20 June 2023, Volume 37 Issue 6

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  • Review
    Zahra Hoseini-Tavassol, Hanieh-Sadat Ejtahed, Fateme Ettehad-Marvasti, Faezeh Saghafian, Shima Ghannadi, Kazem Khalagi, Seyed-Davar Siadat, Shirin Hasani-Ranjbar
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2855-2861. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.283
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    Nowadays, obesity as a widespread disorder challenges health system worldwide. Obesity is a multifactorial disease. It may cause by various interactions between host genetic and environmental factors. Gut microbiota also have been recognized as a conclusive influential factor in obesity. While it is now widely accepted that the gut microbiota plays an important role in host metabolism, recent researches revealed that gut microbiota are also associated with genetic variations. Current knowledge about the influence of host genetics on specific gut microbiota is limited. But some of these heritable microbiota have a role in obesity incidence based on previous studies. So, it seems that an investigation about association of heritable gut microbiota with obesity is needed. In this study, we summarized recently known hereditary bacteria colonized in the gut and their effects on obesity. Here we discussed about, Akkermansia, Blautia, Christensenella and Faecalibacterium genera belong to Firmicutes, and Bifidobacterium genus is included in Bacteroidetes, as heritable taxa. This review can provide a perspective to advance studies on the developing of probiotics for obesity treatment and modifying individuals' gut microbiota based on their genetics to resolve obesity problem and its prevention.

  • Review
    Kaiser Wani, Balvir Kumar, Iram Saba, Shaun Sabico
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2863-2876. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.284
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    The Metabolically Healthy Obese (MHO) is a unique phenotype of obesity in which individuals match the operational definition of obesity but do not display metabolic complications. Given this attribute, MHO has gained rapid interest in the field of adiposity research over the recent decades. Whether the MHO phenotype is apparently free of cardiometabolic abnormalities or simply a transient state of the metabolically unhealthy obese (MUO) remains controversial, but this ambiguous phenotype deserve clinical merit as it may serve as a missing conduit to further understand the complex nature of human obesity. Furthermore, shedding light in the still controversial MHO may help further research in in terms of customizing interventions aimed at decreasing the cardiometabolic risks associated with the MUO phenotypes and/or maintaining the “normalcy” of MHO over time. In this review, we aim to promote and update existing knowledge on the different metabolic health phenotypes of obesity as gathered from recent literature, primarily for the obese population and for primary care physicians who are first in-line in encountering these phenotypes. This may also help healthcare providers to have better awareness in identifying which obese phenotypes can actually benefit from weight loss programs. In light of available evidence, more longitudinal and translational studies are still needed to reach a universal definition of MHO.

  • Article
    Yuan Wang, Weiyi Zhang, Jianan Wang, Caiju He, Xianwu Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2877-2887. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.285
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    Background: Known for its myriad health benefits, konjac glucomannan (KGM), a fermentable fiber, has alleviated constipation and enhanced the population of beneficial gut bacteria. The purpose of this study was to investigate the effects of different concentrations of KGM on the intestinal microorganisms of mice.

    Methods: We utilized the Illumina HiSeq high-throughput sequencing platform to scrutinize mouse gut bacteria's 16S ribosomal RNA (rRNA) V3+V4 region, investigating the effects of feeding low, medium and high KGM doses on the intestinal flora. The multi-faceted analysis included species composition, alpha, and beta diversity analysis, Linear discriminant analysis effect size (LEfSe) flora differential analysis, correlation of flora correlation, and predictive functional analysis, offering comprehensive insights into the varying impacts of KGM dosages.

    Results: The investigation revealed intriguing distinctions in gut microbiota between KGM and control groups. A phylum-level breakdown showed that Firmicutes and Bacteroidetes as the primary microflora across all samples. Notably, the high-dose KGM group exhibited an increased abundance of Firmicutes compared to the control group, coupled with a contrasting decrease in Bacteroidetes. Furthermore, Actinobacteria proliferation was markedly enhanced within the high-dose KGM group. Compared with the control group, all KGM dose groups (low, medium and high) displayed a decline in Deferribacteres, Verrucomicrobia and Proteobacteria. Moreover, mice treated with high-dose KGM showed significantly increased gut populations of Coriobacteriales, Eggerthellaceae, Enterorhabdus, Lactobacillales, Lactobacillaceae, Lactobacillus, Lachnospiraceae_NK4A136_group and others. Interestingly, at the genus level, a positive correlation was observed among Staphylococcus, Corynebacterium and Jeotgalicoccus. In the medium-dose KGM group, amino acid metabolism surged noticeably compared to the control group.

    Conclusions: Our study demonstrates that KGM significantly influences gut microbiota composition in mice. Key shifts include the enhancement of Firmicutes and Actinobacteria, decreasing Deferribacteres, Verrucomicrobia and Proteobacteria, and augmented amino acid metabolism. These findings underline KGM's potential as a prebiotic agent.

  • Article
    Min Xu, Yujing Hu, Yingxin Sun, Rongqiang Wu, Tongbao Feng, Ping Zhang, Min Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2889-2896. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.286
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    Background: Gastric cancer (GC) is a common malignant tumor associated with high mortality rates. Phosphodiesterase 4B (PDE4B) has been identified as a key participator in the progression of some malignancies by facilitating tumorigenesis. The Wnt/β-Catenin pathway has been established as a critical pathway in the progression of cancers, including GC. However, the effects of the PDE4B/Wnt/β-catenin/Forkhead box M1 (FoxM1) axis on GC progression are yet to be investigated.

    Methods: The protein expressions of PDE4B, BCL-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved-caspase3, β-catenin and FoxM1 were examined through western blot. The AGS-cytotoxin-associated gene A (CagA) and MKN45-CagA cell lines were used to assess cell proliferation ability via cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EDU) assays, cell migration and invasion via wound healing and Transwell assays, and cell apoptosis via flow cytometry.

    Results: Analysis of the Ualcan and Gene Expression Profiling Interactive Analysis (GEPIA) databases revealed that PDE4B exhibited higher expression in GC tissues. The PDE4B protein expression was significantly enhanced after CagA induction in gastric epithelial cell line (GES-1), AGS and MKN45 cells. In addition, PDE4B overexpression facilitated, while PDE4B knockdown suppressed, CagA-induced cell proliferation, migration and invasion in GC. However, PDE4B overexpression was suppressed, while PDE4B knockdown accelerated CagA-induced GC cell apoptosis. Additionally, the enhanced β-catenin and FoxM1 expressions mediated by PDE4B up-regulation were reversed after XAV-939 (Wnt inhibitor) treatment, suggesting that PDE4B can regulate FoxM1 through β-catenin. Additionally, the aggravated GC progression mediated by PDE4B overexpression was rescued after FoxM1 knockdown, indicating that PDE4B can aggravate the CagA-induced malignant progression of GC through FoxM1.

    Conclusions: The PDE4B/β-catenin/FoxM1 axis might be involved in CagA-induced gastric carcinogenesis and progression, suggesting PDE4B is a promising biomarker for comprehending the underlying mechanisms of GC development.

  • Article
    Zhiqian Sun, Fengxia Luo, Peng Feng, Wenzhen Luo, Ning Wang, Kunzu Ge, Qing Liu, Zhenggang Shi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2897-2902. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.287
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    Background & Objective: Nutritional iron deficiency anemia (NIDA) is caused by decreased hemoglobin biosynthesis due to iron deficiency. It is the most common anemia in children, and a serious danger to health. This study was aimed at investigating the efficacy of iron dextran oral solution in children with NIDA.

    Methods: This is a prospective randomized controlled trial on 70 children with NIDA from August 2020 to September 2021. The enrolled subjects were divided into group A and group B, with 35 children in each group. Group A received ferrous sulfate oral solution, while group B received iron dextran oral solution. Hemoglobin, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), clinical treatment outcomes, and adverse events were determined and compared between the 2 groups.

    Results: Group B had higher levels of hemoglobin, MCHC and MCV than group A (p < 0.05). Moreover, group B had significantly higher total treatment effectiveness and lower incidence of adverse reactions than group A (p < 0.05).

    Conclusions: The use of iron dextran oral solution is a promising strategy in the treatment of children with NIDA. It alleviates symptoms of NIDA and optimizes hemoglobin, MCHC and MCV, and it has a favorable safety profile. Therefore, iron dextran oral solution is suitable for clinical application for treatment of NIDA.

  • Article
    Hong Qi, Xuewen Yang, Chunsheng Xu, Huiwen Shi, Shushang Liu, Xiang Zhang, Ting'an Wang, Mingwei Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2903-2911. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.288
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    Background: Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies worldwide. Cetuximab treatment appears to prolong the survival of CRC patients, although some patients do not respond or they develop drug resistance. We aimed to identify favorable subtypes and genes in CRC that are sensitive to cetuximab to better manage CRC patients.

    Methods: Data were retrieved from the online public databases. Differential expression analysis, weighted gene co-expression network analysis, and univariate COX analyses were utilized to identify prognostic genes that are sensitive to cetuximab in CRC. All samples were divided into several subgroups using ConsensusClusterPlus based on prognostic genes. Survival, immune features, and mutation features among the subgroups were analyzed. In addition, the optimal prognostic genes were further screened to construct a risk score model and nomogram combined with the clinical information.

    Results: A total of 26 prognostic sensitive genes were screened. All of these genes were allocated into cluster 1 and cluster 2. Cluster 2 exhibited better survival, immune status, and a lower tumor mutation burden. Five optimal genes (ADAMTS13, HAMP, MMP10, SLC6A1, and TMEM220) were filtrated, and a risk score model was established. The risk score model based on these five genes showed promising predictive value at 1, 3, and 5 years, with an area under the receiver operator characteristic curve of more than 7. The nomogram based on the risk score and clinical features also possessed good performance in predicting the survival status after 1, 3, and 5 years.

    Conclusions: The identified genes and the subtypes exhibit potentially useful prognostic abilities and may be indicators of CRC sensitivity to cetuximab.

  • Article
    Xuliang Xia, Zhiqiang Jiang, Wei Liu, Yunlong Li, Xin Zheng, Li Tang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2913-2925. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.289
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    Objective: Thyroid cancer (TC) is a malignant tumor. The incidence of this disease has increased progressively yearly, seriously threatening the lives safety of Chinese residents. The aim of this study was using the Cancer Genome Atlas (TCGA) database, combined with the means of bioinformatics, to screen the candidate gene targets that affect the occurrence, prognosis and survival of TC, and verify the influence of candidate genes on the phenotype of TC through experiments, so as to supply a basis for the search for new TC treatment targets.

    Methods: Differential micro-ribonucleic acids (miRNAs) and messenger-ribonucleic acids (mRNAs) associated with TC were obtained from the TCGA database and analyzed using bioinformatics. The target gene of microRNA (miR)-1258 was verified, through a double luciferase assay. The proliferation, migration and invasion capability of TC cells were detected through 5-ethynyl-2'-deoxyuridine (EDU) staining and the Transwell experiment. The expressions of miR-1258, Mex-3 RNA binding family member A (MEX3A), protein kinase B (AKT), Vimentin, E-Cadherin and Snail in TC cells and animal models were tested through quantitative polymerase chain reaction (qPCR) and Western blot. In animal models, hematoxylin-eosin (HE) staining was applied to observe the pathological conditions of tumor tissues, and TdT-mediated dUTP nick end labeling (TUNEL) was used to detect apoptosis.

    Results: This project proved that MEX3A was the target gene of miRNA and miR-1258 could inhibit its expression. Overexpression of miR-1258 could significantly decrease the propagation, migration and invasion ability of TC cells, inhibit tumor growth in TC animal models and improve the pathological conditions of tumor tissues. After miR-1258 and MEX3A were overexpressed simultaneously, the proliferation, migration and invasion of TC cells were weaker than the overexpression of MEX3A alone (p < 0.05). MiR-1258 increased E-Cadherin and reduced Vimentin, Snail and AKT’s phosphorylation form (p-AKT) expression through targeted inhibition of MEX3A.

    Conclusions: MiR-1258 suppressed the AKT pathway through targeted inhibition of MEX3A, thereby inhibiting the proliferation and epithelial-mesenchymal transition (EMT) of TC cells.

  • Article
    Bigao Deng, Xiaozhu Zheng, Xinxin Zheng, Lu Tian, Yin Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2927-2934. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.290
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    Purpose: Propofol is a sedative and hypnotic drug widely used in inducing and maintaining anesthesia. Previous studies have shown that propofol has an inhibitory effect on several types of inflammation, but its use in the treatment of myocarditis has not been reported. This study explored the therapeutic effect of propofol on lipopolysaccharide (LPS)-induced myocarditis.

    Methods: H9c2 cells (embryonic rat cardiomyocytes) were treated with LPS to induce inflammation, and then treated with propofol or transfected with miR-142-5p mimic or inhibitor. The cells were divided into control, LPS, LPS+propofol, LPS+propofol+ negative control (NC) mimic and LPS+propofol+miR mimic groups. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was utilized to measure the relative level of miR-142-5p and suppressor of cytokine signaling 1 (SOCS1). Cell viability and apoptosis were further detected to investigate the efficacy of propofol. SOCS1 and the nuclear factor-kappaB (NF-κB) pathway-related protein levels were quantified using western blot.

