20 May 2023, Volume 37 Issue 5

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  • Review
    Peng-yu Mai, Yue Jiang, Xiao-na Chen, Ming-shan Fu, Ming-kun Liang, Min Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2327-2337. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.229
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    Background: As a medical specialty, andrology deals with all aspects of male health, including various diseases of the reproductive system and specific components of the urinary system. With the development of the profession and increase in the number of publications in andrology, it is important to identify the most important and prominent manuscripts that have affected research and practice in clinical settings over the past nearly 30 years.

    Methods: Published studies on andrology from 1992 to 2020 were retrieved from the Web of Science Core Collection. In this study, CiteSpace was used to visualize and analyze the productive journals, countries, institutions, contributing authors, keywords, and research trends.

    Results: A total of 6109 articles were retrieved from the database. CiteSpace was used to examine the dynamics and the leading and collaborating institutions in andrology since 1992, to provide references for novel technologies and rigorous studies. There was a substantial increase in the number of papers in andrology every year. The author who published the most was A. Agarwal. China had the greatest number of papers and total citation frequency. Revista Internacional de Andrologia published the most papers in andrology. Keyword analyses showed that spermatogenesis, sperm motility, and impotence were the most studied topics in this field, thus more studies in these areas are predicted in the future.

    Conclusions: CiteSpace was used to characterize the dynamics and leading and collaborating institutions in andrology since 1992, providing references for novel technologies and research.

  • Review
    Florin Onisor, Andra Piciu, Simion Bran, Alexandru Mester
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2339-2343. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.230
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    Background: Oral lichen planus (OLP) is a chronic inflammatory disease associated with T-cell-mediated immunological dysfunction. Hepatitis C virus (HCV) infection has been related to OLP. The aim of this systematic review was to assess the efficiency of direct-acting antivirals (DAA) in patients with HCV on the oral lichen planus.

    Methods: This systematic review was conducted under the recommendations of Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA guidelines. PubMed, Scopus and Web of Science databases were searched up to 30 December 2022. Specific keywords were used to search the electronic databases. Titles and abstracts were firstly screened for eligibility. Then, full-text articles for eligible studies were examined. In the end, studies which respected the inclusion criteria were considered. Risk of bias was assessed according to The Strengthening the Reporting of Observational studies in Epidemiology Statement (STROBE).

    Results: Types of OLP presented were erosive, reticular or mixed. OLP localization was on buccal mucosa (uni/bilateral), sublingual mucosa, tongue, or lower lip. At 24 weeks, most of the patients showed OLP disappearance with no adverse events; only 1 patient developed oral squamous cell carcinoma of the tongue. HCV elimination via DAA therapy improved also OLP present in those patients and reduced the periodontal pathogens.

    Conclusions: The use of DAA in patients with HCV and OLP might be a promising treatment in both diseases without using an adjuvant therapy.

  • Review
    Erick Martínez-Herrera, Gabriela Moreno-Coutiño, Claudia Erika Fuentes-Venado, Rigoberto Hernández-Castro, Roberto Arenas, Rodolfo Pinto-Almazán, Carmen Rodríguez-Cerdeira
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2345-2356. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.231
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    Background: Trichophyton rubrum (T. rubrum) is the most common etiological agent of human dermatophytosis worldwide. T. rubrum has various phenotypic virulence factors that allow the infection to establish and evolve. Several enzymes, including keratinase, protease, lipase, deoxyribonuclease, elastase, and collagenase, are some of these virulence factors. This systematic review aimed to determine the main phenotypic virulence factors in T. rubrum.

    Methods: We performed a search in the databases PubMed, Scopus, and Scielo, including the words T. rubrum, virulence factors, lipase, phospholipase, keratinase, protease, deoxyribonuclease, elastase, collagenase, and biofilms.

    Results: We found 98 articles in the search databases. Twenty-eight were eliminated, as the information did not correspond to our purpose, and five articles were not retrieved. Thus, in the end, we included 65 papers. The articles highlighted many virulence factors associated with T. rubrum that could facilitate attachment, germination, formation of infection structures, penetration, and host colonization.

    Conclusions: Tolerance to high-stress environments and resistance to host defenses were reported. Some of the virulence factors found in the review were subtilisins, metalloprotease, oxidative stress fungal defenses (Catalases, Cu/Zn superoxide dismutase), hydrophobin, hydrolases, peptidase, chitinase, glucanase scw1, glutamate 5-kinase, GCN5-related N-acetyltransferase (GNAT family), heat shock proteins, LysM domains, other cell wall-associated, and biofilms. The review provided evident pathogenic mechanisms associated with T. rubrum ensuring its sustenance and survival.

  • Review
    Davide Gerardi, Nicolò Santostasi, Diana Torge, Fabiola Rinaldi, Sara Bernardi, Serena Bianchi, Maurizio Piattelli, Giuseppe Varvara
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2357-2369. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.232
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    Background: Platelet-rich Fibrin (PRF) represents a type of autologous biomaterial investigated through the years by in vitro and in vivo studies to assess the real inductivity properties, presumed due to the growth factors presence. This systematic review aims to evaluate the efficacy of PRF in sinus lift procedures, compared and/or in addition to Deproteinized Bovine Bone Materials (DBBM) according to emerging scientific evidence.

    Materials and Methods: Selected databases were PubMed, Scopus, and Cochrane Library. The search strategy included the following terms: “PRF”, “platelet concentrate”, “autologous platelet concentrate”, “platelet-rich fibrin”, “bone grafts” or “DBBM”, “xenografts” or “Bio-Oss”, “maxillary sinus lift”, “maxillary sinus elevation”, “maxillary sinus augmentation”. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used.

    Results: Four studies were included in the systematic review, evaluating clinical, histological, histomorphometric, and radiological data. Three of four studies reported no statistically significant differences between the test and control groups. In one study, the presence of Leukocyte-Platelet Rich Fibrin (L-PRF) could allow earlier implant placement, achieving the same clinical, histological, histomorphometric, and radiological results of bone regeneration at an earlier time, compared to the DBBM used alone.

    Conclusions: The regenerative potential of PRF associated with DBBM resulted in a valid alternative in the bone regeneration procedure to DBBM grafts. Further new studies are needed, with more rigid protocols, to investigate the potential of platelet concentrates in sinus lift techniques and to evaluate the real inductivity properties of DBBM.

  • Article
    Zhe Kai, Zhuming Chen, Huaiwen Xu, Ya Chen, Shaowen Liu, Jian Fang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2371-2376. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.233
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    Objective: To compare and analyze clinical efficacy and inflammation status of elderly patients with colon cancer (CC) treated with laparoscopy and those treated with traditional open surgery.

    Methods: This study was designed as a retrospective trial. A total of 128 elderly patients with CC diagnosed in our hospital from January 2020 to December 2021 who were scheduled for surgical treatment were recruited as initial subjects. After excluding those who did not meet the inclusion criteria, 122 patients were finally enrolled in the study. All patients were assigned to two groups: Experimental group (n = 62) and traditional group (n = 60), based on surgical method used. The traditional group underwent traditional open surgery, while the observation group received laparoscopic surgery. The general data of all patients were collected, and the perioperative indices, clinical efficacy, changes in inflammatory factor levels, and occurrence of complications the two groups were compared.

    Results: The size of surgical incisions, intraoperative blood loss, recovery time of gastrointestinal function, time lapse before eating, time lag before flatulence, time lag before getting out of bed, and hospitalization time were lower in the experimental group than in the traditional group (p > 0.05). The experimental group presented markedly higher total clinical efficiency than the traditional group (p < 0.05). There were no significant differences in levels of inflammatory factors between the two groups before therapy (p > 0.05). However, after therapy, the experimental group presented lower levels of CRP (C-reactive protein), IL-6 (interleukin 6) and TNF-α (tumor necrosis factor-α) levels, and lower incidence of complications than the traditional group (p < 0.05).

    Conclusions: For elderly patients with colon cancer, laparoscopic surgery effectively lowered the levels of inflammatory factors, decreased the probability of complications and provided better safety, thereby offering better clinical efficacy, less trauma and better perioperative conditions than traditional open surgery. Therefore, laparoscopic surgery has highly beneficial potential for clinical application in elderly CC patients.

  • Article
    FangQin Xie, JunRong Li, XiuHui Yang, ZhiFei Chen, HaiRong Zhang, RongDong Huang, KuiCheng Zheng, LiNa Zhang, DongJuan Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2377-2384. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.234
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    Objective: To study the immunogenicity of COVID-19 (Corona Virus Disease 2019) booster vaccines, produced via different technical routes, following the first two doses of inactivated COVID-19 vaccine.

    Methods: A total of 320 healthy subjects, aged 18 to 59 years old, who had already received the first two shots of the inactivated COVID-19 vaccine were recruited. They were randomly divided into four groups (A, B, C, and D), with 80 subjects in each group. These subjects then received a booster dose of the same inactivated COVID-19 vaccine as in the first two shots, or a booster dose of a different inactivated COVID-19 vaccine, adenoviral vector vaccine, and recombinant protein vaccine (CHO cells). Blood samples were collected before the booster immunization and on days 14 and 28 after booster immunization, to determine the level of neutralizing antibodies.

    Results: There was no statistically significant difference between the four groups in age or gender between all four study groups (p > 0.05). All four groups showed a significant increase in COVID neutralizing antibody level on day 14 and day 28 (p < 0.05). Group C and group D showed a significant increase compared with group A or group B (p < 0.05). And, the highest GMT (geometric mean titer) level was observed in group C on day 14 among all four groups and all three time points. The antibody positive conversion rate was 100% on day 28.

    Conclusions: A booster dose of heterologous COVID-19 vaccine six months after the first two shots led to significantly higher immunogenicity than when the same type of vaccine used for basic immunization was used for the booster. Heterologous booster immunization is of high importance for raising the immunization efficiency.

  • Article
    Jie Xu, Na Xiao, Hailang He, Ailing Cao, Xianmei Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2385-2396. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.235
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    Background: Asperuloside has an antitumor effect on various cancers, but its relationship with non-small cell lung cancer (NSCLC) has yet to be established. Hence, the aim of this study was designed to explore the action and mechanism of Asperuloside on NSCLC.

    Methods: After A549 and H226 cells were treated with Asperuloside (1, 2, 3, 4, 5 and 10 mM), transforming growth factor-β1 (TGF-β1) or SB431542 (TGF-β1/Smad signal inhibitor) or not, cell biological behaviors were detected by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), flow cytometry, colony formation, Transwell, and scratch assays. The tumor xenograft model was established in nude mouse, and the size and weight of tumors were measured. The levels of proteins related to epithelial-mesenchymal transition (EMT) and TGF-β1/mothers against decapentaplegic homolog 2 (Smad2) signaling in treated NSCLC cells and mouse tumors were quantified using Western blot.

    Results: Asperuloside significantly dampened the viability as well as abilities to proliferate, invade and migrate, while facilitating apoptosis of A549 and H226 cells, and significantly decreased mouse tumor size and weight. Asperuloside and SB431542 significantly down-regulated the protein levels of TGF-β1, p-Smad2, N-Cadherin and Vimentin, but up-regulated E-Cadherin protein level in treated A549 and H226 cells and mouse tumors. However, TGF-β1 had the opposite effect on NSCLC cells. Besides, the impact of TGF-β1 upon the A549 and H226 cells was inhibited by Asperuloside and SB431542.

    Conclusions: Asperuloside represses the malignant capabilities of NSCLC cells both in vitro and in vivo by inhibiting TGF-β1/Smad2 pathway.

  • Article
    Wei Lv, Jing Li, Qiu Meng, Rui Li, Na Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2397-2404. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.236
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    Background: Long non-coding RNAs (LncRNAs) play an important role in the immune response of T helper-1 (Th1) cells. This study evaluated LncRNA NEAT1 expression in peripheral blood mononuclear cells (PBMCs) and thyroid tissues of Hashimoto's thyroiditis (HT) patients and its correlation with Th1 cell response.

    Methods: LncRNA nuclear enriched abundant transcript 1 (NEAT1) expression, T-box factor expressed in T cells (T-bet) mRNA and interferon-γ (IFN-γ) mRNA in PBMCs from HT patients and healthy population were detected by quantitative realtime reverse transcription polymerase chain reaction (qRT-PCR). The extraction results of Th1 cells from HT patients and healthy population were measured by flow cytometry. si-NC and si-LncRNA NEAT1 were transfected into CD4 helper T cells (CD4+ T) cells to measure the effects of LncRNA NEAT1 on T-bet mRNA and IFN-γ mRNA levels. The levels of necrosis factor alpha (TNF-α), interleukin-2 (IL-2) and IFN-γ in HT patients and healthy population were measured by enzyme linked immunosorbent assay (ELISA). The levels of thyroglobulin antibody (TgAb), anti-thyroid peroxidase antibody (TPOAb) and thyrotropin (TSH) in HT patients and the healthy population were also measured.

