20 April 2023, Volume 37 Issue 4

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  • Review
    Gu-Hao Cai, Tian-Yi Yuwen, Tian-Pu Wang, Xiang Shi
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1745-1752. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.173
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    Hepatogenic diabetes (HD) is secondary to chronic liver parenchymal damage. The main manifestations of HD are hyperglycemia and impaired glucose tolerance, which is caused due to the destruction of the islet cells of pancreas, resulting in the disruption of glucose metabolism. Liver disease and diabetes mellitus are closely related and influence each other. Liver disease may lead to a rise in blood glucose and hence diabetes, which further affects the recovery and treatment of liver disease. It also promotes the deterioration of the liver to a certain extent, because the relationship between cirrhosis and diabetes is highly significant. However, in clinical practice, it is easy for medical personnel to ignore blood glucose in patients with early liver disease, possibly missing the early diagnosis of HD. Therefore, it is important to monitor the blood glucose in patients with liver disease. In this study, we discuss several mainstream blood glucose monitoring techniques to facilitate further research especially in HD.

  • Review
    Ningbin Du, Yunxia Niu, Zuhao Tian, Yongqi Hao, Jinying Meng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1753-1760. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.174
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    Background: Esophageal cancer is a malignant tumor of the upper gastrointestinal tract caused by environmental and genetic factors. Genetic polymorphisms and expression variations of esophageal cancer susceptibility genes are key influencing factors of individual susceptibility to tumors. Due to the insufficient screening of risk factors for esophageal cancer by traditional epidemiology, identification of esophageal cancer risks at the molecular level may benefit esophageal cancer prevention and therapy. The p53 gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT) gene, P16 gene, mismatch repair gene, and Phospholipase C Epsilon 1 (PLCE1) gene have been heavily studied in recent years given their roles in the genesis and progression of esophageal cancer. Therefore, this paper briefly outlines the significance of esophageal cancer susceptibility gene testing for subsequent treatment, providing a feasible pathway for early diagnosis, prognosis assessment and gene therapy of esophageal cancer.

  • Article
    Guangda Xin, Guangyu Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1761-1773. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.175
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    Objective: Emerging evidence has confirmed the involvement of infiltrating immune cells and immune-related genes in membranous nephropathy (MN) pathogenesis. This study aimed to explore immune-related signatures for risk prediction in patients with MN.

    Methods: Transcriptome sequencing data associated with MN were collected from public databases to screen for differentially expressed genes (DEGs). Immune cell infiltration was evaluated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) software (Stanford University, San Francisco, CA, USA), and immune-related genes were screened. Functional enrichment analysis was performed, followed by construction of regulatory networks. The optimal signature genes were identified using multiple bioinformatics methods. A nomogram model was established and validated for the diagnostic prediction of patients with MN. Co-expression associations between hub genes and the proportion of immune cells were investigated.

    Results: A total of 576 DEGs were identified between the MN and control samples. Eight immune cell types with differential proportions were identified and 325 DEGs were selected as immune-related genes. These DEGs were primarily involved in cell adhesion, inflammatory response, complement and coagulation cascades, cytokine-cytokine receptor interactions, and HTLV-I (human T-lymphotropic virus type I) infection. Finally, a total of eight immune genes were selected as the optimal biomarkers associated with MN, such as APOBEC3F, IL1RL1, MDK, and NR4A3. A diagnostic nomogram model consisting of eight genes was established and verified using the combined and validation datasets. There was a significant correlation between the signature genes and infiltrated immune cells (p < 0.05).

    Conclusions: Eight immune-related genes that may serve as potential diagnostic biomarkers for MN were identified. A nomogram model incorporating signature genes is convenient for facilitating individual risk prediction of MN.

  • Article
    Juan Dong, Shanshan Cheng, Xiaoqun Yang, Bing Liao, Zhen Ruan, Shuangqing Zhang, Fukang Luo
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1775-1781. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.176
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    Background: There is a primary pathogen responsible for Mycoplasma pneumoniae pneumonia (MPP) in children called Mycoplasma pneumoniae (MP). Patients with mild symptoms usually complain of paroxysmal dry cough by stimulation and fever, while those with severe conditions may develop bronchopneumonia, pleural effusions, and lung abscesses, and even accompanied by lesions in the nervous system or urinary system. We aimed to develop a rapid detection method for MP adhesion protein P1 by merging recombinase polymerase amplification (RPA) and Clustered Regularly Interspaced Short Palindromic Repeats/associated proteins (CRISPR/Cas12a) gene editing.

    Methods: In this study, the sequence of P1 adhesion protein region (GenBank: AF290001.1) of MP was obtained from the national center of biotechnology information (NCBI) database. Five groups of primers and probes were designed using Primer Premier 5 software (Premier Canada Inc., Charlotte, NC, USA), and the best primers were selected. Furthermore, in the meantime, the corresponding real-time fluorescence quantitative polymerase chain reaction (RT-PCR) primers were designed for subsequent validation tests to determine the reagent proportion, reaction time, reaction temperature, and primer-probe concentration of the reaction system. Finally, diseased clinical samples (strong positive, medium positive, weak positive) and healthy clinical samples (1, 2, 3) were used to verify the optimized cutting system.

    Results: Through the experiments, we verified that the optimal reaction time for RPA at 37 °C was 30 min, and the best product was obtained by cleaving Cas12a-crRNA for 60 min, with a result fetched within 2 h.

    Conclusions: This method is not only fast and convenient in operation but also ensures the specificity, rapid efficiency and visualization of the test results without relying on instruments and professional personnel. It provides a solution to the subjective judgment of the culture test method and the difficulty of smear preparation.

  • Article
    Yanqing Yang, Huanhuan Wang, Shengjun Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1783-1790. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.177
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    Background: The diagnostic value of microRNA in glioma was comprehensively evaluated by meta-analysis.

    Methods: PubMed, Embase, The Cochrane Library, China biology medicine, China national knowledge infrastructure, Wanfang database, and Chinese Weipu database were searched by computer from inception to June 2022. Meta-analysis was performed with Meta-Disc 1.4 (Hospital Univeritario Ramón y Cajal, Madrid, Spain) software and Stata 12.0 (StataCorp LLC, College Station, TX, USA, http://www.stata.com/) software to calculate the pooled sensitivity, pooled specificity, pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio (DOR). The presence of publication bias was assessed using Deek's funnel plot asymmetry test. Subgroup analysis was performed according to the sample type and the region of the included population. Fagan's nomogram was used to evaluate the pre- and post-probabilities of positive likelihood ratio (PLR) and negative likelihood ratio (NLR) after microRNA application.

    Results: Finally, 9 literature were included, including 455 patients with glioma and 342 controls. The heterogeneity test showed that there was obvious heterogeneity caused by non threshold effect. Meta-analysis showed that pooled SEN was 0.74 (95% CI (confidence intervals): 0.70, 0.78), pooled SPE (specificity) was 0.81 (95% CI: 076, 0.85), pooled PLR was 4.53 (95% CI: 3.81, 5.38), pooled NLR was 0.26 (95% CI: 0.23, 0.30), pooled DOR was 20.53 (95% CI: 9.09, 40.53). The SROC (summary ROC) curve shows area under the curve (AUC) was 0.8935. The asymmetric test of deek's funnel chart suggests that there is no significant publication bias. Conclusion the expression level of microRNA has a certain value in the diagnosis of glioma.

    Conclusions: MicroRNA expression level has a certain value for the diagnosis of glioma.

  • Article
    Xiang-Yang Tang, Juan Chen, Cheng Lei, Run Zhou, Pan Wang, Wen-Bing Deng, Fang-Fang Tan, Yu-Ling Bin, Ai-Jun Liao, Wei-Sheng Xiao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1791-1801. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.178
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    Background: Cancer stem cells (CSCs) are important factors for metastasis and recurrence. The relationship between miR-711 (small non-coding RNA) and gastric CSCs remains unclear. Thus, this study aimed to analyze the effect of miR-711 on the characteristics of gastric cancer stem cells.

    Methods: SGC-7901 gastric cancer cells were cultured in serum-free medium and CD44+ cells were sorted by magnetic separation. The colony forming ability, the expression of stem cell markers (CD133, Oct4 and Nanog), the cell invasion and migration ability were determined. In addition, the influence of miR-711 transfection was explored.

    Results: Previous studies have demonstrated that upregulation of miR-711 could inhibit epithelial mesenchymal transition (EMT) of gastric cancer cells. In addition, miR-711 has been proven to down-regulate the expression of Akt. LY294002, a commonly used PI3K inhibitor, was used to analyze the mechanism of miR-711 on gastric cancer stem cells. The RT-PCR assay and western blotting assay showed that LY294002 could decrease the expression of p-PDK1 (S241), p-Akt (T308) and Snail in CD44+ SGC-7901 cells transfected with miR-711 mimics.

    Conclusions: MiR-711 may down-regulate CD44+ SGC-7901 gastric CSCs characteristics by inhibiting PI3K/Akt/ Snail signaling pathway. MiR-711 may therefore serve as a new target for tumor therapy.

  • Article
    Jiongwei Pan, Zaiting Ye, Xiaoping Cai, Hao Zheng, Yiwei Jiang, Xin Wang, Zhuo Cao
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1803-1811. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.179
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    Background: Abnormal telomerase activity in cells is a warning sign of cancer. MiR-491-5p is related to a decline in telomerase activity, but the specific mechanism of action is still not clear. This study conducted research through bioassay combined with a series of molecular experiments.

    Methods: Bioassay was engineered to predict miR-491-5p binding site. The relationship between miR-491-5p and telomerase reverse transcriptase (TERT) was verified by double luciferase assay. Gene transfection assay was used to evaluate the miR-491-5p impact on telomerase activity via targeted genes. Cell viability, invasion, migration and angiogenesis were assessed by Cell Counting Kit-8 (CCK-8), Transwell, wound scratch and angiogenesis assays. Vascular endothelial growth factor (VEGF) expression levels and basic fibroblast growth factor (bFGF) in supernatant were tested exploiting ELISA (enzyme-linked immunosorbent assay). HIF-1α (hypoxia inducible factor-1α)/mTOR (mechanistic target of rapamycin) signaling pathway-related protein level were quantified with Western blotting.

    Results: TERT had a targeted binding relationship with miR-491-5p. Strengthened viability, invasion, angiogenesis and migration were found in telomerase-immortalized endothelial (TIVE) cells, which were reversed by miR-491-5p upregulation. TIVE cells showed telomerase activity, levels of VEGF, bFGF and HIF-1α upregulation as well as mTOR phosphorylation level, while overexpressed miR-491-5p inhibited the up-regulation of these changes in TIVE cells.

    Conclusions: MiR-491-5p reduced TIVE cell migration, viability, invasion and angiogenesis by inhibiting telomerase reverse transcriptase activity. Thus, targeting miR-491-5p might regulate the invasion, migration and angiogenesis of endothelial cells, thereby controlling tumors development.

  • Article
    Jinsong Zhang, Junguo Wang, Tao Xing, Yafeng Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1813-1828. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.180
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    Objective: To investigate the effect of long-term deviated nasal septum (DNS) on the structure of the nasal cavity in patients of different ages.

    Study Design: A retrospective study.

    Setting: A total of 152 patients with DNS and 121 hospitalized patients without DNS in Huai'an hospital, China, were recruited from January 2013 to December 2018.

    Methods: The CT (computed tomography) measurements of the transverse diameter of nasal cavity (A) and paranasal sinus (B), bilateral angles between alveolar process of maxillary bone and palatal bone, interalveolar distance and maxillary rotation distance were compared between both groups. Then, those parameters in patients with DNS in four age groups (≤23, 23~31.5, 31.5~43 and >43 years old) were analyzed using tendency tests.

    Results: DNS group showed lower ratio of A/B (0.38 vs. 0.39) and A/(B – A) (0.60 vs. 0.64) than control, while showed higher B – A (54.54 ± 9.9 vs. 51.43 ± 8.98) compared with that of control (p < 0.05). Furthermore, DNS group had wider interalveolar distance (41.53 ± 3.73 vs. 38.82 ± 3.06) and maxillary rotation distance (11.65 vs. 10.10) than control group (p < 0.001). Then the parameters of ratio of A/B, A/(B – A) and B – A significantly differed among subgroups according to the age of patients with DNS. Lastly, tendency tests showed that the ratio of A/B and A/(B – A) shortened, but the B – A extended as age decreased (p < 0.05).

    Conclusions: The present study demonstrated that patients with long-term DNS had significant changes in nasal cavity and paranasal sinus. Especially, younger patients with DNS underwent more severe developmental defects of nasal cavity and paranasal sinus.

  • Article
    Jingsong Cui, Haiping Wang, Fang Yang, Qian Peng, Weiling Li, Kanghong Hu, Binlian Sun
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1819-1828. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.181
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    Background: Sono-photodynamic therapy (SPDT) is a novel anti-cancer strategy that has showed excellent preclinical antitumor effects by combining the advantage of photodynamic and sonodynamic therapy. Sensitizer is the most important element in SPDT, which directly influences the cytotoxicity of SPDT. This study investigated the effect of using sensitizer PCN 224 (PCN224-SPDT) in SPDT on mouse hepatocellular carcinoma Hepa1-6 (mouse hepatoma cells).

