Abstract Nonalcoholic steatohepatitis (NASH) has emerged as a major cause of liver failure and hepatocellular carcinoma. Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology. Here, we present comprehensive multi-omic profiles of preclinical animal models to identify genes, non-coding RNAs, proteins, and plasma metabolites involved in this progression. In particular, by transcriptomics analysis, we identified Growth Differentiation Factor 3 (GDF3) as a candidate noninvasive biomarker in NASH. Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH, and differences in these levels provide a high diagnostic accuracy of NASH diagnosis (AUROC = 0.90; 95% confidence interval: 0.85−0.95) with a good sensitivity (90.7%) and specificity (86.4%). In addition, by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH, we show that ferroptosis may be a potential target to treat NASH. Moreover, by using competing endogenous RNAs network analysis, we found that several miRNAs, including miR-582-5p and miR-292a-3p, and lncRNAs, including XLOC-085738 and XLOC-041531, are associated with steatosis-to-NASH progression. Collectively, our data provide a valuable resource into the molecular characterization of NASH progression, leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.
Objective: To analyze the risk factors of catheter-related bloodstream infection in outpatients and propose feasible prevention and control measures. Methods: The medical records of outpatients with peripherally inserted central catheter (PICC) from January 2020 to December 2021 were selected for retrospective analysis, and the factors that may be related to the occurrence of catheter-related bloodstream infection were analyzed by logistic multivariate analysis. Results: The incidence rate of catheter-related bloodstream infection among the enrolled patients was 4.78%. It was found that age, duration of catheterization, catheter site, number of punctures, and diabetes were all risk factors for catheter-associated bloodstream infection, and the differences were statistically significant. Conclusion: Age, duration of catheterization, catheterization site, and diabetes are all risk factors for catheter-related bloodstream infection, and medical personnel should fully understand and learn more about these risk factors and actively develop countermeasures to reduce the risk of catheter-related bloodstream infection.
To evaluate the protective effect of the angiotensin-converting enzyme inhibitor perindopril on diabetic glomerulopathy in rats with experimentally induced diabetes and explore its possible mechanisms.Ninety-two adult male Wistar rats were randomly allocated into diabetes mellitus (DM), diabetes mellitus + perindopril (DMP) and control (C) groups. According to the duration of diabetes or observation (1, 3, 6 months), each group was randomly subdivided into DM1, DM3, DM6; DMP1, DMP3, DMP6; and C1, C3, C6 groups. Diabetes was induced by intraperitoneal injection of streptozotocin. The rats in the DMP groups received perindopril 1 mg.kg-1.d-1, through gastric intubation. Urinary protein excretion rate was determined by the method of Coomassie brilliant blue. Plasma renin activity, renal tissue renin activity, and plasma and renal tissue angiotensin II concentration were assayed by radioimmunoassay (RIA). Renal tissue total RNA was extracted by the Chomezymskis AGPC method. Renal angiotensinogen mRNA expression level was assessed by slot blot hybridization using a full length rat angiotensinogen cDNA probe labelled with 32P-dCTP and a random primer.There was increased activity of the renin angiotensin system in diabetic rats. Perindopril decreased proteinuria and delayed the progression of glomerular basement membrane thickening. However, it did not reduce the expansion of the mesangial matrix (P < 0.05). Renin activity increased and angiotensin II concentration decreased significantly in both plasma and renal tissue in diabetes + perindopril groups (P < 0.05).Perindopril may help prevent the progression of diabetic glomerulopathy, and the inhibition of renin angiotensin system activity may be a mechanism for this action.
[Objective] To explore the insulin sensitivity and glucose metabolism in rats of intrauterine growth retardation (IUGR) caused by malnutrition during pregnancy. [Methods] IUGR rat models were established by maternal protein-malnutrition. Male offsprings were studied. The body weights of rats since birth to 12 weeks of age were weighted. The weight of perinephric fat pads at W3, W8 and W12 were examined. At 8 weeks of age, rats were subjected to an insulin tolerance test to evaluate insulin sensitivity in IUGR animals. [Results] Birth weight of IUGR animals were significantly lower than that of control groups until 4 weeks of age, when IUGR rats caught up to controls. Between 8~12 weeks, the growth of IUGR rats surpassed that of controls with perinephric fat pads significantly increased. No significant differences were observed in blood glucose and insulin levels at 3 week. However by 8 week IUGR rats developed hyperinsulinemia and high IRI. At age 12 weeks, IUGR rats had mild fasting hyperglycemia besides high IRI. Insulin tolerance test showed a significantly blunted glycemic response to exogenous insulin in IUGR rats. [Conclusions] These data suggest that malnutrition during pregnancy can induce permant changes in glucose homeotasis and lead to type 2 diabetes in adulthood.
Objective To investigate the effect of intravenous intralipid infusion elevating the plasma free fatty acids(FFA) level at different times on glucose infusion rate in rats.Methods Intralipid+heparin(IH) and saline(SAL) were intravenously infused for 2 h,5 h,7 h,and 48 h,respectively.Insulin sensitivity was assessed with glucose infusion rate(GIR) and determined by hyperinsulinemic-euglucemic clamp method.The levels of plasma glucose and FFA were measured.Results Compared with the SAL group,the plasma FFA level was elevated by 2 times(P0.01) in group IH at 2 h,while GIR decreased 27%(P0.05) at 2 h,decreased 52% at 5 h(P0.01),decreased 56% at 7 h(P0.01),and decreased 58% at 48 h(P0.01),however there was no significant difference between the GIR values at 5 h,7 h and 48 h.Conclusion A rat model of insulin resistance mediated by lipotoxicity has been successfully established by intravenous intralipid infusion,when the plasma FFA concentration reaches 3 times of the basic level and still maintaining such a high level for a longer time period.
Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR–dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.
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