    Results: LPS significantly increased the levels of inflammatory factors, and apoptosis rate in H9c2 cells (p < 0.05). Propofol ameliorated the LPS-induced H9c2 cell damage by inhibiting miR-142-5p. SOCS1 was proved to be directly regulated by miR-142-5p. Furthermore, propofol inactivated the NF-κB pathway and increased SOCS1 level by decreasing miR-142-5p expression (p < 0.05).

    Conclusions: Propofol regulated miR-142-5p/SOCS1 axis to exert anti-inflammatory and cell-activating properties in LPS-induced myocarditis by inactivating the NF-κB pathway.

  • Article
    Wenhui Zhao, Ting Lin, Ziyi Fang, Huilin Zhou, Yangguang Du, Hexu Han
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2935-2946. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.291
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    Purposes: N-acetyltransferase 10 (NAT10), a newly discovered specific N-acetyl transferase, plays a vital role in human disease. However, its role in the malignant progression of hepatocellular carcinoma (HCC) has not been fully elucidated.

    Methods: We first investigated the expression of NAT10 in HCC and the correlation between the expression of NAT10 and patient prognosis by using multiple groups of clinical tissues combined with data from The Cancer Genome Atlas (TCGA) database. We next constructed stable cell lines from HCC cells to confirm the tumor-promoting effects of NAT10 in HCC. In addition, we conducted various molecular experiments combined with mass spectrometry and transcriptome sequencing were conducted to further explore the internal molecular mechanism of NAT10 enhancing the HCC malignant process.

    Results: We found that NAT10 expression was markedly elevated in HCC tissues and the elevated levels of NAT10 were associated with worse prognoses in HCC patients. Cell function experiments showed that NAT10 overexpression enhanced HCC cell proliferation and migration, implying that NAT10 promoted the malignant progression of HCC. Furthermore, a sorafenib killing experiment showed that knocking out NAT10 enhanced the drug sensitivity of Hep3B cells. In addition, after overexpression of NAT10 in SMMC-7721 cells, the cells were significantly more resistant to sorafenib. Our study also showed that NAT10 activated the nuclear factor-kappa B (NF-κB) signaling pathway by directly binding RelA/p65 to promote lysine 310 acetylation. Moreover, NAT10 promoted HCC proliferation by promoting acetyl-NF-κB p65 (Lys310) in vivo and in vitro.

    Conclusions: Our study showed that NAT10 promoted the occurrence and development of HCC, which provides a corresponding theoretical basis for subsequent related research and translational application.

  • Article
    Zijuan Chang, Yanli Guo, Qin Song
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2947-2952. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.292
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    Objective: To study the correlation of expression levels of serum activin-A (ACT-A), Clara cell secretary protein-16 (CC-16), and Krebs von den lungen-6 (KL-6) with disease severity in patients with acute respiratory distress syndrome (ARDS).

    Methods: A retrospective study was conducted on 170 ARDS patients at Yantaishan Hospital between May 2020 and May 2022. Patients were categorized into light (LG), moderate (MG), and severe (SG) groups based on their oxygenation index (OI) values. We then measured the serum levels of ACT-A, CC-16, and KL-6 in these patients. Finally, the correlation between these serum expression levels and ARDS severity was analyzed using Pearson correlation.

    Results: Among 170 patients, there were 53 cases in the LG, 60 cases in the MG, and 57 cases in the SG, with the mean OI values of 247.90 ± 28.61 mmHg, 151.05 ± 25.96 mmHg and 83.13 ± 8.04 mmHg, respectively. The serum levels of ACT-A, CC-16, and KL-6 increased with the disease severity, and there were apparent differences in the comparison of serum levels in all groups (p < 0.05). The serum levels of ACT-A, CC-16, and KL-6 were negatively correlated with OI values (r = –0.841, –0.799, –0.869, p < 0.001).

    Conclusions: As the severity of ARDS escalates, the serum levels of ACT-A, CC-16, and KL-6 have been observed to increase correspondingly, which is closely related to the disease severity. Therefore, monitoring ACT-A, CC-16, and KL-6 serum levels could be a valuable reference for future diagnostic procedures and treatment strategies.

  • Article
    Yuyan Bao, Bing Hong, Guoli Qi, Zhenjian Lin, Kaiping Liu, Jie Zhou, Yanjie Yu, Xiaomin Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2953-2963. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.293
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    Objective: Lung cancer is characterized by high mortality and disability, but its pathogenesis has not been fully clarified. This study aimed to determine the mechanism of the beneficial effect of crocin in lung cancer cells.

    Methods: The effect of different concentrations of crocin on cell viability, proliferation, migration and invasion in lung cancer cells was studied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing and cell invasion assays. Western blot was harnessed to evaluate β-catenin protein level. To clarify the effects of crocin and β-catenin on lung cancer cells, A549 and H23 cells were transfected with or without β-catenin overexpression plasmid or its negative control, and/or stimulated with 4 mg/mL crocin for 48 h, followed by determination of the expressions of β-catenin and proliferation-related proteins (western blot), cell proliferation (colony formation assay), cell migration (wound healing assay) and cell invasion (cell invasion assay).

    Results: Crocin concentration-dependently inhibited cell biological characteristics as well as β-catenin protein levels in lung cancer cells. The inhibitory effect of crocin was significant when the concentration of crocin was equal to or greater than 4 mg/mL (p < 0.01). Moreover, crocin rescued the enhancing effects of β-catenin overexpression on the proliferation, as well as the expressions of β-catenin and proliferation-related proteins in lung cancer cells (p < 0.01). Furthermore, crocin offset the enhancing effects of overexpressed β-catenin upon the abilities of lung cancer cells to migrate and invade (p < 0.01).

    Conclusions: Crocin inhibits the biological functions of lung cancer cells by inhibiting β-catenin gene and downstream genes.

  • Article
    Jialu Bao, Yan Zhang, Xian Zhang, Xiaodan Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2965-2974. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.294
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    Background: Escherichia coli pollution is a significant microbial pollutant that affects human and animal health and is an important factor that restricts the development of the poultry industry. This study aimed to investigate the antibacterial effect of Schisandrin A on Escherichia coli.

    Methods: Escherichia coli was divided into a control group and a Schisandrin A treatment group. The minimal inhibitory concentration (MIC) of Schisandrin A on Escherichia coli was determined. The growth curve was drawn by measuring absorbance values at 600 nm at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h, and the antibacterial effect of Schisandrin A on Escherichia coli was observed. The integrity of the cell membrane and cell wall of Escherichia coli was detected using an electron microscope. The permeability of the Escherichia coli wall was measured using Alkaline phosphatase (AKP) activity and Propidium Iodide (PI) staining. Transcriptome sequencing was carried out to explore the antibacterial mechanism of Schisandrin A on Escherichia coli. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the expression of virulence genes in Escherichia coli.

    Results: The study found that Schisandrin A has a minimum inhibitory concentration (MIC) of 3.13 mg/mL against Escherichia coli. When added at a concentration of ½ MIC, Schisandrin A can slow down the growth rate of Escherichia coli, damage the cell structure, and significantly downregulate the virulence genes ferric aerobactin receptor IutA (iutA), yersiniabactin non-ribosomal peptide synthetase HMWP2 (irp2) and type 1 fimbriae periplasmic chaperone (fimC) (p < 0.05). Transcriptome results showed that Schisandrin A could downregulate the expression of 50S ribosomal subunit protein L24 (rplX), 30S ribosomal subunit protein S12 (rpsL), 50S ribosomal subunit protein L13 (rplM), 50S ribosomal subunit protein L5 (rplE) and 30S ribosomal subunit protein S5 (rpsE) in ribosomes and upregulate 50S ribosomal subunit protein L31B (ykgM) expression.

    Conclusions: Schisandrin A has an inhibitory effect on Escherichia coli. It can destroy the bacterial structure and affect bacterial colonization and metabolism. Its bacteriostatic mechanism is related to the damage to ribosome function.

  • Article
    Xing-Yu Luo, Li Zhuan, Qin Xu, Ji-Wen Tian, Yan-Ping Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2975-2988. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.295
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    Objective: This study aimed to investigate the effect and possible mechanism of kallistatin (KS) in protecting against endometrial fibrosis.

    Methods: Human endometrial tissues from patients with intrauterine adhesions and normal uterine cavities were collected, and the expression of KS was analyzed. Fibrosis was induced in human endometrial epithelial (AN3CA) cells and human endometrial stromal cells (HESCs) using transforming growth factor beta 1 (TGF-β1). The cells were cultured with the KS protein, and the expression of fibronectin (FN) was assessed. Kallistatin expression was knocked down in the AN3CA cells, and the cells' proliferation activity, apoptosis rate, and migration rate, along with the expression of related fibrosis factors, were tested. A rat intrauterine adhesion model was established, treatment was provided to each group of rats, and the pregnancy outcomes of the rats were noted.

    Results: Compared with the control group, the KS expression of the human endometrium in the adhesion group decreased. After treatment with TGF-β1, the FN expression of the AN3CA cells and HESCs increased. However, compared with the TGF-β1 treatment, the FN expression decreased after the culture with the KS protein. The knockout (KO) of KS expression in the AN3CA cells resulted in decreased cellular proliferation activity, an increased cellular apoptosis rate, and a decreased cellular migration rate. There was an increase in the expression of FN, TGF-β1, mothers against decapentaplegic homolog 3 (SMAD3), phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK), and phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. After uterine curettage, the rat endometrium became thinner, the number of glandular organs decreased, the expression of TGF-β1, SMAD3, and FN increased, and the number of embryos from pregnancy decreased. Endometrial fibrosis occurred after KS expression KO, and the overexpression of KS improved intrauterine adhesion to some extent.

    Conclusions: Kallistatin exhibited a protective effect on intrauterine adhesion. Kallistatin regulated and controlled TGF-β1 expression by inhibiting the p-p38 MAPK and nuclear factor kappa B pathways, which reduced endometrial fibrosis and improved pregnancy outcomes in rats.

  • Article
    Qihong Cai, Ninggao Dai, Liming Xu, Qiandong Zhu, Qiyu Zhang, Qingqing Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2989-2995. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.296
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    Objectives: To investigate the inhibitory effect of capsaicin on the activation of hepatic stellate cells (HSCs) and elucidate the underlying mechanism.

    Methods: Cultured HSCT6 cells were treated with capsaicin at various concentrations. The Cell Counting Kit-8 (CCK-8) assay was performed to detect cell proliferation, and western blot analysis was used to evaluate the expression of fibrotic and apoptotic proteins, and the activation of the PI3K/AKT/mTOR pathway.

    Results: Capsaicin dose-dependently inhibited HSC cell proliferation and suppressed HSC cell fibrosis, as demonstrated by reduced protein levels of Fibronectin, Collagen I, Collagen III, α-SMA, and tissue inhibitors of metalloproteinase 1 (TIMP-1). Furthermore, capsaicin-induced HSC cell apoptosis is characterized by decreased Bcl-2 levels and increased Bax protein expression. Capsaicin also inhibited HSC activation by downregulating epidermal growth factor (EGF)-induced PI3K/AKT/mTOR signaling. Additionally, the inhibitory effects of capsaicin were enhanced with PI3K inhibitor LY294002 in HSCs.

    Conclusions: Capsaicin attenuates HSC activation by inhibiting the PI3K/AKT/mTOR pathway.

  • Article
    Lanfang Kang, Juan Che, Xiaoshuang Liu, Yating Zhao, Xiaobo Nie, Wei Wang, Jiao Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 2997-3005. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.297
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    Background: A high-fat diet is an important risk factor for cardiovascular diseases (CVD). A diet high in saturated fat leads to the development of hypertension and CVD by increasing the serum concentration of angiotensin converting enzyme. However, different sources of saturated fats do not have the same cardiovascular risks. The effect of diets containing different fat concentrations on cardiac function is not clear. We explored the effects and mechanisms of diets containing different concentrations of saturated fat on lipid metabolism, cardiac function, and CVD risk factors.

    Methods: Healthy male C57BL/6 mice aged 12–14 weeks were fed with normal diet or diets containing different concentrations of saturated fat for 8 weeks as follows: normal diet group and 10%, 20%, and 30% saturated fat content groups. At the end of the intervention period, body weight was measured. Fasting for 12 h, left ventricular ejection function measured by M-mode echocardiography, and serum triglyceride and cholesterol levels were measured. The calcium transient was measured in isolated cardiomyocytes, and the amplitude of calcium transient change (F/F0) and calcium recovery rate in myocardial cells were measured. The mRNA and protein expression of fatty acid-binding protein 3 (FABP3) and fatty-acid binding protein 4 (FABP4) were assessed.

    Results: Weight gain of mice in each saturated fat group was higher than that in controls. The levels of fasting blood glucose, and serum total cholesterol and triglyceride in mice fed a 30% saturated fat diet were significantly higher than those in control mice. The ejection fraction of mice in each saturated fat group was lower than that in controls. The calcium recovery rate of cardiomyocytes in the 10%, 20%, and 30% saturated fat groups was significantly higher than that in controls. The mRNA expression of FABP3 and the mRNA and protein expression of FABP4 in the 20% and 30% saturated fat groups were significantly up-regulated.

