AIMS AND OBJECTIVES:This study aimed to evaluate the pharmacological mechanism of Hederagenin (HD) combined with oxaliplatin (L-OHP) in treating gastric cancer (GC) through network pharmacology combined with experimental verification. MATERIAL AND METHODS:Network pharmacology methods were used to screen potential targets for HD, L-OHP, and GC-related targets from public databases, and the intersection of the three gene sets was taken. Cross genes were analyzed through protein-protein interaction (PPI) networks to predict core targets, and related pathways were predicted through GO and KEGG enrichment analysis. The experimental results were verified by the in vitro experiments. HD was applied on AGS/L-OHP cells, and then cellular chemosensitivity and the expressions of P-gp, Survivin, Bcl-2, p-Akt, and p-PI3K genes were detected. Wound assay and Transwell Chamber assay were employed to detect the effect of HD on AGS/L-OHP cells. Nude mice xenograft models transfected using AGS/L-OHP cells were also treated with HD in order to verify the results. The size and weight of the tumor, as well as the expressions of P-gp, Survivin, Bcl-2, p- Akt and p-PI3K genes, were also measured. RESULTS:KEGG analysis showed that the anti-gastric cancer effect of HD was mediated mainly by PI3K-Akt signaling pathways. The PI3K-Akt signaling pathway containing more enriched genes may play a greater role in anti-gastric cancer. It was observed that for AGS/L-OHP cells jointly treated with HD and L-OHP, their activity, migration and invasion were significantly lower than those treated only using HD or L-OHP group. Moreover, expressions of p-Akt, p- PI3K, Bcl-2, P-gp, and Survivin for the HD+L-OHP group decreased significantly. Results of the in vivo experiments showed that the sizes and weights of tumors in the HD+L-OHP group were the lowest compared to the HD group and L-OHP group. CONCLUSION:Our findings suggest that HD may reduce the resistance of AGS/L-OHP cells to LOHP by regulating the PI3K/Akt signaling pathway.

BACKGROUND:This study was designed to investigate the mechanism by which miR-30a-5p mediates cardiomyocyte apoptosis after acute myocardial infarction (AMI) induced by hypoxia/reoxygenation (H/R). METHODS:Differentially expressed miRNAs were analyzed by RNA high-throughput sequencing in acute myocardial infarction (ST-elevation myocardial infarction) patients versus healthy individuals (controls). The H/R model was used to assess the regulatory mechanism of miRNAs in AMI. Lentivirus-associated vectors were used to overexpress or knock down miR-30a-5p in cellular models. The pathological mechanisms of miR-30a-5p regulating the development of acute myocardial infarction were serially explored by qPCR, bioinformatics, target gene prediction, dual luciferase, enzyme-linked immunosorbent assays (ELISAs) and Western blotting. RESULTS:The results showed that the expression of miR-30a-5p was significantly increased in AMI patients and H9C2 cells. Hypoxia decreased cardiomyocyte survival over time, and reoxygenation further reduced cell survival. Bax and Phosphatase and tensin homolog (PTEN)were suppressed, while Bcl-2 was upregulated. Additionally, miR-30a-5p specifically targeted the PTEN gene. According to the GO and KEGG analyses, miR-30a-5p may participate in apoptosis by interacting with PTEN. The miR-30a-5p mimic decreased the expression of apoptosis-related proteins and the levels of the proinflammatory markers IL-1β, IL-6, and TNF-α by activating the PTEN/PI3K/Akt signaling pathway. Conversely, anti-miR-30a-5p treatment attenuated these effects. Additionally, silencing PTEN and anti-miR-30a-5p had opposite effects on H/R-induced cell apoptosis. CONCLUSIONS:miR-30a-5p plays a crucial role in cardiomyocyte apoptosis after hypoxia-induced acute myocardial infarction. Our findings provide translational evidence that miR-30a-5p is a novel potential therapeutic target for AMI.

