Growing evidence suggests that oxidative stress contributes to the pathophysiology of several disorders, making antioxidant-based interventions an active research area. Astaxanthin (ASTX) is a powerful antioxidant attracting research interest. Notably, the biological effects of ASTX depend on its natural source. We recently shown that an ASTX-rich extract derived from the freshwater crab Dilocarcinus pagei mitigates metabolic disturbances in major tissues involved in energy homeostasis (adipose tissue, liver, and skeletal muscle). Whether similar beneficial effects occur in cardiac tissue remains unknown. The aim of this work was to evaluate the effect of an ASTX rich-extract derived from D. pagei on cardiac redox disturbances developed in rats fed a high-sucrose diet (HSD), a model of Metabolic Syndrome (MetS). Male Wistar rats were fed for 90 days with a reference diet, a HSD, or a HSD plus a daily oral dose of an ASTX-rich extract (HSD + ASTX) (10 mg/kg body weight). Results showed that ASTX-rich extract prevented the HSD-induced increase in cardiac reactive oxygen species levels, alleviated oxidative stress, improved antioxidant capacity and was associated with changes in the protein expression of Nrf2 and phosphorylated NF-κB p65. Besides, HSD + ASTX-fed animals had lower blood pressure than HSD-fed rats at 30, 60 and 90 days of the experimental period. Serum CK-MB, AST, glucose and lipid levels were lower than those found in HSD-fed animals. The study provides novel insights into the beneficial effects of an ASTX-rich extract derived from D. pagei on cardiac redox imbalance and associated alterations induced by a HSD in male rats.
Disruption of the glomerular filtration barrier (GFB) is a key feature of diabetic kidney disease (DKD), but the underlying mechanisms remain incompletely understood. We investigated the role of angiogenic factor 1 (AGGF1) in glomerular endothelial barrier dysfunction in DKD. AGGF1 expression was examined in kidney samples from patients with DKD and in db/db mice. We also used endothelial cell-specific Aggf1 knockout mice and in vitro endothelial cell experiments to assess the effects of AGGF1 on vascular leakage and endothelial junctions. AGGF1 expression was increased in kidneys from patients with DKD and db/db mice. Endothelial Aggf1 deletion reduced vascular leakage in diabetic mice. Mechanistically, AGGF1 promoted Src-dependent VE-cadherin phosphorylation and dissociation of the VE-cadherin/β-catenin complex. Semaglutide treatment was associated with reduced renal AGGF1 expression and improved endothelial barrier-related outcomes in db/db mice. In vitro, AGGF1 overexpression attenuated the beneficial effect of semaglutide on endothelial junctional proteins under high-glucose conditions. Together, these findings identify endothelial AGGF1 as a contributor to GFB dysfunction in DKD and suggest that it may be a potential therapeutic target.
Background Mesothelial cells, which have long been regarded as an inert cell population, form a depot-specific mesothelium structure surrounding visceral adipose tissue. Although emerging evidence has elucidated the previously unrecognized functionality of mesothelial cells in adipose tissue, their role in metabolic regulation remains largely unknown. Methods Single-cell transcriptomes of mesothelial cells obtained from human omental adipose tissues were analyzed to determine cellular secretory function. Primary mesothelial cells were isolated from epididymal white adipose tissue (eWAT) of male C57BL/6 mice to validate the single-cell data. Adeno-associated viruses (AAVs) were bilaterally injected into eWAT of C57BL/6 mice to evaluate the effect of mesothelial cell-derived interleukin-18 (IL-18) on adipose homeostasis. Co-culture assays and recombinant IL-18 were administered to determine the direct effect of mesothelial cell-derived IL-18 on adipocyte lipolysis. Results Mesothelial cells were the dominant producers of IL-18 in visceral adipose tissues at steady state. Downregulation of IL-18 in eWAT by AAV injection reduced eWAT mass and adipocyte size, without changing basal metabolic rate or whole-body glucose homeostasis. Meanwhile, downregulation of IL-18 significantly increased adipose lipolysis and led to high levels of serum free fatty acids and glycerol. In vitro co-culture assays further showed that, mesothelial cell-derived IL-18 inhibited adipocyte lipolysis, and this effect was reversed by an IL-18 neutralizing antibody. Mechanistically, IL-18 suppressed adipocyte lipolysis by affecting the expression of hormone-sensitive lipase and adipose triglyceride lipase. Conclusions This study reveals a previously unrecognized role for mesothelial cell-derived IL-18 in preserving lipid stores, thereby highlighting a physiological function of mesothelial cells in the maintenance of adipose tissue energy homeostasis.
The present study aimed to explore the involvement of oxidative stress (OS) and fibrosis in the metabolic impairment of skeletal muscle (SkM) induced in the short (3 weeks) and long term (15 weeks) by a sucrose-rich diet (SRD) and the effects of dietary chia seed as a preventive therapeutic strategy. Male Wistar rats were fed with a reference diet (RD), an SRD or an SRD whit whole chia seed incorporated as the source of dietary fat (SRD + Chia) for two time periods 3 and 15 weeks. Results showed that OS and fibrosis contribute from the early stages of SRD-induced SkM impairment and that chia administration exerts time-dependent protective effects. At long-term, chia prevented the increase in visceral adiposity and preserve gastrocnemius muscle mass lost induced by the SRD. At both time points chia prevented dyslipidemia, hyperuricemia, lipid peroxidation, and the increase in blood pressure, while preserve glucose serum level at 15 weeks. In SkM, short-term intervention preserved reduced glutathione (GSH) levels, whereas in long-term chia partially prevented lipid accumulation and markedly improved antioxidant defenses by maintaining GSH levels and glutathione peroxidase activity while increasing glutathione reductase activity. Moreover, preventive chia administration attenuated both early and late SkM collagen deposition, accompanied by reduced TGF-β mRNA expression. This work provides novel evidence supporting the early involvement of OS and extracellular matrix remodeling in SkM deterioration. Moreover, it expands current knowledge of the preventive potential of chia seeds against SkM alterations associated with metabolic disease.
Granulosa cells (GCs) are essential for follicular development, and their apoptosis is a key determinant of follicular atresia in mammals. Circular RNAs (circRNAs) have emerged as critical post-transcriptional regulators in reproductive biology; however, their roles in porcine GC apoptosis remain incompletely characterized. A novel circRNA derived from exon 2 of the INHBA gene (circINHBA) was identified from previous circRNA sequencing data. Its circular structure was verified by RNase R digestion assay, and subcellular localization was assessed by nucleocytoplasmic separation and fluorescence in situ hybridization. The functional role of circINHBA was investigated by siRNA-mediated knockdown, FACS, and Western blotting. The ceRNA mechanism was examined using dual-luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation. circINHBA exhibited significantly higher expression in healthy follicles than in early atretic follicles and was predominantly localized in the cytoplasm. Knockdown of circINHBA promoted GC apoptosis and decreased the BCL2/BAX ratio. Mechanistically, circINHBA functioned as a molecular sponge for miR-196b-5p, which directly targets the 3′UTR of PARP8, thereby upregulating PARP8 expression to inhibit apoptosis. Furthermore, EIF4A3 physically interacted with circINHBA, and its knockdown significantly reduced circINHBA expression, indicating that EIF4A3 promotes circINHBA biogenesis. The EIF4A3/circINHBA/miR-196b-5p/PARP8 axis constitutes a novel regulatory mechanism governing GC apoptosis and follicular atresia in pigs, providing new insights into circRNA–RNA-binding protein crosstalk in ovarian physiology.
