Henan University of Traditional Chinese Medicine

Associations between sleep duration and incident diabetic microvascular complications remain uncertain. The potential biological pathways underlying the association are unclear.

This prospective cohort study included 24,081 participants with type 2 diabetes from the UK Biobank. Habitual sleep duration was obtained via a baseline questionnaire. Associations of sleep duration with microvascular complications were analyzed using Cox regression models.

The association of sleep duration with composite microvascular complications followed U-shaped patterns. Compared with sleeping for 7 hrs/day, the hazard ratios (95 % confidence intervals) of ≤ 5 and ≥ 10 hrs/day were 1.21 (1.09, 1.35) and 1.24 (1.09, 1.42) for the composite outcome, 1.20 (1.04, 1.38) and 1.30 (1.09, 1.54) for diabetic kidney disease, 1.61 (1.30, 2.00) and 1.35 (1.01, 1.79) for diabetic neuropathy, and 1.10 (0.93, 1.30) and 1.17 (0.95, 1.44) for diabetic retinopathy. Body mass index, gamma-glutamyl transferase, C-reactive protein, alkaline phosphatase, total cholesterol, and low-density lipoprotein cholesterol collectively explained 20.34 % of the association between sleep duration and composite microvascular complications.

Our study demonstrated that both short and long sleep durations were independently associated with increased risk of diabetic microvascular complications. The associations were partially mediated by metabolic biomarkers related to obesity, systemic inflammation, liver function, and lipid profile.

Silicosis is a severe interstitial lung disease resulting from prolonged exposure to silica dust in working environment, characterized by inflammation and fibrosis. This condition is closely associated with immune dysregulation, although the precise regulatory mechanisms remain elusive. Immune checkpoints (ICs) comprise receptor-ligand pairs crucial for immune cell activation and coordination of immune responses. Among these, PD-1 and its ligand PD-L1 have garnered significant attention in tumor research and have recently been implicated in the regulation of fibrotic diseases. Nonetheless, their involvement in silicosis remains unexplored. In this study, we observed a global upregulation of PD-1 and PD-L1 expression concomitant with the progression of silicosis, exhibiting cell specificity. Targeting PD-1/PD-L1 signaling mitigated silicosis in mice by modulating T cell homeostasis, macrophage polarization, and activation of fibrotic effector cells. Notably, PD-L1 expression on activated fibroblasts emerged as a pivotal driver of silicosis progression. Mechanistically, elevated PD-L1 levels in fibroblast activation fostered a positive feedback loop by binding to p-Smad2/3 and p-STAT3 proteins, thereby facilitating their nuclear translocation and augmenting protein stability, ultimately promoting fibroblast transdifferentiation. Consistently, knockdown of PD-L1 in lung fibroblasts significantly ameliorated silicosis in mice. In summary, PD-1/PD-L1 signaling mediates critical profibrotic signals during the progression of silicosis.

To investigate the role of the BNIP3-PI3K/Akt signaling pathway in mediating the inhibitory effect of Buyang Huanwu Decoction (BYHWT) on mitochondrial autophagy in human synovial fibroblasts from rheumatoid arthritis patients (FLS-RA) cultured under a hypoxic condition.

Forty normal Wistar rats were randomized into two groups (n=20) for daily gavage of BYHWT or distilled water for 7 days to prepare BYHWT-medicated or control sera. FLS-RA were cultured in routine condition or exposed to hypoxia (10% O₂) for 24 h wigh subsequent treatment with IL-1β, followed by treatment with diluted BYHWT-medicated serum (5%, 10% and 20%) or control serum. AnnexinV-APC/7-AAD double staining and T-AOC kit were used for detecting apoptosis and total antioxidant capacity of the cells, and the changes in ROS, ATP level, mitochondrial membrane potential and Ca²⁺ homeostasis were analyzed. The changes in mRNA and protein expressions of BNIP3, PI3K and AKT and mRNA expressions of LC3, Beclin-1 and P62 were detected using RT-qPCR and Western blotting.

Treatment with BYHWT-medicated serum dose-dependently lowered apoptosis rate of IL-1β-induced FLS-RA with hypoxic exposure. The treatment significantly decreased T-AOC concentration, increased ROS production, autophagosome formation and ATPase levels, and lowered mitochondrial membrane potential and Ca²⁺ level in the cells. In IL-1β-induced FLS-RA with hypoxic exposure, treatment with BYHWT-medicated serum significantly increased BNIP3 protein expression, decreased the protein expressions of PI3K and AKT, increased the mRNA expressions of BNIP3 and P62, and lowered the mRNA expressions of PI3K, AKT, LC3 and Beclin-1 without significantly affecting Beclin-1 protein expression. The cells treated with 5% and 10% BYHWT-medicated serum showed no significant changes in LC3 expression.

BYHWT inhibits mitochondrial autophagy in IL-1β-induced FLS-RA with hypoxic exposure possibly by inhibiting BNIP3-mediated PI3K/AKT signaling pathway.