    Results: LncRNA NEAT1, T-bet mRNA and IFN-γ mRNA expression were abnormally increased in the PBMCs and thyroid tissue of HT patients compared to healthy population (p < 0.05). Th1 cells number and the expression of Th1 cellrelated transcription factors in HT patients increased abnormally compared to healthy population (p < 0.05), which was enhanced by LncRNA NEAT1, increasing the ability of Th1 cells to secrete inflammatory cytokines and significantly improving TNF-α, IL-2 and IFN-γ levels (p < 0.05). In addition, the TgAb (A), TPOAb (B) and TSH (C) levels in HT patients increased.

    Conclusions: LncRNA NEAT1 can promote Th1 cell response during HT development.

  • Article
    Zonglang Lai, Jing Wang, Na Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2405-2419. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.237
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    Background: The phosphatidylinositol 3 kinase (PI3K) family member phosphatidylinositol-3-kinase regulatory subunit 2 (PIK3R2) is essential for controlling the development, proliferation, survival and angiogenesis of tumor cells. The purpose of this study was to explore the potential value of the PIK3R2 mediating tumor angiogenesis in pan-cancer.

    Methods: The PIK3R2 gene expression patterns and distribution in various tumor tissues as well as in healthy syngeneic normal tissues were analyzed, using Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. COX (proportional hazards model) analysis was used to draw Kaplan–Meier survival curves. A study of the relationship between PIK3R2 and immune infiltration of various tumors was also performed. In addition, the correlations between PIK3R2 and DNA repair genes, microsatellite instability, tumor immunological neoantigens, and DNA methyltransferases were investigated.

    Results: The results demonstrated that PIK3R2 is highly expressed in a variety of cancers and significantly correlated with poor prognosis in tumor patients, particularly in kidney renal clear cell carcinoma (KIRC), where it is closely related to the patients' overall survival (OS) and human immune checkpoints. Gene Set Enrichment Analysis (GSEA) indicated that the expression of PIK3R2 in most tumors has a direct effect on pathways involved in immune and tumor activation.

    Conclusions: Overall, the expressions of PIK3R2 in most cancer tissues are closely associated with poor prognosis in cancer patients as well as immune checkpoint levels. Moreover, the high expression of PIK3R2 gene is correlated with the OS and tumor mutational burden of KIRC patients, and may become an early screening biomarker for KIRC treatment.

  • Article
    Fang Yang, Shuanghai Hu, Mengsi Liao, Jinsong Wu, Ningfang Zhang, Haibo Zhao, Qiaoyun Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2421-2427. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.238
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    Background: Scedosporium/Lomentospora species are filamentous fungi that can cause a wide range of infections, but it is resistant to many clinical antifungal drugs. Therefore, alternative antifungal drugs need to be found.

    Objective: The present investigation endeavored to ascertain the in vitro and in vivo efficacy of chlorhexidine (CHX) and azoles against fungi.

    Methods: The checkerboard method was used to determine the sensitivity of drugs against 16 Scedosporium/Lomentospora strains in in vitro experiments. The combined antifungal effect of CHX with itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) against Scedosporium/Lomentospora species was tested in vivo with Galleria mellonella larvae.

    Results: In vivo tests showed that none of the examined strains was significantly affected by CHX's antifungal properties, but satisfactory synergistic effect was observed in vitro when CHX was combined with ITR, VOR, or POS against 13 (81.25%), 11 (68.75%), and 13 (81.25%) strains, respectively. Moreover, the minimum inhibitory concentration (MIC) ranges of CHX combined with azoles against Scedosporium and Lomentospora decreased significantly (p < 0.05). No antagonism was observed in any combination. Experiments in vivo showed that CHX combined with an azole (except for ITR) significantly increased the survival rate of G. mellonella larvae and considerably reduced the number of fungal clusters in infected tissues.

    Conclusions: The combinations of CHX and azoles enhanced the antimicrobial activity of these agents against Scedosporium/Lomentospora species, indicating potential for preventing azole resistance. However, the in vivo antimicrobial effect of the combination of CHX and ITR did not achieve ideal effects.

  • Article
    Yuliang Xiao, Huifen Ding, Lijuan Wu, Chuqi Xia, Juan Sheng, Fubing Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2429-2437. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.239
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    Background: Although developing serum microRNAs (miRNAs) as noninvasive diagnostic biomarkers for the identification of colorectal adenomatous polyps (CAP) and early-stage colorectal cancer (CRC) is more promising, CAP and CRC serum exosomes miRNAs have more research values. This study was designed to assess the diagnostic and prognostic values of serum exosomal candidate miRNAs as biomarkers of CAP and CRC.

    Methods: Serum and serum exosomes were obtained from 60 CRC patients, 60 CAP patients and 60 healthy controls (HC). Then, the expression of miR-21, miR-31, miR-135b, miR-145 in serum and serum exosomes as well as serum exosomal miR-31 and miR-145 expression in subjects 1 month after surgery was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The correlation of clinicopathological features of CRC with the serum exosomal miR-31 and miR-145 expression was analyzed, and the independent predictors of CRC were analyzed by univariate logistic regression. Receiver operating characteristic (ROC) curves were adopted to examine the diagnostic accuracy of serum exosomal miR-31 and miR-145.

    Results: CAP and CRC patients had elevated serum exosomal miR-31 expression but declined miR-145 expression. The serum exosomal miR-31 and miR-145 expression was affected by tumor diameter, degree of differentiation, TNM (tumor node metastasis) staging, distant metastasis, and lymphatic metastasis. Serum exosomal miR-31 was more specific and sensitive as a diagnostic and prognostic biomarker for CAP and CRC compared with miR-145.

    Conclusions: Therefore, compared with serum exosomal miR-145, serum exosomal miR-31 is a superior diagnostic biomarker for the diagnosis of CAP and CRC.

  • Article
    Li Song, Pei-Jun Wang, Mei-Ping Zhang, Chun-Xiao Ji, Ling Wang, Ying Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2439-2443. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.240
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    Objective: The aim of this study was to investigate the therapeutic effect of rituximab on Epstein–Barr virus (EBV) infection, following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

    Methods: This study involved 10 patients who were diagnosed with EBV viremia after allo-HSCT, treated in Qingdao Central Hospital from January 2015 to June 2017. These patients received rituximab and the therapeutic effect was observed during the follow-up visits.

    Results: Of the 10 patients, 5 patients died after treatment with rituximab for EBV infection after allo-HSCT. Analysis of the 5 expired patients revealed that 4 patients died due to recurrence of the primary disease while 1 patient died of severe pneumonia. The five surviving patients achieved complete remission.

    Conclusions: Early treatment with rituximab was effective in treating EBV infection after allo-HSCT. We recommend that in high-risk patients, EBV levels should be closely monitored soon after transplantation and rituximab therapy should be initiated at the earliest.

  • Article
    Eatemad A. Awadalla, Abd El-Kader M. Abd El-Kader, Samia A. Gbr, Amna H. Nour, Mohammed H. Hassan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2445-2455. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.241
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    Objectives: Octylphenol (OP) is a member of the category of substances known as endocrine-disrupting chemicals and can interfere with the actions of steroid hormones, having negative implications on reproductive health. Alpha lipoic acid (αLA), a naturally occurring nutraceutical, has been shown to provide therapeutic benefits due to its antioxidant activity and capacity to reverse oxidative damage. Consequently, the current study is attending to estimate the protective effects of αLA against OP-induced male infertility.

    Methods: Forty male albino rats were randomly divided equally into four groups. Group I (control group) didn't received any materials, Group II (αLA-group) received alpha lipoic acid (40 mg/Kg/day), group III (OP-group) received octylphenol (50 mg/Kg/day), and group IV (protective group) received octylphenol (50 mg/Kg/day) plus alpha lipoic acid (40 mg/Kg/day) for 30 days. Serum reproductive hormones (gonadotropin releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, total oxidant status (TOS), and total antioxidant capacity (TAC) levels were measured. Histological and histochemical examinations of the hypothalamus, pituitary gland and testis, as well as immunohistochemical detection for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the pituitary gland and testis were performed.

    Results: Rats of OP-group showed significant reduction of serum GnRH, FSH, LH, testosterone and TAC levels and significant rise of TOS levels. In parallel with these outcomes, several histopathological and histochemical abnormalities were observed in their hypothalamus, pituitary and testicular tissues. Additionally these structural abnormalities were associated with increased TNF-α and IL-6 expressions in both pituitary and testicular tissues. On other hand, rats of protective group showed enormous improvements in biochemical, histopathological, and immunohistochemical derangements induced by OP. Insignificant differences in the biochemical, histopathological, and immunohistochemical examinations were observed between control group and αLA-group.

    Conclusions: Short-term exposure of OP at low doses disturbs the hypothalamic-pituitary-gonadal (HPG) axis associated with increased oxidative stress, inflammation and structural abnormalities with successful reversion of theses derangements by αLA via its antioxidant and anti-inflammatory properties.

  • Article
    Xingsheng Cha, Qiujun Wang, Yong Zhang, Jun He
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2457-2464. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.242
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    Background: Tibial plateau fractures are complex injuries caused by high or low energy trauma, usually accompanied by soft tissue damage. Staged treatment is strongly encouraged for complex fracture types. Traditionally, open reduction and internal fixation (ORIF) is mostly performed through an anterolateral approach, but this is usually traumatic. The present study was carried out to evaluate the efficacy of arthroscopic minimally-invasive internal fixation for tibial plateau fractures, and to determine its effect on pain stress.

    Methods: Patients with tibial plateau fractures diagnosed and treated in our hospital from January 2020 to December 2021 were subjected to eligibility assessment, out of which 70 patients were eventually included in the study. The subjects were assigned to two groups: ORIF (control group) and arthroscopic minimally-invasive internal fixation (observation group), with 35 patients in each group. Clinical indices, functional recovery, postoperative pain, and stress indices were measured and compared between the 2 groups.

    Results: The observation group had significantly smaller surgical wound, less intraoperative bleeding, shorter time-lapse before off-bed activity, and faster fracture healing than the control (ORIF) (p < 0.05). Patients in the observation group had significantly higher postoperative Rasmussen scores and Lysholm scores, and lower VAS (visual analogue scale) scores than those in control group (p < 0.05). Moreover, the observation group had significantly lower levels of substance P, neuropeptide Y, and prostaglandin E2 than the control group (p < 0.05).

    Conclusions: Arthroscopic minimally-invasive internal fixation surgery was less invasive, and it resulted in faster recovery of functionality in patients with tibial plateau fractures, than ORIF. Moreover, it reduced postoperative pain and stress. Therefore, the procedure may provide a good prognosis for tibial plateau fractures.

  • Article
    Hong-hong Wang, Xue-qing Wu, Hai-xia Song, Ze Wang, Mei Sun, Ying Wang, Yu-hua Shi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2465-2471. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.243
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    Objective: This study sought to determine how the concentration of progesterone on the trigger day of fresh embryo transfer cycles affected the live birth rate.

    Materials and Method: Re-analysis of a multicenter randomized trial was used in this study (ChiCTR-IOR-14005405). In the investigation, fresh single blastocyst transfers utilizing the gonadotropin-releasing hormone (GnRH) antagonist procedure were performed on normal ovarian response of 536 women and with a high ovarian response of 200. Live birth was the main result.

    Results: There is greater levels of progesterone on the human chorionic gonadotropin (hCG) of women with a high ovarian response trigger day than women with a normal ovarian response (1.31 ± 0.56 and 1.07 ± 0.45 ng/mL, respectively; p < 0.001). With the decrease of live birth rate when the progesterone levels were ≥1.5 ng/mL in women with a high ovarian response this was not seen in women who had a normal ovarian response (p = 0.141); The difference was (p = 0.039). The high ovarian response in women, but not in those with a normal ovarian response (p = 0.293), the logistic regression analysis of multivariate showed that the level of progesterone on the hCG trigger day correlated negatively with the live birth rate (odds ratio: 0.48, 95% confidence interval: 0.23–0.99, p = 0.046). On the hCG trigger day, the progesterone cut-off point for women with a high ovarian response was 1.54 ng/mL (p = 0.041), according to the receiver operating characteristic (ROC) curve analysis.

    Conclusions: Employing the GnRH antagonist on the embryo transfer cycles, increased the levels of progesterone on the hCG trigger day that may impact live birth rates negatively.