    Conclusions: This study demonstrates that eating a diet containing 10%, 20%, and 30% saturated fat for 8 weeks increased body weight, blood sugar, and blood lipids; affected cardiac function; and adversely affected cardiomyocyte contraction. The decrease of heart function induced by saturated fat diet may be related to FABP4 up-regulation.

  • Article
    Ling Xu, Long Sui
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3007-3015. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.298
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    Background: While the methylation status of the tumor suppressor Paired Box-1 (PAX1) is recognized as a cervical cancer diagnostic biomarker, PAX1's exact role is unclear. This study delves into PAX1's possible contribution to cervical cancer progression.

    Methods: We engineered overexpression of PAX1 in the human cervical cancer cell line, HeLa, via cell transfection. Quantitative reverse transcription-polymerase chain reaction evaluated PAX1 expression. The Cell Counting Kit-8 assay was employed to gauge cell proliferation, and apoptosis rates alongside cell cycles were determined by flow cytometry. Invasion and migration capacities were evaluated via transwell and wound healing assays. Differential gene expression and pathway analysis were conducted using bioinformatics tools, while the levels of PAX1 protein were quantified via Western blotting.

    Results: Cervical cancer cells were prevented from proliferation (p < 0.05), invasion (p < 0.01), and migration (p < 0.05) by overexpression of PAX1. The apoptosis rate of cervical cancer cells rose, and the cell cycle was restrained in the first gap (G1) phase after PAX1 transfection (p < 0.001). Furthermore, overexpression of PAX1 led to abnormal retinol metabolism in cervical cancer.

    Conclusions: PAX1 could potentially impede cervical cancer development by modulating retinol metabolism. This study could illuminate novel aspects of the progression pathways in cervical cancer.

  • Article
    Qian Wang, Wenjing Ye, Fangfang Chen, Minrui Liang, Weiguo Wan, Wenyu Guo, Hejian Zou, Yu Xue
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3017-3027. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.299
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    Background: Cytokine interleukin (IL)-6 is involved in the development of systemic sclerosis (SSc). IL-6 forms a complex with soluble IL-6 receptor (sIL-6R), which binds to gp130 and initiates the transmitter signal for pro-inflammatory effects. TJ301 (sgp130-Fc or olamkicept) binds to IL-6-sIL-6R complex, reducing IL-6-sIL-6R binding to gp130 and inhibiting the transmitter signal. The aim of this study was to determine whether TJ301 can be used to treat SSc by inhibiting the IL-6 transmitter signal.

    Methods: Wild-type C57BL/6 mice were randomly distributed into experimental and control groups. Mice were injected subcutaneously with bleomycin (BLM, saline in the control group) for 28 days to induce SSc. Meanwhile, MR16-1, saline and TJ301 (saline in the control group) were separately injected to mice. On day 29, IL-6 and IL6Rα levels of blood, skin and lung tissues histological analysis, and collagen I, CD31 and α-smooth muscle actin (α-SMA) of skin tissue expression were determined. The human foreskin fibroblast (HFF-1) cells and human dermal microvascular endothelial cells (HDMEC) were treated using transforming growth factor (TGF)-β1, with or without TJ301. For HFF-1 cells, cell viability, IL-6 and IL-6Rα levels and collagen I and αSMA expression were determined. For HDMEC, migration rate, IL-6 and IL-6Rα levels, αSMA and CD31 expression and endothelial-to-mesenchymal transition (EndoMT) were detected.

    Results: Higher concentrations of IL-6 and sIL-6R were found in BLMtreated animals' blood. Additionally, their skin and lungs exhibited greater collagen accumulation and myofibroblasts that were positive for α-SMA. Inflammation level, immune cells that entered quantity, and profibrotic genes expression in skin and lung tissues were all reduced when TJ301 was used to block IL-6 transmitter signal. When triggered by TGF-1 in the lab, TJ301 may prevent dermal fibroblast and microvascular endothelial cells from expanding and migrating.

    Conclusions: Using TJ301 to inhibit the IL-6 transmitter signal may be a novel approach to treat SSc.

  • Article
    Fei Li, Li-Zhong Yan, Yi-Fan Zhang, Zhou-Jun Lin, Yin Li, Xiao Han, Lu Sun, Xiao-Lin Pei, Ya Feng, Qiao Liu, Juan Yang, Qiao Wu, Di Shao, Cheng-Gang Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3029-3042. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.300
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    Background: Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies, ranking third in morbidity and second in mortality among all cancers in the world. The dysregulation of acid ceramidase (ASAH1) which is involved in sphingolipid metabolism, is known to promote tumorigenesis. As an inhibitor of ASAH1, carmofur (1-hexylcarbamoyl-5-fluorouracil) is used as a chemotherapeutic agent clinically and plays a critical role in ASAH1-induced tumorigenesis. The aim of this study was to explore targeting ASAH1 as a new therapeutic mechanism for CRC.

    Methods: Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) assay were performed to detect protein expression levels and transcript expression levels. Lentivirus-mediated shRNA (short hairpin RNA) was used to silence ASAH1 and establish ASAH1-knockdown cell lines. Thiazolyl Blue Tetrazolium Bromide (MTT) assay, colony formation and transwell assay were performed to assess cell viability, colony formation ability, migration and invasion ability. Xenograft tumor model was established to study the therapeutic effect of ASAH1 inhibition on tumor growth.

    Results: Firstly, ASAH1 expression in CRC tissues was higher than normal tissues. In addition, ASAH1 inhibition decreased the proliferation of CRC cells and protected mice from the onset and progression of CRC in the xenograft tumor model. Moreover, ASAH1 was possibly associated with autophagy activation in DLD-1 cells.

    Conclusions: ASAH1 played a key role in regulating tumorigenesis and cell autophagy in CRC. Therefore, ASAH1 has the potential to be developed as a potential therapeutic target for preclinical studies in CRC.

  • Article
    Tao Chen, De-wen Deng, Zhen Wang, Qian Sun, Jian-Jun Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3043-3056. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.301
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    Background: Hepatic ischemia-reperfusion injury (HIRI) is an unavoidable event associated with liver relevant surgeries. Long-chain non-coding RNA, metastasis associated in lung denocarcinama transcript 1 (LncMALAT1) plays important role in tissue ischemia-reperfusion injury. The aim of the study is to characterize the mechanism of LncMALAT1 in the HIRI promotion.

    Methods: The constructed LncMALAT1 lentivirus was employed to stablish LncMALAT1 up- and down-regulating mice that were all subjected to 70% liver ischemia to create HIRI. The degree of liver tissue injury and hepatocyte apoptosis were visualized using hematoxylin-eosin staining, terminal dexynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick end labeling (TUNEL) method. LncMALAT1 expression was monitored using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Western blot analysis was performed to evaluate autophagy and apoptosis-related proteins expression. Additionally, autophagosome rate was quantified employing transmission electronic microscopy (TEM). Finally, the confocal microscopy was used to observe specific mecherry-green fluorescent protein-microtubule-associated protein 1 light chain 3 (mcherry-GFP-LC3) in LncMALAT1 overexpressed/knockout cell under 1 hour hypoxia/12 hours re-oxygenation condition. The relative rescue experiment was performed using autophagy regulator of 3-methyladenine (3-MA)/rapamycin. The cell survival rate was detected by 3-(4,5-dimethylthiahiazol-2-yl)-2,5-diphenytetrazoliumromide (MTT) assay.

    Results: Compared to the sham-operated group, both the RNA expression of LncMALAT1 and liver damage were increased in all HIRI groups (p < 0.05). And 6 hours after reperfusion reached to the peak liver damage in line with the RNA expression of LncMALAT1. Upregulated LncMALAT1 in vivo and in vitro, TUNEL positive rate, autophagosome rate and mcherry-GFP-LC3 autophagy dots were significantly increased compared to the control group (p < 0.05). The protein expression of Caspase8, Cleaved-Caspase3, microtubule-associated protein 1 light chain 3 (LC3), autophagy related gene 12 (Atg12) were increased (p < 0.05), but the protein expression of sequestosome 1 (SQSTM1/p62), B cell lymphoma-2 (Bcl2), phosphorylated mechanistic target of rapamycin (p-mTOR) were decreased in LncMALAT1 upregulated group liken to the control group (p < 0.05). Nevertheless, downregulation of LncMALAT1 could alleviate the liver damage in vivo and in vitro. Importantly, the LncMALAT1 induced liver autophagy elevation that was responsible for severe apoptosis in HIRI, at least partially.

    Conclusions: LncMALAT1 enhanced liver autophagy leading to apoptosis aggravation and further hepatic ischemia-reperfusion injury in mice.

  • Article
    Bingjie Lin, Guojun Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3057-3068. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.302
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    Background: Tectorigenin can impede inflammation, cell apoptosis, and has hepatoprotective effects. This study was designed to elucidate how Tectorigenin impacts fulminant hepatic failure (FHF).

    Methods: Intraperitoneal injections of lipopolysaccharide (LPS; 50 μg/kg) and d-galactosamine (d-GalN; 300 mg/kg) were applied to establish an FHF rat model. FHF rats were given different concentrations of Tectorigenin (12.5, 25 and 50 mg/kg) before LPS/d-GalN treatment. Histological analysis was achieved through Hematoxylin-eosin (H&E) and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, followed by detection of serum factor levels by using Enzyme-linked immunosorbent assay (ELISA). BRL cells were treated with 200 μM H2O2 (48 h) to induce the FHF model in vitro. After BRL cells were treated with H2O2, Tectorigenin (200 μM) and transfected with miR-338-3p inhibitor or small interfering (si)-apoptosis-associated tyrosine kinase (AATK), the apoptotic factors, inflammatory factors, miR-338-3p and AATK expression levels, and biological function were evaluated by real-time quantitative PCR (RT-qPCR), western blot, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry. TargetScan v7.2 prediction and dual luciferase assay were performed for target relationship verification.

    Results: Tectorigenin reduced histopathological damage, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory factors, apoptosis, mortality, and AATK protein expression, while increasing miR-338-3p mRNA levels in vivo (p < 0.001). Tectorigenin exerted the opposite effects of H2O2 on cell viability, cell cycle, cell apoptosis and inflammatory factors. The effect of Tectorigenin was reversed by miR-338-3p inhibitor. Furthermore, there was a targeting relationship between miR-338-3p and AATK and a negative interplay between miR-338-3p inhibitor and siAATK on the above-mentioned biological behaviors.

    Conclusions: Tectorigenin may protect against FHF through the miR-338-3p/AATK cascade.

  • Article
    Ruidong Liu, Xiaoli Wang, Guoliang Ma, Yuanhao Zhao, Jiude Qi, Yuguo Ren
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3069-3076. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.303
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    Purpose: Osteosarcoma (OS) is a serious malignant tumor in orthopedics, which seriously endangers the life and health of adolescents. Ras homolog family member B (RhoB) is known to function as an anti-oncogene in a series of cancers, including OS. This study focused on the function of RhoB on cell growth and apoptosis in OS.

    Methods: Immunohistochemistry (IHC), Western blot and Real-time quantitative polymerase chain reaction (RT-qPCR) assay were performed to examine RhoB level in OS tissues and cells (HOS, MG63, Saos-2). The effect of RhoB overexpression on the proliferation ability of MG63 and HOS cells was verified by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and plate clone formation assay. The impact of RhoB overexpression on OS cell apoptosis was verified by flow cytometry (FCM) and the detection of apoptosis-related proteins. The function of RhoB overexpression on lung metastasis and tumor growth in vivo was studied by xenograft experiments. In addition, the regulation of RhoB on the PI3K/AKT pathway in OS was investigated by Western blot assay.

    Results: The reduced expression of RhoB was verified in 62 OS tissues and 3 OS cell lines (HOS, MG63, Saos-2). The enhanced expression of RhoB notably impaired cell proliferation but facilitated cell apoptosis in MG63 and HOS cells. Furthermore, RhoB overexpression blocked xenograft tumour growth and lung metastasis in vivo. Additionally, the phosphorylation of AKT and PI3K was decreased by RhoB overexpression but elevated by RhoB knockdown.

    Conclusions: Altogether, our findings displayed that enhanced expression of RhoB suppressed OS cell progression by inactivating the PI3K/AKT pathway.

  • Article
    Yuefei Wang, Ling Qin, Caixia Zhu, Fei Fan, Jingbo Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3077-3083. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.304
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    Objectives: To investigate the proliferation, autophagy and mechanism of curcumin in the treatment of cervical cancer cells complicated with human papillomavirus (HPV) infection.

    Methods: The C33A-E6 cell line which interfered with the human papillomavirus type 16-E6 (HPV16-E6) oncoprotein overexpression and small interfering RNA (siRNA) were constructed. The cell proliferation, oxidative stress injury, autophagy levels and lysosomal fluorescence intensity were compared by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) proliferation assay, reactive oxygen species (ROS) assay, and real-time polymerase chain reaction (RT-PCR) assay as well as lysosomal labeling assay.