    Methods: Hepa1-6 cells were divided into a control group, PCN224 alone group (PCN224), ultrasound treatment alone group (US), PDT (photodynamic therapy) group (PCN224 + 5 J/cm2 laser), SDT (sonodynamic therapy) group (PCN224 + 1 W/cm2 ultrasound) and SPDT group (PCN224 + 5 J/cm2 laser + 1 W/cm2 ultrasound). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole ammonium bromide (MTT) was used to detect cytotoxicity. The uptake and distribution of PCN224 in Hepa1-6 cells were determined by fluorescence staining. Flow cytometry was used to analyze intracellular reactive oxygen species (ROS) levels, cell membrane permeability, DNA damage, cell apoptosis levels, and mitochondrial membrane potential. Scanning transmission electron microscopy (SEM) was used to observe the changes in cell microstructure.

    Results: PCN224-SPDT induced severe damage to the cell membrane, mitochondrial and deoxyribonucleic acid (DNA), ultimately resulting in cell apoptosis.

    Conclusions: This work suggests that PCN224 is a new sensitizer for SPDT, and PCN224-SPDT can cause Hepa1-6 cells multisite damage and induce cell apoptosis via ROS production.

  • Article
    Han-Yong Luo, Le-Tian Huang, Meng Cui, Ming-Lin Li, Jia-He Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1829-1842. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.182
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    Background: Centrosomal protein 55 (Cep55) is a mitogenic phosphoprotein that moves from the centrosome to the midbody of the cell and contributes to dislodging during late mitosis. It cooperates with the constituents of the intrasomal sorting complex, extracts the endosomal sorting complex required for transport (ESCRT) machinery, and promotes intercellular bridges contraction. Many studies have claimed an association between Cep55 expression and clinical performance prognosis. To verify this claim, a meta-analysis and bioinformatics analysis was performed to assess Cep55 prognostic and clinicopathological significance.

    Objective: The purpose of this study was to determine Cep55 prognostic value in neoplasms by analyzing the relationship between its expression and neoplasia patients clinico-prognosis.

    Methods: A meta-analysis and bioinformatics analysis was performed. Relevant studies were extracted from Pubmed, Embase, Cochrane Library, Web of Science, TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) databases using an appropriate search strategy. Quality of studies was evaluated by Newcastle-Ottawa Quality Weighted Assessment Scale (NOS). Meta-analysis was performed using the Stata 15.1 MP (multiprocessor) software (StataCorp company, College Station, TX, USA). Next, bioinformatics analysis was conducted to evaluate Cep55 expression in cancer patients. Cep55 expression data were retrieved from the Oncomine and GEPIA2 (Gene Expression Profiling Interactive Analysis 2) databases to compare Cep55 expression in dissimilar types of cancer and their relative health counterparts. Moreover, the association between Cep55 expression and the outcome of different carcinomas was evaluated.

    Results: A total of 11 studies involving 1535 cancer patients were included in the meta-analysis. Survival analysis showed that high Cep55 expression was associated with poor overall survival in patients with cancer (hazard ratio (HR): 1.58, 95% CI (confidence interval): 1.28–1.95, I2 = 0%, p = 0.589). Bioinformatic analyses indicated that high Cep55 expression was associated with prognosis in patients with different tumors.

    Conclusions: Cep55 may be used as a potential prognostic biomarker for the identification of patients with tumors.

  • Article
    Zhen Li, Zhirong Tan, Wei Xu, Liang Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1843-1851. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.183
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    Background: Neuropathic pain (NP) is a complex pain disorder caused by injury or dysfunction of the somatosensory nervous system. This study aimed to investigate the therapeutic effect of ANA-12 (a BNDF (brain-derived neurotrophic factor) inhibitor, N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl] benzo [b] thiophene-2-carboxamide, C22H21N3O3S, CAS No. 219766-25-3) on NP and its molecular mechanism.

    Methods: Rats were set into sham, model and ANA-12 groups (n = 10 mice/group). NP was induced in rats by sciatic nerve ligation. Astrocytes were treated with lipopolysaccharide (LPS, 100 ng/mL), ANA-12 (50 µM) and MHY1485 (10 µmol/L, C17H21N7O4, CAS No. 326914-06-1) to explore the role of ANA-12. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed. Rat spinal dorsal horn astrocytes were activated by LPS induction. Then, rats were treated with ANA-12 and mechanistic target of rapamycin (mTOR) agonists. Cell viability was monitored with cell counting kit 8 (CCK8). Immunofluorescence was used to test activated astrocytes and low complexity communications codec (LC3B) expression. Enzyme linked immunosorbent assay (ELISA) was conducted to measure interleukin (IL)-1β, IL-6 and tumour necrosis factor alpha (TNF-α) concentrations. The expression of autophagy and signaling pathway-related proteins and genes was analyzed by western blot and reverse transcription quantitative-polymerase chain reaction (RT-qPCR).

    Results: MWT and TWL of NP rats were significantly reduced compared to normal rats. The number of activated astrocytes increased in the spinal cord tissue of NP rats. The concentration of inflammatory factors and the expression of brain-derived neurotrophic factor (BNDF) and its specific receptor tropomyosin-receptor kinase B (TRKB) proteins increased in the spinal cord of NP rats. After ANA-12 treatment, astrocytes cell viability did not change significantly. Interestingly, ANA-12 treatment significantly reduced LPS-induced activation of astrocytes and pro-inflammatory factors compared to NP rats. Meanwhile, BNDF and TRKB proteins expression decreased, and LC3B and Beclin 1 genes and proteins expression increased after ANA-12 treatment in NP rats. mTOR agonists reversed the autophagy-promoting effect of ANA-12.

    Conclusions: Many astrocytes were abnormally activated in NP rats. ANA-12 inhibited inflammation and targeted mTOR to promote autophagy and reduce the activation of LPS-induced astrocytes. In summary, ANA-12 can alleviate NP.

  • Article
    Xin Liu, Xiangu Ning, Zhen Yang, Ruiling Zhu, Weiqing Kong, Guilan Xia, Xiaobo Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1853-1864. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.184
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    Objective: This study aimed to identify gene markers that can predict the response to neoadjuvant chemoradiotherapy (neo-CRT) in esophageal cancer.

    Methods: Three datasets were used. After pre-processing, weighted gene co-expression network analysis (WGCNA) was used to screen the key module. Differentially expressed genes (DEGs) were selected, followed by screening of chemoradiotherapy (CRT) response markers by least absolute shrinkage and selection operator (LASSO) regression analysis.

    Results: Pink and yellow modules were screened using WGCNA. In total, 763 DEGs were identified. Ninety-eight common genes were identified after Venn analysis. Finally, LASSO regression analysis revealed 12 predictive gene markers, including LCE3D, PPP4R4, CTNNA2, ALOX12b, GLIS3, LINC00592, RIBC2, IQCF5-AS1, WIF1, MRAP2, ZIC1, and AkR1C1. The model constructed using these 12 genes accurately predicted the CRT response.

    Conclusions: The 12 screened genes, such as CTNNA2, WIF1, and GLIS3 may serve as predictive markers of neo-CRT response in esophageal cancer.

  • Article
    Guoqing Zhu, Yanping Ma, Xue Fu, Xiaofei Ai, Gang An, Hui Cheng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1865-1872. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.185
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    Objectives: This study evaluates the potential exosomal microRNAs (miRNAs) and associated molecular mechanisms during the progression of multiple myeloma (MM).

    Methods: Serum exosomes RNA isolation and transcriptome sequencing were assessed in MM patients and healthy individuals. The differentially expressed miRNAs (DEmiRNAs) were assessed depending on the sequencing data. miRNA-mRNA relations analysis, enrichment analysis, protein-protein interaction (PPI) network investigation, miRNAs and mRNAs and competing endogenous RNAs (ceRNA) network analysis were performed.

    Results: 665 miRNAs were identified from the raw exosome RNA sequencing data. A total of 46 DEmiRNAs and 419 miRNA-mRNA interaction relations were found in the two groups. The mRNAs in miRNA-mRNA interactions were gathered in functions of salivary gland development and pathways like PI3K (phosphoinositide 3-kinases)-Akt (protein kinase B) signaling. Finally, a ceRNA network constructed with several lncRNA-miRNA-mRNA interactions including SPACA6P-AS-miR-125b-5p-signal transducer and activator of transcription 3 (STAT3) was created.

    Conclusions: Salivary gland development function and PI3K-Akt signaling pathway enriched by exosome-based gene contributed to the development of MM. Moreover, exosome-derived miR-125b-5p and STAT3 in SPACA6P-AS-miR-125b-5p-STAT3 axis may potentially be used as biomarkers for the progression of MM.

  • Article
    Jiazhe Liu, Xiaoli Xie, Weiyan Liu, Gaofeng Pan, Anwei Mao, Qing Zhang, Lang Tang, Bin Hu, Hongchang Li
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1873-1882. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.186
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    Background: Exosomes play crucial roles in cell-to-cell communication and metastatic progression in triple-negative breast cancers (TNBC). However, the intercellular communication between different metastatic potential cancer cells is not fully understood in TNBC. Thus, we aimed to evaluate miR-525-5p mechanism in the communication between different metastatic potential TNBC cells.

    Methods: Exosomes were collected from high-metastatic (HM)- and low-metastatic (LM)-TNBC cells and then identified by nanoparticle tracking analysis (NTA) and transmission electronic microscopy (TEM), and miR-525-5p level was evaluated by real-time quantitative-polymerase chain reaction (RT-qPCR). Additionally, in vitro assays were used to clarify the role of exosomal miR-525-5p to regulate the crosstalk between HM- and LM-TNBC cells. Moreover, dual-luciferase reporter assay was used to identify the relationship between miR-525-5p and its target gene Bcl-2 associated X (Bax). Western blot assay was performed to determine Bax, Bcl-2 and cleaved caspase 3 levels in TNBC cells.

    Results: MiR-525-5p level in HM-TNBC cells exosomes significantly increased compared to LM-TNBC cells exosomes. Additionally, HM-TNBC cells exosomes can deliver miR-525-5p to LM-TNBC cells. Moreover, exosomal miR-525-5p derived from HM-TNBC cells enhanced the migration of LM-TNBC cells. Furthermore, Bax was found as a potential target of miR-525-5p. Exosomal miR-525-5p inhibited anoikis of recipient cancer cells via downregulation of Bax and cleaved caspase 3 and upregula-tion of Bcl-2.

    Conclusions: Our results show that exosomal miR-525-5p could suppress anoikis and facilitate LM-TNBC cells metastasis via Bax downregulation.

  • Article
    Kui Yan, Liqiang Zhou, Jun Tan, Bing Xu, Zhi Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1883-1891. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.187
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    Background: The aim of this study was to explore the action and mechanism of action of nuclear protein 1 (NUPR1) in spinal cord injury (SCI).

    Methods: P12 cells were treated with thapsigargin (TG) and transfected with small interfering RNA targeting NUPR1 (siNUPR1) and CCAAT/enhancer binding protein homologous protein (CHOP) overexpression plasmid. In terms of the determination on cell viability, proliferation and apoptosis, cell counting kit (CCK)-8, 5-ethynyl-2’-deoxyuridine (EdU) and flow cytometry assays were harnessed. NUPR1, CHOP, B-cell lymphoma-2 (Bcl-2) associated X (Bax), B-cell lymphoma-2 (Bcl-2), cleaved (C)-cysteinyl aspartate specific proteinase (caspase)-12, protein disulfide isomerase (PDI), glucose-regulated protein 78 kDa (GRP78) and death receptor 5 (DR5) levels were tested using Western blot as well as quantitative reverse transcription-polymerase chain reaction (qRT-PCR).

    Results: NUPR1 expression was significantly boosted in TG-stimulated P12 cells. TG significantly repressed cell viability, proliferation and Bcl-2 level yet facilitated apoptosis and expression levels of Bax, CHOP, PDI, GRP78 and DR5. NUPR1 knockdown reversed the above effects of TG, whilst CHOP overexpression impaired the reversing effect of NUPR1 knockdown.

    Conclusions: NUPR1 knockdown significantly restrains TG-induced P12 cell loss, via inhibition of CHOP/DR5 axis.

  • Article
    Qian Zhao, Yarui Li, Mudan Ren, Guifang Lu, Yan Zhao, Yaping Liu, Zhenwei Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1893-1903. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.188
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    Background: Diarrhea is a common complication of enteral nutrition affecting the gastrointestinal tract. Curcumin has been shown to prevent a wide range of gastrointestinal maladies by improving the intestinal mucosal barrier function via inhibition of the RhoA (Ras homologyA)/Rho-associated kinase (RhoA/ROCK1) pathway.

