The FASEB Journal最新文献

Chronic stress is associated with inflammatory activation and oxidative stress responses leading to endothelial dysfunction, which promotes the development of atherosclerosis (AS). SGLT2 inhibitors, such as Dapagliflozin (DAPA), exhibit a protective effect against cardiovascular diseases. However, the effects and mechanisms of DAPA on chronic stress-induced AS are largely unknown. The aim of this study was to determine whether DAPA confers a protective effect against chronic stress-induced AS and to elucidate its further molecular mechanisms. The combined high-fat diet-fed and chronic unpredictable mild stress in ApoE-/- mice and lipopolysaccharides- and corticosterone-induced human umbilical vein endothelial cells (HUVECs) were employed to evaluate the antiatherosclerotic effect of DAPA under chronic stress in vivo and in vitro. Histological staining, western blot analysis, siRNA transfection, reactive oxygen species (ROS) staining, and apoptosis assessment were used to investigate the potential mechanisms of DAPA against AS under chronic stress. The results indicate that DAPA significantly improved plaque size and increased plaque stability in the aorta under chronic stress and reduced inflammation and oxidative stress and inhibited apoptosis in the aorta and HUVECs. Chronic stress upregulated regulated in development and DNA damage response 1 (REDD1) expression, which exacerbated cellular inflammation, oxidative stress, and apoptosis levels, leading to endothelial dysfunction. In contrast, DAPA downregulated REDD1 expression and activated the AKT/FoxO1 pathway. In addition, p53 was a transcriptional regulator of REDD1 under chronic stress. More importantly, p53 agonists prevented DAPA from downregulating REDD1 and inhibited AKT/FoxO1 activation, thereby exacerbating chronic stress-induced endothelial dysfunction. These results suggest that DAPA effectively attenuates chronic stress-induced endothelial dysfunction and AS by downregulating REDD1 to activate the AKT/FoxO1 pathway.

Androgenetic alopecia (AGA) is a progressive hair loss disorder affecting young men and significantly impairs psychosocial well-being. Current therapies, including minoxidil and finasteride, have limited efficacy and tolerability. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hUCMSC-sEVs) have demonstrated regenerative potential by delivering bioactive molecules that stimulate follicular regeneration. This single-center, prospective, randomized controlled trial will be conducted at Shenzhen People's Hospital. 59 male patients between 18 and 35 years old will be enrolled. In Phase I (dose-escalation), 9 participants will be randomized into three dosing cohorts (1 × 10⁸, 1 × 10⁹, or 1 × 10¹⁰ particles/point intradermally every 2 weeks for 4 times). In Phase II, 50 participants will be randomized 1:1 to hUCMSC-sEVs treatment (optimal dose from Phase I) or topical 5% minoxidil. The primary endpoint is the safety outcomes and the change in terminal hair count/cm² at 24 weeks to determine the best dosage. Secondary outcomes include changes in hair density, shaft diameter, global photographic and dermoscopic assessment, and patient self-assessment. This investigation will determine the best dosage of hUCMSC-sEVs in treatment of androgenic alopecia in young men and evaluate the safety and efficacy of hUCMSC-sEVs compared with minoxidil in young male AGA patients. This is the first randomized climbing test of a controlled clinical trial of hUCMSC-sEVs for young male AGA. Positive findings could establish a novel regenerative treatment for hair restoration. Trial Registration: Clinical Trials: ChiCTR2500109770.

The extremely complex, multivariate, and systemic pathophysiology of diabetic nephropathy is brought on by prolonged exposure to hyperglycemia, making the quest for the best therapeutic approach crucial and urgent. Accumulating evidence suggests that pyroptosis and inflammation contribute to the development of diabetic nephropathy. Zinc fingers and homeoboxes 2 (ZHX2) were recently discovered to be a new regulator of inflammatory response. However, the role and potential molecular mechanisms of ZHX2 in diabetic nephropathy remain unclear. Exosomes derived from gingival mesenchymal stem cells (GMSCs-Exo) were successfully isolated and characterized. GMSCs-Exo reversed high glucose-induced podocyte pyroptosis and inflammation. ZHX2 was highly expressed in GMSCs-Exo. Furthermore, ZHX2 derived from GMSCs-Exo reversed podocyte pyroptosis and inflammation induced by HG. Additionally, ZHX2 was enriched in the FABP4 promoter region and transcriptionally inhibited the mRNA and protein levels of FABP4. GMSCs-Exo-derived ZHX2 abolished HG-induced podocyte pyroptosis and inflammation by inhibiting FABP4 and blocking the advanced glycation endproducts/the receptor of advanced glycation endproducts/NOD-like receptor family pyrin domain-containing 3 (AGEs/RAGE/NLRP3) pathway. Similarly, GMSCs-Exo-derived ZHX2 alleviated renal injury, pyroptosis, and inflammation in diabetic nephropathy mice. In conclusion, our findings demonstrated that ZHX2 protects against diabetic nephropathy by binding to the FABP4 promoter and reducing the expression of FABP4. We also showed that GMSCs-Exo-derived ZHX2 reversed HG-induced podocyte pyroptosis and inflammation by inhibiting the AGEs/RAGE/NLRP3 pathway. ZHX2 derived from GMSCs-Exo also alleviated tubular injury, pyroptosis, and inflammation in diabetic nephropathy mice. The therapeutic potential of targeting ZHX2 to treat diabetic nephropathy is clarified by these findings.