    Results: The interference efficiency of HPV16-E6 was significant. Compared with the negative cells, the growth rate of SiHA-E6-Si cells increased faster. The fluorescence interval of HPV16 E6 positive cells was significantly increased compared with that of negative cells. Induction of autophagy did not affect SIHA-E6-Si cell proliferation. The expression levels of Beclin-1, light chain 3-II (LC3-II), and dynactin 4 (P62) in HPV-positive cells were significantly increased compared with those in negative cells. Moreover, the expression of Beclin-1, LC3-II, and P62 increased significantly after autophagy induction. In addition, the fluorescence intensity of lysosomes decreased after autophagy induction. The content of ROS did not change significantly after autophagy induction.

    Conclusions: Curcumin regulates the expression of autophagy-related proteins (Beclin-1, LC3-II, and P62) in cervical cancer cells with HPV16 persistent infection.

  • Article
    Jizhong Chen, Sheng Zhang, Yuan Yuan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3085-3093. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.305
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    Objectives: To explore the expression proportion and absolute count of CD4+CD25+Foxp3+ regulatory T (Treg) cells, programmed cell death protein 1 (PD-1), lymphocyte-activation gene 3 (LAG-3) and cluster of differentiation 39 (CD39) in peripheral blood of patients with gastric malignant tumor.

    Methods: Peripheral blood samples were collected from 50 patients with gastric malignancy (tumor group) and 15 healthy controls (control group). The absolute count of leukomonocyte, and the proportion of CD3+ T cells and CD4+ T cells, the proportion and absolute count of Treg cells, PD-1, LAG-3 and CD39 subsets of Treg cells were assessed by flow cytometry in the two groups. Moreover, the correlation between Treg cells and their immune checkpoints was analyzed.

    Results: Compared with the healthy control group, total leukomonocyte [(1.19 ± 0.37) × 103/μL vs (2.04 ± 0.29) × 103/μL] and CD3+ T cell proportion [31.85% (18.63%, 43.61%) vs 45.08% (41.77%, 53.70%)] in peripheral blood of patients with gastric malignant tumor were decreased (p < 0.05), while CD4+ T cell proportion was not statistically significant (p > 0.05). The proportion of Treg cells in the tumor group was higher than that in the healthy control group [10.06% (7.04%, 14.14%) vs 3.39% (2.97%, 4.38%)] (p < 0.05). The proportion and absolute count of PD-1+Treg, LAG-3+Treg and CD39+Treg cells in the tumor group were higher than those in the healthy control group (p < 0.05). The proportion of Treg and PD-1+Treg cells, CD39+Treg and PD-1+LAG-3+Treg cells, LAG-3+Treg cells and PD-1+LAG-3+Treg cells, and PD-1+Treg and PD-1+LAG-3+Treg cells were positively correlated in the tumor group (p < 0.05).

    Conclusions: The expression of Treg cells in the peripheral blood of patients with gastric malignant tumor increased. PD-1, LAG-3 and CD39 molecules were highly expressed and co-expressed in Treg cells, which had a complex regulatory relationship with each other. Therefore, it is crucial to monitor the characteristics of tumor microenvironment and biomarkers of immune efficacy represented by Treg cells.

  • Article
    Jijuan Zhang, Ningning Bu, Hong Zhang, Haiyun Shao, Chenghe Sun
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3095-3104. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.306
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    Background: Ilexgenin A is a natural triterpenoid compound with a certain role in inflammation, atherosclerosis and tumor, and can regulate endoplasmic reticulum stress. The relevant effects of Ilexgenin A on Alzheimer's disease (AD) are discussed in the present study.

    Methods: Following the indicated transfection and treatment of Ilexgenin A (0.1, 1, 10 μmol/L) or 25 μmol/L amyloid-beta (Aβ)25-35, the assays of both 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry were adopted to estimate the viability and apoptosis of PC12 cells. Meanwhile, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and Reactive Oxygen Species (ROS) were determined by the assay kits of SOD and MDA and flow cytometry. Besides, the expressions of estrogen receptor 1 (ESR1), B-cell lymphoma-2 (Bcl-2), BCL2-Associated X protein (Bax), Glucose-Regulated Protein 78 (GRP78), C/EBP homologous protein (CHOP), and nuclear/cytoplasmic nuclear factor kappa B (NF-κB) p65 were quantified by Western blot or quantitative real-time polymerase chain reaction (qRT-PCR) as needed.

    Results: Aβ25-35 decreased viability, promoted apoptosis, suppressed Bcl-2 and ESR1 protein expression levels, and enhanced the Bax protein level of PC12 cells (p < 0.001). Conversely, Ilexgenin A reversed the Aβ25-35 effects on these aspects in PC12 cells (p < 0.05). Besides, Aβ25-35 diminished SOD level and downregulated cytoplasmic NF-κB p65 protein expression while increased the levels of MDA, ROS and upregulated protein expressions of GRP78, CHOP, Caspase-12, nuclear NF-κB p65 (p < 0.001). On the other hand, Ilexgenin A exerted the opposite effects, which were overturned following the downregulation of ESR1 (p < 0.001).

    Conclusions: In PC12 cells with the intervention of Aβ25-35, which mimicked an in vitro AD model, Ilexgenin could alleviate the initiated oxidative stress and endoplasmic reticulum stress-induced apoptosis via upregulating ESR1.

  • Article
    Qing-qin Luo, Xue-lian Feng, Qian He, Ying Zhang, Zhijun Pei, Pei Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3105-3114. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.307
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    Objective: Although previous studies have suggested an association between Trp64Arg mutation in adrenergic, beta-3-, receptor (ADRB3) and susceptibility to type 2 diabetes mellitus (T2DM), there is no consistent conclusion on this association amongst the Chinese Han population. Thus, this research was carried out to evaluate the impact of Trp64Arg mutation in ADRB3 on the risk of T2DM in the Chinese Han population.

    Methods: An electronic search was used to collect relevant literature in English and Chinese from databases such as PubMed, Embase, China National Knowledge Infrastructure (CNKI), WanFang, Sinomed and VIP. Minor allele frequency was calculated and tested in the control groups. The relationship was verified in six genetic models: Allelic, dominant, recessive, homozygous, heterozygous, and codominant. The odds ratio (OR) and 95% confidence interval (CI) were calculated with Metafor package in R (version 3.5.1, developed by Ross Ihaka and Robert Gentleman, Auckland, New Zealand). Sensitivity analysis and publication bias analysis were performed.

    Results: A total of 22 studies involving 3620 T2DM patients and 2841 healthy participants were included in the quantitative analysis. The frequencies of Arg64 allele and Arg64 homozygous were 0.148 and 0.019 in Chinese Han population. Pooled results showed that Trp64Arg polymorphism was associated with increased risk of T2DM in allele genetic model (OR = 1.72, 95% CI = 1.15–2.58); Dominant model (OR = 1.25, 95% CI = 1.09–1.44); Recessive model (OR = 1.60, 95% CI = 1.10–2.32); Homozygous model (OR = 1.72, 95% CI = 1.18–2.49); Heterozygous model (OR = 1.21, 95% CI = 1.07–1.36), and codominant model (OR = 1.19, 95% CI = 1.05–1.3).

    Conclusions: The frequency of minor allele Trp64Arg polymorphism in the Chinese Han population was 0.148. The mutation was linked to an increased risk of T2DM in Chinese Han population. Large-sized, well-designed studies adjusted for more confounders should be conducted to confirm and explain this association.

  • Article
    Li Zhang, Shanshan Zheng, Yan Qin, Xuelian Chen, Shengyu Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3115-3122. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.308
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    Background: Combination therapy including immune checkpoint inhibitors (ICIs) may be a promising option for patients with anaplastic thyroid carcinoma (ATC) or poorly differentiated thyroid carcinoma (PDTC). This study aimed to explore the efficacy of ICIs combined with kinase inhibitors (KIs) or chemotherapy (CT) for ATC/PDTC.

    Methods: The data of five patients with ATC and two patients with PDTC who received treatment of ICIs combined with CT or KIs were retrospectively analyzed. The patients' response status was evaluated by the response evaluation criteria in solid tumors (RECIST v1.1) criteria. Progression-free survival (PFS) and overall survival (OS) were also collected.

    Results: The overall response rate was 42.9%, including 14.3% (1/7) with a complete response and 28.6% (2/7) with a partial response, 14.3% (1/7) had stable disease. The median PFS of the included seven patients after ICIs treatment was 9 months, median OS was 17 months, and one-year OS rate was 71.43%. Notably, the condition of one patient with PDTC and brain metastasis was significantly reduced after treatment of a programmed death (PD)-1 inhibitor. However, the patient might not tolerate the side effects of CT and died three months after discontinuation of treatment, with an OS of 13 months. The other three patients were treated with ICIs when their condition was in the stage of rapid disease progression, but did not benefit from ICIs.

    Conclusions: ICI therapy, whether combined with CT or KIs, may help achieve a better therapeutic effect than monotherapy alone. Early use of ICIs may be necessary for patients with ATC or PDTC to increase therapeutic benefits.

  • Article
    Zi Ye, Xiaomin Guan, Wenyuan Shan, Baojun Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3123-3129. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.309
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    Background: Microglia activation, a defining feature of brain inflammation, plays a crucial role in the pathogenesis of epilepsy. Tripchlorolide (T4) is capable of inhibiting inflammatory threats to the central nervous system (CNS). However, relevant mechanisms of action for T4 in epilepsy treatment have not been well reported. We aimed to evaluate the effect of Tripchlorolide (T4) on microglial activation and stimulator of interferon genes—nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (STING-NLRP3) signaling pathway in epilepsy by the uses of both in vivo and in vitro experiments.

    Methods: Forty mice were divided into four groups: Blank control, status epilepticus (SE), SE+vehicle, and SE+T4. Following establishment of pilocarpine-induced SE mouse model, T4 was administered to mice in SE+T4 group, while saline or dimethyl sulfoxide to other groups. The induction frequency was once every three days for total of 60 days. The treatment outcomes were assessed after each experiment. Inflammatory cytokines were measured by Enzyme linked immunosorbent assay (ELISA) to analyze the microglial activation and effect of T4. The effect of T4 on STING-NLRP3 signaling pathway was evaluated in vivo by western blotting (WB). With cell lines, the alterations of STING-NLRP3 signaling pathway were assayed in vitro by WB.

    Results: The latency to SE and mortality were improved after T4 treatment (p < 0.001). T4 markedly reduced levels of the inflammatory factors following their significant rise after SE induction (all p < 0.01). Application of pilocarpine increased the expressions of relevant proteins associated with inflammation and STING-NLRP3 signaling pathway and apoptosis in mouse brain tissue, whereas T4 treatment altered these abnormal upregulations (p < 0.001). The abundance of STING and NLRP3 in cells and endoplasmic reticulum (ER) was up-regulated in the SE groups but inhibited by T4 treatment (all p < 0.05).

    Conclusions: T4 may inhibit the activation of microglia and improve SE by regulating the STING-NLRP3 pathway. This discovery provides new insight for the treatment of epilepsy.

  • Article
    Xia Shao, Fu-min Zheng, Yan Wang, Guang-tian Chen, Wei-jin Gao, Jing-xiao Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3131-3139. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.310
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    Purpose: How to reliably promote osseointegration has long been a research hot spot. The study aims to find a promising novel way to promote osteointegration. We proposed the construction of different kinds of phytoestrogen biomimetic coatings with different concentrations of phytoestrogens on titanium surfaces using the layer-by-layer self-assembly (LBL) technology to evaluate the effects on mouse preosteoblast proliferation and differentiation.

    Methods: We proposed the construction of three kinds of phytoestrogen biomimetic coatings (the puerarin group, the genistein group and the daidzein group) with four concentrations of phytoestrogens (1 × 10-5 mol/L, 1 × 10-6 mol/L, 1 × 10-7 mol/L and 1 × 10-8 mol/L) on titanium surfaces using layer-by-layer self-assembly technology to evaluate effects on mouse preosteoblast proliferation and differentiation, the Blank Group and the Coating Group as a control. In addition, the proliferation and differentiation of mouse preosteoblasts and expression of osteogenesis-related genes in mouse preosteoblasts were also assessed.

    Results: Under field emission scanning electron microscopy, the small undissolved phytoestrogen particles indicated that the plant hormones were assembled successfully on the titanium surface. Regardless of the absorbance values of each group or the messenger RNA (mRNA) expression of alpha1 (I) collagen (Colla1), runt-related transcription factor 2 (Runx2) and alkaline phosphatase (AKP)-2, the ability of the phytoestrogen bionic coating to promote the proliferation of mouse preosteoblasts was stronger than that in the blank group or the coating group. Additionally, all three plant hormones contributed to osseointegration using layer self-assembly technology, and the peak concentration for the intervention was 1 × 10-6 mol/L.

    Conclusions: We have successfully incorporated phytoestrogen on the surface of titanium using the LBL technology with a promising novel strategy for promoting osteointegration.

  • Article
    Xin Liu, Fasiha Tariq, Umer Farooq, Mostafa A. Abdel-Maksoud, Saeedah Musaed Almutairi, Wahidah H. Al-Qahtani, Muhammad Akram, Guangliang Bai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3141-3150. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.311
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    Background: Hypertrophic cardiomyopathy (HCM) is a genetically complex disorder. This study aimed to investigate the expression pattern of differentially expressed genes (DEGs) and explore hub genes in HCM patients via in silico analysis.