    Objective: To explore the effect of curcumin on intestinal mucosal barrier dysfunction in lactose-induced diarrheal rats and identify its related mechanisms.

    Methods: Rat fecal parameters, growth and intestinal absorption functions were scored after curcumin treatment. Intestinal mucosal injury and intestinal permeability were evaluated by hematoxylin and eosin (H&E) staining and serum concentrations of FITC (Fluorescein Isothiocyanate)-labeled dextran (FD4). Immunohistochemistry and western blotting were used to measure intestinal epithelial tight junction proteins. The RhoA/ROCK1 pathway was investigated by using western blotting and qRT-PCR (quantificational Real-Time Polymerase Chain Reaction) methods. The findings demonstrated that rat feces abnormalities, growth and intestinal absorption function were corrected by a high dose of curcumin.

    Results: Curcumin alleviated intestinal mucosal barrier dysfunction and increased intestinal permeability and expression of tight junction proteins by inhibiting RhoA/ROCK1 signaling in diarrheal rats.

    Conclusions: Our findings indicated that curcumin attenuated intestinal mucosal barrier dysfunction in lactose-induced diarrheal rats via the RhoA/ROCK1 signaling pathway.

  • Article
    Meng Dou, Yingcong Guo, Bingxuan Zheng, Yang Li, Jin Zheng, Bo Wang, Xiaoming Ding, Wujun Xue, Puxun Tian, Huaibin Sun, Chenguang Ding
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1905-1914. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.189
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    Background: A recent study has reported that miR-223 inhibits renal ischemia/reperfusion (I/R) injury and pyroptosis. Mesenchymal stem cells derived exosomes (MSCs-exo) have been observed to improve renal functions after I/R injury, but the relationship between MSCs and miR-223 is not fully understood.

    Methods: Renal I/R mouse models were established. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to assess cell viability and proliferation. Renal histopathologic changes were visualized using H&E staining. Enzyme linked immunosorbent assay (ELISA) was performed to assess interleukin (IL)-18, IL-1β, serum creatinine, and blood urea nitrogen concentrations. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess RNA levels and western blot was used to assess protein levels. MSCs-exo characteristics were observed and evaluated using a transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA). The targeting relationship was verified by luciferase reporter assay.

    Results: MSCs promoted mouse kidney tubular epithelium cells (TCMK-1) and miR-223 level viability, while the exosome inhibitor reversed this effect. In the I/R mice, pyroptosis was exacerbated, and miR-223 expression was inhibited. MSCs-exo exhibited circular/elliptical shape by TEM, with particle sizes mostly 85–110 nm. Exosome-specific proteins CD9 and CD63 surface antigens were positive in MSCs-exo, with higher levels than MSCs. It was verified that NLR Family Pyrin Domain Containing 3 (NLRP3) was the target gene of miR-223. Furthermore, NLRP3 specific inhibitor promoted cell viability, reduced pyroptosis related genes and cytokines in hypoxia/reoxygenation TCMK-1 cells, which were reversed by miR-223 inhibition. Additionally, NLRP3 - miR-223 interaction was confirmed in the I/R mice.

    Conclusions: Exosomal miR-223 participated in renal I/R-induced pyroptosis by targeting NLRP3, prompting a novel therapeutic strategy for kidney I/R injury.

  • Article
    Weili Tian, Jun Li, Wenya Liu, Wenchao Ji
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1915-1922. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.190
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    Objective: To explore the feasibility of establishing a cell model with high expression of Echinococcus protoscolex calcium binding protein 1 (EPC1) in vitro.

    Methods: The target gene EPC1 (AF481884) information was synthesised and connected to the expression vector pcDNA3.4. The constructed positive plasmid was named EPC1-pcDNA3.4. The constructed overexpression plasmid vector was transfected into six groups, A1, A2, B1, B2, C1 and C2, after ultrapure extraction to remove the endotoxin. Each group contained three replicates, with A1, B1 and C1 as control groups and A2, B2 and C2 as experimental groups. Group A1 consisted of human lung cancer cells H1299. Group A2 consisted of human lung cancer cells H1299 + EPC1 vector transfection. Group B1 contained human liver cancer cells, HepG2. Group B2 comprised human liver cancer cells HepG2 + EPC1 vector. Group C1 consisted of normal hepatocyte HL7702. Group C2 contained normal hepatocyte HL7702 + EPC1 vector. The messenger ribonucleic acid (mRNA) and protein expression of EPC1 in groups A1, A2, B1, B2, C1 and C2 were determined by quantitative real-time PCR (qPCR) and western blotting, respectively.

    Results: The qPCR results showed that EPC1 mRNA was detected in groups A2, B2 and C2 but not in groups A1, B1 and C1. Western blotting results showed that EPC1 protein level was not expressed in any group.

    Conclusions: The high-expression cell model of EPC1 in hepatic alveolar echinococcosis was constructed in vitro, which is of great significance for diagnosing hepatic echinococcosis. The EPC1 protein is not expressed in vitro, which may be related to the expression vector and inflammatory response.

  • Article
    Yanbo Fan, Hailong Yin, Qin Zhou, Qiuyun Liu, Zijia Liu, Qiang Yin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1923-1931. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.191
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    Background: Hanchuan zupa granule (H granule) is a traditional prescription in treating cough and asthma in China. Nevertheless, the underlying mechanism by which H granule improve asthma is unclear. Evidences have demonstrated the involvement of extracellular-signal-regulated kinase (ERK) pathway in airway remodeling. Therefore, this study aimed to investigate whether ERK pathway involves the underlying mechanism of H granule on asthma.

    Methods: Fourty male Sprague-Dawley rats were randomly assigned into control, asthma, H granule and dexamethasone (positive control) groups. Asthma rat model was established by OVA (ovalbumin) sensitization and challenge. Lung histopathology was assessed by hematoxylin-eosin staining, followed by the measurement of bronchial basement membrane perimeter (Pbm), total bronchial wall area (WAt), inner wall area (WAi) and smooth muscle area (WAm). Levels of interleukin (IL)-13, IL-1β and IL-17 in bronchoalveolar lavage fluid (BALF), and serum immunoglobulin E (lgE) level were examined using ELISA (enzyme-linked immunosorbent assay). Western blotting and immumohistochemical staining were conducted to explore the expression of members in ERK pathway.

    Results: Structure of bronchus in asthma model changed, reflecting by increased WAt/Pbm, WAi/Pbm and WAm/Pbm, and such changes were reversed after H granule treatment (p < 0.05). Besides, levels of inflammatory cytokines IL-13, IL-1β and IL-17 in BALF and serum lgE were up-regulated in asthma model, while down-regulated after H granule treatment (p < 0.05). Additionally, ERK pathway was activated in asthma model, reflecting by up-regulated expression of C-FOS (Fos Proto-Oncogene, AP-1 Transcription Factor Subunit), C-JUN (Jun Proto-Oncogene, AP-1 Transcription Factor Subunit), p-ERK (Phosphorylated ERK), MEK1 ( Mitogen-Activated Protein Kinase Kinase 1), MMP9 (Matrix Metallopeptidase 9), TIMP1 (TIMP Metallopeptidase Inhibitor 1), RAF1 (Raf-1 Proto-Oncogene, Serine/Threonine Kinase) and RASA1 (RAS P21 Protein Activator 1), and the elevated expression for these genes were significantly down-regulated after the H granule treatment (p < 0.05).

    Conclusions: The therapeutical effect of H granule on asthma probably by regulating airway remodeling through ERK pathway and inhibiting inflammation.

  • Article
    Fangxiang Mu, Xin Yang, Mei Wang, Lin Liu, Fang Wang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1933-1947. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.192
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    Objective: This meta-analysis aimed to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on the treatment of recurrent miscarriage (RM) and recurrent implantation failure (RIF).

    Methods: Eligible randomized controlled trials (RCTs) and cohort studies were retrieved from the Web of Science, Cochrane, and PubMed databases and evaluated using the Jadad scale or Newcastle-Ottawa Scale. Cochran’s Q test and I2 statistics were used to assess heterogeneity. The effect sizes for clinical pregnancy and abortion rates of patients were pooled as risk ratios (RRs) and 95% confidence intervals (CI) using RevMan 5.3. Publication bias was assessed using funnel plots.

    Results: Thirteen studies (nine RCTs and three cohort studies) involving 1262 participants were included. Compared to the control/placebo group, the use of G-CSF significantly improved the clinical pregnancy rate [RRs (95% CI) = 1.73 (1.41, 2.12), p < 0.00001] of RIF patients; Whereas it had no significant impact on their abortion rate [RRs (95% CI) = 1.13 (0.43, 2.95), p = 0.80]. Both subcutaneous and intrauterine injections of G-CSF could improve the clinical pregnancy rate in RIF patients. However, subcutaneous injection showed a tendency to increase the abortion rate [RRs (95% CI) = 1.98 (0.40, 9.87), p = 0.40], whereas intrauterine injection showed a tendency to decrease the abortion rate for RIF patients [RRs (95% CI) = 0.93 (0.24, 3.53), p = 0.11]. In addition, G-CSF use had no significant impact on the clinical pregnancy rate of RIF patients in a South American study [RRs (95% CI) = 1.20 (0.60, 2.38), p = 0.60]. For RM patients, the use of G-CSF showed improved clinical pregnancy rates [RRs (95% CI) = 1.43 (0.76, 2.70), p = 0.27] and lower abortion rates [RRs (95% CI) = 0.80 (0.46, 1.14), p = 0.44] than control/placebo group; However, the difference was not significant. Similar results were observed in the subcutaneous, intrauterine injection, and regions subgroups of RM patients.

    Conclusions: This meta-analysis confirmed the benefits of G-CSF in improving the clinical pregnancy rate of RIF patients. No conclusive evidence supports the link between G-CSF use and increased abortion rate in RIF patients and clarifies the association of G-CSF use with clinical pregnancy and abortion rates in patients with RM.

  • Article
    Songyuan He, Yingkai Li, Wen Jian, Zichao Cheng, Yuchen Shi, Jinghua Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1949-1959. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.193
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    Background: Vascular calcification (VC) is associated with high rates of morbidity and mortality. It can complicate efforts to safely and effectively complete percutaneous interventions and surgical procedures. While fibroblast growth factor 21 (FGF21) has been identified as a potential therapeutic candidate for non-alcoholic steatohepatitis and type 2 diabetes, whether it exerts beneficial cardiovascular effects by modulating atherosclerosis-associated VC remains to be determined.

    Methods: FGF21 therapeutic benefits were evaluated using an AAV (adeno-associated virus)-based approach to overexpress this protein in an atherosclerotic model system consisting of ApoE-/- (Apolipoprotein E) mice fed with a Western diet.

    Results: The persistent FGF21 overexpression resulted in reductions in murine body weight and a concomitant improvement in the lipid profiles of mice. VC rates were significantly reduced in response to FGF21 overexpression without affecting the function of other major organs. Mechanistically, FGF21 protective effects were found to be mediated by the suppression of endothelial activation and the endothelialmesenchymal transition (EndMT) as confirmed in an in vitro ox-LDL (oxidized low-density lipoprotein)-treated mouse aortic endothelial cell model system.

    Conclusions: Together, these data suggest that FGF21 therapeutic benefits as an inhibitor of atherosclerotic calcification may be related to its ability to inhibit endothelial activation and EndMT induction.

  • Article
    Gang Jin, Qilong Deng, Lingjun Jiang, Ming Chen, Yu Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1961-1968. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.194
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    Background: Spinal cord injury (SCI) is a central nervous system injury with a high disability rate. Traditional SCI animal models have high mortality and cannot simulate clinical diseases well. Therefore, this study was aimed to develop a new SCI rat model by selecting new injured spinal segments, so as to provide a better animal model for clinical research.

    Methods: A new SCI rat model was generated by injuring thorax 12 (T12) and T13 segments. Hematoxylin-Eosin (HE) staining and toluidine blue staining were used to observed the histopathological changes of the spinal cord. The operating time, amount of bleeding, surgical incision length, and death rate in two SCI model groups were collected. Basso-Beattie-Bresnahan (BBB) locomotor score, the action recovery ability, the score of auditory recovery, the score of tactile ability, and the dietary recovery score were determined by behavior experiments.

    Results: Relative to the conventional model, the operating time, amount of bleeding, surgical incision length, and death rate in novel SCI model were significantly reduced. However, BBB locomotor score was consistent with the conventional model. The histopathological examinations showed that the spinal cord injury and number of large and medium-sized neurons was significantly decreased in novel SCI rat model.

    Conclusions: The novel SCI rat model was successfully established, which may helpful in the exploring the mechanistic and treatment strategy of SCI.

  • Article
    Chunlei Zheng, Bing Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1969-1978. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.195
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    Objective: The Hippo signalling pathway is involved in cell proliferation, apoptosis, invasion and metastasis of osteosarcoma (OS). The purpose of the study is to explore the prognostic role of long non-coding RNAs (lncRNAs) related to Hippo signalling pathway and identify the molecular subtypes of OS.