Objective To analyze the levels and correlation of vitamin D,ACE2,ACE and inflammatory factors in patients with type 2 diabetes mellitus and explore the interaction of vitamin D with ACE2 and inflammatory factors and the mechanism of action on the occurrence and development of diabetes.Methods A total of 87 non-diabetic controls and 96 patients with type 2 diabetes mellitus were chosen,who visited Hebei People's Hospital and were hospitalized from July 2021 to November 2021,and they were divided into non-diabetic normal vitamin D group(47 cases)and insufficient vitamin D group(40 cases),and diabetic normal vitamin D group(52 cases)and insufficient vitamin D group(44 cases)according to serum 25-hydroxyvitamin D level.Detect inflammatory indicators such as ACE,ACE2,IL-6 and TNF-α in each group,and analyze the correlation and influencing factors between vitamin D and each indicator.Results Compared with the normal vitamin D group,the vitamin D insufficiency group had significantly higher HOMA-IR,Ang Ⅱ,IL-6,and TNF-α levels and significantly lower ACE2 and IL-10 levels in both non-diabetic and diabetic patients(P＜0.05).Compared with the non-diabetic vitamin D insufficiency group,with the increase in severity of vitamin D deficiency,blood glucose,ACE and inflammatory factors were significantly increased,insulin resistance was more serious,and ACE2 and IL-10 were significantly decreased(P＜0.05).Pearson correlation analysis showed that vitamin D was negatively correlated with Ang Ⅱand IL-6,and positively correlated with IL-10 in the non-diabetic group(P＜0.05).In the diabetic group,vitamin D was positively correlated with ACE2 and IL-10,and negatively correlated with ACE,Ang Ⅱ,IL-6,TNF-α,HOMA-IR and HbA1c(all P＜0.01).Multiple linear regression analysis showed that IL-10 and Ang Ⅱ were the main influencing factors of vitamin D deficiency in the non-diabetic group(P＜0.05),which explained 33.6％of the total variation of the regression equation.In the diabetes group,ACE2,IL-6,TNF-α,IL-10 and HOMA-IR were the main influencing factors of vitamin D deficiency(P＜0.05),which explained 55.8％of the total variation of the regression equation.Conclusions Vitamin D deficiency may lead to dysregulation of ACE2,ACE/Ang Ⅱ and increased levels of inflammatory factors.Vitamin D deficiency exacerbates insulin resistance by mediating the RAS system,which is involved in the potential pathogenesis of diabetes.ACE2,ACE/Ang Ⅱ and inflammatory factors can be used as susceptible markers of vitamin D deficiency in diabetes.

BACKGROUND:Gastric cancer (GC) is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis. Resveratrol, a non-flavonoid polyphenolic compound found in a variety of Chinese medicinal materials, has shown excellent anti-GC effect. However, its exact mechanisms of action in GC have not been clarified.AIM:To identify the effects of resveratrol on GC progression and explore the related molecular mechanisms.METHODS:Action targets of resveratrol and GC-related targets were screened from public databases. The overlapping targets between the two were confirmed using a Venn diagram, and a "Resveratrol-Target-GC" network was constructed using Cytoscape software version 3.9.1. The protein-protein interaction (PPI) network was constructed using STRING database and core targets were identified by PPI network analysis. The Database for Annotation, Visualization and Integrated Discovery database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A "Target-Pathway" network was created by using Cytoscape 3.9.1. The RNA and protein expression levels of core target genes were observed using the Cancer Genome Atlas and the Human Protein Atlas databases. DriverDBv3 and Timer2.0 databases were used for survival and immune infiltration analysis. Subsequently, the findings were further verified by molecular docking technology and in vitro experiments.RESULTS:A total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases, and 181 intersection targets between the two were screened by Venn diagram. The top 20 core targets were identified by PPI network analysis of the overlapping targets. GO function analysis mainly involved protein binding, identical protein binding, cytoplasm, nucleus, negative regulation of apoptotic process and response to xenobiotic stimulus. KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, ErbB signaling pathway, etc. FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9) were selected by differential expression analysis, and they were closely associated with immune infiltration. Molecular docking results showed that resveratrol docked well with these two targets. Resveratrol treatment arrested the cell cycle at the S phase, induced apoptosis, and weakened viability, migration and invasion in a dose-dependent manner. Furthermore, resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression.CONCLUSION:The anti-GC effects of resveratrol are related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.

While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear. Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy. We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR−661 and miR−671−5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD−1 therapy. Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.