    Methods: The GSE133054 and GSE36961 expression profiles were downloaded from the Gene Expression Omnibus (GEO) database for the identification of differentially expressed genes (DEGs) and to explore hub genes and their expression confirmation. Then, bioinformatics tools were employed to perform STRING, Long noncoding RNA (lncRNA)‑MicroRNA (miRNA)‑Messenger RNA (mRNA) regulatory network, gene enrichment, and drug prediction analyses.

    Results: Our results indicated a total of 495 DEGs, including 345 up-regulated and 150 down-regulated genes via differential expression analysis. From these DEGs, we subsequently identified 8 most important hub genes, including 4 up-regulated genes (COL14A1, UCP3, MOSPD1, and LUM) and 4 down-regulated genes (CAPNS1, GPX1, FLNB, and BCL3). Next, we further investigated hub genes' regulatory 5 miRNAs (has-mir-16-5p, has-mir-107, has-mir-1-3p, has-mir-7b-5p, and has-mir-155-5p) and 6 lncRNAs (LINC0103, LINC00909, PCBP1-AS, TMEM147-AS1, XIST, and LINC00662) in this study via lncRNA-miRNA-mRNA regulatory network. Later on, gene enrichment analysis revealed that hub genes were enriched in various important pathways including mitochondrial uncoupling proteins, the fatty acid cycling model, and the proton buffering model, etc. Finally, the drug prediction analysis highlighted different candidate potential drugs for altering the expression of hub genes in the treatment of HCM.

    Conclusions: A detailed in silico analysis was performed in this study to unravel the molecular regulatory mechanisms of HCM. The identified hub genes and their associated potential therapeutic drugs are predicted to be beneficial for treating HCM patients.

  • Article
    Yang Lan, Kaibin Lin, Xincheng Song, Ai Wang, Shaoyan Liu, Tzuchun Lin, Yan Yan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3151-3160. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.312
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    Background: Systemic inflammation and glucose metabolism dysfunction were closely relevant to cardiovascular disease. Glucose to lymphocyte ratio (GLR), a novel inflammatory marker, has been recognized as a reliable prognosis factor in inflammatory diseases. However, there are no published studies on the association of cardiovascular disease with GLR, and this study aims to elucidate the potential relationship between cardiovascular disease and GLR.

    Methods and Results: We conducted a cross-sectional analysis in participants who were recruited in the survey of NHANES (2015–2020), with 8642 participants included in this study, including 1807 participants with cardiovascular disease (CVD). Compared with the non-CVD group, GLR and neutrophils lymphocyte ratio (NLR) were significantly higher in the CVD group (GLR: 3.78 ± 2.40 vs 2.88 ± 1.71, p < 0.001; NLR: 2.58 ± 1.62 vs 2.07 ± 1.15, p < 0.001). After adjusting for cardiovascular risk factors, the prevalence of individual CVD was independently and positively related to GLR, with an odds ratio of 1.08 (95% CI: 1.01–1.15). In subgroup analysis, stratified by age, gender, body mass index (BMI), ratio of income to poverty, smoking status, and diabetes mellitus (DM), the significant positive associations of GLR levels with CVD were found in participants who were female, smokers, higher BMI, lower income, with hypertension and DM. Furthermore, there was a positive relationship between GLR and CVD (OR ¼: 2.10 (95% CI: 1.30–3.60, p < 0.001)) only in the elder.

    Conclusions: This study reveals that GLR levels are positively and independently correlated to the prevalence of CVD, suggesting that GLR may be an effective predictor of systemic inflammatory response levels, plasma glucose levels, and cardiovascular risk.

  • Article
    Chun-feng He, Zheng-lei Meng, Song Xue, Yu-feng Chen, Qing-chuan Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3161-3172. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.313
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    Background: Bladder cancer is a genitourinary tumor which threatens the health of a large segment of the population. Surgical treatment and chemotherapy have severe side effects and a high risk of recurrence. Thus, effective adjuvant drugs are urgently needed. Herein, we set out to examine whether bufalin might improve the therapeutic effect of atezolizumab on bladder cancer cells.

    Methods: 5-ethynyl-2'-deoxyuridine (EdU) and methyl tetrazolium (MTT) methods were used to examine cell proliferation, while flow cytometry and Transferase-Mediated dUTP Nick-End Labeling (TUNEL) staining were used to test cell apoptosis. A tumor xenograft model in nude mice was also applied. Western blot detection of the phosphorylated-Yes-associated protein (p-YAP), Cyclin E, TEA domain transcription factor 1 (TEAD1), Mammalian sterile 20-like kinase 1 (MST1) and p-LASTS1 protein expression was performed.

    Results: Both bufalin and atezolizumab suppressed bladder tumor cell proliferation, migration and invasion. They also reduced Yes-associated protein (YAP)/TEAD1 signaling which was counteracted by YAP overexpression. In addition, bufalin or atezolizumab alone inhibited the activity of tumor growth in vivo, blocked the growth of cells in the G1 phase and triggered apoptosis. Furthermore, combined bufalin and atezolizumab showed additional inhibitory activity in the above experiments, indicating an improved therapeutic effect.

    Conclusions: Atezolizumab combined with bufalin may be an effective therapeutic approach for bladder cancer. The mechanism of action of the combined treatment may be correlated with activating the MST1/LASTS1 pathway and inhibiting the YAP/TEAD1 signaling pathway.

  • Article
    Jie Tang, Aimin Liu, Xiaoying Chen, Suwa Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3173-3183. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.314
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    Background and Objective: Postpartum depression (PPD), a severe psychiatric disorder, affects more than 10% of women worldwide. Traditional screening for depression cannot identify patients without a history of mood disorders. This study aimed to identify new candidate biomarkers in exosomes isolated from peripheral blood and explore their function in patients with PPD.

    Methods: Forty-four patients with PPD and 20 healthy controls were recruited fofr plasma collection. Isolation of extracellular vesicles (EVs) was confirmed by immunoblotting and transmission electron microscopy. Five candidate miRNAs in exosomes were quantified using quantitative reverse transcription PCR (RT-qPCR). Genes repressed by the miRNAs (microRNAs) were identified using a luciferase assay.

    Results: The levels of miR-211 and miR-744 in plasma exosomes were significantly upregulated in patients with PPD. MiR-211 interacted with the mRNAs of estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2), and repressed their expression. miR-744 can inhibit ESR1 expression but not that of ESR2. Upregulation of miR-211 and miR-744 inhibited estradiol (E2) signaling and repressed the expression of downstream genes including brain-derived neurotrophic factor (BDNF) and cyclin D1 (CCND1). Bioinformatic analysis indicated that 85 genes were directly targeted by both miR-211 and miR-744. These potential target genes were enriched in neuron differentiation, nervous system, and miRNA function. ESR1, SRY-box transcription factor 11 (SOX11), BDNF, EPH receptor B2 (EPHB2), and argonaute 3 (AGO3) were the hub genes in the gene ontology map.

    Conclusions: The expression of miR-211 and miR-744 was upregulated in exosomes from patients with PPD, which may contribute to the development of PPD by targeting ESR1 and ESR2.

  • Article
    Jianjun Wang, Qun Lv, Changqing Xu, Zhaoyang Ruan, Yifan Dai, Zhangdan Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3185-3196. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.315
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    Background: Lung cancer is a malignant tumor that seriously threatens human life and health. Gefitinib is a first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), but drug resistance is a major obstacle limiting its efficacy. This work aims to examine the effect and underlying mechanism of programmed death ligand 1 (PD-L1) on gefitinib-resistant LUAD cell growth and migration.

    Methods: Bioinformatics prediction was utilized to predict the targeted binding microRNAs (miRNAs) of PD-L1, after which further verification was performed through dual-luciferase reporter assay and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Transfection of gefitinib-resistant cells was completed with PD-L1 overexpression plasmid and miR-526b-3p mimic. XAV-939, an inhibitor of Wnt/β-catenin, was also used to treat gefitinib-resistant cells. Measurement of β-catenin and PD-L1 protein levels were performed using Western blotting. Cellular biological behaviors were determined using relative functional assays.

    Results: miR-526b-3p directly targeted PD-L1, and miR-526b-3p level was lower in gefitinib-resistant cells gefitinib-resistant HCC827 (HCC827GR) and gefitinib-resistant PC9 (PC9GR) than in sensitive cell lines HCC827 (containing EGFR deletion from E746 to A750; CC-Y1188) and PC9 (containing EGFR exon 19 deletion; CC-Y1418) (p < 0.001). Moreover, miR-526b-3p mimic reduced gefitinib-resistant cell viability, proliferation, migration and invasion, while PD-L1 up-regulation offset the roles of miR-526b-3p mimic (p < 0.05). XAV-939 diminished PD-L1 and β-catenin levels, and suppressed gefitinib-resistant cellular biological behaviors, which further enhanced the inhibitory effects of miR-526b-3p mimic (p < 0.05).

    Conclusions: miR-526b-3p and Wnt/β-catenin pathways regulate PD-L1, thereby inhibiting the growth, invasion and migration of gefitinib-resistant LUAD cells.

  • Article
    Cheng Yang, Xiao-Peng Gu, Teng Zhang, Hong Hu, Jie Bai
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3197-3206. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.316
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    Background: The possible molecular mechanism and the influence of microRNA-182-5p (miR-182-5p) in the oxidative stress and inflammatory response in osteoarthritis (OA) were expected to be explored in this study.

    Methods: Interleukin-1β (IL-1β)-induced human chondrocytes (CHON)-001 cell line was utilized to construct in vitro OA models. Real-time quantitative polymerase chain reaction (qRT-PCR) was executed for measuring silent information regulation of transcription 1 (SIRT1) and miR-182-5p expression in clinical cartilage tissue and CHON-001 cells; enzyme-linked immuno sorbent assay (ELISA), biochemical assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to measure the levels of inflammatory factors, the levels of oxidative stress substances, and the proliferation rate in CHON-001 cells, respectively. Further, the targeting association of this miRNA with SIRT1 was identified via dual-luciferase reporter assay, and the expression of nuclear factor erythroid 2-associated factor 2 (Nrf2) signaling pathway-related protein in chondrocytes was checked via western blot.

    Results: Firstly, the OA model was successfully built via the stimulation of IL-1β in CHON-001 cells. The expression of that miRNA was observed to be high in IL-1β-induced chondrocyte samples and cartilage tissues of OA patients. Knocking down miR-182-5p triggered the Nrf2 signaling pathway in the chondrocytes and increased the cell proliferation, inhibited inflammation and oxidative stress. Furthermore, the dual-luciferase reporter assay and bioinfomatics analysis hinted that SIRT1 acted as a target gene of that miRNA. Besides, low SIRT1 expression was exhibited in OA tissues and the chondrocytes, and a negative association existed between SIRT1 expression and miR-182-5p expression. Knocking down SIRT1 counteracted the protective effects of miR-182-5p knockdown and the activation of Nrf2 pathway in the CHON-001 cells.

    Conclusions: Knocking miR-182-5p down in human chondrocytes prevented IL-1β-stimulated oxidative stress injury and cell inflammation by targetedly controlling SIRT1/Nrf2 signaling pathway, implying the potential of this miRNA serving as a target for treating OA.

  • Article
    Zhaojun Zeng, Ying Liu, Jingxian Xia
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3207-3212. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.317
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    Background: Uterine fibroids are the most common benign tumors of the female reproductive tract. Open surgery and laparoscopic myomectomy are clinically recommended for the management of uterine fibroids. However, the selection of appropriate surgical methods for patients remains a critical issue to be addressed.

    Objective: To assess the clinical efficacy and safety of laparoscopic myomectomy for uterine fibroids.

    Methods: This study used 60 patients diagnosed with uterine fibroids in our hospital from July 2019 to July 2021, as research subjects. The patients were randomly and equally assigned to 2 groups which received either open surgery (control group) or laparoscopic myomectomy (experimental group), with 30 patients in each group. The choice of surgical method was open to all the patients. The primary endpoint was clinical efficacy, while secondary endpoits comprised surgical indices, serum levels of estradiol (E2) and follicle-stimulating hormone (FSH), and postoperative complications.

    Results: The two groups of patients had well-balanced baseline profiles (p > 0.05). Laparoscopic myomectomy was associated with less intraoperative hemorrhage (67.16 ± 15.49 mL vs. 141.42 ± 36.57 mL, p < 0.01) and shorter surgical wound length (24.39 ± 1.96 mm vs. 65.76 ± 2.14 mm, p < 0.01), operation time (79.25 ± 4.19 min vs. 96.33 ± 5.64 min, p < 0.01), and hospital stay (5.33 ± 1.89 days vs. 9.82 ± 2.04 days, p < 0.01), when compared with open surgery. After laparoscopic myomectomy, patients exhibited a 58.46 ± 5.98 pmol/L decrease in E2 level and a 2.68 ± 1.22 U/L increase in FSH level. The final levels of E2 and FSH in laparoscopic myomectomy patients were significantly lower than the corresponding levels in patients treated with open surgery (254.91 ± 7.41 vs. 216.87 ± 5.14 pmol/L, 24.54 ± 1.46 vs. 21.25 ± 1.21 U/L, p < 0.01). Laparoscopic myomectomy resulted in lower incidence of complications (6.66%) than open surgery (60%), and in significantly better clinical efficacy than open surgery (p < 0.05).