    Methods: Gene expression data of OS were obtained from the TCGA (The Cancer Genome Atlas) and GEO databases. The correlation between lncRNAs and Hippo signalling pathway-related genes was investigated. Next, prognostic lncRNAs were selected through univariate Cox regression analysis, followed by disease subtype analysis and prognostic model construction.

    Results: A total of 57 lncRNAs significantly correlated with Hippo signalling pathway-related genes and prognosis were then screened. A total of 16 independent prognostic lncRNAs were obtained, including eight lncRNAs with optimised lncRNAs combination. A prognostic score (PS) model was then constructed. Finally, a nomogram survival model for independent survival prognostic factors was constructed. Patient’s age, tumour metastasis and PS status were identified as the three factors with significant independent prognostic correlation.

    Conclusions: Eight Hippo signalling pathway-related lncRNAs, such as ABHD11-AS1, SPACA6P-AS and SNHG5, may serve as novel prognostic factors for OS.

  • Article
    Yan Su, Kai Liu, Yuanyuan Du, Mengyang Wang, Bochao Xiong, Lingqi Kong, Xinxiu Zhao, Peng Shi, Hongdang Qu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1979-1994. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.196
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    Background: Ferroptosis is a new form of iron-dependent cell death associated with the pathophysiology of vascular dementia (VD). However, the specific mechanism of action is still unclear. This study aims to explore the specific mechanism of action between ferroptosis and VD to find effective therapeutic targets.

    Methods: Mice were treated with bilateral common carotid artery stenosis (BCAS) to mimic VD models. Neurological function was evaluated using a Morris water maze and mouse hippocampal pathology. Transcriptomic sequencing was performed on hippocampal tissue to search for target genes related to ferroptosis, which was validated in oxygen-glucose deprivation (OGD) treated PC12 cells. Iron content, reactive oxygen species (ROS), and lipid hydroperoxide (LPO) levels were measured. Glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase 4 (ACSL4) levels were measured using WB (Western Blot) and qPCR (Quantitative Polymerase Chain Reaction), respectively.

    Results: Plasma prekallikrein (KLKB1, PK) levels were elevated in the hippocampal of BCAS-induced mice and OGD-exposed PC12 cells. Compared with the blank group, KLKB1 knockdown protected PC12 cells from OGD-induced apoptosis, and KLKB1 knockdown reduced ROS production and lipid peroxidation in PC12 cells. Besides, KLKB1 knockdown decreased iron content and elevated GPX4 expression.

    Conclusions: KLKB1 knockdown alleviates cognitive disorder via inhibiting ferroptosis in VD. Inhibition of oxidative stress, lipid peroxidation and reduction of iron content are involved in the underlying mechanisms.

  • Article
    Lihong Deng, Zhenlu Li, Jiafan Song, Chao Yue, Qingjing Yang, Huimin Lu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 1995-2002. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.197
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    Background: To investigate the short-term efficacy of the modified FOLFIRINOX regimen in the therapy of advanced pancreatic cancer and its effect on the immune function and serum tumor markers of subjects.

    Methods: 96 subjects with advanced pancreatic cancer were admitted to our hospital from January 2020 to January 2022. The subjects were divided into two subgroups according to different therapy plans, with 48 subjects in each subgroup. The control and observation subgroups were treated with gemcitabine (GEM), combined regimen and modified FOLFIRINOX regimen, respectively. In addition, at least three cycles of chemotherapy, the short-term curative effect, immune function, serum tumor marker level and adverse reaction between the two subgroups were compared.

    Results: Compared with the control subgroup, the disease control rate (DCR) in the observation subgroup was significantly higher (72.92% vs 52.08%) (p < 0.05). After chemotherapy, CD4+, CD4+/CD8+ ratio and serum immunoglobulin (Ig) A, IgG, IgM levels in the observation subgroup were significantly higher than those in the control group (p < 0.05). Versus the control subgroup, the level of CD8+ was significantly lower (p < 0.05). After chemotherapy, the levels of serum carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA) and macrophage inhibitory gytokine-1 (MIC-1) in the two subgroups decreased. Compared to the control subgroup, the levels in the observation subgroup were lower (p < 0.05). There was no notable difference in the incidence of adverse reactions between the two subgroups (37.50% vs 41.64%) (p > 0.05).

    Conclusions: Compared with the GEM combined chemotherapy scheme, the modified FOLFIRINOX scheme can improve the short-term efficacy of advanced pancreatic cancer, improve immune function, and reduce the expression of serum tumor markers. In addition, the patients can tolerate the FOLFIRINOX treatment scheme.

  • Article
    Sha Liu, Hang Lin, Yurong Duan, Xiang Gao, Zhun Wei
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2003-2010. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.198
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    Background: Artemisia annua (A. annua) is a traditional herb native to Asia which has great therapeutic value. However, it’s the most common aeroallergen in autumn responsible for seasonal allergic rhinitis in northern China. Art an 3 is a major allergen of A. annua pollen, it belongs to the non-specific plant lipid-transfer protein (nsLTP) family and its immunoglobulin E (IgE)-binding epitope has not been reported. This study aims to identify the linear IgE-binding epitopes of Art an 3.

    Methods: Recombinant Art an 3 protein was prepared and its allergenicity was confirmed by Western blot assay. Overlapping peptides covering full-length Art an 3 protein were synthesized and the linear IgE binding epitopes of Art an 3 were characterized by dot-blot assay. The specific immunoglobulin G (IgG) antibody levels induced by immunizing the mice with carrier-coupled Art an 3 peptides were measured by enzyme-linked immunosorbent assay (ELISA). The inhibition of human IgE binding to rArt an 3 by peptide-specific mouse antibodies was analyzed by ELISA competition assay. Art an 3 homology model was built based on the Art v 3 crystal structure.

    Results: The recombinant Art an 3 has been prepared and two linear IgE-binding epitopes of Art an 3 were characterized. When coupled to a carrier protein and immunized mice, both of the epitope peptides induced Art an 3-specific IgG antibody, which could inhibit Artemisia allergic patients’ serum IgE binding to Art an 3. The IgE-binding epitopes were well-exposed on the protein surface.

    Conclusions: Two linear IgE-binding epitopes of Art an 3 were identified, and antisera raised from carrier-bound epitope peptides could inhibit patients’ IgE binding to Art an 3.

  • Article
    Xiaoying Li, Hui Gao, Beibei Yan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2011-2018. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.199
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    Background: Bronchopulmonary dysplasia has become one of the most common adverse outcomes in premature infants, however, the pathogenesis remains unanswered. This was a prospective pilot study to investigate potential biomarkers of the development of bronchopulmonary dysplasia, which could help in the understanding and management of this disease.

    Methods: Exosomes were separated from the sputum samples of bronchopulmonary dysplasia patients at 28 days of life (early group) and the time when bronchopulmonary dysplasia was diagnosed (confirmed group). Exosomal micro-RNA was compared with a control group to find differentially expressed micro-RNA.

    Results: Microvesicles isolated from sputum samples of three groups were assessed by transmission electron microscopy, particle size analysis, as well as flow cytometry. The shape and size of the isolated vesicles from the three groups all matched the typical appearance of exosomes. The micro vesicles isolated from the sputum samples expressed clusters of differentiation (CD), the exosomal biomarkers strikingly, including CD63, CD9, and CD8. There were 1308 exosomal micro-RNA captured in total, in which, miR-320c (micro-RNA 320c) was significantly upregulated in the patients with bronchopulmonary dysplasia, starting at 28 days of age. Compared with the control group, the p value was 0.0046 in the early group and 0.021 in the confirmed group, respectively. There was no significant difference in the expression of miR-320c between the early and confirmed bronchopulmonary dysplasia groups (p = 0.062).

    Conclusions: The up-regulation of exosomal micro-RNA 320c may serve as a potential biomarker in the early stage of bronchopulmonary dysplasia.

  • Article
    Ke Wang, Kai Ming Huang, Yong Wei Zhuang, Ying Peng
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2019-2029. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.200
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    Background: Noncatalytic region of tyrosine kinase associated protein 5 like (NCKAP5L) (Cep169) is a conservative centrosome protein in vertebrates. Its main function is to regulate the dynamics and stability of microtubules (MT). However, its role in colon adenocarcinoma (COAD) is unknown. The aim of this study was to explore the molecular mechanism and clinical influence of NCKAP5L in COAD.

    Methods: Relevant information on COAD patients was downloaded in the public database TCGA (The Cancer Genome Atlas). The expression level of NCKAP5L in COAD was analyzed, and its impact on the prognosis of COAD patients was explored to understand the relevant mechanism.

    Results: The expression of NCKAP5L in colon adenocarcinoma was significantly higher than that in normal tissues. Cox proportional hazard model showed that higher levels of NCKAP5L expression predicted worse survival in COAD patients (HR >1, p < 0.05). Chemotherapy drug resistance analysis revealed the fact that higher NCKAP5L expression closely linked to chemotherapy drug resistance. The analysis of immune infiltrating cells revealed that NCKAP5L significantly correlated with CD4+ T cells and macrophages in immune cells. In addition, NCKAP5L was significantly involved in multiple tumor pathways (p < 0.05, p > 0.4).

    Conclusions: NCKAP5L makes important influences on the tumorigenesis and evolvement of COAD. It may be an effective prognostic indicator and a potential therapeutic target for COAD.

  • Article
    Aiping Xu, Xiuli Xia, Ting Xu, Ruxia Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2031-2042. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.201
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    Background and Purpose: Lung ischemia/reperfusion injury (LIRI) is common during early postoperative periods. However, the effects of TP53-induced glycolysis and apoptosis regulator (TIGAR) on LIRI in vivo and its associated mechanism of action are still undefined. We focus on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, also known as Akt) pathway to elucidate the underlying mechanism of TIGAR in LIRI in this study.

    Methods: We constructed a LIRI rat model through blockade of the left pulmonary artery for 1 h, followed by 5 h of reperfusion. Lentiviral vectors encoding TIGAR (LV-TIGAR) or PI3K/Akt pathway inhibitor (LY294002) was injected into LIRI rats to examine the protective effects of TIGAR on LIRI and the related mechanism. TIGAR expression, pathological changes of lung tissue, PI3K/Akt activation, reactive oxygen species (ROS) production and inflammation were assessed in both lung tissue and in bronchoalveolar lavage fluid.

    Results: We found that TIGAR is down-regulated in LIRI rats, and restoration of its expression can improve the pathological changes of lung tissue in rats, the oxygen partial pressure (PO2) and carbon dioxide partial pressure (PCO2) to normal levels. Exogenous TIGAR overexpression also reduced the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total leukocyte counts, the content of malondialdehyde (MDA) and ROS, but increased the activity of catalase (CAT) in peri-operative myocardial injury (PIMI) rats. Furthermore, LV-TIGAR increased the levels of PI3K and p-Akt/Akt in LIRI rats, and the protective effects of TIGAR in response to PIMI were alleviated by LY294002 in vivo.

    Conclusions: These findings demonstrate that overexpression of TIGAR exerts protective roles in the lungs of rats with PIMI through the activation of the PI3K/Akt signaling pathway.

  • Article
    Xin-lian WU
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2043-2054. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.202
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    Background: Affluent studies have confirmed the spectrum anti-oxidant and anti-inflammatory effects of paeoniflorin (PF). Therefore, the present work deliberates PF-mediated protection against pancreatitis. Gene expression data set GSE41418 was analyzed.

    Methods: A cells-based pancreatitis model was generated by lipopolysaccharide and cerulein, and the stimulated mouse pancreas cancer (MPC-83) cell line and human pancreatic cancer (HPAC) cell line were subjected to treatment with 0, 5, 10, and 20 μM of PF. A mouse model of pancreatitis was established using cerulein, and the mice were treated by intraperitoneal injection of PF (50 and 100 mg/kg). Bioinformatics analysis was performed to uncover the main biological processes related to pancreatitis. For MPC-83 and HPAC cells, cell viability, apoptosis and oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathway activation were evaluated. For mice, inflammatory factor, pancreatic pathological injury, ER stress, oxidative stress and NF-κB/MAPK activation were particularly analyzed.

    Results: GO (Gene Ontology)-BP (biological process) enrichment analysis presented that the up-regulated genes in pancreatitis mice model were related to MAPK activity, NF-κB pathway and apoptotic pathway. PF concentration-dependently promoted viability and autophagy and inhibited apoptosis, oxidative stress and ER stress of MPC-83 and HPAC cells. PF weakened pancreatitis-induced inflammatory injury, as well as oxidative stress and ER stress in mice. Either in the cell model or the animal model of pancreatitis, PF suppressed NF-κB/MAPK pathway activation.

    Conclusions: PF inhibits pancreatitis-induced oxidative stress and ER stress through blocking NF-κB/MAPK pathway activation, serving a clinical promising direction for the disease control.

