95% CI [3.44–206.11], p = 0.002. Platelets: OR = 3.71, 95% CI [1.97–7.02], p < 0.001). However, there were no significant differences in WBC, neutrophil cell, lymphocyte, and PLR (p > 0.05). Similar results were obtained after adjusting for age and gender. The receiver operating characteristic curve (ROC) analysis indicated that the NLR and MLR were useful parameters to identify the inflammatory states of methylamphetamine dependence (AUC (area under the curve): NLR = 0.89, MLR = 0.82, platelet = 0.64, monocyte = 0.77, p < 0.001). Furthermore, the NLR was significantly and positively associated with severity of dependence scale (SDS) score and hallucination in methylamphetamine-dependent patients (p < 0.05). However, the MLR was uncorrelated with those variables (p > 0.05).

    Conclusions: The NLR might serve as a useful clinical biomarker in inflammatory states of methylamphetamine dependence, and positively correlated with hallucination and severity of methylamphetamine dependence.

  • Article
    Xi-juan Zhao, Kui Wang, Rong Li, Yang Lu, Pan Lu, Pei Fan, Yu-ying Lv, Xin-lin Chen, Hao-zheng Yuan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 499-506. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.49
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    Background: During brain development, isoflurane exposure-induced brain neuronal damage may be associated with cognitive impairment in adulthood. Simvastatin has a particular neuroprotective effect. However, it is unclear whether simvastatin protects cortical neurons exposed to isoflurane. The aim of this study was to explore the action of simvastatin on cortical neurons exposed to isoflurane and establish the mechanism of this action.

    Methods: An in vitro model of free primary cultured Sprague-Dawley rat neurons was constructed. Neuronal Class III β-Tubulin (Tuj1) staining was used to identify primary neurons. Cell Counting Kit-8 (CCK-8) assay was used to test neuron cell viability. Propidium Iodide (PI)/Hoechst 33342 staining was used to determine the levels of apoptosis in the neurons and western blot was used to check the caspase-3, B-cell lymphoma-2 (Bcl-2), protein kinase B (Akt) and p-Akt protein expression levels in cortical neurons.

    Results: Exposure to isoflurane significantly increased apoptosis during neuronal development. Cortical neurons exposed to isoflurane showed significantly decreased Bcl-2 and p-Akt expression and increased caspase-3 expression. Simvastatin significantly reversed these changes. PI3K (phosphoinositide 3-kinase) inhibitor LY294002 significantly inhibited the reversal of isoflurane-induced neurotoxicity by simvastatin.

    Conclusions: Simvastatin pretreatment protects neurons from isoflurane-induced neurotoxicity in vitro. The phosphoinositide 3-kinase (PI3K)/Akt pathway participates in inhibiting the effect of simvastatin on isoflurane-induced neuronal apoptosis.

  • Article
    Aoyu Chen, Chunyan Liu, Ru Song, Jiaxu Ma, Zhenjie Wu, SiYuan Yin, Guoqi Cao, Guang Zhang, Rui Sun, Yibing Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 507-516. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.50
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    Background: The inner mitochondrial membrane protein prohibitin 2 (PHB2) has potential to promote chronic wound healing. The aim of this study was to investigate the effect and mechanism of action of PHB2 in wound healing.

    Methods: Chronic wound tissues and the corresponding ischaemic wound tissues of mice, on D1, D3, D5, and D7 (Day 1, Day 3, Day 5, Day 7) were selected to analyse the differential expression of PHB2. Human keratinocytes (HaCaT) were used to generate an in vivo ischaemic wound model, through oxygen-glucose deprivation. Stably transfected cell lines (PHB2 overexpression and PHB2 inhibition) were constructed, and the effects of PHB2 overexpression and inhibition on cell proliferation, under oxygen-glucose deprivation, were determined, using Cell Counting Kit-8 (CCK8) and 5-Ethynyl-2’-deoxyuridine (EdU) assays. The effects on cell apoptosis were analysed, using flow cytometry, the effects on cell migration were analysed, using cell scratch assays, and the effects on the statement of related proteins were examined, using western blots and immunocytochemistry.

    Results: In vivo, PHB2 expression did not change significantly during the acute wound proliferation phase but significantly increased during the ischaemic wound proliferation phase (p < 0.01). PHB2 overexpression significantly stimulated HaCaT cell multiplication, migration and autophagy under oxygen-glucose deprivation conditions in vivo, and the inhibition of PHB2 expression significantly inhibited cell migration and promoted apoptosis. Under oxygen-glucose deprivation conditions, PHB2 expression levels negatively correlated with light chain 3 (LC3) II/I , autophagy protein 5 (ATG5), Beclin-1, and Vimentin expression and positively correlated with sequestosome 1 (P62) and E-cadherin expression.