  • Article
    Wenbing Liu, Fan Sun, Xiaodong Li, Xueyun Liu, Xiaowei Wang, Qiang Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2473-2485. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.244
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    Background: Acute lung injury (ALI) is involved in reactive oxygen species (ROS)-induced ferroptosis.

    Purpose: The aim of the study was to explore the participation of ferroptosis and the mediation of forkhead transcription factor O1 (FOXO1) ubiquitination through tripartite motif containing 37 (TRIM37) in lipopolysaccharide (LPS)-induced ALI.

    Methods: Murine lung endothelial cells (MLECs) were isolated from mouse lungs and treated by LPS. The empty and experimental vectors were transfected into MLECs by lipofection. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), C11-BODIPY, and ROS generation assays were used to evaluate cell viability, lipid peroxidation, and ROS level. UbiBrowser was used to predict the potential ubiquitin ligases targeting FOXO1. Immunoprecipitation (IP) and Co-IP assays were used to confirm the connection between TRIM37 and FOXO1. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were utilized to calculate the messenger RNA (mRNA) and protein expressions of examined genes in MLECs.

    Results: In LPS-induced MLECs, TRIM37 expression was significantly high. Meanwhile, LPS significantly increased lipid peroxidation and ROS, but significantly decreased cell viability as well as expressions of FOXO1 and ferroptosis-related proteins (solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4)) in MLECs. These changes were significantly reversed by FOXO1 overexpression. TRIM37 was predicted as a high-confidence ubiquitin ligase of FOXO1. TRIM37 and FOXO1 could bind with each other and TRIM37 degraded FOXO1 through ubiquitination in MLECs. TRIM37 overexpression significantly inhibited FOXO1 level and enhanced the effect of LPS on MLECs, which was reversed by overexpressing FOXO1.

    Conclusions: TRIM37-mediated ubiquitination of FOXO1 significantly elevates LPS-induced ferroptosis in lung endothelial cells.

  • Article
    Fanliang Meng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2487-2495. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.245
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    Objective: To explore miR-325-5p expression after subarachnoid hemorrhage (SAH) and its impact on early brain injury in SAH rats.

    Methods: Forty-eight male Sprague-Dawley (SD) rats were used in this study, 12 in the sham group, 12 in the SAH group, 12 in the SAH+miR-325-5p mimic group, and 12 in SAH+miR-325-5p mimic+oe-HDAC3 group. The SAH model was established using a common occipital cistern secondary blood injection. Brain water content and SAH grades were measured. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) assay was used to measure miR-325-5p expression. Apoptosis was assessed by flow cytometry. Cell Counting Kit-8 (CCK8) assay was used to examine cell proliferation. Luciferase reporter assay was used to confirm the relationship between miR-325-5p and HDAC3 (histone deacetylase 3).

    Results: MiR-325-5p expression decreased in the SAH rats and oxyHb induced PC12 cells. Apoptosis decreased induced by miR-325-5p mimic. Cell proliferation significantly increased, and inflammation related protein level was inhibited in the miR-325-5p mimic group. MiR-325-5p was predicted to specifically combine with the HDAC3 3′UTR region using the targetscan. MiR-325-5p mimic significantly regulated HDAC3-wt activity and HDAC3 level was lower in the miR-325-5p mimic group. Furthermore, overexpressed HDAC3 reversed miR-325-5p protecting effects on early brain injury (EBI) in SAH.

    Conclusions: MiR-325-5p targeted HDAC3 to protect early brain injury in SAH via NF-κB signal pathway.

  • Article
    Qiao Li, Yanyun Shen, Zhidong Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2497-2504. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.246
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    Background: Atopic dermatitis (AD) is an inflammatory skin disease with a considerable prevalence globally. The anti-inflammatory ability of salubrinal has been expounded in various disease models. However, the effect of salubrinal on AD was unknown.

    Methods: The AD model was constructed in mice via the administration of 1-chloro-2,4-dinitrochlorobenzene (DNCB). The effect of salubrinal on the symptoms and pathology of AD mice was assessed by clinical skin score, hematoxylin-eosin (HE) and toluidine blue (TB) staining and enzyme-linked immunosorbent assay (ELISA). The role of salubrinal in inflammation, endoplasmic reticulum (ER) stress and oxidative stress were investigated by ELISA, colorimetric detections and western blotting. Additionally, the potential mechanisms were explored by western blot.

    Results: Salubrinal ameliorated AD-like symptoms, such as increased skin thickness, erythema, scarring and dryness, and dermatitis scores in DNCB-stimulated mice. Salubrinal also improved DNCB-induced pathology in AD mice, as evidenced by the remittance of pathological manifestations, and the reduction of the infiltration of mast cells and the serum concentration of histamine. Moreover, salubrinal counteracted the DNCB-induced production of inflammatory factors, reactive oxygen species (ROS) and malondialdehyde (MDA) and the enhanced expression of proteins involved in the endoplasmic reticulum (ER) stress, but restored the expression of glutathione peroxidase (GSH-Px) and catalase (CAT) in AD mice. Mechanically, salubrinal decreased the relative protein levels of p-p65/p-65, and the relative expression of proteins involved in the NOD (nucleotide-binding domain)-like receptor protein 3 (NLRP3) inflammasome.

    Conclusions: Salubrinal ameliorated DNCB-induced atopic dermatitis through suppressing inflammation, ER stress and oxidative stress via attenuation of the nuclear factor-kappa B (NF-κB)/NLRP3 axis.

  • Article
    Jiangtao Ni, Xiaotao Zhou, Li Wang, Yuerong Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2505-2512. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.247
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    Background: Gastric carcinoma (GC) is the third leading cause of malignant tumor mortality worldwide. The morbidity of gastric carcinoma is noticeably increased in Eastern Asia. MicroRNA-21 is a specific member of microRNAs, which is involved in carcinogenesis. This study aimed to analyze and investigate the influence of anti-microRNA-21 on the apoptosis and proliferation of gastric carcinoma MKN28 cells to determine the effect of anti-microRNA-21 on the development and progression of gastric carcinoma.

    Methods: Human gastric carcinoma MKN-28 cell lines were obtained and microRNA-21 inhibitor and mismatched sequence negative control were synthesized by GenePharma (B03001, Shanghai, China). After the MKN-28 cells were cultured, the total RNA was extracted from cells and reversely transcribed using the Moloney Murine Leukemia Virus (M-MLV) First Strand cDNA Synthesis kits. A quantitative PCR (qPCR) was performed to detect maspin, Bcl-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) protein levels. Flow cytometry was applied at 72 h after transfection to detect the MKN28 cell apoptosis. Western blot was completed following the standard procedures to determine the effects of downregulated microRNA-21 on the expression of proteins, including maspin, Bcl-2, Bax, FAS-associated death domain protein (FADD), and pro-caspase3 in the MKN28 cells. Transwell® assays were also performed for cell infiltration.

    Results: The proliferation of MKN28 cells was prominently decreased in the anti-microRNA-21 transfected groups relative to the control group, and apoptosis was increased dramatically in MKN28 cells 72 h after transfection with anti-microRNA-21 (p < 0.05). The protein expression levels of Bax and pro-caspase3 increased, whereas the Bcl-2 levels were markedly decreased in MKN28 cells when transfected with anti-microRNA-21 (p < 0.01), but there were insignificant differences in the levels of FADD between the two groups (p > 0.05). Relative to the negative control group, the levels of mRNA and maspin were increased in the anti-microRNA-21 groups (p < 0.05). The MKN28 cells transfected with anti-microRNA-21 migrated and invaded more slowly than those in the negative control (p < 0.05).

    Conclusions: This study shows that inhibition of microRNA-21 at the transcriptional level can inhibit the proliferation and metastasis of gastric cancer cells by regulating the mitochondrial apoptosis pathway. Since the transcription of the tumor suppressor gene, maspin, may be blocked by microRNA-21 in gastric cancer, microRNA-21 inhibition is a promising treatment for gastric cancer patients.

  • Article
    Peijie Liu, Hongrui Zhang, Fulian Qu, Liying Lv, Fengqian Shen, Ning Li, Xiaojing Tie, Yan Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2513-2524. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.248
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    Background: Sarsasapogenin (SAR), a sapogenin from the Chinese herbal medicine Anemarrhena asphodeloides Bunge (Asparagaceae), is reported to exhibit antitumor effects on cervical cancer. The aim of this study was to explore whether SAR affects pancreatic cancer and the mechanism of this effect.

    Methods: SAR was applied to treat pancreatic cancer cells (HPAC/PANC-1) and human normal pancreatic cells. To explore the impact of SAR upon pancreatic cancer in vitro, HPAC and PANC-1 cells underwent treatment with 2 or 10 μmol/L SAR and N-Acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) inhibitor. Thiazolyl Blue Tetrazolium Bromide (MTT) and colony formation assays were carried out to detect cell growth. Cell apoptosis and cell cycle distribution were assessed using flow cytometry assay. ROS fluorescent images were observed under confocal laser microscope. Mitochondrial membrane potential alterations were measured using JC-1 staining. Expression levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1), Cyclin D1, Cyclin A, janus-activated kinase (JAK), signal transducer and activator of transcription 3 (STAT3), phosphorylated (p)-JAK and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) were quantitated via Western blot.

    Results: SAR significantly reduced growth and mitochondrial membrane potential, while significantly promoting apoptosis, cell cycle arrest at G2/M phase and ROS production of pancreatic cancer cells. Besides, SAR significantly augmented cleaved caspase-3 and cleaved PARP1 levels, but significantly down-regulated Cyclin D1, Cyclin A, p-JAK/JAK and p-STAT3/STAT3 levels. NAC significantly reversed the above alterations caused by SAR.

    Conclusions: SAR exhibits promising efficacy in treating pancreatic cancer involving the blockage of JAK/STAT3 pathway, via ROS-dependent mitochondrial dysfunction.

  • Article
    Chunyan Liu, Zhifei Qiao, Ying Zhou, Fei Liu, Shuwei Huang, Fulong Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2525-2530. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.249
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    Objective: To investigate the correlation between serum interleukin-17 (IL-17) and Clara cell protein 16 (CC-16) levels and the clinical prognosis in patients with acute respiratory distress syndrome (ARDS).

    Methods: The data of 120 ARDS patients treated in the First Affiliated Hospital of Hebei North University, in Hebei, China, between Feb. 2020 and Feb. 2022 were retrospectively analyzed. With death as the endpoint event, they were divided into death group (DG) and survival group (SG), based on whether they experienced the endpoint event within 28 days of treatment. All patients underwent serological testing to determine serum IL-17 levels and CC-16 levels, and the scores of Acute Physiology and Chronic Health Evaluation II (APACHE-II) and Sequential Organ Failure Assessment (SOFA) were calculated after enrollment. The IL-17 levels, CC-16 levels, APACHE-II scores and SOFA scores were compared between the two groups. Receiver operator curves (ROC) were adopted used to analyze the predictive value of IL-17 and CC-16 levels for the endpoint event. The correlation of IL-17 and CC-16 levels with clinical prognosis of ARDS patients was evaluated by R analysis.

    Results: No significant difference was observed in background data between the two groups (p > 0.05). Patients in the DG had significantly higher serum IL-17 and CC-16 levels (p < 0.001), and significantly higher APACHE-II and SOFA scores compared with those in the SG (p < 0.05). The area under the curve of serum IL-17 for predicting 28-day mortality was 0.976 (p < 0.001), while that under the curve of CC-16 was 1.000 (p < 0.001), R analysis demonstrated that serum IL-17 and CC-16 levels significantly correlated with APACHE-II and SOFA scores.

    Conclusions: Serum IL-17 and CC-16 levels have predictive value for the clinical prognosis of ARDS patients, and higher IL-17 and CC-16 levels indicate a worse prognosis.

  • Article
    Sha Liu, Yuting Xia, Min Zhang, Jiaojiao He, Yulin Chen, Ya Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2531-2538. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.250
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    Background: Osteoporosis, an osteolytic disease, is characterized by excess osteoclast activity. Warfarin, a widely prescribed oral anticoagulant, has been linked to an increased risk of long-term osteoporosis and fractures. However, the precise role of warfarin plays in osteoclast function remains unclear.

    Objective: This work aims to assess the impact of warfarin on the Receptor Activator of Nuclear Factor-κ B Ligand (RANKL)-caused osteoclastogenesis, as well as the underlying mechanisms.

    Methods: We extracted the bone marrow-derived macrophages (BMMs) from C57BL/6 mice (aged 6 weeks, male). A Microplate reader (450 nm, Tecan, RNE-90002, Hong Kong, China) was applied to assess the absorbance. Before the experiment, we extracted several drops of BMMs in equal quantities after cell culture for control and warfarin. The effect of warfarin on RANKL-modulated osteoclast differentiation was assessed by Tartrate-resistant acid phosphatase (TRAP) staining and F-actin detection, which was verified by examining osteoclast-related gene level. We also examined the expression of matrix gla protein (MGP) via Quantitative Real-time PCR (qRT-PCR) and western blot. Osteoclastogenesis-associated signaling pathways were assessed by western blot.