  • Article
    Han Xie, Qing-yan Lin, Hong-yu Kuang, Hong-lei Yin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2055-2064. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.203
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    Objective: Diabetic patients have increased susceptibility to pulmonary fibrosis, and chronic tissue hypoxia caused by hyperglycemia can lead to the elevation of hypoxia-inducible factor-1α (HIF-1α). HIF-1α, a major transcription factor and core regulator of cell adaptation to hypoxia, is involved in the fibrosis process. However, its role in diabetes-related pulmonary fibrosis remains unclear. The aim of this study was to analyze the functional role of HIF-1α in the development of pulmonary fibrosis in diabetic mice and explore whether HIF-1α may be a therapeutic target for diabetic pulmonary fibrosis.

    Methods: Forty male C57BL/6 mice were randomized into four groups of ten: Control group; Control+YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole, HIF-1 inhibitor); DM (diabetes mellitus); And DM+YC-1. A high-fat diet and streptozotocin-induced diabetic mouse model was established. The lung tissue structure of mice in each group was examined using optical and electron microscopes. HIF-1α and α-smooth muscle actin (α-SMA) in lung tissue were checked for using immunohistochemistry and immunofluorescent staining respectively, western blotting and real-time quantitative PCR (polymerase chain reaction) were used to determine HIF-1α, Zinc finger protein (snail) and β-catenin which were the transcription mediators of epithelial-mesenchymal transformation (EMT), and the content of epithelial cells and mesenchymal markers α-SMA, calcium-adhesion protein (N-cadherin), tight junction protein 1 (ZO-1).

    Results: Lung coefficient (lung weight/body weight) and mitochondrial numbers in type II alveolar epithelial cells were significantly increased in the DM group, compared to the control group. Diabetic mice had with pulmonary fibrosis. In DM group, the level of α-SMA and HIF-1α were significantly increased in lung homogenate, the expression of mesenchymal markers, snail, and β-catenin were significantly increased, and epithelial cell marker expression was significantly decreased. These indicators were significantly reversed after treatment with the HIF-1α inhibitor YC-1, which ultimately and significantly attenuated pulmonary fibrosis.

    Conclusions: HIF-1α mediates pulmonary fibrosis in type 2 diabetic mice, through the snail/β-catenin pathway. HIF-1α was involved in the process of EMT and could be a target for prevention and treatment of early pulmonary fibrosis in diabetes.

  • Article
    Kaiyuan Shi, Liyu Chen, Guoliang Shao, Dinghu Zhang, Lulu Liu, Linyin Fan, Xiaochun Kan
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2065-2075. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.204
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    Background: Aberrant expression of long non-coding RNAs (lncRNAs) is associated with various malignant tumors, including hepatocellular carcinoma (HCC). Huai'er Qinggao is a traditional Chinese herbal medicine that exerts anti-cancer effects. In this study, we aimed to determine the roles and underlying molecular mechanisms of Huai'er Qinggao in HCC via lncRNA sequencing.

    Methods: We determined the viability of the human HCC cell line, SMMC-7721, treated with Huai'er Qinggao using the cell counting kit-8 assay. We also screened the differentially expressed (DE)-lncRNAs in Huai'er Qinggao-treated HCC cells using lncRNA sequencing. Expression levels of four selected DElncRNAs and several markers associated with cell growth were determined using quantitative reverse transcription-polymerase chain reaction. Long intergenic non-protein coding RNA 2154 (LINC02154) was knocked down to determine its roles in apoptosis, migration, proliferation, and invasion of SMMC-7721 cells.

    Results: Huai'er Qinggao significantly inhibited SMMC-7721 cell proliferation. Moreover, treatment with Huai'er Qinggao (half-maximal inhibitory concentration) resulted in 341 upregulated and 359 downregulated DElncRNAs. LINC02154 expression levels were significantly increased in treated cells than in control cells. Moreover, inhibition of LINC02154 expression significantly rescued the effects of Huai'er Qinggao on cell proliferation, clone formation, apoptosis, invasion, and expression of cell growth-related markers, such as cyclin B1, phosphatase and tensin homolog, (B cell lymphoma-2) Bcl-2, ras homolog family member A, and small mothers against decapentaplegic (SMAD) family member 2, in SMMC-7721 cells.

    Conclusions: Our results indicate that Huai'er Qinggao inhibits HCC progression by upregulating LINC02154 expression.

  • Article
    Ran You, Qing-Yu Xu, Hao Jiang, You Lu, Hui Yu, Jun Liu, Guo-Dong Feng, Guo-Wen Yin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2077-2083. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.205
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    Objective: To examine the relationship between the early increase in platelet and leukocyte counts and the prognosis in patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) combined with sorafenib.

    Methods: In this retrospective cohort study, a rise in both the platelet and leukocyte counts seven days after receiving TACE combined with sorafenib compared with three days before treatment was considered the early increase (positive group). If none or only one of the platelet or leukocyte counts increased, this was considered the rest situation (negative group). Blood samples were collected in Vacutainer tubes and immediately tested for leukocyte and platelet counts. In the study, overall survival (OS) was the primary outcome. Time to progression (TTP) serves as another secondary endpoint. Risk factors were analyzed using the logistic model.

    Results: 75 HCC patients received TACE combined with sorafenib were enrolled in this study. There were 61 patients in the positive group and 14 patients in the negative group. Compared with the negative group, patients in the positive group had a shorter median OS (14.8 vs 31.9 months; Hazard ratio (HR): 2.7; 95% confidence interval (CI): 1.3–5.4) and median TTP (3.0 vs 9.0 months; HR: 2.6; 95% CI: 1.2–5.4) in univariate analysis. Multivariate analysis indicated that the early increase in platelet and leukocyte counts was an independent indicator of a poorer OS (HR: 2.4; 95% CI: 1.1–5.2) and TTP (HR: 2.7; 95% CI: 1.3–6.0).

    Conclusions: The early increase in leukocyte and platelet counts might be a convenient and effective predictive factor in HCC patients received TACE combined with sorafenib, but larger prospective studies are needed for further confirmation.

  • Article
    Peng-Fei Liu, Jing Zhang, Rong-Rong Zhao, Qing-Qiu Zhou, Bao-Ming Sun
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2085-2093. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.206
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    Background: Depression is a multifactorial mood disorder with a high prevalence worldwide. To date, advances in drug discovery have widened therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors. Fluoxetine is the first selective serotonin reuptake inhibitor with a proven clinical efficacy and safety profile. Metformin, a first-line antiglycemic drug, has been shown to have antidepressant effects in patients with type 2 diabetes. However, the effectiveness of the combination of metformin and fluoxetine in the treatment of depression has not been investigated.

    Methods: PC12 (rat adrenal pheochromocytoma) cells were subjected to high-level corticosterone (200 μM) and drug administration. Then the cell apoptosis was measured by a flow cytometry assay. The potential mechanism of the combined application of metformin and fluoxetine on PC12 cells was discussed using reactive oxygen species, intracellular Ca2+ analysis, immunofluorescence, and Western blotting.

    Results: Our results showed that a combination of metformin and fluoxetine decreased apoptosis, the level of reactive oxygen species, and intracellular Ca2+ accumulation. Furthermore, the combined administration lowered the P62 protein expression and the autophagosome ratio, while promoting the expression of LC3B (microtubule-associated protein B-light chain 3) proteins.

    Conclusions: The combined use of metformin and fluoxetine in PC12 was found to have a protective effect against corticosterone. Mitochondrial apoptosis inhibition, autophagy flux unblocking, and activation of the AMPK (AMP-activated protein kinase)/BDNF (brain-derived neurotrophic factor) pathway may represent new approaches to enhance neuroprotection.

  • Article
    Zhenzong Tan, Wang Huang, Peng Yu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2095-2103. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.207
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    Background: Colon cancer (CC) is associated with high morbidity and mortality rates. AT-rich interaction domain 2 (ARID2) is a tumor suppressor that is commonly mutated in various cancers. In this study, we aimed to explore whether ARID2 functions in CC and its underlying mechanisms.

    Methods: ARID2 expression was measured by quantitative real-time PCR (polymerase chain reaction) immunohistochemical assay, and western blotting. After CC cells were transfected with ARID2 overexpression vector and/or treated with SRI-011381 (transforming growth factor beta 1 (TGF-β1)/Smad (small mothers against decapentaplegic) pathway activator), the cells were divided into oe-negative control (NC), oe-ARID2 (the ARID2 overexpression vector), and oe-ARID2 + SRI-011381 groups, the biological functions, including cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), were analyzed using cell counting kit-8, colony formation analysis, Transwell assay, and western blotting, respectively. The TGF-β1/Smad pathway affected by ARID2 were measured by western blotting. Effects of ARID2 on tumor weight and volume were evaluated in a xenograft tumor model in the adenovirus (Ad)-NC and Ad-ARID2 groups.

    Results: ARID2 was downregulated at the mRNA and protein levels in CC tissues and cells. Aberrant ARID2 expression has diagnostic and prognostic value. ARID2 overexpression suppresses CC cell proliferation, invasion, migration, and EMT. ARID2 downregulated TGF-β1, p-Smad2, and p-Smad3 protein levels. Upregulation of TGF-β1 partly abrogated the effects of ARID2 on biological behavior. Moreover, ARID2 overexpression inhibits tumor growth in vivo.

    Conclusions: ARID2 suppressed the malignant advancement of CC by inactivating the TGF-β1/Smad pathway, providing valuable insights into the treatment of CC.

  • Article
    Ruchao Zhang, Xin Zhou, Guangsheng Wang, Zhongsheng Li, Youzhen Luo, Aijun Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2105-2116. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.208
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    Background: This study aimed to establish new molecular classifications of gastric cancer (GC) based on metabolism-related genes.

    Methods: Gene expression and clinical data of stomach adenocarcinoma from The Cancer Genome Atlas (TCGA) database were downloaded for analysis. Metabolite-protein interactions were retrieved from different public databases to identify metabolism-related genes in the TCGA dataset. Differential expression was analyzed using the Limma package. ConsensusClusterPlus was used to conduct clustering analysis. Survival, clinical data, immune cell infiltration, and tumor mutation burden (TMB) were compared between the clusters. Next, gene set variation analysis (GSVA) was conducted to analyze differential hallmark pathways between clusters. Finally, the GSE66229 dataset in the Gene Expression Omnibus (GEO) database was used for validation.

    Results: In total, 269 metabolism-related genes were differentially expressed in GC, of which 35 genes associated with prognosis were identified. Two metabolism-related molecular clusters were established based on these 35 prognostic genes. Samples in cluster 1 showed poor survival in both the TCGA and GSE66229 datasets. This cluster contained many patients with high histologic grade, lymph node metastasis, and advanced tumor stage. Three hundred fifty-four genes were aberrantly expressed between the two clusters and were enriched in focal adhesion, leukocyte migration, and ECM (extracellular matrix)-receptor interaction. GSVA indicated that epithelial-mesenchymal transition, angiogenesis, inflammatory response, and hypoxia were markedly enriched in cluster 1. Moreover, cluster 1 showed higher immune and stromal scores and a higher abundance of infiltrating M2 (tumor-promoting phenotype) macrophages, cluster of differentiation (CD) 8-positive (CD8+) T cells cells, cluster of differentiation (CD) 4-positive (CD4+) T cells, and neutrophils, as well as lower TMB than cluster 2.

    Conclusions: We successfully developed two metabolism-related molecular clusters of GC, which differed in terms of clinical pathological characteristics, prognosis, immune status and mutation spectrum. This contributed to stratify GC pateints so as to develop personalized therapy.

  • Article
    Dong Li, Mingguo Dong, Zhike Fang, Linshi Huang, Jiying Chen
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2117-2127. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.209
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    Purpose: Elucidation of the role and molecular mechanism of proteasome inhibition in the induction of autophagy in prostate cancer (PCa) cells by Fangchinoline.

    Methods: The role of Fangchinoline on the growth of PC-3 human prostate cancer cells was Explored using Methylthiazolyl Tetrazolium (MTT) assay. The role of Fangchinoline on the growth of PC-3 tumours was examined using the PC-3 Ho nude mouse model. The effect of Fangchinoline on c-Jun N-terminal kinase (JNK), Phosphorylated JNK (p-JNK), P38 and P-P38 protein expression in PC-3 tumor tissues was checked using Western Blot. The role of Fangchinoline on autophagy-related molecules Ki-67, LC3B and P62 was assessed using immunohistochemistry. The protein expression of Proteasome subunit beta type-6 (PSMB6), JNK, p-JNK, P38 and P-P38 in PC-3 cells after PSMB6-Small Interfering Ribonucleicacid (PSMB6-siRNA) was estimated using Western Blot. PSMB6, JNK, p-JNK, P38 and P-P38 Messenger RNA (mRNA) expression in PC-3 cells after Fangchinoline intervention was checked using Reverse Transcription-Polymerase Chain Reaction (RT-PCR).