    Conclusions: PHB2 significantly advances the expansion and movement of HaCaT cells and significantly inhibits cell apoptosis by regulating the outflow of autophagy- and migration-related proteins, ultimately promoting the healing of ischaemic wounds.

  • Article
    Yong Chen, Ya-dan Tu, Lei Du, Qiu-ju Yao, Jie Wang, Tong Yang, Rui-xue Nan, De-ying He, Yi Ren
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 517-524. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.51
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    Objectives: To examine the role of Salvianolic acid B (Sal-B) in cardiac fibroblasts (CFs) proliferation and extracellular matrix metabolism.

    Methods: An in vitro model of myocardial fibrosis was constructed by treating primary CFs with isoprenaline (ISO) for 48 h. CFs were extracted from neonatal male Sprague-Dawley rats. CFs were allocated to one of the following groups: Control group (untreated), model group (ISO-treated CFs) and Sal-B groups (pre-treated with 50, 100, and 200 µM of Sal-B for 24 h). Immunofluorescence staining was conducted to examine Galectin-3 expression. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine miR-296-5p expression in CFs. Western blotting and qRT-PCR were employed to respectively detect the protein and mRNA expression of Matrix Metallopeptidase 2 (MMP2), MMP9, transforming growth factor-β 1 (TGF-β1), Collagen I (Col I), Collagen III (Col III), small mother against decapentaplegic (SMAD) family member 3 (Smad3), and Smad7. Ultimately, dual-luciferase reporter assay was applied to explore the targeting relationship between TGF-β1 and miR-296-5p.

    Results: Sal-B treatment weakened cell viability in the Sal-B group compared to the model group (p < 0.05). Sal-B notably down-regulated MMP2, MMP9, Col I, and Col III mRNA expression in the Sal-B group compared to the model group. Meanwhile, Sal-B treatment reversed the increasing TGF-β1 and Smad3 protein and mRNA expression induced by ISO. The Sal-B group displayed a rise in miR-296-5p expression compared to the model group. Dual-luciferase reporter assay demonstrated that TGF-β1 was the downstream gene of miR-296-5p.

    Conclusions: Sal-B reduced CFs proliferation and the buildup of extracellular matrix through the miR-296-5p/TGF-β1/Smads axis.

  • Article
    Xinran Li, Lin Zhou, Yuxin Chen, Na Li, Jian Meng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 525-530. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.52
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    Objective: Preoperative neutrophil-to-lymphocyte ratio (NLR) prognostic value in patients with cephalic and cervical adenoid cystic carcinoma (ACC).

    Methods: A retrospective analysis was performed on 71 ACC patients that attended the Xuzhou Central Hospital from August 2005 to November 2020. NLR and platelet-to-lymphocyte ratio (PLR) values were collected before treatment. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. PLR was calculated by dividing the absolute platelet count by the absolute lymphocyte count. Time-dependent ROC (receiver operating characteristic) curves of NLR and PLR predicting the postoperative survival status of patients at 3 years and 5 years were respectively drawn by the R program and the ideal cutoff value for the preoperative NLR was calculated for grouping. According to NLR >2.071 or NLR ≤2.071, patients were classified into low NLR group (n = 34) and high NLR group (n = 37), and the correlation between clinicopathological features and NLR of ACC patients was analyzed. The relationship between NLR and overall survival (OS) in ACC patients and disease-free survival (DFS) was examined by Cox regression analysis and Kaplan–Meier curves.

    Results: The area under the curve (AUC) for NLR was 0.743 (3 years) and 0.665 (5 years), and the AUC for PLR was 0.645 (3 years) and 0.512 (5 years). The ideal cutoff value for preoperative NLR was 2.071. Patients were divided into high NLR (NLR >2.071) (n = 37) and low NLR groups (NLR ≤2.071) (n = 34) for survival analysis. The level of preoperative NLR was linked to lymph node metastasis (LNM) and tumor stage. Kaplan–Meier survival analysis revealed that the high level of NLR was associated with a shorter OS but was not associated with DFS (p > 0.05). High age (>54 years) and high NLR (>2.071) were independent risk factors that predicted worse prognosis in ACC patients, as revealed by multivariate Cox regression analysis.

