Air Force Medical University

Cardiac involvement is a major cause of morbidity in systemic lupus erythematosus (SLE). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is elevated in SLE, but its contribution to lupus-associated cardiac injury is unclear. We investigated the role of TWEAK/Fn14 signaling in SLE-related cardiomyopathy and its potential as a biomarker and therapeutic target. Serum TWEAK, inflammatory cytokines, autoantibodies, and oxidative stress markers were measured in 242 SLE patients and 66 age- and sex- matched controls, with correlation to echocardiographic, electrocardiographic, and myocardial enzyme findings. Cardiac pathology and redox signaling were assessed in pristane-induced lupus models using wild-type and Fn14-deficient mice by histopathology, immunoblotting, immunofluorescence, and quantitative proteomics. Direct effects of TWEAK on mitochondrial oxidative stress, antioxidant signaling, and apoptosis were examined in primary cardiomyocytes isolated from lupus-prone MRL/lpr mice. Serum TWEAK levels were significantly elevated in patients with SLE and were highest in those with cardiac abnormalities compared with healthy controls. TWEAK correlated positively with malondialdehyde, 8-hydroxy-2' -deoxyguanosine, disease activity, and inflammatory cytokines, and inversely with superoxide dismutase. Elevated baseline TWEAK predicted new cardiac abnormalities during follow-up and declined with clinical improvement. In lupus mice, Fn14 deficiency reduced cardiac reactive oxygen species accumulation, restored Nrf2/HO-1 antioxidant signaling, attenuated histopathological injury, and preserved cardiac function. In vitro, TWEAK induced mitochondrial superoxide production, suppressed Nrf2 signaling, and promoted apoptosis in lupus-prone cardiomyocytes. TWEAK/Fn14 signaling drives oxidative stress- mediated cardiomyocyte injury in SLE and represents a promising biomarker and therapeutic target for lupus-associated cardiac damage.

This study aims to explore the therapeutic efficacy of stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-Exo) in age-related osteoporosis (OP) and clarify its mechanism via mitophagy activation in senescent bone marrow mesenchymal stem cells (BMSCs). SHED-Exo were isolated, characterized and proteomically profiled. In vitro, H2O2-induced senescent bone marrow mesenchymal stem cells (BMSCs) were treated with SHED-Exo, with mitophagy modulators used for mechanistic validation. In vivo, SHED-Exo were systemically administered to aged osteoporotic mice, assessing biodistribution, safety and therapeutic effects via micro-computed tomography, and molecular analyses of bone tissue/BMSCs. SHED-Exo possessed canonical exosomal properties and were enriched in osteogenic/mitophagic proteins. In vitro, SHED-Exo restored mitochondrial function, activated mitophagy and enhanced osteogenic differentiation of senescent BMSCs. In vivo, SHED-Exo showed no organ toxicity and effectively ameliorated bone loss by upregulating mitophagic/osteogenic markers in aged osteoporotic mice. SHED-Exo ameliorate age-related OP by activating mitophagy in senescent BMSCs, serving as a novel translational nanotherapeutic for age-related bone disorders.

Autoimmune diseases (AIDs) result from intricate interactions among genetic, environmental and immune factors, with emerging evidence underscoring the role of the central nervous system (CNS) in their pathogenesis. In this study, we utilized two-sample Mendelian randomization to systematically explore the causal relationships between 3,935 brain imaging-derived phenotypes (IDPs) and eight AIDs, including atopic dermatitis, inflammatory bowel disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis and type 1 diabetes. We identified nine IDPs with causal associations to eight representative AIDs. Mediation analysis uncovered eight potential immune cells or inflammatory factors bridging IDPs and AIDs. These findings provide compelling evidence for the CNS's involvement in autoimmune progresses through neuro-immune pathways and underscore potential diagnostic and therapeutic targets within the neuro-immune axis. This study introduces a novel framework for investigating interdisciplinary interventions that target CNS-immune interactions in the context of AIDs.