    Results: MTT showed a dose- and time-dependent significant inhibition of PC-3 cell proliferation by Fangchinoline. WB showed that Fangchinoline significantly promoted the expression of JNK, p-JNK, P38, and P-P38 in PC-3 tumor tissues. Immunohistochemistry showed that Fangchinoline significantly promoted LC3B expression and significantly inhibited Ki-67 and P62 expression. WB showed that PSMB6-siRNA significantly inhibited the expression of PSMB6 in PC-3 cells and significantly promoted the expression of JNK, p-JNK, P38, and P-P38. Compared with the control group, RT-PCR results showed that PSMB6 mRNA expression was significantly down-regulated and JNK, p-JNK, P38, P-P38 mRNA expressions were up-regulated in a dose-dependent manner in the Fangchinoline group.

    Conclusions: Proteasome inhibition of Fangchinoline activated autophagy and apoptosis in PC-3 human prostate cancer cells, which may be related to the activation of protein expression of JNK and P38 signaling pathways.

  • Article
    Hua Chen, Yu-guang You, Wei-hua Chen, Ling Ren, Yi-long Ge, Jun Ye
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2129-2137. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.210
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    Objective: The aim of this study was to clarify the clinical significance and molecular mechanism of hexokinase 2 (HK2) in papillary thyroid carcinoma (PTC).

    Methods: The observational study enrolled 279 PTC patients during January 2018 to January 2020. Immunohistochemistry (IHC) was utilized for evaluating the HK2 expression in PTC tissues. Enzyme linked immunosorbent assay (ELISA) was utilized for measuring the serum cancer antigen of cancer antigen (CA) 125, CA199 and carcinoembryonic antigen (CEA). The relationship between HK2 and clinical outcomes and 2-year prognosis of PTC patients was analyzed. Additionally, an in vitro study was carried out to assess the impact of silencing HK2 on cell viability, apoptosis and autophagy in PTC cell.

    Results: A significant upregulation in HK2 was observed in PTC cell lines and tissues. Patients with higher HK2 expression showed significantly larger tumor diameter, higher tumor number, higher frequency of infiltration and lymph node metastasis, as well as higher serum CEA, CA125 and CA199 levels. The combination of HK2 and color Doppler ultrasound could be utilized to diagnose PTC patients’ lymph node metastasis. Higher HK2 predicted shorter 2-year disease-free survival (DFS) rate. Logistic analysis showed that HK2, multifocal and CEA were independent risk factors for 2-year recurrence of PTC patients. The in vitro study showed that knockdown of HK2 not only significantly decreased cell viability and autophagy, but also significantly promoted cell apoptosis in PTC cells.

    Conclusions: HK2 expression is related to poor clinical outcomes and prognosis of PTC patients. Silence of HK2 can promote cell apoptosis, inhibit cell viability and block autophagy.

  • Article
    Dejun Chai, Cheng Fang, Xue Sun, Zhixia Zhou, Zhonghang Chen, Guangchao Xu, Bin Hu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2139-2149. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.211
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    Context: Geniposide (GE) has a neuroprotective effect.

    Objective: Our study examines whether GE can alleviate nerve injury after cardiac arrest and cardiopulmonary resuscitation (CA/CPR).

    Materials and Methods: Male Sprague Dawley rats were randomly assigned to the following treatment groups by the random number table method: Sham, CA (CA model established by asphyxiation, and then CRP), CA + saline (same volume of normal saline, gavage), CA + GE (60 mg/kg, orally), CA + Aniso (5 mg/kg anisomycin (JNK agonist), intraperitoneal injection) and CA + Aniso + GE. The water maze test and neurological deficit scale were used to assess the neurological function of the rats. Western blot assays were used to quantify interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-8, as well as c-Jun N-terminal kinase (JNK) pathway-associated protein expression levels.

    Results: The CA + GE group had higher neurological scores (61 vs 77) and better performance in the water maze test [longer escape latency (46 s vs 28 s), lower platform crossing time (1.8 vs 6.3), and a smaller percentage of time spent in target quadrant (13% vs 22%)] than the CA/CRP group. Furthermore, IL-6 (0.82 vs 0.61), TNF-α (1.35 vs 0.98), IL-8 (1.29 vs 1.01), p-JNK/JNK (1.14 vs 0.48), p-extracellular signal-regulated kinase (ERK)/ERK (1.22 vs 0.55), and p-p38/p38 (1.51 vs 1.03) protein expression levels were decreased in the hippocampus of GE-treated CA/CRP rats. Administration of the JNK agonist anisomycin aggravated the inflammatory response and neurological impairment in the CA/CRP rats. In contrast, GE treatment played a neuroprotective role by partially reversing the effect of anisomycin on CA/CRP rats.

    Conclusions: GE may have a neuroprotective role against CA/CRP-induced cognitive impairment and inflammatory responses in the brains of CA/CRP rats, which is mediated via the JNK pathway. Therefore, GE may be used as a novel potential therapeutic agent for CA/CRP.

  • Article
    Zhi-yuan Chen, Yu-mei Lin, Yi Zhang, Jian-hua Wu, Xiao-hua Gao, Chun-ling Huang, Xiao-ting Xu, Ai-mei Lin, Wen-xi Xie
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2151-2157. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.212
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    Objective: This study aimed to assess the effects of penehyclidine hydrochloride on rats diagnosed with chronic obstructive pulmonary disease (COPD) concerning their respirational mechanism and oxidative stress responsiveness during induced ventilation.

    Methods: A total of 36 rats in the modeling group were randomly divided into a model group (group M), a model + normal saline group (group N), and a penehyclidine hydrochloride group (group H) with 12 rats in each. Another 12 rats were randomly selected from a normoxia group as the control group (group C). After intubation, the rats in each group were mechanically ventilated. Group H was given a real-time intravenous injection of penehyclidine hydrochloride 1.0 mg/kg, while groups C and N were given a real-time intravenous injection of a similar volume of normal saline. Peak airway pressure (Ppeak) was monitored immediately after the injection (T0), 30 min after the injection (T1), 60 min after the injection (T2), and 120 min after the injection (T3); The rats were collected after mechanical ventilation lasting a total of 120 min. The partial pressure of oxygen (PaO2) and the partial pressure of carbon dioxide (PaCO2) were measured, and malondialdehyde (MDA) and superoxide dismutase (SOD) lung tissue changes were observed.

    Results: Typical pathological COPD changes were found in the lung tissue of the rats in groups M, N, and H. Compared with group C, the Ppeak, PaCO2, and MDA levels in groups M, N, and H had increased (p < 0.05), while the levels of PaO2 and SOD had decreased (p < 0.05). Compared with group N, the Ppeak, PaCO2, and MDA levels in group H had decreased (p < 0.05), and the levels of PaO2 and SOD had increased (p < 0.05).

    Conclusions: Penehyclidine hydrochloride can reduce airway resistance and improve pulmonary ventilation in COPD rats during mechanical ventilation. It can also decrease the oxidative stress level during mechanical ventilation and lessen lung membrane damage.

  • Article
    Yinghui Wang, Zilin Wang, Ya Zhang, Zixin Zhu, Qiuju Mou, Lirong Liu, Lili Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2159-2170. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.213
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    Background: The study was designed to decipher the impact of platelet-rich plasma (PRP) on lipopolysaccharide (LPS)-mediated inflammation in BV2 (A murine cell line has been generated by infecting primary microglial cell cultures with a v-raf/v-myc oncogene carrying retrovirus (J2)) microglia.

    Method: BV2 microglia activation was induced by lipopolysaccharide (LPS) to establish an in vitro model of neuroinflammation. After pretreatment with different concentrations of PRP, the apoptosis of BV2 microglia was determined by flow cytometry, terminal deoxynucleotidyl transferase fluorescence labeling (TUNEL) and JC-1 assay. The production level of nitric oxide (NO) was determined by Griess method, and the mRNA (messenger RNA) expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The contents of TNF-α, IL-1β, IL-6, and prostaglandin E2 (PGE2) cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The phosphorylation of nuclear factor kappa-B (NF-κB/P65), inhibitor of NF-κB α (IκBα), c-Jun N-terminal kinase (JNK), extracellular signal-regulated MAP kinases 1/2 (ERK1/2), and p38 mitogen-activated protein kinases (p38 MAPKs) in the NF-κB/MAPKs pathway was analyzed by Western blot. The nuclear translocation of phosphorylated NF-κB/P65 subunits was evaluated by laser confocal microscopy.

    Results: PRP decreased LPS-stimulated apoptosis of BV2 microglia (p < 0.05). Moreover, PRP inhibited the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 and the NO level (p < 0.05), in addition, PRP also reduced the production of inflammatory mediators including TNF-α, IL-1β, IL-6, and PGE2 (p < 0.05), inhibited the protein levels of p-NF-κB/P65, p-IκBα, p-JNK, p-ERK1/2, and p-p38 in the NF-κB/MAPKs pathway in LPS-induced BV2 microglia (p < 0.05), decreased the nuclear translocation of p-NF-κB/p65 subunit (p < 0.05). Particularly, PRP at a concentration of 10% showed the optimal the inhibition effects.

    Conclusions: PRP attenuates LPS-mediated inflammation in BV2 microglia by blocking the TLR4-NF-κB/MAPKs axis.

  • Article
    Yuman Sun, Yan Wang, Xinyi Sun
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2171-2179. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.214
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    Background: There are reports on the early diagnosis of diabetic kidney disease (DKD) with a single serum index, but all of them have certain limitations. The role of methylenetetrahydrofolate reductase (MTHFR) gene promoter methylation in DKD still lacks evidence-base. The aim of this study was to analyze the factors associated with DKD and the value of MTHFR gene promoter methylation in the diagnosis of DKD.

    Methods: The study included a diabetes mellitus (DM) group (n = 138) and DKD group (n = 82). Clinical data, such as age, gender, disease duration, body mass index (BMI), serum indicators, and urine biochemical indicators were collected, and logistic regression was used to analyze the independent risk factors affecting the occurrence of DKD. Receiver operating curve (ROC) was used to analyze the diagnostic value of biochemical indicators individually and in combination for the detection of DKD.

    Results: The levels of glycosylated hemoglobin (HbA1c), serum creatinine (SCr), homocysteine (Hcy), cysteine (Cysc), urinary microalbumin and blood urea nitrogen (BUN) in the DKD group were significantly higher than those in the DM group, while MTHFR gene promoter methylation and glomerular filtration rate (eGFR) levels were significantly lower than those in the DM group (p < 0.05). Elevated levels of Hcy and urinary microalbumin were independent risk factors for DKD in patients with DM (p < 0.05). MTHFR gene promoter methylation level and elevated eGFR were protective factors affecting DKD in patients with DM. The methylation level of MTHFR gene promoter negatively correlated with the severity of DKD (p < 0.05). The area under the curve (AUC) of Hcy, urinary microalbumin, MTHFR gene promoter methylation and eGFR level for diagnosis of DKD were 0.617 (0.483–0.751), 0.720 (0.594–0.846), 0.657 (0.526–0.788) and 0.792 (0.688–0.896) respectively. The AUC of combined risk factors for diagnosis of DKD was 0.845 (0.758–0.932).

    Conclusions: Elevated levels of Hcy and urinary microalbumin were independent risk factors for DKD in patients with DM. The methylation level of MTHFR gene promoter negatively correlated with the severity of DKD. Therefore, attention should be paid to the changes of the methylation level of MTHFR gene promoter in clinical work.

  • Article
    Sen Li, Jie Wang, Kun Yu, Wei Li, Xian-ke Si, Wen-tao Wu, Zhi-sheng Chen, Zhen Wang, Dai-hai Mo, Gang Li, Jiahua Yang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2181-2190. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.215
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    Background: LINC00857 plays an oncogenic role in several cancer types. The aim of this study is to evaluate the role of LINC00857 in pancreatic ductal adenocarcinoma (PDAC) and understand its mechanism.

    Methods: Firstly, LINC00857 expression in PDAC was predicted using TCGA (The Cancer Genome Atlas) database followed by its determination in clinical PDAC tissues by RT-PCR (reverse transcription-polymerase chain reaction) analysis. Then, MIA PaCa-2 and PANC-1 pancreatic cancer cells were transfected with siRNAs of LINC00857, followed by CCK-8 (Cell Counting Kit-8), cell colony formation, cell apoptosis, cell scratch, and trans-well invasion assay. Besides, p-AKT(phosphorylated protein kinase B), β-catenin, Bax, and cleaved caspase3 levels were detected by western blot analysis. Finally, subcutaneous nude mouse models were created with PANC-1 cells transfected with si-LINC00857 or si-NC.

    Results: LINC00857 was overexpressed in PDAC and related to poor prognosis. This was validated in clinical PDAC tissues. When LINC00857 was silenced the proliferation, migration, and invasion was impaired but apoptosis of PDAC cells was induced. In addition, western blot analysis showed a correlation between LINC00857 and AKT/β-catenin. Si-LINC00857 reduced the protein level of p-AKT and β-catenin. Tumor volume and tumor weight declined in si-LINC00857 transfection group, compared to that in si-NC transfection group.