    Results: Warfarin significantly inhibits the expression of MGP (p < 0.05). TRAP staining illustrated that the warfarin treatment group formed more TRAP-positive osteoclasts. Under a fluorescence microscope, the area of F-actin rings was significantly increased in the warfarin treatment group (p < 0.01). On the other hand, Warfarin up-regulated osteoclast-related gene levels, including Cathepsin K (CTSK), TRAP, Calcitonin receptor (CTR), Dendritic cell-specific transmembrane proteins (DC-STAMP), Guided growth factor (c-Fos). Warfarin up-regulates the expression of RANKL-induced osteoclast differentiation marker genes (p < 0.01 or p < 0.001) significantly. Studies on molecular mechanisms have confirmed that warfarin inhibits the matrix gla protein (MGP) level and activates RANKL-induced ERK (extracellular signal-regulated kinase) signaling.

    Conclusions: These findings suggest that warfarin's promotion of osteoclast differentiation may be linked to the inhibition of MGP and activation of ERK signaling. Consequently, this sheds light on the causes of bone loss associated with warfarin treatment and could have significant implications for clinical practice.

  • Article
    Xiao-hu Yang, Chen Wang, Zhen-yu Guo, Guang-lang Zhu, Long-hua Fan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2539-2549. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.251
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    Background: It has been known that circadian locomotor output cycles kaput protein (CLOCK) can not only regulate circadian rhythm but also participates in various biological processes. However, the association between CLOCK expression and plaque stability has not been well examined. This study aims to explore the role of CLOCK in the stability of atherosclerotic plaque and its potential molecular mechanism.

    Methods: The expression of CLOCK in stable plaque and ruptured plaque in the GSE41571 dataset was analyzed. The qRT-PCR (quantitative real-time polymerase chain reaction) and western blot were used to analyze the mRNA (messenger ribonucleic acid) and protein expression levels of CLOCK and phenotypic transformation markers of vascular smooth muscle cells (VSMCs) in human carotid atherosclerotic plaque samples or HAVSMCs (Human aortic vascular smooth muscle cells) cells, respectively. Cell Counting Kit-8 (CCK-8) and Transwell® assays were used to evaluate the cell proliferation and migration ability, respectively.

    Results: This study revealed that the CLOCK mRNA levels were reduced in unstable plaques (USP), following a similar pattern as the expression of vascular smooth muscle cells contractile markers such as calponin, α-smooth muscle actin (α-SMA), and smooth muscle protein 22α (SM22-α). Meanwhile, vascular smooth muscle cell synthetic phenotypic marker osteopontin (OPN) was increased. In addition, we found that oxidized low-density lipoprotein (ox-LDL) exposure accelerated phenotypic switching in VSMCs, a process promoted by knocking down the expression of CLOCK and inhibited by CLOCK overexpression. Further mechanisms studies showed that the Y-27632-mediated suppression of the RhoA/ROCK (Rho-Rho kinase) pathway rescued the phenotype induced by CLOCK deletion in VSMCs.

    Conclusions: Our results showed that decreased expression of CLOCK could contribute to phenotype switching of VSMCs and could be associated with atherosclerotic plaque instability.

  • Article
    Zhijie Shi, Deqi Wu, Yangying Hu, Shusen Zheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2551-2560. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.252
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    Objectives: Prenyl diphosphate synthase subunit 2 (PDSS2) has been closely linked to malignant behaviors in several cancers, including gastric cancer, melanoma and lung cancer, but its significance and mechanism in breast cancer (BC) are not still clarified. The purpose of this study was to look into the function of PDSS2 in BC and elucidate how it affects the survival of BC patients.

    Methods: The tumor tissues (BC) and histologically normal tissues (Normal) were obtained from 40 BC patients. BC cell lines HCC1937, MCF-7 and human normal breast cells MCF10A were cultured. Western blotting, Quantitative real-time polymerase chain reaction (qRT-PCR), and bioinformatics were performed to detect the PDSS2 expression in BC tissues and cells. Plasmids carrying PDSS2 siRNA (si-PDSS2) or overexpression plasmid (oe-PDSS2) were transferred into MCF-7 and HCC1937 cells. Functional experiments were conducted to determine the impact of PDSS2 on BC cell invasion, migration, and angiogenesis. In addition, the western blot determined the protein expression of Vimentin, N-cadherin, E-cadherin, p-IKBα, p-P65, P65, and p-IKBα proteins.

    Results: In BC tissues and cells, PDSS2 expression was notably elevated (p < 0.01), and worse overall survival (OS) were associated with the high PDSS2 expression (p < 0.01). Besides, overexpression of PDSS2 significantly increased the invasion, migration and tube formation ability of BC cells and encouraged epithelial-mesenchymal transition (EMT) (p < 0.01). However, PDSS2 knockdown inhibited cancer cell progression (p < 0.01). Moreover, PDSS2 enhanced the phosphorylation of the NF-κB pathway proteins IKBα and P65 (p < 0.01).

    Conclusions: PDSS2 can promote the invasion, migration, angiogenesis and EMT of BC cells through stimulation of the NF-κB pathway.

  • Article
    Shenghui Tang, Junhua Zuo, Haonan Zhang, Songsong Wu, Biru Liang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2561-2567. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.253
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    Objective: To analyze the effects of kaempferol (KAE) on the viability and osteogenic differentiation of bone mesenchymal stem cells (BMSCs) in aging rats and provide new insights into the prevention and treatment of age-related bone metabolic diseases.

    Methods: BMSCs were isolated and cultured from femurs of 12-month-old Sprague Dawley (SD) rats. The senescent BMSCs were divided into untreated normal control (NC) group, KAE group treated with KAE intervention and decaying Dimethyl sulfoxide (DMSO) group with DMSO intervention. β-galactosidase staining was used to observe the effect of KAE on cell growth and expression of senescence markers p53 and p21 and reactive oxygen species (ROS) production in BMSCs. The effect of KAE on the osteogenic differentiation of senescent BMSCs was subsequently studied by alizarin red staining and measuring the expression of osteogenic-related markers alkaline phosphatase (ALP), RUNX family transcription factor 2 (Runx2), osteocalcin (OCN) and osteopontin (OPN).

    Results: Many β-galactosidase-positive cells were seen in the BMSCs cells, confirming that the obtained BMSCs were senescent cells. Compared with the NC and DMSO groups, KAE treatment decreased the distribution of β-galactosidase-positive cells and levels of p53 and p21 and production of ROS. Moreover, cell growth capacity was higher in the KAE group than in the NC and DMSO groups. In the KAE group, alizarin red staining showed large numbers of red calcified nodules in the interstitium of cells, and the highest protein expression of ALP, Runx2, OCN and OPN among the three groups (p < 0.05).

    Conclusions: KAE alleviated the aging profile of BMSCs, promoted their activity and osteogenic differentiation, and inhibited the production of ROS.

  • Article
    Dara Aldisi, Mohammed G.A. Ansari, Syed Danish Hussain, Abdulrahman Al–Matary, Fahima Mohamad AlSomali, Reem Ibrahem Alturaif, Ihtisham Bukhari
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2569-2574. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.254
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    Background: Diabetes Mellitus (DM) is a common disorder affecting people of all ages, from neonates to seniors, and even occurs during pregnancy. In addition to type 1 (T1DM) and type 2 (T2DM), the rate of gestational diabetes mellitus (GDM) and neonatal diabetes mellitus (NDM) is dramatically increasing. Interestingly, the genetic causes and relationship between GDM and NDM are not yet established, especially in the Arab population. Therefore, the prevalence of ABCC8 and KCNJ11 variants (well-known genetic causes of NDM) in Saudi neonates were explored and also analyzed for the influence of a history of parental diabetes and GDM on NDM.

    Methods: A total of 1101 Saudi pregnant women and their newborns were included in the study. Serum glucose levels were measured in mothers and neonates, while genetic screening for ABCC8 and KCNJ11 variants was performed for neonates only.

    Results: Among the 1101 neonates' families, 59 (5.4%) mothers and 36 fathers (3.3%) had a history of type 1-DM (T1DM), whereas 35 (3.2%) mothers and only one father had a history of type-2 DM (T2DM). Furthermore, the prevalence of GDM was 8.1%. Only one hyperglycemia (NDM suspect) case was detected, with no physical abnormalities. Additionally, no association between GDM and NDM was observed. Genotyping of the neonates for KCNJ11 and ABCC8 genes revealed a homozygous mutant (GG) form of the rs80356611 KCNJ11 in only one neonate. All other tested polymorphisms rs193929358 (KCNJ11) and rs193922402, rs377686759, and rs143557848 of (ABCC8 ) produced single normal genotype.

    Conclusions: The data of this study showed that GDM is not associated with NDM in Saudi neonates and suggest that genetic screening in larger samples may show the role of KCNJ11 and ABCC8 variants in developing neonatal and postnatal diabetes.

  • Article
    Chun-Mei Zeng, Yan-Mei Zhao, Zhi-Hai Lin, Wen-Chao Xie, Zheng Ling, Jian-Ping Tan, Kai-Fang Pang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2575-2580. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.255
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    Background: Among the cases of coronary angiography (CAG)/percutaneous coronary intervention (PCI), men count higher for these cases, and they are more prone to renal injury when they have renal insufficiency. Recent research suggests that enhanced external counterpulsation (EECP) could be a new technique for preventing contrast-induced acute kidney injury (CI-AKI). In the current study, we aimed to conduct evaluation on the prevention of CI-AKI in makes through efficacy of EECP with chronic kidney disease (CKD) through the comparison on the change in renal function indexes after CAG/PCI.

    Methods: The male patients totaling to 234 with CKD who underwent CAG/PCI from December 2020 to February 2022 were selected and assigned to two distinct categories: Control group (n = 80) and observation group (n = 154). Patients in the control group received hydration treatment before and after CAG/PCI, while in the observation group patients received EECP regarding on the treatment received in the control group. Changes in renal function indexes were compared in both groups before and after CAG/PCI.

    Results: The group of patients under the observations showed significant lower blood urea nitrogen (BUN) and Cystatin-c (Cys-c) after CAG/PCI (6.5 ± 2.4 vs 7.3 ± 3.1, p = 0.040 and 1.7 ± 0.6 vs 1.6 ± 0.4, p = 0.038) than the control group. BUN and Scr (serum creatinine) was significantly lower in the observation group which indicated (6.5 ± 2.4 vs 8.2 ± 3.0, p < 0.001 and 146.4 ± 38.3 vs 155.1 ± 37.6, p < 0.001). It shows significant higher rate of estimated glomerular filtration (eGFR) was significantly higher (47.8 ± 13.5 vs 43.9 ± 10.7, p < 0.001) after CAG/PCI. More patients had increased eGFR (62.3% vs 47.5%, p = 0.030) the incidence of contrast-induced nephropathy (CIN) and acute kidney injury (AKI) in the observation group was lower (2.6% vs 10.0%, p = 0.015 and 1.3% vs 6.3%, p = 0.035). EECP was an independent protective factor for AKI odds ratio [OR] = 0.244, 95% confidence interval [CI] 0.069–0.857, p = 0.028) and the same trend was seen for CIN, but it did not show significant statistics in (p = 0.065).

    Conclusions: The application of EECP can enhance the reduction of the risk of CI-AKI/CIN and renal function in elderly males with CKD after CAG/PCI.

  • Article
    Yunfang Jia, Xianming Hou, Xiaomeng Lang, Yali Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2581-2589. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.256
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    Objective: To explore the mechanism of Shugan Jianpi Qingre Fang in the treatment of functional dyspepsia (FD) by using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS).

    Methods: 30 clean healthy Wistar rats were randomly divided into 3 groups, of 10 rats: Normal Group, Model Group and Shugan Jianpi Qingre Group. The functional dyspepsia model was made by “Guo's clamping tail method” and “irregular feeding method”. The model time was 7 days. The rats in the traditional Chinese Medicine Group were given 13.98 G/kg/D of Shugan Jianpi Qingre Fang, and the rats in the normal group and the model group were given the same volume of distilled water once daily for 14 days. On the 22nd day of the experiment, the rats in each group were euthanized, blood was collected, plasma samples were prepared and metabonomics analysis was performed, to estimate the differential metabolites (15 potential biomarkers, such as Choline, proline, Taurine, glutamic acid, Glutathione, l-citrulline, Tryptophan, and eicosapentaenoic acid (EPA)) and find the main differential metabolic pathways.