    Conclusions: This study suggests that the preoperative NLR, with better predictive value than PLR, is an effective biomarker for the prognosis of ACC patients.

  • Article
    Wei-Jian FAN, Ling-Di LAO, Feng XIAO, Yu-Xiang WENG, Jian-Wei PAN
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 531-542. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.53
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    Objective: Intracranial aneurysm (IA) is one of the most lethal cerebrovascular diseases, and vascular smooth muscle cells (VSMCs) abnormal proliferation and apoptosis are important features of IA. Microarray analysis showed that long non-coding RNA (lncRNA) NR2F1-AS1 (nuclear receptor subfamily 2 group F member 1 antisense RNA 1) was upregulated in patients with IA, while angiotensin II receptor type 1 (AGTR1) was downregulated. The purpose of this study was to investigate NR2F1-AS1 effect on regulating VSMC proliferation and apoptosis in IA.

    Material and Methods: NR2F1-AS1 and AGTR1 expression levels in blood samples of 30 IA patients and 30 healthy controls were determined by RT-qPCR (Reverse Transcription-Quantitative Polymerase Chain Reaction). The correlation between them was calculated by Spearman’s correlation test. Moreover, the VSMCs overexpressing NR2F1-AS1, AGTR1, NR2F1-AS1+AGTR1 were created, and their effects on cell proliferation and apoptosis in vitro were assessed by cell counting kit-8 (CCK-8), clone formation, and flow cytometry. Their effects on NF-κB (nuclear factor kappa-B) signal were further investigated using Western blotting.

    Results: NR2F1-AS1 expression level increased, while AGTR1 expression level decreased in patients with IA. NR2F1-AS1 overexpression inhibited the proliferation and increased the apoptosis of VSMCs by down-regulating AGTR1. This was followed by the inhibition of the phosphorylation level of IκB and p65 but the promotion of the IκBα expression.

    Conclusions: LncRNA NR2F1-AS1 downregulates AGTR1 and NF-κB signaling pathway, which inhibits the proliferation of VSMCs and promotes apoptosis, therefore promoting the development of IA.

  • Article
    Yang Mu, Beiqiang Deng, Zhiwen Yang, Chunxiang li, Juan Xia
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 543-553. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.54
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    Background: Nerve blocks that deliver lidocaine to specific neural structures are often considered for patients with neuropathic pain. However, there is evidence that lidocaine may induce neuronal cell apoptosis. Dexmedetomidine (DEX) can be used for nerve block and has neuroprotective effects. Therefore, we explored the effects of DEX (20 nM) + lidocaine (6 mM) on neuronal cell apoptosis and its underlying mechanism.

    Methods: In this study, we used SH-SY5Y cells, which were differentiated by all-trans retinoic acid (ATRA) treatment, were cultured in vitro and subsequently treated using lidocaine, lidocaine + DEX or DEX + compound C (CC, AMPK (adenosine monophosphate-activated protein kinase) inhibitor). Cell counting kit 8 (CCK-8) assay was employed to examine the viability of the cells. Apoptotic cell proportion was assessed by flow cytometry (FCM) and staining with Hoechst 33258, while the ROS (reactive oxygen species) and mitochondrial membrane potential (∆ψm) were immunofluorescently evaluated. Apoptotic and mitochondrial biogenesis regulatory protein markers (cleaved caspase 3/9, Bax, Bcl-2 (B-cell lymphoma-2), p-AMPK, and PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α)) were analyzed by Western blotting.

    Results: Lidocaine treatment increased the apoptotic ratio and levels of cleaved caspase 3/9 and Bax while leading to dropped anti-apoptotic protein and Bcl-2 levels. After lidocaine treatment, there were an aggregation of ROS and a decline in ∆ψm. Dex treatment reversed such alterations partially. Mechanistically, DEX increased the lidocaine-induced mitochondrial biogenesis protein, PGC-1α, while DEX’s effects were reversed by the AMPK inhibitor (CC) partially.

    Conclusions: Through the regulation of mitochondrial biogenesis, reduction of ROS and prevention of ∆ψm loss, DEX attenuates the SH-SY5Y cell apoptosis elicited by lidocaine. DEX reduces lidocaine-induced neurotoxicity and provides a better way for the clinical use of lidocaine.

  • Article
    Ran Yang, Shanzi Yu, Lu Chen, Jiahui Ma, Zhenxing Li, Dong Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 555-562. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.55
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    Objective: To establish the action and mechanism of action of Alkbh5 on trigeminal neuralgia (TN).