    Conclusions: LINC00857 knockdown suppressed proliferation, migration and invasion of PDAC cells through AKT/β-catenin signaling in part.

  • Article
    Lanlan Zhang, Ziguan Zhu, Xiaodong Yang, Qi Liu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2191-2200. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.216
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    Background: Rosmarinic acid (RA) exerts an antioxidant property and alleviates some tissues’ ischemia/reperfusion (I/R) injury. However, its role in I/R-induced flap injury is still unknown. Therefore, this study investigates RA’s feasibility in treating flap injury caused by I/R.

    Methods: Rats were given the same dose of normal saline or RA for 7 days, and the flap operation was performed on day 8. The survival of the flap was observed after 7 days of operation, and the flap tissues were taken for hematoxylin-eosin (H&E) staining. Besides, human keratinocytes (HaCaT) were cultured under an anoxic environment for 12 h and reoxygenated for 1 h to induce I/R model in vitro. RA pre-treatment and small interfering (si) for nuclear factor erythroid 2-related factor 2 (Nrf2) transfection were conducted before I/R treatment. Western blot was used to detect Nrf2, heme oxygenase-1 (HO-1), PTEN-induced kinase 1 (PINK1), Parkin, light chain 3 (LC3)II/LC3I, p62, p38, p-p38, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) expression levels in flap tissues or HaCaT cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry were employed to measure cell viability and apoptosis, respectively.

    Results: RA alleviated I/R-induced flap injury in rats and apoptosis of HaCaT cells and increased cell viability. Besides, I/R inhibited Nrf2, HO-1, Bcl-2, PINK1, Parkin and LC3II/LC3I levels, but enhanced p62, p-p38 and Bax levels. RA could partially reverse the effect of I/R. siNrf2 counteracted the effects of RA on the viability, apoptosis and expression levels of HO-1, Bcl-2, PINK1, Parkin, LC3II/LC3I, p-p38 and Bax in HaCaT cells.

    Conclusions: RA alleviated I/R-induced flap injury by regulating Nrf2/HO-1 and p38 MAPK (mitogen-activated protein kinase) signaling pathways.

  • Article
    Zhiming Wu, Minjie Lin, Hongjun Huang, Zhiqiang Huang, Jinsong Zhou, Chennan Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2201-2210. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.217
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    Objective: This study aimed to clarify the potential role of SYVN1 (synoviolin 1) in pancreatic cancer biology.

    Methods: Panc-1 and AsPC-1 cells were independently transfected with SYVN1 overexpression or knockdown plasmid, and injected into nude mice to induce tumor formation. Tumor volume was measured 4 weeks after tumor induction. Then, the mRNA expressions of SYVN1 and mammalian Sterile 20-like kinase 1 (MST1) were determined by quantitative real-time PCR (polymerase chain reaction). After the tumor isolation or co-culture of immature dendritic (imDC) cells and CD4+ T cells, the percentage of regulatory T (Treg) cells was detected by flow cytometry, and MST1 and sirtuin 1 (sirt1) protein levels were measured by Western blot. MST1 ubiquitination in imDC cells was assessed by immunoprecipitation.

    Results: SYVN1 overexpression facilitated tumor growth in mice after 4 weeks, while silencing SYVN1 exerted tumor suppressive effect. Besides, SYVN1 up-regulation promoted Treg cell infiltration and sirt1 protein expression, but suppressed MST1 protein expression in tumorigenic mice. Similarly, overexpressed SYVN1 down-regulated MST1 protein expression, but up-regulated Treg cell percentage and sirt1 protein level in imDC cells after co-culture with CD4+ T cells. SYVN1 was predicted as E3 ubiquitin ligase of MST1, and SYVN1 overexpression was able to promote MST1 ubiquitination in imDC cells. Moreover, MST1 overexpression reversed SYVN1-induced Treg production and decreased sirt protein expression in imDC cells.

    Conclusions: SYVN1 facilitates Treg production in imDC cells to accelerate pancreatic cancer progression via MST1 ubiquitination degradation and sirt1 up-regulation.

  • Article
    Jie Yao, Wei Tang, Juan Cheng, Xin Li, Qiang Zhou
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2211-2215. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.218
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    Background: Accurate and rapid detection methods can provide a scientific basis for improving the coincidence rate of clinical diagnosis and etiological diagnosis of bacillary dysentery. This study aims to explore the application value of polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP) and bacterial culture in diagnosing bacillary dysentery.

    Methods: The feces samples and serum of 90 patients with diarrhea were collected as the observation group, and feces samples and serum of 90 healthy persons with physical examination in the same period were enrolled as the control group. PCR, LAMP, and bacterial culture were used to detect bacterial dysentery and to compare the advantages of the three methods.

    Results: The diagnostic accuracy of PCR and LAMP was much higher than that of bacterial culture. The sensitivity of PCR, LAMP and bacterial culture was 61.11%, 58.89% and 11.11%, and the specificity was 71.11%, 77.78% and 8.89%, respectively. The expression levels of interleukin (IL)-8, IL-12 p40 and procalcitonin (PCT) in the observation group were higher than in the control group. Levels of the cluster of differentiation (CD)3+, CD4+, and CD4+/CD8+ in the observation group were all lower than in control.

    Conclusions: After a comprehensive comparison of the three methods, PCR and LAMP showed better specificity and sensitivity, which could be better applied in detecting Shigella.

  • Article
    Junjie Ni, Pu Wu, Lin Lv, Chaoyang Xu, Zhongwu Hong
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2217-2229. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.219
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    Background: The upregulation of extracellular leucine-rich repeat fibronectin type III domain containing 1 (ELFN1) has implications in various malignancies. Conversely, its vital role in colon adenocarcinoma (COAD) is still not clearly defined. This study aimed to uncover the ELFN1 role in the progression and immuno-microenvironment of COAD.

    Methods: This study investigated the ELFN1 expression in 398 tissues of COAD vs 39 normal tissues from The Cancer Genome Atlas (TCGA), 18 tissues of colorectal cancer vs paired normal tissues of GSE50760, and across pan-cancer types. Then, associations between ELFN1 and prognosis and clinical features were analyzed using the Kaplan–Meier and Cox regression (multivariate) model. Meanwhile, a nomogram was also constructed. The method of gene set enrichment analysis (GSEA) was employed to investigate the pathways related to ELFN1. The data of TCGA-COAD cohort was used to find out the correlations between ELFN1 and immune microenvironment, immunophenoscore (IPS), and tumor mutational burden (TMB).

    Results: The analysis revealed that ELFN1 levels were significantly high in patients with COAD tissues, involvement of lymph nodes and advanced stages. The higher expression of ELFN1 in patients had the inferior result, and for overall survival (OS), the ELFN1 served as an independent risk predictor. The nomogram showed a good predictive capability in 1-, 3-, and 5-year OS. The result of GSEA exhibited a positive correlation with cancer-related and immunosuppressive pathways, such as myogenesis, epithelial-mesenchymal transition (EMT), angiogenesis, IL6-JAK-STAT3 (Interleukin 6-Janus Kinase 1-Signal Transducer and Activator of Transcription 3) signaling pathway, inflammatory response, and IL2-STAT5 (Interleukin 2-Signal Transducer and Activator Of Transcription 5) pathways by up-regulation of ELFN1. This study focused on exploring the relationship between EMT and ELFN1, as 50% of the total genes were highly significant and positively co-expressed with ELFN1 in this pathway. In addition, an increased ELFN1 was related to a higher Immune/Stromal Score, elevated infiltration levels of macrophages M0 and Tregs, and a lower IPS and TMB.

    Conclusions: Increased ELFN1 in COAD patients correlated with worse prognosis and may influence the tumor progression by activating EMT and formatting immunosuppressive microenvironment, which may help predict the response to immunotherapy.

  • Article
    Chengcheng Li, Xiaoshuang Guo, Xinhang Dong, Hong Du, Xiaolei Jin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2231-2242. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.220
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    Objective: Low-molecular-weight hyaluronic acid (LMW-HA) enhances osteoclast differentiation in vitro. However, whether LMW-HA promotes bone resorption in vivo remains unclear. This study aimed to identify the effect of LMW-HA on osteoclast formation and bone resorption in vivo and explore the underlying molecular mechanism.

    Methods: Phosphate-buffered saline (PBS), high-dose lipopolysaccharide (LPS), low-dose LPS, low-dose LPS + LMW-HA, and LMW-HA were subcutaneously administered into the calvariae in mice. Micro-computed tomography, tartrate-resistant acid phosphatase (TRAP) staining, and enzyme-linked immunosorbent assay (ELISA) for C-telopeptide of type I collagen (CTX-I) and TRAP-5b were conducted to analyze osteoclast formation and bone destruction. Serum levels of inflammatory cytokines were measured using ELISA. Real-time quantitative reverse transcription PCR (Polymerase Chain Reaction) was performed to evaluate cathepsin K (CTSK), matrix metallopeptidase 9 (MMP-9), TRAP, toll-like receptor-4 (TLR-4), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in peritoneal murine macrophages (PMMs), receptor activator of nuclear factor kappa-B (RANKL), and bone marrow stromal cells (BMSCs). Immunohistochemistry was used to evaluate the infiltration of F4/80 positive cells into the skin. Finally, we evaluated whether LMW-HA-enhanced osteoclast formation was inhibited by the TLR-4 inhibitor (Resatorvid, TAK-242).

    Results: Co-injection of LMW-HA and low-dose LPS significantly boosted skull destruction and increased the number of osteoclasts. The expression levels of osteoclast genes (TRAP, CTSK, MMP-9) expression, CTX-I, TRAP-5b, and inflammatory cytokines in the low-dose LPS + LMW-HA group were significantly higher than those in the low-dose LPS or LMW-HA groups (p < 0.01). Moreover, RANKL, TNF-α, IL-1β, IL-6, and TLR-4 mRNA expression and inflammatory cytokines (TNF-α, IL-1β, IL-6) levels in serum were significantly higher in the group administered with LPS + LMW-HA than those in the group administered low-dose LPS (p < 0.01). Furthermore, LMW-HA could promote infiltration of F4/80 positive cells into the skin and elevate TNF-α, IL-1β, and IL-6 mRNA expressions in PMMs and RANKL mRNA expression in BMSCs. TAK-242 reduced osteoclast formation enhanced by LMW-HA in vivo.

    Conclusions: Our findings indicate that LMW-HA increases the secretion of inflammatory cytokines and exacerbates LPS-induced osteolysis in vivo. However, further studies are required to elucidate this potential mechanism.

  • Article
    Yuanxin Chen, Zhijie Huang, Jianjiang Zhao, Bo Jia
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2243-2257. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.221
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    Background: This study aimed to verify the effect of Fusobacterium nucleatum (F. nucleatum) in oral squamous cell carcinoma (OSCC) and explore the possible molecular mechanism.

    Methods: The abundance of F. nucleatum was analyzed by 16S rRNA sequencing and fluorescence in situ hybridization (FISH). Human normal oral keratinocytes (HOK), human OSCC cell lines CAL-27 and SCC-9 cells were cultured and infected with F. nucleatum, respectively. The proliferation, migration and invasion of cells were detected by Cell Counting Kit-8 (CCK-8), wound healing, transwell migration and invasion assay. A mouse OSCC model induced by 4-nitroquinolin-1 oxide (4NQO) was constructed. F. nucleatum was applied to the oral cavity of mice. Tumor number, volume and body weight were recorded. The promotion of F. nucleatum on 4NQO-induced OSCC in mice was evaluated by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). The chemokines with the highest differential expression in CAL-27 cells after infection of F. nucleatum were screened out by transcriptomics. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot and small interfering RNA (siRNA) interference assay were used to verify the mechanism of the selected chemokines in the tumor-promoting process of F. nucleatum.

    Results: Compared with paracancerous tissues, the abundance of F. nucleatum was higher in OSCC. F. nucleatum could regulate the proliferation, migration, and invasion of CAL-27 cells and promote the progression of OSCC in mice. Transcriptomic analysis showed that chemokine ligand 20 (CCL20) was the most differentially expressed chemokine in CAL-27 cells infected by F. nucleatum, consistent with the qRT-PCR and western blot results. siRNA interference experiment showed that the migration and invasion ability of CAL-27 cells was significantly weakened after the reduction of CCL20 expression.

    Conclusions: This study confirmed that F. nucleatum was enriched in OSCC and can promote the progression of OSCC through CCL20.

  • Article
    Xiaoling Yu, Zhonghua Hu, Juan Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2259-2265. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.222
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    Objective: This study aims to explore and analyze the clinical efficacy of Sevelamer Carbonate tablets in combination with hemodialysis for treating uremia with hyperphosphatemia.

    Methods: Participants who suffered from hyperphosphatemia were included. A total of 144 participants were assigned to a single dialysis group (n = 70), treated with routine hemodialysis, and a drug group (n = 74), treated with Sevelamer Carbonate tablets combined with routine hemodialysis according to different therapy schemes. All the participants did not fall off. The indexes of renal function, lipid metabolism, and bone metabolism were compared between the two groups before and after therapy.