    Results: In the model group, the level of estrone significantly increased whereas the level of the other metabolites significantly decreased. After the intervention of “Shugan Jianpi Qingre Fang”, the level of Choline, proline, Taurine, glutamic acid and mannose in the plasma of the model group significantly regressed. It is better to include figures and p values.

    Conclusions: Shugan Jianpi Qingre Fang may play an important role in the treatment of Functional Dyspepsia, by regulating glucose metabolism, energy metabolism, affecting nerve signal transduction and enhancing antioxidant capacity. Compound Chinese medicine has the characteristics of multi-angle and multi-target.

  • Article
    Yucheng Yan, Lu Zhou, Peng Song, Jincai Fan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2591-2599. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.257
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    Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease, and the only known cause is the haploinsufficiency of the forkhead box L2 (FOXL2). The purpose of this study was to study the functional changes of a novel FOXL2 missense mutation in a Chinese family and provide insights into the pathogenic mechanisms.

    Methods: Two patients with typical clinical features within one family were enrolled in the present study. DNA was extracted from peripheral venous blood, and Sanger sequencing was used to detect the mutation. Then, the bioinformatic analyses were performed by the online software, and the experiments of western blotting, subcellular localization, luciferase reporter assays, and quantitative real-time PCR (qRT-PCR) were used to identify the function changes.

    Results: A novel FOXL2 missense mutation (c.292T>A) was detected in the forkhead domain. Subtle changes in structure and physicochemical properties were predicted in the bioinformatic analyses. However, the mislocalization of the mutant protein and impaired transcriptional activity in affecting the expressions of downstream genes explained the pathogenicity of this mutation. The odd-skipped related 2 transcription factor gene was more sensitive to the quantity change of FOXL2 and the presence of the detected mutation in the present study.

    Conclusions: This study not only expands the spectrum of FOXL2 mutations but also provides reference data and insights into the pathogenesis and subtyping of blepharophimosis-ptosis-epicanthus inversus syndrome.

  • Article
    Hui Li, Xiaosong Li, Ying Wang, Hongyou Zhao, Jing Zeng, Yidi Liu, Defu Chen, Shan Long, Wenwen Liu, Jiakang Shao, Haixia Qiu, Ying Gu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2601-2614. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.258
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    Background: Colorectal cancer (CRC) is the second most common cause of cancer-related death globally, characterized by high rates of recurrence and metastasis. Photodynamic therapy (PDT) is a promising CRC treatment that controls the primary tumor effectively and triggers host immunity to prevent tumor recurrence and metastasis. Fluence rate is a crucial regulator of tissue oxygenation and inflammatory response and may play a critical role in antitumor immunity associated with PDT. This study examined the effect of fluence rate on antitumor immunity of PDT mediated by hematoporphyrin derivatives (HpD) in the CT26 tumor model.

    Methods: Mice with subcutaneous CT26 tumors were subjected to an 80 J/cm2 light dose administered at fluence rates of 10, 50, 100, and 150 mW/cm2. All PDT-treated tumor-free mice were rechallenged with the same tumor cell line in the contralateral flank 90 days after PDT. Treatment outcome and immune infiltration in tumors were examined to investigate the antitumor immunity of HpD-PDT at varying fluence rates. Transcriptomic sequencing analysis and exposure of danger-associated molecular patterns (DAMPs) on tumors were also investigated to study the mechanism of antitumor immunity.

    Results: HpD-PDT at 10–150 mW/cm2 induced systemic immune responses that mediated protection against tumor rechallenge in survivor mice (p < 0.05). Analysis of infiltrating lymphocytes revealed that HpD-PDT increased T-cell infiltration and enhanced the cytotoxicity of CD8+ T cells in tumors and spleens (p < 0.05), which was shown to be fluence rate-dependent. As the fluence rate increased from 10 mW/cm2 to 150 mW/cm2, the antitumor immunity of HpD-PDT showed a trend of first decreasing and then increasing. Furthermore, the expression of DAMPs on tumor cells was upregulated following HpD-PDT (p < 0.05).

    Conclusions: These results indicate that fluence rate affects HpD-PDT-induced immune response by provoking systemic antitumor immunity and reshaping the tumor immune microenvironment. Our findings establish a correlation between fluence rate and antitumor immunity of PDT in the CT26 tumor model and provide an experimental basis for optimizing the PDT regimen.

  • Article
    Jin Li, Chenhui Zheng, Yue Pan, Bangyi Lin, Qi Chen, Zhibao Zheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2615-2628. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.259
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    Background: As a member of RING (Really Interesting New Gene)-finger type E3 ubiquitin ligases, ubiquitin-like with plant homeodomain (PHD) and Ring Finger domains 1 (UHRF1) exerts its functions as a key epigenetic regulator for target genes by mediating histone deacetylation and DNA methylation. Several evidences indicate UHRF1 as an oncogene in multiple cancer types. Here, the aim of this study was to explore the action and mechanism of UHRF1 in breast cancer (BRCA), so as to elucidate the unclear effect of UHRF1 in BRCA.

    Methods: The TCGA database was used to detect UHRF1 expression in BCRA tissues and BCRA subclasses; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, colony formation assays, in vitro cell motility assays, Annexin V & propidium iodide staining were used to detect the proliferation, invasion, migration and apoptosis of MDA-MB-231 and NDA-MB-468 cells after UHRF1 transfection or silencing; Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathway enrichment analysis, combined with RNA-seq and differentially expressed gene analysis to screen for differentially expressed genes after UHRF1 overexpression; Western blotting, qRT-PCR (Real-time polymerase chain reaction) and immunohistochemistry (IHC) were used to verify the expression of UHRF1, N-cadherin, E-cadherin, early growth response factor 1 (EGR1) and TNF-alpha-induced protein 3 (TNFAIP3).

    Results: UHRF1 expression level is highest in TNBC (a subclass of BRCA) (p < 0.01), while patients with higher UHRF1 expression had significantly lower overall survival. UHRF1 can drive BRCA progression by promoting cancer proliferation and metastasis. The study also identified EGR1 and TNFAIP3 as potential target genes of UHRF1 using RNA sequencing, which was validated by cellular assays and immunohistochemistry data from BRCA tissues. In addition, the study further identified UHRF1 as supporting EGR1, through methylation epigenetic pathway, as 5-aza could effectively recover its expression. Rescue experiments using ectopic expression of EGR1 not only attenuated the effect of UHRF1 (p < 0.01, p < 0.05), but also upregulated TNFAIP3 expression accompanying with inactivation of the NF-κB signaling pathway (p < 0.01, p < 0.05).

    Conclusions: UHRF1 plays an important role in BRCA progression by promoting cell proliferation and motility, accelerating colony formation, and inducing epithelial-mesenchymal transition (EMT) by inhibiting EGR1 and TNFAIP3 through DNA methylation modifications. Therefore, UHRF1 may be a novel potential therapeutic strategy for BRCA.

  • Article
    Liling Xu, Yan Jiang, Lin Zhu, Ying Yuan, Hu Yu, Xiaojuan Su, Le Song
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2629-2636. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.260
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    Objectives: The incidence of acute myocardial infarction (MI) is increasing year by year, which seriously affects people's life quality. It is very important to prevent and treat myocardial infarction. The purpose of this study was to examine how exercise training affects the phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway in mice with acute myocardial infarction and to determine whether microRNA-21 (miR-21) could also be affected.

    Methods: 24 C57BL/6 mice were randomly assigned into four groups, including the sham operation group (Sham group) the myocardial infarction Group (MI group), the myocardial infarction + post-exercise training group (MI + TT group), the pre-exercise training + myocardial infarction group (TT + MI group). The expression levels of the b-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cysteine-aspartic acid protease 3 (Caspase-3) and phosphorylated Akt (p-Akt) were analyzed by western blot, and the mRNA expression levels of collagen type I alpha 1 (Col-1a1), Col-3a1, Fibronectin and miR-21 were detected by reverse transcription polymerase chain reaction (RT-PCR).

    Results: The protein expression levels of Bax and Caspase-3, which reflect myocardial apoptosis, were inhibited after exercise intervention (p < 0.01), and the Bax protein expression was markedly inhibited in the MI + TT group compared to the TT + MI group (p < 0.01). The protein expression levels of Bcl-2 and p-Akt, indicative of anti-myocardial apoptosis, were increased in the MI + TT and TT + MI groups, with a notable elevation in the MI + TT group (p < 0.01). Cardiac fibrosis indexes (Col1a1, Col3a1, Fibronectin1) in the MI + TT, TT + MI and MI groups were significantly higher than in the Sham group, while the elevation in the MI + TT and TT + MI groups was significantly lower than in the MI group (p < 0.05). The miR-21 expression was increased after myocardial infarction, while the miR-21 expression in the MI + TT and TT + MI groups was lower than in the MI group (p < 0.001).

    Conclusions: Exercise training can alleviate myocardial cell apoptosis and cardiac fibrosis via the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway, and protect myocardial cells. Early exercise after myocardial infarction is more beneficial. Exercise training can reduce the increase of miR-21 and the scope of myocardial infarction.

  • Article
    Junchi Cheng, Jing Zhao, Yun Cheng, Wei Li, Rong Wang, Xiaohong Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2637-2642. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.261
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    Background: The long non-coding RNA (lncRNA) AC010536.1 is abnormally expressed in multiple cancer types, suggesting it may function as an oncogene. Despite this, its role in colon cancer has not been extensively investigated. This study aimed to assess the diagnostic and prognostic value of AC010536.1 in colon cancer.

    Methods: The cancer genome atlas database (TCGA) was utilized to examine the clinical significance of AC010536.1 in colon cancer. Survival analysis was performed using the Kaplan–Meier and Cox regression analyses. Nomograms were constructed to predict patient survival. The association between AC010536.1 expression patterns and immune cell features was investigated using the CIBERSORT method (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts).

    Results: The abnormal high expression of AC010536.1 was observed in 12 types of malignancies, including colon cancer. Survival analysis revealed that higher levels of AC010536.1 were linked to poorer clinical outcomes. Multivariable Cox analysis confirmed that AC010536.1 was an independent prognostic indicator for colon cancer. The receiver operating curve (ROC) analysis demonstrated a strong diagnostic capacity of AC010536.1, and the area under the curve (AUC) is 0.829. Furthermore, the study investigated the relationship between AC010536.1 expression, tumor-infiltrating immune cells and the effectiveness of chemotherapeutic agents.

    Conclusions: Our findings demonstrated that AC010536.1 was overexpressed in colon cancer and could be used to predict survival of patient with colon cancer. Moreover, the data also indicated that the expression of AC010536.1 could predict the efficacy of specific anti-tumor drugs.

  • Article
    Jing Xia, Bin Wang, Shuai Han, Xuequan Liu, Haichen Chu, Yanlin Bi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2643-2654. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.262
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    Background: Opioid-induced constipation not only directly affects the quality of life of patients, but also causes complications that seriously affect their health. This study aimed to observe the effect of berberine (BBR) on morphine (MP)-induced acute constipation in mice.

    Methods: The acute constipation model was tested by subcutaneous injection of MP at doses of 2, 5, or 10 mg/kg. According to the degree of constipation, MP (10 mg/kg) was selected as the MP dose for the MP-mediated model in the following experiment that included eight groups: Vehicle, MP, BBR (2 mg/kg), BBR (5 mg/kg), BBR (10 mg/kg), MP+BBR (2 mg/kg), MP+BBR (5 mg/kg), and MP+BBR (10 mg/kg). BBR was injected once intraperitoneally 30 minutes before a single injection of MP in each mouse. Defecation function, as reflected by accumulated fecal weight, fecal pellet number, and fecal water content, was measured over a 6-hour period. At the end of the experiment, colonic tissues of mice were extracted under general anesthesia. The expression of mRNA level of phosphatidylinositol 3-protein kinase (PI3K) and protein kinase B (Akt) was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). The expression levels of phosphorylated PI3K, Akt and nuclear factor kappa-B (NF-kB) and the total protein expression levels of PI3K, Akt, NF-kB, interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were detected by western blot assays. The ratio of phosphorylation levels of PI3K, Akt and NF-kB to total protein levels was calculated. The distribution of phosphorylated Akt (p-Akt) and p-NF-kB in colonic tissue was stained by immunohistochemistry and the mean intensity value was calculated.

    Results: Single administration of MP caused acute constipation in mice. BBR did not change defecation function compared with the blank group (p > 0.05). When BBR was used in combination with MP at doses 2, 5, and 10 mg/kg, no statistically significant differences from MP alone were observed (p > 0.05). Compared with the blank group, BBR caused no significant difference in the expression of PI3K and Akt at the mRNA level (p > 0.05). However, at the protein level, MP increased the relative expressions of p-PI3K, p-Akt, and p-NF-kB compared with the blank group (p < 0.05), and BBR completely reversed the activation (p < 0.05). Similar changes were observed in the expression of TNF-α and IL-6 that is downstream of NF-kB (p < 0.05).