Studies have shown that T cell exhaustion (TEX) indirectly influences the onset and progression of osteoarthritis (OA). This study aimed to ascertain biomarkers associated with TEX-related genes (TEXRGs) in OA, offering potential targets for therapy and prognosis. OA related datasets were obtained from public databases. Candidate genes were ascertained by intersecting differentially expressed genes (DEGs) with TEXRGs. The expression quantitative trait locus (eQTL) data were then used as instrumental variables, and genes causally associated with OA were screened through Mendelian randomization (MR) analysis. Gene expression and receiver operating characteristic (ROC) analyses were carried out to identify biomarkers. Finally, functional enrichment, immune infiltration, drug prediction, molecular docking, and single-cell analyses were conducted to explore the underlying biological mechanisms of OA. GPR65, LDLR, PLIN2, and TRIM14 were ascertained as biomarkers for OA. MR analysis revealed that PLIN2 acted as a protective factor, whereas GPR65, LDLR, and TRIM14 were risk factors of OA. LDLR and PLIN2 exhibited significantly lower expression in OA samples, whereas GPR65 and TRIM14 showed significantly higher expression. These four biomarkers were notably co-enriched in the "lysosome" pathway. Six differential immune cell types were identified. Puromycin and gossypol were predicted as potential OA treatments. Finally, single-cell analysis highlighted T cells and mast cells as key cell types in OA, with dynamic expression of GPR65 and PLIN2 observed throughout their differentiation. This study identifies GPR65, LDLR, PLIN2, and TRIM14 as biomarkers for OA, offering valuable insights that could support the development of targeted therapies.

Obesity is one of the most prevalent public health issues worldwide, which substantially increases the risk of many metabolic disorders. Anti-obesity medications and bariatric surgery are clinical treatments for obesity, but suffer from certain limitations. Gene therapy with effective and safe targets provides a novel approach for obesity intervention. Tks4 has been shown to play an essential role in preadipocyte to adipocyte differentiation. However, it is still elusive if it could be a drug target against obesity in vivo. Here, we found the expression levels of Tks4 correlate with adipocyte development and hypertrophy in mice. By generating a Tks4 KO mouse model, we showed Tks4 deletion significantly restricted adipocyte hypertrophy and reduced blood glucose and lipid levels. We further used an adeno-associated viral (AAV) vector to mediate sustained Tks4 silencing. For a single administration, the adipocyte hypertrophy at the injection site was significantly reduced in a dosage-dependent manner. The TAG biosynthesis defect was also verified by lipidomics analysis of the infected WAT, though an elevation of TAG in blood was also detected. These data support the potential of Tks4 gene therapy to treat obesity.

To better understand the crosstalk between the placenta and the fetus, we aimed to identify proteins released by the placenta into the fetal circulation, as well as proteins taken up by the placenta. This study included 75 healthy term pregnancies, analyzing proteins from plasma samples collected from the umbilical artery and vein using the Somalogic 5000-plex platform. Placental protein release and uptake were determined by comparing protein abundances in the umbilical artery and vein. Additionally, transcriptomic data mapping and gene ontology enrichment analysis were conducted to assign cellular and tissue origin and functions to the proteins. After controlling for the false discovery rate, we identified 766 proteins released by the placenta into the fetal circulation and 926 proteins taken up by the placenta (q < 0.05). Among the released proteins, 70% were previously recognized as expressed in the placenta, affirming their placental origin. Conversely, the proteins taken up from the fetal circulation showed an overrepresentation of proteins specific to bone marrow, tongue, and skeletal muscle, while proteins specific to salivary glands, liver, and placenta were underrepresented. Enrichment analysis revealed molecular functions and biological processes that promote tissue growth and differentiation. Our findings demonstrate a considerable interaction between the placenta and fetus in healthy term pregnancies, with a high number of proteins being exchanged. This research enhances our understanding of the fetal-placental interactions, paving the way for new insights into pathophysiological processes and potential therapeutic strategies in utero.

Cardiac hypertrophy represents a complex remodeling process involving extensive reprogramming of gene expression. While transcriptional regulation has been well characterized, post-transcriptional RNA processing has recently emerged as a crucial determinant of cardiac homeostasis. This review summarizes current knowledge of RNA modifications, alternative splicing, mRNA stability, and RNA editing in physiological and pathological hypertrophy. We highlight key epitranscriptomic marks such as N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), and 7-methylguanosine (m⁷G), as well as the functions of RNA-binding proteins and adenosine deaminases acting on RNA (ADAR1/2). In exercise-induced hypertrophy, RNA processing contributes to adaptive remodeling by supporting sarcomere organization, calcium handling, and survival pathways, exemplified by RBFOX2-dependent splicing of CACNA1C, RBM20-directed regulation of titin isoforms, and METTL14-mediated m⁶A signaling that enhances Akt activity. Conversely, pathological stress leads to dysregulated RNA programs that promote maladaptive remodeling through aberrant splice variants, perturbation of circular RNAs, and persistent pro-inflammatory signaling, thereby facilitating contractile dysfunction and progression to heart failure. Context-dependent regulators, including METTL3, YTHDF2, RBM24, and ADAR2, orchestrate the balance between adaptive and maladaptive responses. Targeting specific nodes, such as METTL3-driven m⁶A methylation or RBM24-dependent splicing fidelity, may provide innovative therapeutic strategies. Advances in RNA-targeted interventions, including ADAR-mediated editing and small molecule inhibitors of methyltransferases, highlight the translational potential of RNA processing as a novel avenue for precision cardiovascular therapy.