    Conclusions: Laparoscopic myomectomy reduced intraoperative bleeding of patients with uterine fibroids, lowered the incidence of postoperative complications, reduced serum levels of E2 and FSH, shortened operation time and hospital stay, and enhanced clinical outcomes. However, there is need for further trials before clinical promotion of this surgical approach for fibroids.

  • Article
    Qiongjing Zeng, Fang Lu, Huici Jiang, Mingxu Fu, Yingying Bi, Jiajing Cheng, Jinlong Qin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3213-3220. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.318
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    Objective: To explore the expression of cyclooxygenase-2 (COX-2) in Uterine Myomas (Ums) model rats and its effect on the development of Ums.

    Methods: Six rats were randomly selected from 18 rats and divided into the model and control groups, with three rats in each group. The UMs model was established in the model group. Serum estradiol (E2), progesterone (P) and COX-2 expression in rat uterine tissues of both groups were detected, and the uterine tissue damage of UM rats was observed by hematoxylin-eosin (HE) staining. Then, the remaining nine rats were stochastically assigned to model, vehicle and Anti-COX-2 groups for UM modeling again, with three rats in each group. In the Anti-COX-2 group, the COX-2 small interfering RNA (siRNA) expression vector was injected into the tail vein. The other three rats were left untreated as the control group. After modeling, B-cell lymphoma-2 associated X (Bax)/B-cell lymphoma-2 (Bcl-2) expression in rat uterus was detected, and the pathological changes of UM rats after silencing COX-2 were observed by Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) and HE staining.

    Results: The model group showed higher E2, P and COX-2 at messenger RNA (mRNA) and protein levels than the control group (p < 0.05), with obvious connective tissue hyperplasia, thickening of the uterine smooth muscle, and severe infiltration of inflammatory cells. The COX-2 and Bcl-2 protein levels in uterine tissue were lower, while the Bax protein was higher in the Anti-COX-2 group versus model and vehicle groups (p < 0.05). TUNEL and HE staining identified an increased number of positive cells in the Anti-COX-2 group, obviously decreased area of smooth muscle hyperplasia, neatly arranged smooth muscle cells, and decreased infiltration of inflammatory cells.

    Conclusions: COX-2 is expressed at a higher level in UMs. After silencing COX-2, UMs cell apoptosis is increased and tissue damage is significantly improved in UM rats, suggesting that COX-2 plays a vital role in the occurrence and development of UM.

  • Article
    Junbo Chuai, Dan Wu, Zipeng Li, Wei Chen, Chang Liu, Dawei Li, Chunfeng Zhang, Yang Zhou, Hai Tian
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3221-3239. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.319
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    Background: Acute Stanford type A aortic dissection (ATAAD) is a potentially fatal outcome of cardiac surgery with a high mortality rate and an unclear pathogenesis. This study aimed to investigate the prospective diagnostic biomarkers and molecular pathways in ATAAD.

    Methods: We identified autophagy-related differentially expressed genes (DEGs) between control ATAAD groups using three Gene Expression Omnibus (GEO) datasets (GSE153434, GSE98770, and GSE52093). The potential pathways and biomarkers were then determined through protein-protein interaction (PPI) network and enrichment analysis. The autophagy-related hub genes and their corresponding diagnostic values were determined using receiver operating characteristic analysis and the significant immune-associated pathways were identified using Gene-Set Variation Analysis (GSVA) enrichment.

    Results: A total of 90 genes were screened as autophagy-related DEGs and 10 hub genes were ultimately identified using a PPI network in patients with ATAAD. Autophagy-related DEGs were enriched in pathways related to autophagy, protein binding, regulation of autophagy, and the relaxin signaling pathway according to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Gene-set enrichment analysis suggested that the regulation of autophagosome assembly, focal adhesion, and calcium-signaling pathways are enriched mainly in ATAAD development. In addition, GSVA showed that DEGs in ATAAD are primarily involved in the metabolic pathways of myocardial diseases and autophagy. Finally, it was found that the immune infiltration between the control and ATAAD groups was significantly different.

    Conclusions: Through the comprehensive analysis of GEO data, our study provides insights into autophagy-related biomarkers and therapeutic targets to diagnose and treat patients who are susceptible to ATAAD.

  • Article
    Jun Jin, Haihong Liu, Haiyan Yang, Guanghui Xu, Xinkuan Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3241-3245. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.320
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    Objectives: To appraise the clinical value of combined detection of serum tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 724 (CA724), cytokeratin segment 211 (CYFRA211)] in advanced non-small cell lung cancer (NSCLC).

    Methods: Retrospective analysis of the clinical data of 60 patients with advanced lung cancer (lung cancer subgroup) admitted to the First People's Hospital of Lianyungang from January 2021 to September 2022. Other 35 individuals in the same period were selected as the control subgroup; the serum CEA, CA125, CA724 and CYFRA211 levels of all subjects were compared, and the diagnostic value of the single index and combined detection for advanced NSCLC was analyzed by receiver operating characteristic curve (ROC) curve.

    Results: Compared to the control subgroup, the serum CEA, CA125, CA724 and CYFRA211 levels in the lung cancer subgroup increased. It was confirmed by ROC curve analysis that joint detection was the most effective in diagnosing advanced NSCLC. The area under the curve (AUC) was 0.928, the sensitivity was 78.33%, and the specificity was 91.43%. In each index, CEA and CYFRA211 have similar diagnostic values for NSCLC, which were superior to CA125 and CA724.

    Conclusions: The concentrations of CEA, CA125, CA724 and CYFRA211 in the serum of patients with advanced NSCLC are increased, which has a certain diagnostic value for the disease, and the combined analysis is more effective.

  • Article
    Ningzi Zang, Shiwen Wang, Jiyu Zou, Pin Li, Yongming Liu, Lijian Pang, Xiaodong Lv
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3247-3261. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.321
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    Objective: Recently, the study of pulmonary fibrosis drugs has been increasing steadily. The value of the clinical application of these drugs has been widely concerned. This study aimed to analyze the current status, hot contents, research frontiers and developing trends surrounding drugs for treating patients with pulmonary fibrosis.

    Methods: Articles concerning drug therapy for pulmonary fibrosis published between 1 January 1980 and 5 October 2022 were retrieved from the Web of Science Core Collection (WOSCC) database. Only articles published in English were included. Collaborative network analysis of annual publications, countries/regions, institutions, journals, keywords, authors and co-citation analysis of references were shown by CiteSpace 6.1.R2 and VOSviewer 1.6.18 software.

    Results: 502 articles and 522 keywords on pulmonary fibrosis drugs were included. China was the leading country with the most annual publications and Beijing Univ Chinese Med was the most active institution. The most published journal was Frontiers in Pharmacology and the most cited journal was American Journal of Respiratory and Critical Care Medicine. Maghu Toby TM and Bouros Demosthenes were the most published researchers in this field. 958 articles were cited from 1980 to 2022, mainly derived from influential journals such as The New England Journal of Medicine (Q1, impact factor 176.079). The co-occurrence of keywords showed that the current research hotspots and frontiers were as follows: ① Fully revealing the role and potential of existing drugs, determining the best route of administration, and proposing ideas for drug combinations; ② Conducting further research on the diagnosis, efficacy, survival and evaluation of idiopathic pulmonary fibrosis, cancer, and lung injury; ③Based on star signal transduction pathways and molecules, studying the intervention mechanisms of pulmonary fibrosis surrounding various pathological phenotypes such as the inflammatory response and dysregulation of oxidative stress; ④ Gaining a better understanding of the mechanisms of action of pirfenidone and nintedanib.

    Conclusions: This study reveals the global research hotspots and developing trends of drugs for pulmonary fibrosis patients, and helps researchers quickly understand the current research status and hot contents in this growing field.

  • Article
    Yang Fu, Qi-Feng Peng, Pei Liu, Shi-Xiong Yi, Heng Jiang, Gen Wang, Ren-Jian Jiang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3263-3273. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.322
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    Background: Recently, research has borne out that artesunate (ART), an anti-malaria agent, possesses anti-osteoarthritis function, but the mechanisms whereby ART protects the progression of osteoarthritis (OA) remains to be explored. Hence, the current study was aimed at assessing the potential mechanisms of ART in protecting aginst interleukin-1β (IL-1β) -induced rat primary chondrocytes injuries, focusing on the wingless/integrated (Wnt)/β-catenin pathway.

    Methods: Rat primary chondrocytes isolated from SD rats (4-week-old) were treated with IL-1β to establish an OA model in vitro. Cell viability, lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) generation, lipid peroxide (malondialdehyde (MDA)) content, and antioxidant enzyme (superoxide dismutase (SOD)) activity were assessed by commercial kits. Cell apoptosis was detected by flow cytometry. The protein expression were determined by western blotting. The inflammatory factors levels were measured by enzyme-linked immunosorbent assay (ELISA).

    Results: ART significantly increased cell viability, decreased LDH release, and lowered apoptosis comprising apoptosis rate, caspase-3 activity and anti-apoptotic protein (Bax)/pro-apoptotic protein (Bcl-2) ratio in IL-1β-treated rat primary chondrocytes. Additionally, ART suppressed Wnt3a/β-catenin pathway by decreasing Wnt3a/β-catenin, cyclin D1, and c-Myc expressions in IL-1β-exposed rat primary chondrocytes. Furthermore, LiCl, an activator of the Wnt3a/β-catenin pathway, remarkably blocked the beneficial effects of ART during IL-1β injury. In addition, ART attenuated IL-1β-stimulated oxidative stress by reducing ROS generation and MDA content and increasing antioxidant enzyme SOD activity, while these functions of ART were blocked by LiCl. Also, LiCl reversed the anti-inflammatory activity of ART during IL-1β stimulation as illustrated by the increased in nitric oxide level and pro-inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) secretion in rat primary chondrocytes.

    Conclusions: These findings demonstrated that ART attenuates apoptosis, oxidative stress and inflammation through suppressing the Wnt3a/β-catenin pathway in IL-1β-treated chondrocytes.

  • Article
    Xin Ma, Zi-Qiong Li, Man Wang, Zhi-Yuan Wang, Li Gou, Wen-Jie Kong, Wei-Dong Liu, Yang-Yang Zhao, Mukeremu Yimingniyazi, Feng Gao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3275-3282. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.323
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    Background: Dysregulated ubiquitination may contribute to the inflammation process in ulcerative colitis (UC). Genome-wide association studies indicate the association between ubiquitin-specific peptidases 3 (USP3) and UC. This study investigated the role of USP3 in macrophage activation in UC.

    Methods: The relative USP3 expression was assayed in the peripheral blood mononuclear cells (PBMCs) derived from UC patients and healthy volunteers or bone marrow-derived macrophages (BMDMs) stimulated with lipopolysaccharide (LPS). Myeloid cell-conditional USP3 transgenic (USP3-Tg) mice and wild type mice were treated with 3% dextran sulfate sodium for five successive days to induce colitis, and the relevant pro-inflammatory cytokines were detected in LPS or cytosine guanosine dinucleotide (CpG) stimulated BMDMs.

    Results: Down-regulated USP3 was observed in UC patients (p < 0.005) and LPS stimulated BMDMs (p < 0.05). USP3-Tg mice demonstrated alleviated colitis symptoms, including less weight loss (all p < 0.05 from day 2), better survival (p < 0.01), lower intestinal bleeding (all p < 0.05 from day 4), and longer large intestine length (p < 0.05). On the other hand, diminished nitric oxide synthase 2 (NOS2) (p < 0.05), interleukin (IL)-6 (p < 0.01), and tumor necrosis factor (TNF) expression (p < 0.05) were detected in USP3-Tg mice. Mechanically, USP3 directly bound with transforming growth factor β-activated kinase 1 (TAK1) to deubiquitinate TAK1 and inhibited downstream nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase signals.

    Conclusions: USP3 can function as deubiquitinase to promote the activation of TAK1 in macrophages to impair the inflammatory responses in colitis.

  • Article
    Yiting Jiang, Yuane Lian, Hu Chen, Jianping Huang, Shihan Zhang, Yinghong Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3283-3287. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.324
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    Objective: The purpose of this study was to determine the expressions of programmed death ligand-1 (PD-L1) and nucleophosmin (NPM1) in triple-negative breast cancer (TNBC) tissues, and their relevance and clinical significance.

    Methods: Seventy pathologically-confirmed TNBC tissue specimens were used in this study. The expressions of PD-L1 and NPM1 in TNBC tissues were determined using immunohistochemistry (streptavidin-peroxidase). The association between expressions of PD-L1 and NPM1 and clinicopathological parameters was investigated. The correlation between the two markers was analyzed using Pearson correlation coefficient, and Kaplan-Meier survival curves were generated.