    Conclusions: Though BBR did not affect MP-mediated constipation in mice, it ameliorated colonic inflammation by completely reversing MP-mediated activation of the PI3K/Akt/NF-kB signaling pathway.

  • Article
    Haiyan Yu, Changzhou Li, Xiaoming Niu, Mingying Fan, Shiwei Huo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2655-2661. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.263
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    Objective: This work aims to observe the toxic effects of thyroid peroxidase antibody (TPO-Ab) on human ovarian granulosa cells (KGNs) and to investigate the mechanism of endoplasmic reticulum (ER) stress in TPO-Ab-induced apoptosis in KGNs.

    Methods: TPO-Ab (2 μg/mL, 4 μg/mL, and 8 μg/mL) was used to treat the KGNs. Cell counting kit-8 (CCK-8) and flow cytometry were performed to evaluate the effects of TPO-Ab on ovarian granulosa cell proliferation and apoptosis. The expression of specific proteins was detected by western blot. The levels of estradiol (E2) and progesterone were measured by enzyme-linked immunosorbent assay (ELISA).

    Results: TPO-Ab inhibited KGN proliferation and promoted apoptosis in a concentration-dependent manner. TPO-Ab reduced the levels of E2 and progesterone in KGNs. TPO-Ab increased the expressions of ER stress (ERS)-related proteins and decreased the expression level of Bcl-2.

    Conclusions: TPO-Ab repressed KGN proliferation and apoptosis by promoting ERS and eventually inducing apoptosis.

  • Article
    Xiao Xiao, Xiaoqiang Wan, XiaoFang Yang, Jin Tong, Li Zhou, Lei Deng, Wen Li, Jie Luo, Zhilin Luo, Jia Chen, Ling Lin, Jinjun Guo, Zhechuan Mei
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2663-2677. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.264
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    Objective: The Correa cascade explains the histopathological process of gastric carcinogenesis, including chronic non-atrophic gastritis (CNAG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia and gastric cancer (GC). IM is considered as a precancerous lesion of gastric cancer. Therefore, we aimed to identify stratification markers from IM that could predict GC occurrence and explore the mechanism of precancerous lesions.

    Methods: Whole-transcriptome sequencing (RNA-seq) was performed on 18 clinical gastric mucosal specimens from CNAG, CAG, IM, and GC. Based on weighted gene co-expression network analysis (WGCNA), key modules negatively related to the malignant transformation process were identified and hub genes were found. Expression of candidate lncRNAs (long non-coding RNAs) in human gastric tissues was detected by qRT-PCR (quantitative real-time polymerase chain reaction). Human gastric cell lines GES-1 were treated with chenodeoxycholic acid (CDCA). The GATA6-AS1 (GATA6 antisense RNA 1) overexpression vector and antisense oligonucleotides (ASO) were transfected into gastric cell lines and gastric cancer cell lines, respectively, and qRT-PCR and Western blotting evaluated their effects on the expression of IM markers and the Wnt/β-catenin pathway markers.

    Results: We constructed a hub gene and lncRNAs co-expression network and identified three candidate lncRNAs with the highest connectivity. The expression of GATA6-AS1 was markedly reduced in the IM group and further decreased in the GC group compared with the CNAG group. According to studies in vitro, GATA6-AS1 exhibited negative regulation of intestinal-specific transcription factor CDX2 (Caudal Type Homeobox 2) and its downstream IM marker KLF4 (kruppel-like factor 4) and MUC2 (mouse polyclonal mucin 2), as well as Wnt signaling pathway markers in GES-1 (The human normal gastric epithelial cell line) and SGC7901 cell lines. Furthermore, the overexpressed GATA6-AS1 could reverse CDCA-induced high expression of IM markers and inhibit Wnt signaling pathway marker.

    Conclusions: GATA6-AS1 possibly serves as the potential marker for IM and could reduce the expression of intestinal metaplasia markers by inhibiting the Wnt signaling pathway, thereby inhibiting the occurrence of IM and intestinal-type gastric cancer.

  • Article
    Xia Li, Shaoheng He, Qing Tong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2679-2689. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.265
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    Background: Basophil lysosomal membrane-associated glycoprotein 3 (CD63), cluster of Differentiation 203c (CD203c) and high affinity immunoglobulin epsilon receptor subunit alpha (FcεRIα), as specific markers for allergic disease diagnosis, have been used to diagnose allergic diseases such as pollen food and house dust mites. However, their value in the diagnosis of drug allergic reactions is not clear.

    Objective: The aim of this study was to detect the expression changes of CD63, CD203c and FcεRIα in blood basophil of patients with drug, so as to provide a reference for the in vitro diagnosis of patients with drug allergy.

    Methods: Seventeen patients with drug allergies in Affiliated Hospital of Jinzhou Medical University from October 2018 to December 2019 were recruited as the allergy group, and 17 healthy subjects as the control group. The expression of CD63, CD203c and FcεRIα on the surface of basophil was detected using flow cytometry, and the role of CD63, CD203c and FcεRIα in drug allergy was analyzed.

    Results: The expression rates of CD63, CD203c and FcεRIα in drug allergy group were 99.60%, 98.60% and 98.1%, respectively, which were significantly higher than the control group (91.4%, 75.0% and 87.0%, p < 0.05). Compared with the control group, the median fluorescence intensity (MFI) of CD63, CD203c and FcεRIα in the drug allergy group were significantly increased, with the highest up-regulation by 41%, 57% and 16%, respectively (p < 0.05). Compared with the control group, the expression rate of CD63 in penicillin allergy and = MFI were significantly up-regulated by 8.3% and 32%. The expression rate of CD203c in cephalosporin allergy and MFI were up-regulated by 20% and 48%, respectively, and the expression rate of FcεRIα in penicillin allergy and MFI were significantly up-regulated by 13% and 18%, respectively (p < 0.05).

    Conclusions: CD63, CD203c and FcεRIα are activation markers for the detection of basophils in allergic reactions, which have important clinical significance for diagnosing drug allergic reactions, especially the diagnosis of cephalosporin allergy.

  • Article
    Ruozheng Zhang, Song Yang, Chongqing Yu, Qi Zhang, Bin Sun, Yun Gao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2691-2702. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.266
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    Objective: This study aimed to use N6 adenosine methylation (m6A) regulatory factors to explore the prognosis of oral squamous cell carcinoma (OSCC) patients, and investigate the regulatory mechanism of m6A regulatory factors on the prognosis of OSCC patients.

    Methods: A new sort-based m6A comparison pair method was proposed. The prognostic model of OSCC was established using Cox regression analysis. On this basis, the model was evaluated using the receiver operator curve (ROC), and the gene mutation pattern and prognostic prediction pattern of the high-risk and low-risk groups were described, and the key genes closely related to them were screened out. RNA sequencing (RNA-seq) technology was used, combined with protein expression in the Human Protein Atlas (HPA) database and single cell detection in the Tumor Immune Single-cell Hub (TISCH) database, to find important regulatory factors. Using human squamous cell carcinoma cell line 3 (HSC-3) cells, lentivirus overexpressing WTAP or cyclin-dependent kinase inhibitor 2A (CDKN2A) were transfected and changes in HSC-3 cell viability and apoptosis were checked for. The cluster of differentiation (CD)8+ T cells were isolated from mouse spleen, transfected with WTAP siRNA, and changes in CD8+ T cell viability and apoptosis, as well as the expression levels of CDKN2A, PD-1, and TOX were checked for.

    Results: Univariate Cox analysis showed that risk scores significantly correlated with prognosis in OSCC (HR 1.9, p < 0.001). The ROC curve showed that the AUC (area under curve) was 0.691, 0.720 and 0.706 in 1 year, 3 years and 5 years, respectively. In the experimental group, AUC at 1 year, 3 years and 5 years were 0.680, 0.654 and 0.691, respectively. The prediction result of 6-m6A stabilized current was significantly better than that in the control group. CDKN2A was the most common mutation site in the disease (about 20%) and significantly increased in low-risk patients (p = 0.006). CDKN2A was the most commonly lost gene, accounting for more than 30%. CDKN2A/p16INK4a was significantly associated with the prognosis of OSCC (p = 0.038). GSE139324, GSE172577 and GSE103322 confirmed the high expression of CDKN2A in T lymphocytes, glandular lymphocytes and tumor cells, respectively. Results from in vitro experiments revealed that overexpressed CDKN2A significantly inhibited HSC-3 cell viability but promoted its apoptosis (p < 0.01), while overexpressed WTAP showed an opposite effect. The viability of CD8+ T cells significantly increased, and the apoptosis rate significantly decreased after WTAP siRNA transfection (p < 0.01). Furthermore, the expression levels of PD-1 and TOX also significantly decreased, while the expression of CDKN2A increased with the downregulation of WTAP (p < 0.01).

    Conclusions: This study is helpful to further understand the role of 6-m6A regulator in the prognosis and development of OSCC. CDKN2A is a potential prognostic marker for OSCC.

  • Article
    Xiang Li, Bo Liao, Rongming Liu, Tiantian Zhou, Ning Zhang, Jun Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2703-2711. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.267
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    Background: Ubiquitin-specific peptidase 10 (USP10), a deubiquitinating enzyme, enhances the stability of substrate protein through deubiquitination. While earlier studies have shown that USP10 mitigates kidney damage in sepsis, its role in sepsis-induced intestinal injury remains unclear.

    Methods: A septic intestinal injury model was created in vivo using cecal ligation and puncture (CLP), while an in vitro model was established by treating IEC-6 intestinal epithelial cells with lipopolysaccharide (LPS). Histopathological changes in intestinal tissues were examined using hematoxylin-eosin staining. Interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels in intestinal tissues were measured using enzyme linked immunosorbent assay (ELISA) assay. TdT-mediated dUTP nick end labeling (TUNEL) assay was used to assess intestinal tissue cells' apoptosis, and flow cytometry was employed to determine the apoptosis rate in IEC-6 cells. USP10 impact on Polo-like kinase 1 (PLK1) expression was analyzed using Western blot assay, while immunoprecipitation was employed to detect interactions between USP10 and PLK1. Ubiquitination levels of PLK1 were determined to evaluate USP10's influence, and rescue experiments were conducted to verify whether USP10 alleviates septic intestinal injury by regulating PLK1.

    Results: Treatment with either CLP or LPS increased IL-6, IL-1β, TNF-α, and apoptosis rates in intestinal tissues or cells. However, USP10 overexpression reduced the levels of inflammatory factor and suppressed apoptosis. Mechanistically, USP10 interacted with and positively regulated PLK1 while decreasing its ubiquitination levels. Rescue experiment results demonstrated that the protective effect of USP10 on the septic intestinal injury was reversed by siRNA-PLK1.

    Conclusions: USP10 mitigates septic intestinal injury by stabilizing PLK1 via deubiquitination, reducing inflammation and apoptosis. This finding implies that USP10 might be a promising therapeutic target for managing septic bowel damage.

  • Article
    Xiaoling Tao, Miao Wang, Weidan Zhang, Hongwei Xiong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2713-2724. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.268
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    Background: Epithelial ovarian cancer (EOC) is a kind of malignant tumor in women all over the world. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) play a regulatory role in the progression of many cancers, but the exact mechanism is unknown. This study attempts to reveal the mechanism of taurine up-regulated gene 1 (TUG1) in EOC through transcriptome sequencing analysis and experimental research.

    Methods: Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was applied to detect the TUG1 expression in EOC cell lines. The activity and the metastasis of EOC cells transfected with si-TUG1 and si-NC were observed using Cell Counting Kit-8 (CCK-8) and Transwell® assay, respectively. The possible mechanisms of TUG1 to regulate the development of EOC were analyzed by transcriptome sequencing and verified by qRT-PCR. The sequencing sample grouping mainly included silencing TUG1 (si-TUG1) and silencing negative control (si-NC).

    Results: Abnormally elevated TUG1 was observed in EOC tissues compared with the adjacent tissues and benign tumor tissues (p < 0.01), and silencing TUG1 inhibited the life activities of cancer cells. The differentially expressed genes in two cell samples were screened by sequencing analysis. Functional analysis showed that TUG1 was related to bone mineralization, neuroactive ligand-receptor interaction and various cardiomyopathy, and TUG1 regulated the expression of related proteins. It was verified that silencing TUG1 enhanced the expression of B-cell lymphoma 2 (BCL2) binding component 3 (BBC3), Tumor necrosis factor receptor (TNFR) associated factor 1 (TRAF1), interleukin 1 receptor type 1 (IL1R1) and cyclin G1 (CCNG1) proteins and inhibited the expression of B-cell lymphoma 2 (BCL2)-like (BCL2L) compared with the si-NC group (p < 0.01).

