PGAM5 regulates DRP1-mediated mitochondrial fission/mitophagy flux in lipid overload-induced renal tubular epithelial cell necroptosis.

The pathophysiology of renal lipid toxicity caused by excess adiposity is not well-understood. Necroptosis, a regulated form of cell death, is involved in injuring renal tubular epithelial cells (RTECs). Phosphoglycerate mutase 5 (PGAM5) is a key downstream effector of necroptosis. This study investigated the underlying mechanism of PGAM5 in promoting lipid-induced necroptosis in RTECs. HK2 cells (an immortalized proximal tubule epithelial cell line) were exposed to oleic acid (OA) to mimic the lipid overload environment in vitro. We found that OA suppressed HK2 cell proliferation, triggered cytoskeleton rupture and cell death. In OA-treated cells, upregulated expression of necroptosis pathway proteins, phosphorylated receptor-interacting protein-1/3 (pRIPK1/3), phosphorylated mixed lineage kinase domain-like protein (pMLKL), PGAM5, phosphorylated dynamin-related protein 1 (pDRP1S616), and downregulated pDRP1S637 expression were observed. This was accompanied by mitochondrial dysfunction (mitochondrial ROS overproduction and decreased mitochondrial membrane potential) and increased cellular necrosis, as reflected by Annexin V/ Propidium Iodide (PI) labeling. OA also induced the accumulation of LC3II and P62, blocking autophagosome fusion with lysosomes. Knockdown of PGAM5 could prevent these OA-induced changes. We propose inhibition of PGAM5 protects lipid-induced RTECs from necroptosis by reducing DRP1-mediated mitochondrial fission and improving mitophagy flux.

Intensive blood pressure treatment in coronary artery disease: implications from the Systolic Blood Pressure Intervention Trial (SPRINT).

To investigate the optimal blood pressure (BP) in patients with coronary artery disease (CAD), we conducted subgroup analysis using SPRINT data. The study sample included 1206 participants with CAD (of whom 692 underwent coronary revascularization) and 8127 participants without CAD. Participants were randomized into two groups (systolic BP target of 140 mm Hg vs. 120 mm Hg). The primary outcome was a composite of cardiovascular events. After a median follow-up of 3.9 years, the hazard ratios (HRs) for the primary outcome were 0.65 (95% confidence interval (CI) 0.53-0.79) and 1.05 (95% CI 0.76-1.46) among those in the non-CAD and CAD subgroups, respectively (P value for interaction 0.02). Intensive BP treatment was a protective factor for all-cause death (HR 0.60, 95% CI 0.37-0.96) in the CAD subgroup, compared with standard BP treatment. The HRs (95% CI) for stroke were 3.57 (1.17-10.85) and 1.03 (0.29-3.62) among those in the coronary revascularization and non-revascularization subgroups, respectively (P value for interaction 0.13). For safety events, intensive BP treatment increased the risk of hypotension (HR 2.00, 95% CI 1.06-3.79) and electrolyte abnormalities (HR 2.38, 95% CI 1.25-4.56) in the CAD subgroup, while the risk of serious adverse events did not increase (HR 1.03, 95% CI 0.88-1.20). These results suggest that positive benefits from intensive BP treatment might be attenuated in patients with CAD who are under better secondary prevention. The risk of stroke might increase at the systolic BP target of 120 mm Hg in case of coronary revascularization, although the confidence interval was wide.

Pulse Pressure, Cognition, and White Matter Lesions: A Mediation Analysis.

This study aimed to investigate the effects of pulse pressure (PP) on cognition and the role of white matter lesions (WMLs) in mediating this association. We enrolled 3,009 participants from the SPRINT-MIND study. Of those, 755 participants underwent brain magnetic resonance imaging. Cognitive tests were summarized in five cognition domains, including global cognition, executive function, attention, memory, and language. Multiple linear regression models were employed to analyze PP in association with cognition, and mediation analysis was applied to determine the role of WMLs in the association between PP and cognition. We found that PP was negatively linearly associated with global cognition (ß = -0.048, P = 0.008), executive function (ß = -0.014, P = 0.040), attention (ß = -0.013, P = 0.035), memory (ß = -0.021, P = 0.045), and language (ß = -0.020, P = 0.001), respectively. Furthermore, PP was not significantly associated with brain component volume changes, except for WMLs (ß = 0.029, P = 0.044). Additionally, mediation analysis showed that increased WML volume contributed to 10.8% of global cognition, 9.5% of executive function, 10.6% of memory, and 7.2% of language decline associated with PP. Exposure to higher PP levels was associated with poor cognitive performance, and WMLs partially moderated the influence of PP on cognition.

LncRNA-mRNA co-expression analysis discovered the diagnostic and prognostic biomarkers and potential therapeutic agents for myocardial infarction.

Currently, the role of lncRNA in myocardial infarction (MI) is poorly understood. 17 co-expression modules were determined, specifically, the greenyellow, saddlebrown, grey60, royalblue, lightgreen, white, and pink modules were specifically expressed in the acute phase of MI, and brown, darkred, and royalblue, while greenyellow modules were specifically expressed in MI compared with CAD. 12 time-dependent of lncRNA/mRNA clusters with consistent expression trends were also identified. MI-associated modules were mainly enriched to immune, cell cycle, and metabolic pathways. We further obtained a network of 1816 lncRNA-mRNAs with higher expression correlations among these lncRNAs by analyzing the topological properties of the network. Herein, lncRNA RP11-847H18.2 and KLHL28, SPRTN, and EPM2AIP1 were determined as gene markers specifically expressed in MI, and they demonstrated a high predictive performance for MI diagnosis and prognosis. Three drugs, namely, Calcium citrate, Calcium Phosphate, and Calcium phosphate dihydrate, were identified as potential precursors of MI. Finally, gene and lncRNA diagnostic models were developed based on these genes and lncRNAs, with their AUCs averaged above 0.89 in both training and validation datasets. The findings of this study improve the diagnosis and prognosis of MI and personalized treatment of MI.

The effects of age on brain cortical activation and functional connectivity during video game-based finger-to-thumb opposition movement: A functional near-infrared spectroscopy study.

OBJECTIVES: This study aims to explore the age-related changes in cerebral cortex activation and functional connectivity (FC) during finger-to-thumb opposition movement based on video games (FTOMBVG). METHODS: A electronic fingercot was developed for FTOMBVG. The oxygenated hemoglobin concentration (Delta [HbO]) signals, measured by functional near-infrared spectroscopy (fNIRS), were recorded from prefrontal cortex (PFC), motor cortex (MC) and occipital lobe (OL) of two groups of subjects (old and young). RESULTS: The cognitive region of the old group showed bilateral activation, while the young group only showed unilateral activation. Both groups showed a wide range of bilateral activation in the motor region. The FC between cognitive region and motor region of the old group was enhanced considerably. CONCLUSION: Changes in cerebral cortex activation and the FC of different brain regions in the old group help explain the decline in cognitive executive and motor control function in the old from the perspective of brain functional structure, and provide a theoretical reference for the prevention of neural diseases caused by aging.