Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.
Mengyuan Qu,Yunhan Zhao,Xingrong Qing,Xinzong Zhang,Honggang Li
Late-onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome with multiple symptoms caused by testosterone deficiency in aging males. An in-depth exploration of the molecular mechanism underlying LOH development is insufficient. We previously identified miR-125a-5p as a dysregulated microRNA in LOH patients and potential diagnostic biomarker for LOH. The present study demonstrated that plasma miR-125a-5p was upregulated after testosterone supplementation in both LOH patients and castrated mice, and positively associated with the testosterone concentrations, suggesting direct regulation of miR-125a-5p expression by testosterone. Androgen response element in the promoter of miR-125a-5p was subsequently identified. Target gene screening and confirmation verified that LYPLA1 , encoding acyl-protein thioesterase 1 which catalyzed protein depalmitoylation process, was a target gene of miR-125a-5p. Furthermore, in cells cultured with testosterone deprivation and organs from castrated mice, testosterone deficiency led to decreased global protein palmitoylation level. In aging males, global protein palmitoylation in peripheral blood showed a notable decline in LOH patients contrast to the normal elderly males. And the palmitoylation level was positively correlative with serum testosterone concentrations. Our results suggested that testosterone could regulate global palmitoylation level through miR-125a-5p/ LYPLA1 signaling pathway. Given that protein palmitoylation is pivotal for protein function and constitutes the pathogenesis of various diseases, testosterone/miR-125a-5p/ LYPLA1 may contribute to the molecular mechanism underlying multiple symptoms caused by testosterone deficiency in LOH patients, and aberrant global palmitoylation could be a potential biomarker for LOH.
Background Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. Methods A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H 2 O 2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. Results DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). Conclusions Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC. Graphical Abstract
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