    Conclusions: This study demonstrated the potential regulatory mechanism and target protein of TUG1 by transcriptome sequencing analysis, which provided a new insight into the role of TUG1 in EOC.

  • Article
    Jian Xu, Jun Li, HongQi Xiong, ZengFu Deng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2725-2732. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.269
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    Background: MicroRNAs (miRNAs), modulatory elements of translation are linked with the pathogenesis of various cerebrovascular illnesses, including intracerebral hemorrhage (ICH), and are considered promising prognostic biomarkers in diseases. The aim of this study was to investigate the diagnostic value of miR-135-5p and miR-34c-5p in predicting nerve injury after ICH.

    Methods: Serum miR-135-5p and miR-34c-5p were checked in 68 patients with acute spontaneous basal ganglia hemorrhage and 68 healthy controls. A multivariate analysis was carried out to assess the association of miR-135-5p and miR-34c-5p with prognosis, National Institutes of Health Stroke Scale (NIHSS) score as well as bleeding severity of hematoma volume indication. The diagnostic value was evaluated using receiver operating characteristic (ROC) curve.

    Results: miR-135-5p and miR-34c-5p were significantly reduced in the serum of patients and independently associated with NIHSS score and hematoma volume. miR-135-5p and miR-34c-5p expression was correlated with the poor prognosis of patients. Analyzing the area under the curve (AUC) showed that serum miR-135-5p and miR-34c-5p have promising diagnostic values.

    Conclusions: Serum miR-135-5p and miR-34c-5p are associated with the severity and clinical outcome of ICH patients, confirming that the two are potential prognostic biomarkers of ICH.

  • Article
    Yan Gu, Wei-Hong Zhao, Ying Wan, Jue-Hui Ren, Jun-Hua Shen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2733-2737. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.270
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    Objective: Globally, the prevalence of chronic kidney disease (CKD) has increased significantly. The objective of this study was to determine the risk factors for a slight decrease in the estimated glomerular filtration rate (eGFR) in a healthy population.

    Methods: Participants aged between 18 to 79 who underwent a physical examination at the Health Management Center of Affiliated Hospital 2 of Nantong University (Nantong, China) were enrolled. The mild reduction in eGFR is defined as 60–90 mL/min/1.73 m2. A multivariate logistic stepwise regression analysis was performed to determine the risk factors for mild eGFR decline in healthy individuals. Using the receiver operating characteristic curve, we determined the predictive value of these factors on the mildly decreased eGFR.

    Results: The eGFR of 7832 participants (11.8%) decreased mildly. Univariate logistic regression analysis identified male, age, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, uric acid (UA), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) as potential risk factors for a mildly decreased eGFR. Multivariate logistic analysis identified male, age, DBP, uric acid, and LDL-C as independent risk factors for eGFR decline.

    Conclusions: In a healthy population, the prevalence of a slight decline in eGFR was 11.8%, and (male) gender, age, DBP, UA, and LDL-C were all independent risk factors for a slight decline in eGFR.

  • Article
    Xingjun Li, Meiqin Huang, Yu'e Yuan, Yun Qin, Li Zhang, Degao Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2739-2747. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.271
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    Background: Although polycytosine binding protein 2 (PCBP2) and nuclear associated Kiel 67 antigen (Ki67) have been extensively studied in non-small cell lung cancer (NSCLC), their prognostic value remains controversial. This aim of this work was to investigate the expression of PCBP2 and Ki67 in NSCLC and their value for its prognosis.

    Methods: This prospective study selected a cohort of 84 NSCLC patients from Chongming Hospital, affiliated with Shanghai University of Medicine and Health Sciences, between November 2017 and December 2022. Univariate analysis and multivariate Logistic regression were carried out to analyze the relationship between expressions of PCBP2 and Ki67 and clinicopathological features in NSCLC patients.

    Results: PCBP2 was mainly expressed in cytoplasm and nucleus, with a positive rate of 70.23%. Ki67 was mainly expressed in the nucleus with a positive rate of 59.52%. Multivariate Logistic regression analysis (MLRA) showed that pathological classification, degree of tumor differentiation, and lymph node metastasis (LNM) were factors influencing the high expression of PCBP2. Gender, pathological type, and degree of tumor differentiation were significantly associated with the high expression of Ki67. Compared with the 2-year survival rate of negative patients, that of PCBP2 positive and Ki67 positive patients was significantly lower (p < 0.05). Compared with shControl group, the proliferation ability of NSCLC A549 cells in shPCBP2 group was significantly decreased (p < 0.05).

    Conclusions: PCBP2 and Ki67 were upregulated in NSCLC tissues, promoting the proliferation of NSCLC. The high expressions of PCBP2 in NSCLC patients were significantly associated with pathological classification, degree of tumor differentiation, and LNM. The high expression of Ki67 in NSCLC patients was significantly associated with gender, pathological type, and degree of tumor differentiation. The prognosis of PCBP2 and Ki67 positive patients was significantly poorer than PCBP2 and Ki67 negative patients.

  • Article
    Shuheng Wang, Bide Liu, Jiuzhi Li, Weili Du, Hongliang Jia, Peng Lei, Xun Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2749-2757. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.272
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    Background: Prostate cancer (PC) is a malignant tumor with higher death rate. Chromodomain-helicase-DNA-binding-protein 1-like (CHD1L) has been shown to be a key facilitator in cancers' progression. High expression of methionine aminopeptidase 2 (METAP2) has been demonstrated in PC. However, the effects of CHD1L/METAP2 axis on PC progression are still undefined.

    Methods: The expressions of genes were confirmed by Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), western bot or Immunohistochemistry (IHC) assay. Cell proliferation was tested by Cell counting kit-8 (CCK-8) and colony formation. Cell invasion and migration were examined using Transwell assay. The angiogenesis ability was assessed using tube formation. Tumor growth was evaluated in vivo assay.

    Results: CHD1L expression was up-regulated in the prostate adenocarcinoma (PRAD) tissues as compared to that in normal tissues using UALCAN and TIMER2.0 online websites. Further studies demonstrated that CHD1L exhibited higher mRNA and protein expression in PC tissues and cell lines. In addition, knockdown of CHD1L suppressed cell proliferation, migration and angiogenesis in PC. Positive correlation between CHD1L and METAP2 was shown in analysis based on TIMER2.0 and GEPIA online websites. Moreover, it was shown that CHD1L upregulated METAP2 expression in PC. METAP2 overexpression was shown to rescue the decreased cell proliferation, migration and angiogenesis mediated by CHD1L knockdown. Suppression of CHD1L was shown to inhibit tumor growth in vivo.

    Conclusions: Knockdown of CHD1L reduced PC cell proliferation, migration and angiogenesis through reducing METAP2. Our findings illustrated that the CHD1L/METAP2 axis may be useful bio-targets for PC treatment.

  • Article
    Jiasheng Yan, Yunqiu Gao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2759-2767. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.273
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    Background: Although tissue inhibitor of metalloproteinase-1 (TIMP1) is crucial for the growth of malignancies, its function in kidney renal clear cell carcinoma is still unknown. The purpose of this research was to learn more about its biological role and clinical importance in human kidney renal clear cell carcinoma (KIRC).

    Methods: The public database TCGA (The Cancer Genome Atlas) provided information on KIRC (Kidney Renal Clear Cell Carcinoma) patients. To assess the impact of TIMP1 on the prognosis of patients with KIRC, the Kaplan-Meier (KM) survival analysis was employed. Critical genes were analyzed and locked using the Protein-Protein Interaction (PPI) network and the Cytoscape software (version 3.7.2, Cytoscape Consortium, San Diego, CA, USA) with the cytoHubba function. To build the prediction model, univariate and multivariate Cox regression analysis were utilized. The expression level of TIMP1 was discovered using UALCAN. TIMP1 mRNA expression levels in KIRC were assessed for their predictive value using the Kaplan-Meier Plotter.

    Results: TIMP1 was expressed more heavily in KIRC tumor cells than in normal tissues. Different tumor subtypes, tumor grades, and tumor stages were all significantly associated with abnormal TIMP1 expression. TIMP1 was identified by the Cox proportional hazard model as a significant predictor marker for overall survival in individuals with KIRC. In addition, we found that TIMP1 is closely related to multiple tumor pathways and the collagen formation pathway.

    Conclusions: TIMP1 might be crucial in facilitating KIRC tumorigenesis and spread. It might serve as a KIRC prognostic predictor.

  • Article
    Yan Yang, Xiangxin Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2769-2775. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.274
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    Background: Periodontitis is a chronic infectious disease that leads to decreased quality of life. However, the relationship between sirtuin 1 (SIRT1) and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) in periodontitis has not been studied.

    Objective: To elucidate the effects of SIRT1 on OPG/RANKL signaling pathway and periodontitis progression.

    Methods: In vivo periodontitis models were constructed using 12 male Wistar rats through ligation methods. Gingival fibroblasts were obtained from rat gingival tissues and treated with 1 μg/mL lipopolysaccharide (LPS) for 24 h to induce in vitro periodontitis models. Cell transfection was performed, using plasmid pcDNA3.1 containing the coding sequence of OPG or SIRT1 and Lipofectamine 3000. Hematoxylin and eosin (H&E) kit was used for evaluating histology and tartrate-resistant acid phosphatase (TRAP) staining was implemented for determining the content of osteoclasts. Enzyme linked immunosorbent assay (ELISA) assay was used to detect inflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. RT-qPCR (real-time quantitative polymerase chain reaction) was utilized for relative mRNA (messenger ribonucleic acid) levels monitoring.

    Results: The expression of RANKL was upregulated, while SIRT1 and OPG were downregulated in rat periodontitis models. Moreover, overexpression of OPG attenuated periodontitis progression in vitro. Further studies showed that overexpression of SIRT1 significantly enhanced OPG/RANKL ratio, inhibited osteoclastogenesis and alleviated periodontitis progression.

    Conclusions: Overexpression of SIRT1 activated OPG/RANKL signaling pathway, inhibited osteoclastogenesis and attenuated periodontitis progression.

  • Article
    Yumei Huang, Dianguo Zhao, Changcheng Ding, Xiangrui Ma, Honghai Fu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2777-2788. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.275
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    Background: The Klotho family comprises a series of newly identified anti-aging genes, including α-Klotho (KL), β-Klotho (KLB), and γ-Klotho (LCTL). However, the role of LCTL in the progression of head and neck squamous cell carcinoma (HNSCC) has not been elucidated.

    Methods: The expression of KL/KLB/LCTL and gene variations in patients with HNSCC were analyzed using the CbioPortal and The Cancer Genome Atlas Program (TCGA) databases. Moreover, KL/KLB/LCTL expression levels in HNSCC tissues were determined using real-time quantitative PCR (Polymerase Chain Reaction) (qPCR) and compared with those in paired non-cancerous adjacent tissues. Cell viability and apoptosis of HNSCC cells were assessed using methylthiazoletetrazolium (MTT) and fluorescence-activated cell sorting assays, respectively. The levels of LCTL and key proteins in the phosphatidylinositol-3-kinase (PI3K)/serine/threonine-protein kinase (Akt) signaling pathway were determined using western blotting.

    Results: The KL/KLB level was decreased, and the LCTL level was elevated in patients with HNSCC compared with that in normal controls. In addition, the LCTL level was increased in HNSCC cell lines compared with that in human keratinocyte (HACAT) cells. Interference with LCTL significantly suppressed the proliferation of HNSCC cells, promoted apoptosis of SCC (Squamous Cell Carcinoma) 15 cells, and increased the expression of (BCL2 Associated X) Bax and p21 by inhibiting PI3K and Akt phosphorylation.

    Conclusions: The data suggest that LCTL is a potential diagnostic biomarker for patients with HNSCC. Interference with LCTL significantly suppressed the viability of HNSCC cells and promoted apoptosis of SCC15 cells via the PI3K/Akt signaling pathway.

  • Article
    Laibijiang Wusiman, Hua Gao, Anwaier Apizi, Lin Wang, Bowei Cao, Wenbin Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2789-2796. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.276
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    Objective: PPP2R1A is a conserved subunit of protein phosphatase 2 (PP2A) and a serine/threonine phosphatase that participates in the dephosphorylation of specific proteins. Previous studies found that PPP2R1A acts as a tumor suppressor. Apart from its phosphorylation function, the specific regulatory mechanism for cancer development through PPP2R1A-mediated transcriptional or post-transcriptional regulation remains unknown. We expected to reveal potential function of PPP2R1A in cells lines.