    Results: The positive expression rates of PD-L1 and NPM1 in 70 TNBC tissue specimens were 54.29 and 51.43%, respectively. Tumor tissue differentiation was positively correlated with positive expressions of PD-L1 and NPM1 (r = 0.248, p = 0.032). Participants with PD-L1-positive, NPM1-positive, and PD-L1 and NPM1 co-positive expressions showed worse prognosis than those with negative expressions. Moreover, PD-L1-positive expression was identified as an independent risk factor for prognosis of TNBC in patients.

    Conclusions: PD-L1 and NPM1 may be involved in the pathogenesis of TNBC. Therefore, their expressions may be helpful for predicting the prognosis of TNBC in patients.

  • Article
    Ling Lin, Youwen Xu, Hongfei Ge, Susu He, Peng Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3289-3298. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.325
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    Aim: The crucial impacts of chromodomain helicase DNA binding protein 4 (CHD4) upon repressing apoptosis and programmed cell death and promoting cancer development have been widely reported. To further complement the findings, this study investigates the apoptosis-modulating role of CHD4 in lung adenocarcinoma (LAC).

    Methods: Quantitative reverse transcription polymerase chain reaction was used to detect the expression of CHD4 and plant homeodomain finger protein 6 (PHF6) in lung cancer tissues and LAC cells. After LAC cells (A549 and Calu-3) transfected with small interfering RNA for PHF6 (si-PHF6) or CHD4 overexpression plasmid, the apoptosis, cell cycle transition and colony formation were examined through functional analyses including flow cytometry and colony formation assays.

    Results: CHD4 and PHF6 expressions were higher in lung cancer tissues than in matched adjacent normal tissues (p < 0.001). Silencing of PHF6 in LAC cells enhanced LAC cell apoptosis and inhibited cell cycle transition and proliferation (p < 0.001). The overexpression of CHD4 increased the PHF6 level and reversed the impact of PHF6 silencing in LAC cells (p < 0.001).

    Conclusions: CHD4 promotes the proliferation of LAC cells and suppresses their apoptosis by elevating the levels of PHF6.

  • Article
    Wenyan Peng, Liwen He, Xiaoyi Li, Qiuju Yin, Shiyou Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3299-3306. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.326
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    Objective: Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and is accompanied by ocular symptoms. We aimed to compare the pharmacokinetics and pharmacodynamics of Cyclosporine A after a single administration in rabbits with 0.05% Cyclosporine A Ophthalmic Gel or 0.05% Restasis Ophthalmic Emulsion (control group).

    Methods: A total of 162 rabbits were randomly divided into Cyclosporine A (0.05%) Ophthalmic Gel (CsA gel) group or cyclosporine A (0.05%) ophthalmic emulsion (Restasis Ophthalmic Emulsion) group. Pharmacokinetic and pharmacodynamics studies were performed.

    Results: CsA gel administration resulted in similar Tmax and increased CsA concentration and concentration (Cmax) in tear, conjunctiva, and cornea compared with Restasis after a single dose administrated to the ocular surface. The area under the curve (AUC)0–96 h in the cornea (15,966.17 vs. 2537.92 h*ng/mL, p = 0.000), conjunctiva (9737.22 vs. 3147.99 h*ng/mL, p = 0.000), and tear (5801.12 vs. 3324.62 h*ng/mL, p = 0.042) were significantly higher in CsA gel group than Restasis group. For the pharmacodynamic study, Schirmer tests showed tear secretion was significantly increased after CsA administration with comparable effect in both groups (p > 0.05).

    Conclusions: CsA gel delivered a higher CsA concentration (Cmax) to the rabbit cornea, conjunctiva, and tear, as well as a better exposition AUC compared to Restasis, and demonstrate a comparable pharmacodynamics effect as measured by Schirmer test, no CsA exposure to systemic circulation after administration.

  • Article
    Cheng Zhu, Xiaofeng Wu, Jian Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3307-3314. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.327
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    Background: Previous studies have identified the role of Runt-related transcription factor 1 (RUNX1) in enhancing bone formation by promoting both chondrogenesis and osteogenesis. However, its precise function in juvenile ischemic osteonecrosis (JIO) remains unclear and needs more comprehensive investigation. This current research aims to determine the influence of RUNX1 and the mechanisms on JIO.

    Methods: Immature C57BL/6 male mice were randomly divided into 4 groups: the Sham, the Osteonecrosis, the Osteonecrosis+negative control (NC), and the Osteonecrosis+RUNX1 groups. Mice in Sham group underwent a sham operation. In Osteonecrosis group, JIO mouse model was established. In Osteonecrosis+NC or Osteonecrosis+RUNX1 group, JIO mouse model was treated with empty lentivirus or RUNX1 overexpression lentivirus. The femoral head tissues of the JIO mice were then evaluated for histopathological changes through hematoxylin-eosin staining. Additionally, the articular chondrocyte necrosis and glycosaminoglycan accumulation in the articular cartilage were examined using Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining and safranin O-fast green staining. The expressions of proteins related to the nuclear factor-kappa B (NF-κB)/interleukin 6 (IL-6) signaling and related to bone remodeling and resorption in the femoral head tissues of the JIO mice were quantified by western blot.

    Results: Our findings demonstrate that long-term treatment with RUNX1 alleviated femur osteonecrosis in JIO mice. The same treatment relieved articular chondrocyte necrosis and enhanced glycosaminoglycan accumulation in the articular cartilage (p < 0.01). Significantly, treatment with RUNX1 impeded the activation of NF-κB/IL-6 signaling, upregulated the expression of bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF), and downregulated the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios in the femoral head tissues of the JIO mice (p < 0.001).

    Conclusions: RUNX1 blocked NF-κB/IL-6 signaling to promote bone remodeling and suppress the bone resorption in JIO mice. These findings provide a new theoretical framework for further research and potential therapeutic strategies in JIO treatment.

  • Article
    Ye-ling Yang, Xiao-Hong He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3315-3320. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.328
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    Objective: The current study was undertaken to provide a scientific basis for the prevention and control of nosocomial infections by monitoring multi-drug-resistant bacterial infections and understanding changes in colonization trends.

    Methods: A retrospective analysis of clinical specimens from patients with multiple types of infections treated in our hospital from January 2019 to December 2021 was carried out. The samples were incubated and isolated, followed by bacterial identification using an identification instrument, and analysis of trends in distribution and variation.

    Results: A total of 1849 strains of bacteria of the same genus were isolated from hospital specimens collected from 2019 to 2021. A total of 103 strains of multi-drug resistant bacteria were detected, accounting for 5.57% of all strains. The multi-drug-resistant bacteria comprised 2 strains of Escherichia coli (E. coli), 13 strains of methicillin-resistant Staphylococcus aureus (MRSA), 10 strains of Klebsiella pneumoniae (K. pneumoniae), 15 strains of multidrug-resistant Acinetobacter baumannii (MDR-AB), and 63 strains of multidrug-resistant Pseudomonas aeruginosa (MDR-PA). The MDR-AB accounted for the largest proportion of multi-drug-resistant bacteria (61.17%), followed by MDR-AB (14.56%), MRSA (12.62%), K. pneumoniae (9.71%), and E. coli (1.94%). The major multi-drug resistant strains detected were from sputum specimens (77.67%), urine specimens (13.59%), secretions (4.85%), and pus and catheters (0.97%). The department with the highest level of multi-drug resistant strains was Respiratory Medicine (25.24%), followed by the intensive care unit (ICU) (22.33%) and Neurosurgery (21.36%).

    Conclusions: These results indicate that analysis of the types and characteristics of multi-drug resistant bacterial infections in our hospital, and implementation of targeted preventive and control measures will provide important guidelines for clinical care.

  • Article
    Rustam Ekbbal, Mohammad Salman Akhtar, Waleed Mohammed Al-Shaqha, Yasheshwar, Santosh Kumar, Aakash Kumar Jaiswal, Mansi Aggarwal, Dinesh Kumar Yadav, Mojahid ul Islam, Gaurav
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3321-3331. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.329
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    Background: Exploration of multi-targeted and therapeutic approaches is critically needed to obviate the therapeutic berries for the treatment of acute or chronic diseases. Interleukin 2 (IL2), Proto-oncogene c-Fos (FOS) and poly (ADP-ribose) glycohydrolase (PARG) are considerable bioregulators in diabetes and associated complications via blocking pancreatic β cells destruction, increasing insulin sensitivity and rate of glycolysis, electron transport, and adenosine triphosphate (ATP) formation. Taking these factors into consideration, the present study is associated to explore the multi-mechanistic and therapeutic effects of rosmarinic acid for applications of diabetes and associated complications.

    Methods: Network biology and poly-pharmacology studies were conducted for the evaluation of the therapeutic effect of rosmarinic acid in the alleviation of diabetes and associated complication. Gene ontology analysis was performed to determine the pathophysiological targets genes and rosmarinic acid in diabetes. In-silico docking analysis was performed to determine the molecular interaction and binding ability of proteins with rosmarinic acid to explore its biomolecular approaches involved in diabetes.

    Results: The outcome of the study showed that rosmarinic acid exhibits a multi-targeted and therapeutic effect in the alleviation of diabetes via regulation of hyperinsulinism, insulin resistance, lipoatrophic diabetes mellitus, lipoatrophy, liver failure, liver cirrhosis, oxidative and inflammatory stress, etc., it regulates the expression of genes such as IL2, lymphocyte-specific protein tyrosine kinase (LCK), an inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB), FOS, C-C motif chemokine receptor 3 (CCR3), Protein C Receptor (PROCR) and PARG that are involved in the pathogenesis of diabetes and associated complication. In-silico docking outcomes revealed that rosmarinic acid is the most potent active therapeutic agent that significantly interacts with IL2 protein and may regulate interleukins-associated inflammatory damage.

    Conclusions: It can be demonstrated that rosmarinic acid reduces oxidative and inflammatory damage, hyperinsulinism, insulin resistance, lipoatrophic diabetes mellitus, lipoatrophy, etc., via regulation of IL2, FOS and PARG genomic expression and attenuates diabetes and associated complications.

  • Article
    Haoyu Yuan, Baohua Wang, Mengxue Sun, Saimei Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3333-3342. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.330
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    Background: Diabetic cardiomyopathy (DCM) is becoming a proverbial diabetes mellitus-induced clinical entity due to the increased risk of heart failure. Glucolipotoxicity is a key feature of DCM. A recent study corroborates the critical roles of amentoflavone in cardiac injury. However, its function in DCM remains unclear.

    Purpose: To explore the role of amentoflavone in DCM.

    Methods: Cardiomyocytes were treated with amentoflavone under exposure to high glucose and high palmitic acid to mimic glucolipotoxicity environment of DCM. Cells were divided into control groups, glucolipotoxicity groups, and glucolipotoxicity and amentoflavone groups at the indicated doses. Then, cell viability, apoptosis and caspase-3 activity were determined using the commercial kits. The effects on glucolipotoxicity-induced oxidative damage, insulin resistance and fibrosis-related protein expression were detected.

    Results: Amentoflavone had little cytotoxicity to rat H9C2 cardiomyocytes (p > 0.05). Subsequently, cardiomyocytes were exposed to glucolipotoxicity conditions and confirmed that amentoflavone reversed glucolipotoxicity-inhibited cell viability (p < 0.05) and reduced cell apoptosis (p < 0.05) and activity of caspase-3 (p < 0.05). Amentoflavone inhibited glucolipotoxicity-triggered oxidative stress insult by increasing levels of antioxidant superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px), and decreasing contents of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) (all p < 0.05). Furthermore, glucolipotoxicity restrained insulin-stimulated glucose uptake and glucose transporter 4 (Glut4) expression (p < 0.05), which were reversed after amentoflavone treatment (p < 0.05). Concomitantly, amentoflavone suppressed glucolipotoxicity-elevated transcripts and protein expression of fibrosis-related collagen I (p < 0.05) and fibronectin (p < 0.05). Mechanistically, glucolipotoxicity inhibited the activation of the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling (p < 0.05), which was offset following amentoflavone treatment (p < 0.05). Moreover, blockage of the AMPK pathway overturned the protective effects of amentoflavone on glucolipotoxicity-induced oxidative injury (p < 0.05), insulin resistance (p < 0.05) and fibrosis protein expression (p < 0.05).

    Conclusions: Amentoflavone may protect against glucolipotoxicity-evoked cardiomyocyte oxidative damage, insulin resistance and fibrosis by reactivating the AMPK/Nrf2 signaling. Thus, this study may support amentoflavone as a promising therapeutic agent for DCM.

  • Article
    Yanbo Zhang, Liang Yan, Xiwen Gao, Hua Zhao, Jianguo Wang, Bin He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3343-3350. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.331
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    Background: Alternatively activated type 2 (M2) macrophage significantly regulates multiple stages of malignant progression, including cancer cell proliferation, drug resistance and immunosuppression. The role of many key receptors including macrophage scavenger receptor 1 (MSR1) in the macrophage polarization process is unclear. This study assessed the effect of MSR1 on M2 type polarization of macrophage and malignant state in lung cancer cells.

