AbstractObjectiveThe aim of this study is to investigate the dysbiosis characteristics of gut microbiota in patients with cerebral infarction (CI) and its clinical implications.MethodsStool samples were collected from 79 CI patients and 98 healthy controls and subjected to 16S rRNA sequencing to identify stool microbes. Altered compositions and functions of gut microbiota in CI and its correlation with clinical features were investigated. Random forest and receiver operating characteristic analysis were used to develop a diagnostic model.ResultsMicrobiota diversity and structure between CI patients and healthy controls were overall similar. However, butyrate-producing bacteria (BPB) were significantly reduced in CI patients, while lactic acid bacteria (LAB) were increased. Genetically, BPB-related functional genes were reduced in CI patients, whereas LAB-related genes were enhanced. The interbacterial correlations among BPB in CI patients were less prominent than those in healthy controls. Clinically, BPB was negatively associated with the National Institutes of Health Stroke Scale (NIHSS), while LAB was positively correlated with NIHSS. Both BPB and LAB played leading roles in the diagnostic model based on 47 bacteria.ConclusionsThe abundance and functions of BPB in CI patients were significantly decreased, while LAB were increased. Both BPB and LAB displayed promising potential in the assessment and diagnosis of CI.

Aim/Introduction Obesity is considered an important risk factor for many metabolic disorders, especially type 2 diabetes mellitus, and microRNAs (miRNAs) play a vital role in the development of type 2 diabetes mellitus. Therefore, we conducted this study to investigate the role of miR‐4431 in the obesity‐associated pathobiology of type 2 diabetes mellitus. Materials and methods Subjects were divided into normal control (n = 36), obese (n = 36), and type 2 diabetes mellitus (n = 12) groups, and serum miR‐4431 levels were analyzed. Adenovirus‐vectored miR‐4431 mimic or sponge was intraperitoneally injected into the normal diet group and the high‐fat diet group (HFD) mice to investigate glucose tolerance, insulin sensitivity, and lipid levels. The downstream target genes of miR‐4431 were predicted using bioinformatics, and they were verified in vitro. Results Serum miR‐4431 levels were significantly high in obese and type 2 diabetes mellitus individuals, and positively correlated with the body mass index and fasting plasma glucose levels. In HFD mice, miR‐4431 levels in the serum, white adipose tissue, and liver were significantly increased. Moreover, miR‐4431 impaired glucose tolerance, insulin sensitivity, and lipid metabolism in mice. Bioinformatic prediction suggested that TRIP10 and PRKD1 could be the downstream target genes of miR‐4431. The HFD mice showed a remarkable reduction in the mRNA levels of TRIP10 and PRKD1 in the liver, which were countered by blocking miR‐4431. In HepG2 and L02 cells, miR‐4431 could downregulate TRIP10 and PRKD1 while blocking glucose uptake. The luciferase reporter assay showed that miR‐4431 could bind TRIP10 and PRKD1 3′‐UTR. Conclusion miR‐4431 targets TRIP10/PRKD1 and impairs glucose metabolism.

Background Endothelial progenitor cell (EPC) dysfunction contributes to vascular disease in diabetes mellitus. However, the molecular mechanism underlying EPC dysfunction and its contribution to delayed reendothelialization in diabetes mellitus remain unclear. Our study aimed to illustrate the potential molecular mechanism underlying diabetic EPC dysfunction in vivo and in vitro. Furthermore, we assessed the effect of EPC transplantation on endothelial regeneration in diabetic rats. Methods Late outgrowth EPCs were isolated from the bone marrow of rats for in vivo and in vitro studies. In vitro functional assays and Western blotting were conducted to reveal the association between C-X-C chemokine receptor type 7 (CXCR7) expression and diabetic EPC dysfunction. To confirm the association between cellular CXCR7 levels and EPC function, CXCR7 expression in EPCs was upregulated and downregulated via lentiviral transduction and RNA interference, respectively. Western blotting was used to reveal the potential molecular mechanism by which the Stromal-Derived Factor-1 (SDF-1)/CXCR7 axis regulates EPC function. To elucidate the role of the SDF-1/CXCR7 axis in EPC-mediated endothelial regeneration, a carotid artery injury model was established in diabetic rats. After the model was established, saline-treated, diabetic, normal, or CXCR7-primed EPCs were injected via the tail vein. Results Diabetic EPC dysfunction was associated with decreased CXCR7 expression. Furthermore, EPC dysfunction was mimicked by knockdown of CXCR7 in normal EPCs. However, upregulating CXCR7 expression reversed the dysfunction of diabetic EPCs. The SDF-1/CXCR7 axis positively regulated EPC function by activating the AKT-associated Kelch-like ECH-associated protein 1 (keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, which was reversed by blockade of AKT and Nrf2. Transplantation of CXCR7-EPCs accelerated endothelial repair and attenuated neointimal hyperplasia in diabetes mellitus more significantly than transplantation of diabetic or normal EPCs. However, the therapeutic effect of CXCR7-EPC transplantation on endothelial regeneration was reversed by knockdown of Nrf2 expression. Conclusions Dysfunction of diabetic EPCs is associated with decreased CXCR7 expression. Furthermore, the SDF-1/CXCR7 axis positively regulates EPC function by activating the AKT/keap-1/Nrf2 axis. CXCR7-primed EPCs might be useful for endothelial regeneration in diabetes-associated vascular disease.

Background In previous study, we found that the content of medium-chain fatty acid Caprylic Acid (FFA C8:0) may be an important risk factor of obesity induced prostate cancer (PCa). However, the relationship between FFA C8:0 and PCa has not been reported. In this study, we explored whether the FFA C8:0 can promotes the progression of PCa by up-regulating Krüppel-like factor 7 (KLF7). Methods We collected tissues from PCa patients and Benign Prostate Hyperplasia (BPH), constructed a primary-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, CCK8 assay, plate cloning, Transwell and scratch experiment were used to detect the changes in biological behavior of PCa cells stimulated by FFA C8:0. Results First, we found that the expression level of KLF7 is higher in PCa tissues of patients, and the expression of KLF7 is positively correlated with tumour-promoting gene IL-6, while it is negative correlated with another tumour-suppressor gene p21. Then, this study found that PCa cells were more likely to form tumors in diet induced obese mice. Compared with the normal diet group (ND), the expression levels of KLF7 in tumor tissues in high-fat diet group (HFD) were higher. Futhermore, we verified that high concentrations of FFA C8:0 can promote the biological behavior of PCa cells by activating KLF7/IL-6/p21 signaling pathway, which is mediated by the GPR84. Conclusions Our research may provide a potential target for clinical prevention and treatment of PCa which induced by obesity.

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