Objective: The value of novel biomarkers for DKD has received increasing attention, and there is an urgent need for novel biomarkers with sensitivity, specificity and ability to detect kidney damage.miR-377 regulates many basic biological processes, plays a key role in tumor cell proliferation, migration and inflammation, and can also increase the expression of matrix proteins and fibronectin, leading to renal tubulointerstitial inflammation and renal fibrosis. Lipoprotein-associated phospholipase A2, as an inflammatory marker, is involved in the pathological process of microalbuminuria production and renal function decline, and is a predictive factor of microalbuminuria production and renal function decline, and can be used as an indicator to evaluate the progression of DKD.The aim of this study was to investigate the effects of miR-377 and phospholipase A2 on the development of diabetic kidney disease through regulation of inflammatory factors and the mechanism of action. Methods: 80 diabetic patients were divided into two groups according to urinary albumin-to-creatinine ratio (UACR): diabetic normal proteinuria group (n = 42) and diabetic proteinuria group (n = 38). Forty-three healthy people were selected as the normal control group. The serum levels of TGF-beta, IL -6, and IL -18 were measured by ELISA, miR377 was detected by qPCR, and the serum levels of phospholipase A2 were detected by electrochemiluminescence. Analyze the correlation of study group indicators, ROC curve was used to evaluate the diagnostic efficacy of miR-377 and phospholipase A2 in diabetic kidney disease. Results: The average levels of serum TGF-beta, IL -6, IL -18, miR-377 and phospholipase A2 in diabetic proteinuria group were significantly higher than those in normal control group and diabetic proteinuria normal group(P < 0.05). miR-377, phospholipase A2 were significantly correlated with inflammatory factors such as glomerular filtration rate and TGF-beta. miR-377 and phospholipase A2 are independent predictors of diabetic kidney disease. The area under the curve of miR-377 and phospholipase A2 in the normal diabetic proteinuria group and the diabetic proteinuria group were 0.731 and 0.744, respectively. Conclusion: miR-377 and phospholipase A2 have good diagnostic efficiency for the early diagnosis of diabetic kidney disease. They can be used as early biomarkers.miR-377 and phospholipase A2 were positively correlated with inflammatory factors and involved in the occurrence and development of diabetic kidney disease.

Acute myocardial infarction(AMI)is one of the main causes of death from cardiovascular and cerebro-vascular diseases worldwide.Rapid and efficient diagnosis of AMI plays an important role in the treatment and prognosis of the disease.Studies suggest that microRNA(miRNA)may be an important molecular marker for the diagnosis of AMI and provide directions for AMI treatment.This review summarizes the feasibility of miRNA as a diagnostic marker for AMI,its effect on AMI and its related molecular mechanisms.

动脉粥样硬化(AS)是一种以脂质积聚和炎症为特征的疾病,是冠心病和心肌梗死的病理基础.在AS发展过程中会出现多种形式的细胞死亡,包括胞葬、细胞焦亡与 自噬,调控细胞死亡进程可能延缓AS过程.三磷酸腺苷结合盒转运体(ABC)A1是细胞内胆固醇外流的关键介质,在胆固醇逆向转运中生成高密度脂蛋白.目前,越来越多研究发现,细胞死亡与AS密切相关,但具体机制尚未阐明.该文综述了 ABCA1调控细胞死亡,如胞葬、细胞焦亡和自噬对AS的影响.

目的:研究中和白介素-17(interleukin-17,IL-17)对博来霉素(bleomycin,BLM)诱导特发性肺纤维化及PI3K/Akt/mTOR信号通路的影响.方法:C57BL/6小鼠随机分为对照组、BLM组、中和抗体组和自噬抑制组.BLM组、中和抗体组和自噬抑制组利用BLM(5 U/kg)诱导特发性肺纤维化模型形成,对照组给予等量生理盐水.造模第1天起自噬抑制组小鼠腹腔注射3-甲基腺嘌呤(3-methyladenine,3-MA),每周5次,连用4周,其他3组则注射等量的生理盐水.中和抗体组和自噬抑制组小鼠分别从造模后第3d起,每隔3d尾静脉注射抗鼠IL-17抗体,于28 d取材,采用Masson三色染色和羟脯氨酸(hydroxyproline,HYP)含量测定评价肺纤维化程度和胶原蛋白的表达变化,利用ELISA检测肺泡灌洗液中转化生长因子-β1(transform growth factor-β1,TGF-β1)的含量,Western blot分析LC3Ⅱ/LC3Ⅰ、Beclin-1、p62、p-PI3K/PI3K、p-Akt/Akt和p-mTOR/mTOR的蛋白表达.结果:与BLM组相比,中和抗体组羟脯氨酸和TGF-β1含量显著下降(P＜ 0.01),肺纤维化程度明显降低(P＜0.01),LC3Ⅱ/LC3Ⅰ比值和Beclin-1表达明显上调(P＜ 0.01,P＜0.05),p62表达减少(P＜0.05),而p-PI3K/PI3K、p-Akt/Akt、p-mTOR/mTOR比值显著降低(P＜0.05).结论:IL-17在肺纤维化中的作用与抑制细胞自噬有关.中和内源性IL-17,能显著改善BLM诱导的肺纤维化,降低TGF-β1产生,抑制PI3K/Akt/mTOR信号通路,激活细胞自噬.