Mitochondria-associated membranes contribution to exercise-mediated alleviation of hepatic insulin resistance: Contrasting high-intensity interval training with moderate-intensity continuous training in a high-fat diet mouse model.

OBJECTIVE: Mitochondria-associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high-fat diet (HFD) mice. METHODS: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin-eosin (H&E) and oil red O staining. The phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K-AKT-GSK3ß) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage-dependent anion-selective channel 1 [VDAC1] and inositol 1,4,5-triphosphate receptor [IP3R]). RESULTS: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3ß signaling pathway, accompanied by a marked reduction in hepatic IP3R-VDAC1 colocalization levels. Both 8-week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3ß signaling and colocalization levels of IP3R-VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R-VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p-AKT) and phosphorylation of glycogen synthase kinase 3 beta (p-GSK3ß), while displaying a negative correlation with serum triglyceride/high-density lipoprotein cholesterol levels. CONCLUSION: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise-induced alleviation of hepatic IR.

Risk factors affecting the mortality of HIV-infected patients with pulmonary tuberculosis in the cART era: a retrospective cohort study in China.

BACKGROUND: Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries. Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis (PTB) would provide important insights for the clinical management of this population, which remains to be well described in current China. METHODS: HIV-infected patients with PTB admitted to Shanghai Public Health Clinical Center from January 2011 to December 2015 were retrospectively enrolled. In this cohort, the survival prognosis was estimated by the Kaplan-Meier method, while univariate and multivariate Cox proportional hazards models were used to determine the risk factors affecting mortality. RESULTS: After reviewing 4914 admitted patients with HIV infection, 359 PTB cases were identified. At the time of PTB diagnosis, the patients' median CD4+ T cell count was 51 /mm3 (IQR: 23-116), and 27.30% of patients (98/359) were on combination antiretroviral therapy (cART). For the 333 cases included in the survival analysis, the overall mortality was 15.92% (53/333) during a median 27-month follow-up. The risk factors, including age older than 60 years (HR: 3.18; 95% CI: 1.66-6.10), complication with bacterial pneumonia (HR: 2.64; 95% CI: 1.30-5.35), diagnosis delay (HR: 2.60; 95% CI: 1.42-4.78), CD4+ T cell count less than 50/mm3 (HR: 2.38; 95% CI: 1.27-4.43) and pulmonary atelectasis (HR: 2.20; 95% CI: 1.05-4.60), might independently contribute to poor survival. Among patients without cART before anti-TB treatment, the later initiation of cART (more than 8 weeks after starting anti-TB treatment) was found to increase the mortality rate (OR: 4.33; 95% CI: 1.22-15.36), while the initiation of cART within 4-8 weeks after starting anti-TB treatment was associated with the fewest deaths (0/14). CONCLUSIONS: The subjects in this study conducted in the cART era were still characterized by depressed immunological competence and low rates of cART administration, revealing possible intervention targets for preventing TB reactivation in HIV-infected individuals under current circumstances. Furthermore, our study indicated that the timely diagnosis of PTB, prevention of secondary bacterial pneumonia by prophylactic management and optimization of the timing of cART initiation could have significant impacts on decreasing mortality among HIV/PTB co-infected populations. These findings deserve further prospective investigations to optimize the management of HIV/PTB-co-infected patients. TRIAL REGISTRATION: NCT01344148 , Registered September 14, 2010.