Synergistic impact of diabetes and cognitive impairment on all-cause and cause-specific mortality in Chinese older adults: A prospective population-based cohort study.

Background: Diabetes mellitus (DM) or cognitive impairment (CI) is known to be strongly associated with mortality. DM commonly coexists with CI and proportionally increases with age. However, little is known about the combined effect of cognitive function and diabetes on mortality. This study aimed to evaluate the combined effects of DM and CI on all-cause and cause-specific mortality in Chinese older adults. Methods: This prospective population-based cohort study was based on the Beijing Elderly Comprehensive Health Cohort Study. A total of 4,499 older adults were included. Cox's proportional hazard models were utilized to calculate the effect of DM and CI on all-cause, cardiovascular disease (CVD) mortality and cancer mortality, and a multiplicative term was introduced to study a potential interaction between DM and CI on outcomes. Results: During a median follow-up of 6.8 years (ranging from 6.6 to 11.7 years), 667 (14.8%) participants died from all causes, 292 from CVD, and 215 from cancer. In the fully adjusted model, participants with coexisting DM and CI had the highest risk of all-cause mortality [hazard ratios (HRs), 3.08; 95% confidence intervals (CIs), 2.30,4.11] and CVD mortality (HRs, 3.85; 95% CIs, 2.60,5.71) compared with individuals with normal cognition and non-DM. We also found a multiplicative interaction between DM and CI in respect to all-cause (HRs, 2.46; 95% CI, 1.87,3.22) and CVD mortality (HRs, 3.15 95% CI, 2.19,4.55). In the diabetic population, CI was associated with an increased risk of all-cause mortality (HRs, 2.09; 95% CIs, 1.51,2.89) and CVD mortality (HRs, 3.16; 95% CIs, 2.02,5.05) compared with the normal cognition group. Restricted cubic spline revealed a linear inverse association between Mini-Mental State Examination (MMSE) score and all-cause, CVD mortality in the total sample and participants without diabetes. However, a nearly reverse J association was observed between MMSE and mortality from all causes and CVD in the diabetes group. Conclusion: The findings highlighted that cognitive impairment concomitant with diabetes further increases the risk of mortality. In addition to strengthening routine screening of cognitive functioning in older adults with early-stage diabetes, more extensive assessment of prognostic risks has high clinical value for developing comprehensive treatment plans.

USP7-SOX9-miR-96-5p-NLRP3 Network Regulates Myocardial Injury and Cardiomyocyte Pyroptosis in Sepsis.

Sepsis is a common life-threatening pathology. This study investigated the role of transcription factor sex-determining region Y (SRY)-box 9 (SOX9) in sepsis-induced cardiomyocyte pyroptosis. A murine model of sepsis was established, followed by detection of cardiac functions and myocardial injury. HL-1 mouse cardiomyocytes were induced by lipopolysaccharides (LPS). The levels of interleukin (IL)-18, IL-1ß, tumor necrosis factor-α (TNF-α), IL-6, malondialdehyde (MDA), and superoxide dismutase (SOD) in myocardial tissues and HL-1 mouse cardiomyocytes were determined. SOX9 ubiquitination level was measured. The binding relationships between SOX9-miR-96-5p and miR-96-5p-NLR pyrin domain containing 3 (NLRP3) were analyzed, and the interaction between ubiquitin-specific peptidase 7 (USP7) and SOX9 was measured. SOX9 was highly expressed in septic mice and LPS-induced HL-1 mouse cardiomyocytes. SOX9 silencing improved cardiac function, alleviated myocardial injury, reduced the levels of IL-1ß, IL-18, cleaved caspase-1, gasdermin D N-terminal domain, TNF-α, IL-6, and MDA in myocardial tissues and HL-1 mouse cardiomyocytes, increased the level of SOD, and alleviated cardiomyocyte pyroptosis. USP7 upregulated SOX9 expression through deubiquitination. SOX9 inhibited miR-96-5p expression and miR-96-5p targeted NLRP3. miR-96-5p silencing or USP7 overexpression reversed the inhibitory effect of SOX9 silencing on cardiomyocyte pyroptosis. Collectively, USP7 upregulated SOX9 expression through deubiquitination, and SOX9 suppressed miR-96-5p expression by binding to the miR-96-5p promoter region, thereby promoting NLRP3 expression and then exacerbating sepsis-induced myocardial injury and cardiomyocyte pyroptosis.

Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway.

This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM's anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM's anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.