    Results: After two-week therapy, notably lower indicators of creatinine, urea nitrogen and uric acid for the drug group versus the single dialysis group (p < 0.05), in terms of lipid metabolism indicators, notably lower total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations for the drug group versus the single dialysis group (p < 0.05). Besides, as to bone metabolism indicators, intact Parathyroid Hormone (iPTH) (p > 0.05), alkaline phosphatase (ALP) (p < 0.05), and phosphorus (p < 0.05) in the drug group were lower, and calcium (p < 0.05) was higher than those in the single dialysis group.

    Conclusions: Sevelamer Carbonate tablets combined with hemodialysis can effectively improve renal function, lipid metabolism, and bone metabolism in patients with uremia and hyperphosphatemia.

  • Article
    Ting Liu, Yan Xue, Ping-Ping Guo, Qi Wang, Shu Lin
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2267-2276. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.223
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    Objective: Drug resistance to the chemotherapeutic drug Adriamycin (ADR) is a key clinical impediment to successful breast cancer treatment (BrCa). However, the molecular mechanism and targets that mediate ADR resistance remain unclear. Therefore, the identification of ADR response biomarkers to improve the treatment of patients with BrCa is an urgent issue.

    Methods: The GSE24460 dataset on Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) was employed in this investigation, which covers gene expression profiles of parental and ADR-resistant cell lines of MCF-7 (cell lines in the human breast cancer). Differentially expressed genes (DEGs) in parental and ADR-resistant cells, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway studies, and the interactions of protein-protein were used to identify the overall biological alterations (PPIs). The most prevalent DEGs in the PPI, GO, and KEGG pathways were discovered and using GSE34138 dataset from the GEO database were validated, and their ability to forecast overall survival (OS) and relapse-free survival (RFS) was clinically validated. The link between the DEGs and OS/RFS was studied after further verification of the most common DEGs in those pathways. The most significant crucial gene, collagen type-IV alpha 1 (COL4A1), was discovered in the MCF-7 and MCF-7/ADR cells using the quantitative real-time reverse transcription PCR, Western blot, and Cell Counting Kit-8 assays to further highlight the distinctions.

    Results: 207 DEGs in total were discovered, with 111 upregulated and 96 downregulated. After mapping the GOs, pathways, and PPI networks, six genes—cyclin-dependent kinase inhibitor 2A (CDKN2A), retinoblastoma 1 (RB1), C-X-C motif ligand 12 (CXCL12), COL4A1, intercellular cell molecule-1 of adhesion (ICAM1), and cadherin 1 (CDH1)—were found to be frequently enriched. COL4A1 was found to be favorably associated with ADR resistance and poor OS, as well as strongly associated with RFS. The correlation between CDH1 and ADR resistance was negative, which was substantial in terms of poor RFS. In MCF-7/ADR cells, COL4A1 also expression was noted to have increased, and COL4A1 knockdown significantly reduced the inhibitory concentration 50% value of ADR in those cells.

    Conclusions: Our data identified the significant pathways and genes for predicting the emergence of ADR resistance and revealed that COL4A1 regulated the proliferation of MCF-7/ADR and played a crucial role in ADR resistance. Therefore, COL4A1 shows that it can be novel target for improving patients' prognosis with ADR-resistant BrCa.

  • Article
    Wei Zhao, Yujuan Su, Yujuan Yu, Mou Zou, Ying Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2277-2290. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.224
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    Background: Necrotizing Enterocolitis (NEC) is a critical illness commonly seen in premature and diseased neonates, characterized by mucosal necrosis of the small intestine and colon, which seriously affects the life and health of patients.

    Objective: The aim of the research was to investigate the role and mechanism of neutrophils in lung injury in mice with NEC.

    Methods: Combinational treatment with formula milk, hypoxia, and lipopolysaccharide (LPS) was performed to establish NEC in 5-day-old C57BL/6J mice. These mice were divided into 4 groups (20 mice in each group) by random number table method: Ctrl group, NEC group, NEC + phosphate-buffered saline (PBS) group, NEC + N-acetyl-L-cysteine (NAC) group. The pathological changes in intestinal and lung tissues were examined through Hematoxylin and Eosin (HE) staining. Lymphocyte antigen 6complex, locus g (Ly6G), neutrophil elastase (NE), myeloperoxidase (MPO) immunohistochemistry (IHC), and flow cytometry were used for qualitative and quantitative analysis of neutrophils in lung tissues respectively. The messenger ribonucleic acid (mRNA) relative expression levels of inflammatory factors in intestinal and lung tissues were detected using Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). The reactive oxygen species (ROS) release level in neutrophils stimulated by N-formyl-methionyl-leucy1-phenylalanine (fMLP) was detected using an enzyme-labeled instrument. The expression levels of genes in the Kelch-like enoyl-CoA hydratase (ECH)-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) pathway were determined using RT-qPCR.

    Results: Compared to the Ctrl group, the intestinal and lung tissues of the mice in the NEC group were significantly damaged (p < 0.0001). However, NAC could significantly relieve the damage (p < 0.0001). Compared to Ctrl group, the mRNA relative expression levels of inflammatory factors and anti-oxidant genes were significantly upregulated (p < 0.05), while the expression levels of anti-ROS genes were significantly downregulated in the NEC group (p < 0.05), and NAC could significantly reverse this result. Mice lung tissue RNA-seq results indicated a significant enrichment in the neutrophil degranulation pathway. The levels of NE, MPO, and ROS released by neutrophils were significantly higher than those in the Ctrl group (p < 0.05). The ROS released by neutrophils is involved in NEC-induced lung injury by regulating the Keap1-Nrf2 pathway, as the inhibition of the release of ROS can alleviate the injury of intestinal and lung tissues.

    Conclusions: Neutrophils play an important role in NEC-induced lung injury and NAC has therapeutic potential for NEC-induced lung injury.

  • Article
    Sushmaa Chandralekha Selvakumar, K Auxzilia Preethi, Kehinde Ross, Deusdedit Tusubira, Durairaj Sekar
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2291-2299. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.225
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    Background: Preeclampsia (PE) is a major health complication for pregnant women that increases the risk of mortality and morbidity. Knowledge of the complex molecular mechanisms associated with PE is incomplete and methods for early diagnosis and treatment options in PE are limited. MicroRNAs (miRNAs) are short non-coding RNAs involved in pathogenesis of various diseases including PE. In our previous studies, we identified a relationship between miR-510-3p and PE. However, the exact molecular mechanisms and genes regulated by miR-510-3p have not been elucidated.

    Methods: In this study, we employed the bioinformatic tools including miRbase, RNAcomposer, RNAfold, TargetScan, miRDB, miRTarbase to analyze the secondary structure and targets of miR-510-3p from the publicly available databases. We compared the miR-510-3p target genes with PE genes retrieved from the NCBI (National Center for Biotechnology Information) genes database. The miR-510-3p target genes that were involved in PE were further subjected to gene ontology (GO) and Kyoto Encyclopaedia for Genes and Genomes (KEGG) pathway analysis to analyse their biological, molecular and cellular role in PE. STRING, Shiny GO, Cytoscape and Metascape were used for the GO and KEGG analysis.

    Results and Conclusions: MicroRNA-510-3p had a minimum free energy of –29.10 Kcal and A+U content of 55.4%, suggesting stability and binding affinity towards its targets. Genes that were involved in the positive regulation of angiogenesis were identified, since angiogenesis is an important process in PE. ADAM12, ANGPT2, CHRNA7, DDAH1, ERAP1, FGF2, GRN, HGF, HIF1A, HK2, HMGB1, HMOX1, IL1A, KDR, NRP1, PRKCB, SERPINE1, SIRT1, TGFBR2, THBS1, TLR3, VEGFA, and WNT5A were the miR-510-3p targets involved in the positive regulation of angiogenesis. In conclusion, miR-510-3p is postulated to play an important role in the pathogenesis of PE. Hence, further studies could define miR-510-3p as a novel therapeutic target for PE.

  • Article
    Chao Long, Yongchun Li, Qiangyou Shi, Fan Guo, Zhipeng Mi, Xueliang Shen, Ruixia Ma
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2301-2309. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.226
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    Purpose: Amygdalin is a natural extract effective in cancer inhibition, though its effects on hypopharyngeal squamous cell carcinoma (HSCC) have not been investigated. This study aims to investigate the in vitro anti-hypopharyngeal carcinoma activity of amygdalin and its potential mechanism.

    Methods: The hypopharyngeal squamous cell carcinoma cell lines (FADU and TU212) were treated with amygdalin. The proliferation of hypopharyngeal carcinoma was tested by mitochondria targeting sequence (MTS) assay. Furthermore, Annexin V-fluorescein isothiocyanate/propidine iodide (Annexin V-FITC/PI) double staining, immunofluorescence and mitochondrial membrane potential (MMP) assays were taken to test apoptosis. Apoptotic mRNA transcript levels and protein expression were evaluated using real-time quantitative PCR (qPCR) and western blot (WB).

    Results: FADU and TU212 cells were treated with amygdalin. MTS assay showed that amygdalin inhibited the proliferation of hypopharyngeal carcinoma cells. Annexin V-FITC/PI double staining, immunofluorescence and MMP detection assays were carried out and confirmed that amygdalin induced apoptosis in hypopharyngeal carcinoma cells. In addition, qPCR and WB analysis suggested that amygdalin exerted a carcinogenic anti-hypopharyngeal effect by mediating the mitochondrial apoptosis pathway.

    Conclusions: Amygdalin can inhibit the proliferation of hypopharyngeal carcinoma cells and promote apoptosis of hypopharyngeal carcinoma cells by inducing the mitochondrial apoptosis pathway. Amygdalin is a potential chemotherapeutic agent for hypopharyngeal carcinoma.

  • Article
    Shiping WANG, Bin YANG, Yanxiu CUI, Zhenpeng ZHOU, Guangyu XU, Xiubin SUN
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2311-2316. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.227
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    Background: Varicocele is one of the common causes of infertility. In this study, we investigated whether levocarnitine could improve sperm density and viability in a varicocele rat model and change the Cation Channel of Sperm 1 (CatSper1) expression.

    Methods: Sixty male rats were randomly divided into six groups (n = 10 in each group): Control group, varicocele group, varicocele + normal saline group, and varicocele + small-, middle-, and large-dose of levocarnitine groups. Varicocele experimental model was established by partial ligation of the left renal vein. Twelve weeks later, the animals in the varicocele + normal saline group were gavaged with normal saline (1 mL⋅kg–1⋅d–1), while the animals in groups varicocele + small-, middle-, large-dose levocarnitine were respectively gavaged with levocarnitine of different concentrations (0.01, 0.02, 0.03 g⋅kg–1⋅d–1) for consecutive 35 days. We measured the semen parameters by computer-assisted semen analysis (CASA) and CatSper1 in sperms by Reverse Transcription-Polymerase Chain Reaction (RT-PCR).

    Results: We found that sperm density, percentage of sperm motility with grade a + b and sperm viability were remarkably higher in the varicocele + small-, middle- and large-dose levocarnitine groups compared to the varicocele + normal saline group (p < 0.01). CatSper1 expression in sperms was significantly increased in varicocele + middle- and large-dose levocarnitine, compared to the varicocele + normal saline group (p < 0.01).

    Conclusions: Middle- and large-dose levocarnitine could increase sperm density and viability by increasing CatSper1 expression. Levocarnitine might be beneficial to asthenozoospermia caused by varicocele.

  • Article
    Yuwen Wu, Haohua Deng, Jiazhong Sun, Yancheng Xu
    Journal of Biological Regulators and Homeostatic Agents. 2023, 37(4): 2317-2325. https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.228
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    Background: In recent years, with the increasing prevalence of diabetes, diabetic nepropathy (DN) has become a serious public health threat. This study investigated the potential role of Nlr family member X1 (NLRX1) in DN and the underlying mechanisms.

    Methods: Diabetic model of mice were injected intraperitoneally (i.p.) with streptozotocin, and fed with the high fat diet (HFD) as the in vivo model of diabetes-induced kidney injury. Rat mesangial cells (MCs) were exposed with high glucose (30 mmol/L glucose) as in vitro cell model.

    Results: NLRX1 mRNA (messenger ribonucleic acid) and protein levels were down-regulated in the kidney tissue of diabetic mouse model of kidney injury. NLRX1 protein administration reduced inflammation and prevented kidney injury in the mouse model. NLRX1 inactivated NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome in both the mouse model and in vitro cell model. Further experiments showed that the administration of NLRP3 attenuated the effects of NLRX1 on inflammation of diabetes-induced kidney injury model.

    Conclusions: In conclusion, NLRX1 attenuates the inflammation in diabetes-induced kidney injury by inhibiting NLRP3 inflammasome, which may serve as be a potent target for preventing the progression of DN through inhibition of NLRP3 inflammasome-dependent inflammation.