    Methods: We cloned and overexpressed PPP2R1A to explore the function and regulatory pattern of PPP2R1A in HeLa cells and used RNA sequencing to analyze PPP2R1A-regulated gene expression as well as alternative splicing (AS) among PPP2R1A overexpressing cells and control cells.

    Results: When compared with the control samples, the overexpression of PPP2R1A resulted in a significant suppression of the proliferation in HeLa cells. Furthermore, it regulated the expression of hundreds of genes in terms of cell adhesion, positive regulation of JUN kinase activity, viral response, cell growth regulation, and positive regulation of inflammatory response. Moreover, the AS of genes involved in the cell cycle, junction adherence, endometrial cancer, and RNA transport were regulated by PPP2R1A. The genes related to tumor metastasis and AS (alternative splicing) genes were verified by quantitative reverse transcription realtime polymerase chain reaction (RT-qPCR) experiments.

    Conclusions: Our findings suggest that PPP2R1A may have a wide range of regulatory functions at the gene expression and post-transcriptional levels via the modulation of AS and messenger ribonucleic acid (mRNA) associated with cancer.

  • Article
    Sara Abdolkhane, Mohammad Reza Rahbar, Sepideh Sadeghiseghdil, Hoora Mazaheri, Sarvenaz Falsafi, Farhad Riazi Rad, Ava Behrouzi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2797-2808. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.277
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    Background: Microorganisms colonizing the gastrointestinal tract interact with the host through epithelial cells. More than 60% of the immune cells in the intestine are located in the intestinal mucosa, making it the body's major defensive barrier. Commensal bacteria, their metabolites, and toll-like receptors interact with the epithelial cells in the intestine to maintain homeostasis and promote immunity. HT-29 is a human colorectal adenocarcinoma cell line with epithelial morphology.

    Materials and Methods: In this study, Escherichia coli strain Nissle 1917 (EcN) bacteria and their outer membrane vesicles (OMVs) exerted influence on the expression of toll-like receptors (TLRs) pathway genes in HT-29 cells. Real-Time PCR was used to measure the expression of TLRs signalling pathway genes after RNA extraction and cDNA synthesis. A real-time quantitative reverse transcription PCR array using SYBR Green method was conducted to determine the mRNA expression of 84 genes involved in the TLR signalling pathway.

    Results: EcN induced the down-regulation of pro-inflammatory genes such as IRAK4, MAP2K4, CCL2, NFRKB, and IRAK1. Further, OMVs derived from EcN stimulated the HT-29 cells by downregulating several genes involved in the inflammatory responses such as IRAK1, IRAK4, CD14, MYD88, and MAP4K4 and up-regulating the anti-inflammatory interleukin-10. However, EcN OMVs caused mild inflammation and anti-inflammatory responses that influenced intestinal homeostasis.

    Conclusions: Postbiotics are non-replicate, so they are unable to cause probiotic-associated risks like bacteraemia fungaemia, etc.

  • Article
    Tianyi Ai, Zhiyun Zhang, Mingli Zhu, Lihui Wang, Hui Wu, Jiajia Tang, An Shi, Zhiqiang Shi, Min Li, Hui Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2809-2817. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.278
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    Background and Objective: Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke with a poor prognosis. The characteristics of ICH-related gut microbiota dysbiosis are unknown. The current study aims to investigate the differences in gut microbiota profiles between ICH patients and healthy controls.

    Methods: From July 8, 2019, to December 31, 2020, we performed a prospective clinical trial (Chinese Clinical Trail Registry, ChiCTR2000034906) and enrolled eligible participants, including ICH patients and healthy controls. Based on the brain computed tomography scan results, ICH patients were further categorized into thalamus hemorrhage (TH) and non-thalamus hemorrhage (NTH) subgroups. All participants were fed with the same principle of nutritional schemes, and their stool samples were collected after 5 days. The gut microbiota profiles in stool samples were determined using 16S rDNA amplicon sequencing. Clinical outcomes of the ICH patients were recorded, including the length of hospital stay, length of intensive care unit stay, neurological functions, and mortality.

    Results: The ICH and healthy control groups had 40 and 47 participants, respectively. The diversity (decreased Simpson and Shannon index, p = 0.002 and 0.001, respectively), microbial community structure, phylogenetic diversity, and abundant gut microbiota taxa in the ICH group were significantly different from those in the control group. However, there was no difference in gut microbiota changes and clinical outcomes between the two ICH subgroups (TH, N = 11, vs NTH, N = 29).

    Conclusions: Compositional alterations in gut microbiota were common in adult patients with ICH, but there was no significant difference between the ICH subtypes.

  • Article
    Ghada M. Ezzat, Ragaa H.M. Salama, Ahmed Abbas, Michel E. Fakhry, Mohammed F. Ramadan, Mustafa M. Kamel, Asmaa S. Shaltout, OA Sayed, Rania Farghaly
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2819-2828. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.279
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    Background: Preeclampsia remains a leading cause of maternal and neonatal morbidity and mortality. It is characterized by altered local and systemic immune regulation and a rise in proinflammatory cytokines. The inflammasome is a cytosolic protein complex that mediates innate immune responses through promoting the secretion of interleukin-1beta (IL-1β). This study aimed to investigate the nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3, inflammasome activation in preeclampsia (PE), its relation to IL-1β and their association with PE outcomes.

    Methods: Placenta and blood were collected from 25 control pregnant women and 50 preeclamptic women. Pyrin domain-containing protein 3 (NLRP3) and IL-1β gene expression were quantified by real-time polymerase chain reaction (PCR).

    Results: Placental and blood relative gene expression levels of NLRP3 and IL-1β were significantly higher in mild and severe PE than in controls. A significantly higher blood expression of NLRP3 was noticed in the low birth weight subgroup compared to the normal birth weight subgroup (p = 0.03) in the severe PE group. Both biomarkers levels in placenta and blood showed significant negative correlations with the weight of newborn. The strong positive correlation (p < 0.0001, r = 0.9) between NLRP3 and IL-1β suggested that IL-1β response mostly depend on NLRP3 inflammasome.

    Conclusions: These results suggest the presence of excessive activation of NLRP3 and subsequently increased production of active IL-1β that may predispose placental inflammation in severe PE and subsequently, low neonatal birth weight and shortened gestational age.

  • Article
    Lei Tang, Shaokui Hua, Guocheng Li, Zhiwei Fang, Jiawang Yu, Houbao Huang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2829-2836. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.280
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    Background: The surgical treatment radical prostatectomy (RP) is an effective treatment for limited prostate cancer. However, some patients experience biochemical recurrence (BCR) after surgery, leading to disease recurrence. The aim of this study is to investigate the relationship between a series of clinical indicators, including postoperative nadir prostate-specific antigen (PSA), the period until nadir PSA, and BCR in pathological T2 stage (pT2), negative surgical margins (NSM) patients, with the goal of identifying the high-risk population of BCR in these patients and promptly intervening clinically.

    Methods: A retrospective study was conducted on 119 patients admitted to our hospital, between October 2015 and December 2020, for RP with pT2 pN0, NSM and no prior use of neoadjuvant chemotherapy or endocrine therapy, and no history of other malignancies. PSA levels were initially measured one month after surgery, followed by weekly checks from one to seven months and monthly checks thereafter. PSA can be detected at PSA >0.01 ng/mL. BCR was defined as two consecutive postoperative PSA ≥0.2 ng/mL or a postoperative nadir PSA ≥0.2 ng/mL. Patients were monitored for BCR for three years following surgery. The prognostic model for BCR after RP was established by univariate and multifactorial analysis through the Cox proportional hazards model. Kaplan-Meier analysis was used to plot the BCR-free rate curves.

    Results: During the three years of follow-up, a total of 57 of 119 patients (48.7%) experienced BCR. In univariate analysis, pathological Gleason score (≤3+4 vs ≥4+3, p < 0.001), pathological maximum tumor diameter (p = 0.035), postoperative nadir PSA (≤0.01 ng/mL vs >0.01 ng/mL, p < 0.001), and period until nadir PSA (≤60 days vs >60 days, p < 0.001) were all associated with postoperative BCR. In contrast, only postoperative nadir PSA (p < 0.001) and the period until nadir PSA (p = 0.05) had statistically significant differences in multifactorial analysis and were independent risk factors for postoperative BCR in pT2 and NSM patients.

    Conclusions: In this paper, we point out that in pT2 and NSM patients, both had a detectable postoperative PSA minimum (>0.01 ng/mL) and a longer PSA decline (>60 days) increasing the risk of BCR.

  • Article
    Ya Zhang, Yi-Qun Ma, Li-Shi Shao, Chen Shi, Chun-Juan Xia, Sui-Xing Zhong, Wei-Hu Zhang, Su-Ping Yang, Hong-Jun Li, Jia-Ping Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2837-2848. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.281
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    Background: Doxorubicin nephropathy (DRN) is a well-known chronic kidney disease (CHKD) model. Doxorubicin (Dox)-induced nephrotoxicity involves high oxidative stress, apoptosis, and necrosis. However, it is still unclear if Dox causes DRN to undergo pyroptosis (PYT), a particular inflammatory-mediated form of cell death. Bone marrow-derived mesenchymal stem cells (BMMSCs) have therapeutic potential in improving the structure and function of DRN. However, whether BMMSCs regulate PYT in DRN is also not clear.

    Objective: Our study was to investigate the possibility of BMMSCs in inhibiting TLR4 (toll-like receptor 4)/NF-κB (nuclear factor kappa B)/NLRP3 (nucleotide oligomerization domain (NOD)-like receptors 3) inflammasome-mediated PYT in the DRN rat model.

    Methods: The rat treatments consisted of four groups (n = 8 rats each): Group A (Nor), normal rats treated with equivalent DMEM (dulbecco's modified eagle's medium) medium; Group B (Con), normal rats receiving no treatment; Group C (Dox), DRN rats treated with phosphate buffer; Group D (Dox + BMMSCs). On days 1 and 15, tail vein injections of Dox (4 mg/kg) were used to develop the rat chronic renal disease model (DRN). By the end of week 11, the DRN model was effectively produced, and it had been successfully treated with a single BMMSC injection in the right renal artery through the carotid artery dissection method. By using Western blotting and ELISA (Enzyme-Linked Immunosorbent Assay), the levels of TLR4, NF-κB, NLRP3, Caspase-1, GSDM-D (gasdermin-D), TNF (tumor necrosis factor), MCP-1 (monocyte chemoattractant protein-1), TGF-1 (transforming growth factor 1), α-SMA (α smooth muscle actin), IL-1 (interleukin-1), IL-18, and IL-6 in the kidney tissues of the animals were determined 8 weeks after the second Dox treatment.

    Results: Our experimental results showed that the levels of TNF-α, MCP-1, TGF-β1, and rats in the BMMSCs treatment (group D) had considerably lower levels of α-SMA than untreated (group C) rats (p < 0.05).

    Conclusions: In a DRN rat model, Dox could induce pyrogenic cell death, but the mortality was attenuated by treating with BMMSCs. Our results bring new insights into the use of the anti-inflammatory activity of BMMSCs as an effective alternative therapy for CHKD.

  • Case Report
    Michele Abate, Vincenzo Salini, Luigi Sammarchi, Carmine Stefano Poerio, Riccardo Del Vescovo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(5): 2849-2854. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233705.282
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    Background: Plantaris tendon (PT) is an accessory muscle with a negligible functional role. Isolated ruptures of the muscle-tendon complex in athletes usually occur in the proximal myo-tendinous junction in the upper part of the calf. The distal ruptures are not frequent and no more than ten cases have been reported in literature. In this paper we are going to describe a new case of distal PT rupture in a young soccer player.

    Methods: An 18 years old semi-professional football player, after kicking the ball with his right foot, reported pain and functional limitation in the distal third of the left leg, at the medial edge of the Achilles tendon. Clinical examination showed tenderness on palpation associated with mild swelling. Walking was associated with pain at the phase of plantar flexion of the left foot. Thompson test and neurological/vascular examinations were negative. The radiological evaluations (ultrasound and magnetic resonance imaging), performed a few days after the event, showed a distal sub-total tear of the left PT. Between the tendon ends, connected by a thin tendinous filament, a fluid collection was present.

    Results: A structured rehabilitation protocol was implemented, allowing the player to come back to his full athletic activity after 9 weeks. Radiological examination after 6 weeks demonstrated scar reconstitution with no residual tear or fibre discontinuity. The tendon demonstrated fusiform thickening reflecting incompletely remodeled scarring.

    Conclusions: At our best knowledge, this is the first case where the spontaneous reconstitution of PT has been demonstrated by imaging techniques.