    Methods: The M0 macrophage model was constructed with the human monocytic leukemia cells (THP-1) treated with Phorbol-12-myristate-13-acetate (PMA). The M2 polarization of macrophages was obtained through M0 macrophages treated with interleukin-4 (IL-4) and IL-13. MSR1 knockdown macrophage model was established. MSR1 expression was identified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence assays in macrophages. The key genes cluster of differentiation 206 (CD206), CD163 and C-C motif chemokine ligand 22 (CCL22) in macrophages were determined by RT-qPCR assay in macrophages. The key proteins CD68 and CD163 in macrophages were determined by immunofluorescence assay. Enzyme linked immunosorbent assay (ELISA) was also used to test IL-10 and CCL18 levels in the macrophage culture. Cisplatin sensitivity tests were performed on A549 and H1975 cells treated with gradient drug dose (0, 1, 2, 4, 8, 16 μM cisplatin). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and transwell assays were used to verify proliferation and migration activity of A549 and H1975 cells in vitro.

    Results: MSR1 levels in M2 macrophage were significantly higher than in M0 macrophage (p < 0.05). Decreased MSR1 expression could restrain M2 macrophage polarization (p < 0.05). Mechanistic research determined that MSR1 deficient M2 macrophages could inhibit the abilities to proliferate and metastasize of H1975 and A549 cells (p < 0.05). Notably, the absence of MSR1 in M2 macrophages significantly reversed the cisplatin sensitivity of cancer cells.

    Conclusions: Our experiments have identified a novel mechanism of M2 type polarization of macrophage during the development of lung cancer. MSR1 can be a potential immunotherapeutic target.

  • Article
    Li Song, Qingrong Xu, Ying Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3351-3361. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.332
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    Background: To construct a signature of methylated sites and subtypes of allergic asthma in children.

    Methods: We identified differentially expressed genes (DEGs) and methylated probes (DEMPs) in children with allergic asthma using the Gene Expression Omnibus database. Weighted gene co-expression network analysis was used to identify key DEMPs and their corresponding genes. Functional analyses were conducted to determine the functions of the DEGs and DEMPs. Subtype analysis was used to explore the clinical features of allergic asthma. Meanwhile, the DEGs were intersected with DEMP corresponding genes, and Least Absolute Shrinkage and Selection Operator (LASSO) was further used to screen the optimal methylated probes to construct a risk score signature. A receiver operating characteristic curve was used to evaluate the performance of the risk score.

    Results: In total, 438 DEGs and 1216 key DEMPs (corresponding to 927 genes) were identified. These DEGs and DEMP-corresponding genes were enriched in pathways and functions related to allergic asthmatic progression, such as natural killer cell-mediated cytotoxicity, defense response to virus, lymphocyte-mediated immunity, and cell adhesion-related biological processes. Subtypes classified based on methylated probes could better reflect the clinical characteristics of asthma. Cluster 1 showed mainly hypomethylation, while cluster 2 showed mainly hypermethylation. A significant correlation was found between our subtypes and previously identified subtypes: cluster 1 contained more PC20 subtypes, whereas cluster 2 contained more lung function subtypes. We identified 14 DEMPs in children with allergic asthma after LASSO regression, and the risk score showed strong efficacy (area under the receiver operating characteristic curve = 0.811) in the diagnosis of allergic asthma.

    Conclusions: The DEGs and DEMPs identified in this study are related to the progression of allergic asthma. In addition, our results provide a diagnostic signature for allergic asthma, which was demonstrated to be effective in the clinical diagnosis of the disease.

  • Article
    Yingqiao Lou, Dandan Wang, Lingling Gu, Wendan Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3363-3373. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.333
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    Background: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable condition that affects many people due to poor management. Our systematic review and meta-analysis aims to investigate the safety and efficacy of active cycle of breathing techniques (ACBT) among COPD patients, as there are still many unresolved issues regarding its use. The primary objective of this study is to evaluate the efficacy and safety of ACBT as a treatment for COPD patients.

    Methods: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and searched for randomized controlled trials (RCTs) from electronic databases such as EMBASE, Web of Science, PubMed, and CINAHL. The Cochrane Collaboration tool was used to assess the risk of bias in each study. The inclusion criteria comprised COPD patients, including those with acute exacerbation, interventions related to ACBT technology, and those reporting sputum production. Only RCTs were considered, even if the intervention was combined with other treatments. Conversely, non-RCTs, systematic reviews, meta-analyses, case studies, editorials, and journals were excluded. The Review Manager software (version 5.4.1) was used for statistical analysis, which included calculating the 95% confidence intervals (CI) and the odds ratio (OR) and measuring heterogeneity.

    Results: Eight randomized controlled trials with 390 participants were included in this meta-analysis. Each study had control and intervention groups comprising elderly and middle-aged individuals. The results showed that ACBT did not statistically significantly improve forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) compared to standard care, with low heterogeneity [df = 1, 95% CI: 0.66 to 1.53, I2 = 0]. The use of ACBT technology in combination with postural drainage did not improve SpO₂ among COPD patients, and there was no effect on sputum production with low heterogeneity [df = 2, 95% CI: 0.74 to 1.35, I2 = 0%, p > 0.05].

    Conclusions: The ACBT intervention did not improve cough efficiency and sputum production among COPD patients. This study was limited by incomplete data, inconsistencies in the control group, underrepresentation of the global population, analysis of short-term effects of COPD, and a high risk of publication bias in the included studies. Therefore, the findings on the effects of ACBT on COPD were inconclusive and found no significant improvements in the condition of patients. Future studies should thoroughly analyze the effects of ACBT across multi-ethnic populations and its effects on musculoskeletal muscles.

  • Article
    Yi Peng, Chongyuan He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3375-3383. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.334
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    Background: Previous reports have shown that partner of NOB1 homolog (PNO1) is associated with several cancers, but the role of PNO1 in clear cell renal cell carcinoma (ccRCC) is unknown. We aimed to investigate the biological significance of PNO1 in ccRCC and the associated molecular mechanisms.

    Methods: PNO1 levels in tumor tissue, as well as the correlation of PNO1 protein expression with clinicopathological indexes. Loss-of-function assays were performed to examine the significance of PNO1 in ccRCC. Protein expression was detected by western blotting and immunofluorescence.

    Results: We revealed that the relative levels of PNO1 in ccRCC tissues were upregulated. PNO1 levels were associated with sex, stage, pathological grade, and metastatic status of ccRCC patients. Kaplan–Meier analyses revealed that suppressed PNO1 levels correlated with better prognostic outcomes. PNO1 knockdown suppressed in vitro cancer cell proliferation and migration. Moreover, PNO1 induced epithelial-mesenchymal transition (EMT) by upregulating vimentin and N-cadherin and downregulating E-cadherin. PNO1 suppression dysregulated cell oncologic metabolism by suppressing focal adhesion proteins.

    Conclusions: In summary, PNO1 was elevated in ccRCC and correlated with ccRCC progression.

  • Article
    Xue Han, Yan Li, Jianrong Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3385-3391. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.335
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    Background: Sepsis is an abnormal immune response to infection with unknown pathogenesis, seeing unacceptably mortality. Identifying biomarkers could help to diagnose sepsis and monitor its progress.

    Objective: We aimed to assess the correlation between plasminogen activator inhibitor-1 (PAI-1) levels, and the severity of sepsis and mortality.

    Methods: PubMed, Cochrane Library, and Excerpta Medica dataBASE (EMBASE) databases were searched based on “plasminogen activator inhibitor-1/PAI-1” and “sepsis”. Weighted mean difference (WMD) with its 95% confidence intervals (CIs) were computed on the eligible trials.

    Results: 11 trials encompassing 1606 sepsis patients were included. The PAI-1 levels were significantly higher in patients with sepsis-related death than in survivors (p < 0.001) and significantly higher in severe sepsis patients than in nonsevere patients (p = 0.001).

    Conclusions: PAI-1 could be considered a pivotal biomarker for the severity of sepsis and mortality.

  • Article
    Aohan Mei, Yini Peng, Xiaowei Liu, Zhengqian Chen, Yiye Zhang, Ruigang Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3393-3401. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.336
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    Objective: Intervertebral disc degeneration (IVDD) causes a variety of symptoms, including low back pain, herniated discs, and spinal stenosis, which impose high social and economic costs. We established a rat model of IVDD and then explored the effect of swimming exercise in IVDD rats. We aimed to investigate the role of the Wingless-Type mouse mammary tumor virus (MMTV) Integration Site Family (Wnt)/β-catenin pathway in this process.

    Methods: 45 three-month-old Sprague-Dawley (SD) rats were randomly divided into three groups: the Control group (267 ± 11 g), the Model group (260 ± 12 g), and the Model+Swimming group (262 ± 13 g). The Control group received no treatment; the Model group underwent surgery to establish an IVDD model; the rats in the Model+Swimming group received swimming training after the IVDD model was established. The intervertebral disc tissues of rats in each group were evaluated for degeneration using hematoxylin-eosin (H&E) staining, safranin O-fast green (SFG) staining, immunohistochemistry, real-time quantitative Polymerase Chain Reaction (RT-qPCR), and western blotting assays. The study assessed the effect of swimming training on IVDD and explored the expression of Wnt/β-catenin pathway-related proteins.

    Results: Based on H&E and SFG staining, the structure of intervertebral disc (IVD) was destroyed and the nucleus pulposus (NP) cells were lost in the Model group rats. However, swimming training could improve the damage to the IVD structure and loss of NP cells. Immunohistochemical results showed that the expressions of β-catenin and interleukin-1beta (Il-1β) in the IVD tissue of the Model group were higher than that in the Control group (p < 0.01). Conversely, the expressions of β-catenin and Il-1β in the IVD tissue of the Model+Swimming group were lower than that in the Model group (p < 0.01). RT-qPCR and western blot analyses showed that compared with the Control group, the expressions of Aggrecan and Collagen II proteins and messager RNAs (mRNAs) in the IVD of the Model group were down-regulated (p < 0.01), while the expressions of Il-1β, Wnt-1, and β-catenin proteins and mRNAs were up-regulated, which was statistically significant. Compared with the Model group, the expressions of Aggrecan and Collagen II in the IVD tissue of the Model+Swimming group were up-regulated, while the expressions of Wingless-type mouse mammary tumor virus (MMTV) integration site family member 1 (Wnt-1), β-catenin, and Il-1β were down-regulated. These findings indicated that swimming training could reduce the expression of inflammatory factors, improve the inflammation of degenerative IVDs in rats and promote the recovery of IVDD.

    Conclusions: Swimming training can improve the IVDD in rats and has positive application values.

  • Article
    Qimi Zheng, Chunxiao Yan, Nana Lv, Hengping Pu, Fatemeh Mollaamin, Majid Monajjemi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(6): 3403-3416. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.337
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    Background: Omicron currently accounts for over 85% of the pandemic cases in the world. Recently, the results of researches have exhibited that Omicron sub-lineages and B lineage (BA).4 and BA.5, evaluated to BA.1, BA.1.1 and BA.2, deserted neutralization from sera of triple vaccinated particulars to a bigger extension. The purpose of this study is because the Omicron variant is the most recent variant of concern (VOC) to emerge and was recognized by the World Health Organization (WHO). The Omicron lineage is phylogenetically distinct from earlier variants. These variants of Omicron threaten many lives, particularly among the unvaccinated, due to its higher transmissibility, pathogenicity. This study helps to realize the essential concepts of the Omicron variant, including its history, genome, transmissibility, clinical manifestations, diagnosis, management, and the effectiveness of existing vaccines against this VOC. Asafoetida (Ferula asafoetida) is known to possess antifungal, anti-diabetic, anti-inflammatory, anti-mutagenic and antiviral activities particularly anti coronavirus. Several studies investigated the effects of F. Asafoetida extract on the contractile responses induced by acetylcholine, methacholine, histamine and potassium chloride (KCl) on different smooth muscles.

    Methods: The method of this work basically is based on molecular mechanics with quantum approach which is known as quantum mechanics/molecular mechanics (QM/MM) method. In addition, for calculating the interaction energies between ligands and enzymes in the Nano-carriers systems containing carbon nanotubes with functional nanostructures, we used docking simulation via using the Gaussian, HyperChem, Chemoffice, Charmm, Autodock, and Schrodinger packages. In this research, asafoetida (asafoetida is also known colloquially as “devil's dung" in English and similar names in most languages of the other countries) as a medicinal plant can be applied in treatment for Omicron sub-units BA.4 and BA.5 through adsorbing of its effective compound of ferulic acid on the surface of (m, m) armchair single-walled carbon nanotube. In addition, we simulated a drug delivery density functional theory (DFT) calculation (QM/MM methods).

    Results: In fact, the achieved results have represented that the feasibility of using (m, m) armchair single-walled carbon nanotube (SWCNT) (m = 6, 5) and ferulic acid are suitable in such drug delivery system due to physico-chemical properties of nuclear magnetic resonance (NMR), infrared (IR) and ultraviolet-visible (UV-VIS) spectroscopy.

    Conclusions: Asafoetida has attracted much attention for the clinical treatment of Omicron subvariants BA.4 and BA.5 through adsorption of its effective compound of ferulic acid on the surface of (6,6) armchair SWCNT which introduces an efficient drug delivery system though charge distribution, NMR and IR spectroscopy on the optimized structure. Moreover, the lowering gap energies (∆E = ELUMO – EHOMO) has illustrated the charge transfer interactions taking place within ferulic acid.