    Methods: Infraorbital nerve-chronic compression injury (ION-CCI) rat model was established, and the expression of Alkbh5 (Alk B homolog 5) in the trigeminal ganglion of rats was detected. The study was divided into six groups, namely, the sham group, the experimental group, the injection group of Alkbh5 overexpressing adeno-associated virus (M+OE-A), the injection group of Alkbh5 overexpressing control virus (M+OE-NC (overexpressing control virus)), the injection group of Alkbh5 interfering control virus (M+sh-NC), and the injection group of Alkbh5 interfering adeno-associated virus (M+sh-A). Each group included six rats, and the mechanical pain threshold of rats in each group was detected. Western blot was used to detect the expression of ERK (extracellular signal-regulated kinase).

    Results: The relative expression level of Alkbh5 and the mechanical pain threshold of rats in the experimental group were significantly lower than those in the sham group 4 d, 7 d and 14 d after modeling (p < 0.05). The relative expression level of Alkbh5 in the M+OE-A group was significantly higher than that in the M+OE-NC group. The mechanical pain thresholds on days 4, 7 and 14 of modeling in the M+OE-A group were significantly higher than those in the M+OE-NC group (p < 0.05). The relative expression level of Alkbh5 in the M+sh-A group was significantly lower than that in the M+sh-NC group. The mechanical pain thresholds of the M+sh-A group were significantly lower than those of the M+sh-NC group 14 d after modeling (p < 0.05). The protein expression levels of p-ERK in the experimental group and M+OE-NC group were significantly higher than that in the sham group, and the protein expression levels of phosphorylated extracellular regulated protein kinases (p-ERK) in M+OE-A group were lower than those in the experimental group and M+OE-NC group (p < 0.05). The protein expression levels of p-ERK in the experimental group and M-sh-NC group were higher than that in the sham group, and the protein expression levels of p-ERK in the M+sh-A group were higher than those in the experimental group and M-sh-NC group (p < 0.05).

    Conclusions: Alkbh5 can alleviate the mechanical hyperalgesia of the trigeminal neuralgia rat model, by negatively regulating the expression of p-ERK.

  • Article
    Zhao-yu Liu, Yan Li, Hong-yan Hu, Lin Wang, Sang-Yhun Ju, Qiao Zhu, Chao-xue Ning, Ting Yang, Ya-li Zhao, Yao Yao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 563-570. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.56
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    Background: Bone turnover markers (BTMs) are modulated by serum estradiol (E2) which is crucial for maintaining the health and physical function of bone in older adults. However, data on the levels and epidemiological distributions of serum BTMs and E2 among older postmenopausal women (such as female centenarians) are limited. This study was aimed to investigate the relationship between BTMs and E2 in the older postmenopausal women.

    Methods: A total of 456 female centenarians were included, and their serum concentrations of BTMs (including phosphorus, calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone [PTH], total type I procollagen amino-terminal peptide [total PINP], β-isomerized C-terminal telopeptides [β-CTX], alkaline phosphatase [ALP], and osteocalcin [OC]) and E2 were assessed. Linear regression models were used to examine the relationship between BTMs and E2. Multivariate regression models were fitted, along with subgroup analysis and robustness tests.

    Results: The median levels with interquartile ranges of serum E2, ALP, phosphorus, calcium, OC, β-CTX, total PINP, PTH, and 25(OH)D were 46.8 (33.9, 70.90), 83.0 (68.0, 105.0), 1.07 (0.97, 1.17), 2.19 (2.11, 2.28), 32.43 (21.62, 44.60), 0.45 (0.30, 0.63), 71.0 (51.0, 97.3), 47.4 (34.7, 65.5), and 19.6 (14.3, 24.4), respectively. A higher E2 level was related to increased β-CTX (0.15 [0.10, 0.20]), total PINP (0.18 [0.10, 0.26]), and PTH (0.075 [0.022, 0.128]) levels in the fully adjusted model. We also found that a higher E2 level was associated with decreased levels of 25(OH)D (–0.35 (–0.51, –0.19)) and calcium (–0.60 [–0.80, –0.40]) among female centenarians (p < 0.001).

    Conclusions: Among centenarian women, bone formation markers (serum calcium and 25[OH]D) were negatively correlated with E2 level, while bone resorption marker (β-CTX) was positively correlation with E2 level.

  • Article
    Fang Yin, Jinjie Li, Tengpeng Zhou, Yanlin Wang, Tiejun Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 571-576. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.57
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    Purpose: To investigate the levels of perioperative cytokines in oral squamous cancer patients who underwent surgery under different types of general anesthesia.

    Methods: Sixty patients who received radical resection and immediate reconstruction with free flap defect repair, were randomized to one of three groups: Propofol-based total intravenous anesthesia group (TIVA, n = 20), sevoflurane-based inhalation anesthesia group (SEVO, n = 20) and propofol combined with sevoflurane intravenous-inhalation anesthesia group (VICA, n = 20). We measured the levels of four cytokines (sIL-2Rα (soluble IL-2R alpha), IL-2 (interleukin 2), IL-6 (interleukin 6) and IL-10 (interleukin 10)) at different time points during perioperative period including 30 min before anesthesia (T0), 3 h after anesthesia (T1), at the end of operation (T2), 6 h (T3), 24 h (T4) and 48 h (T5) after the end of operation.

    Results: The level of circulating sIL-2Rα at T5 was higher in SEVO group than that in TIVA group (p < 0.01) and VICA group (p < 0.05). The concentration of circulating IL-2 was lower in VICA group (p < 0.05) and SEVO group (p < 0.01) than that in TIVA group at T3–T5. The value of IL-6 was higher at T4 and T5 in VICA group and SEVO group than that in TIVA group (p < 0.01). The value of IL-10 was higher at T1–T4 in SEVO group than that in TIVA group (p < 0.01).

    Conclusions: Total intravenous anesthesia led to higher levels of IL-2 and lower levels of IL-6, IL-10 and sIL-2Rα, which may indicate a positive effect on the maintenance of immune function in oral squamous cancer patients during perioperative period.

  • Article
    Yuxiao Liu, Liangming Zhuang, Chao Chen, Xinxin Qi, Siting Ye, Zhongmin Gu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 577-586. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.58
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    Introduction: Sepsis-induced cardiomyopathy is one of the main causes of death in critical patients worldwide. Levosimendan is a diastolic agent with a clinical use in patients with acute decompensated chronic heart failure. In this study, we aimed to explore the molecular mechanism of levosimendan in the treatment of septic cardiomyopathy.

    Methods: Rat cardiomyocytes H9c2 cells were treated with lipopolysaccharide (LPS) and levosimendan for 24 h or were intraperitoneally injected into rats for 12 or 14 h. Cell survival and apoptosis were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and flow cytometry. The secretion levels of inflammatory factors (interleukin-1β, interleukin-18, MCP-1 (monocyte chemoattractant protein-1)) and the expression levels of endoplasmic reticulum stress-related molecules were detected by enzyme-linked immunosorbent assay, western blotting and quantitative PCR (polymerase chain reaction). Hematoxylin-eosin staining was used to observe myocardial tissue lesions.

    Results: Levosimendan alleviated LPS-induced apoptosis, secretion of interleukin-1β, interleukin-18, MCP-1 and expression levels of caspase 12, IRE1 (inositol-requiring enzyme 1) and GRP78 (a glucose regulatory protein with a molecular weight of 78 ku), relieved the inhibition of LPS on cell viability and SIRT7 (silencing regulatory protein 7) expression, and attenuated myocardial damage caused by LPS.

    Conclusions: Levosimendan inhibited inflammation and ER (endoplasmic reticulum stress), and thus rescued LPS induced septic cardiac insufficiency in rats.

  • Case Report
    Yu Tang, Hongwei Deng, Zhihong Lin, Zhengyang Tao, Zefeng Kang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(1): 587-592. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233701.59
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    Background: High myopia (HM) is a hereditary disease affected by multiple genes. Increasingly, more genes related to HM are being discovered. Among them, the ABCA4 and USH2A genes have been included in the ClinVar database as candidate genes for HM; However, they have not been reported in the literature, and there is a lack of clinical evidence for their inclusion in the database. The NYX gene, as a pathogenic gene of night blindness, also still lacks clinical case reports to support its influence in this context.

    Case Report: The case presented herein concerns a 2-year-old boy whose 14-year-old brother had been diagnosed with HM by optometric testing at 4-years of age. The patient’s parents had no history of HM and thus took their child to the Shenzhen Eye Hospital for an examination; He was eventually diagnosed with HM and night blindness. Gene sequencing detected heterozygous mutations in the ABCA4 and USH2A genes and a homozygous mutation in the NYX gene (hemizygote; The hemizygote here and later refers to the XYX gene of this patient).

    Conclusions: This case report provided clinical evidence for the ABCA4 and USH2A genes as pathogenic genetic material for HM and found a new site of NYX gene (c. 199_200insTCGACC) for night blindness.