Renal tubular epithelial cell (TEC) injury and fibrosis are the key factors of the pathogenesis of chronic kidney disease. Here, we reported that tectorigenin is effectively protected against obstructive nephropathy established by unilateral ureteral obstruction (UUO). In vivo, tectorigenin administration significantly alleviated the deteriorations of renal functions including blood urea nitrogen and creatinine. Meanwhile, results from the histology suggested that renal injury characterized by tubular cell damage and fibrosis lesions of kidneys in UUO group were markedly attenuated following tectorigenin treatment. Mechanistically, we found that tectorigenin treatment greatly inhibited Smad3 phosphorylation, and the transcription and protein level of Nox4, a newly identified direct downstream molecule of Smad3 and a modulator of ferroptosis, while it indirectly restored the expression of glutathione peroxidase 4, a negative regulator of ferroptosis. Consistent with in vivo studies, treatment with tectorigenin also suppressed the ferroptosis induced by erastin/RSL3 and fibrosis stimulated by transforming growth factor β1 (TGF‐β1) in primary renal TECs. What is more, treatment with ferroptosis inhibitor, ferrostatin‐1, also impeded TGF‐β1 stimulated the profibrotic effects in TECs, indicating that tectorigenin may relieve fibrosis by inhibiting ferroptosis in TECs. In addition, tectorigenin treatment exhibited a similar tendency, which inhibited Smad3 activation, and the docking analysis revealed that tectorigenin docked well into the Smad3 binding cavity with strong binding affinity (−7.9 kcal/mol). Thus, this study deciphers the protective effect of tectorigenin against obstructive nephropathy through inhibiting Smad3‐mediated ferroptosis and fibrosis.
Beta (β) cell dysfunction or loss is the common pathological feature in all types of diabetes mellitus (diabetes). Resolving the underlying mechanism may facilitate the treatment of diabetes by preserving the β cell population and function. It is known that TGF-β signaling plays diverse roles in β cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-β signaling expands β cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced β cell proliferation. Among canonical TGF-β signaling, Smad3 but not Smad2 is the predominant repressor of β cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves β cell function, apoptosis, and systemic insulin resistance with the consequence of eliminated overt diabetes in diabetic mouse models, revealing Smad3 as a key mediator and ideal therapeutic target for type-2 diabetes. However, Smad7 shows controversial effects on β cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents β cells from autoimmune destruction without influence on β cell function. All these findings reveal the diverse regulatory roles of TGF-β signaling in β cell biology.
Protocatechualdehyde attenuates obstructive nephropathy through inhibiting lncRNA9884 induced inflammation.
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research. Graphical Abstract
Background Cerebral edema, inflammation, and subsequent neurological defecit, are the common consequences of intracerebral hemorrhage (ICH). Mesenchymal stem cells (MSCs) transplantation had been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. However, the survival, viability, and efficacy of MSCs are limited due to the severe inflammatory response after ICH. Therefore, ways to improve the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the metal-quercetin complex via coordination chemistry has been verified positively and studied extensively for biomedical applications, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) has excellent dual functions with a stimulating agent of cell growth and an imaging probe for magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH, while also label MSCs for their tracking by MRI. This study was designed to investigate the effects of the combined treatment of MSCs with IronQ on inflammation and elucidate their underlying mechanisms. Methods A collagenase I-induced ICH mice model was extablished, which were randomly divided into model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ). Then the neurological deficits score, brain water content (BWC), and the protein expression levels of IL-6, TNF-α, NeuN, MBP, and GFAP were investigated. We measured the protein expression levels of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells was used to investigate the neuroprotection of conditioned medium of MSCs co-cultured IronQ in vitro. Results We found that the combined treatment improves the inflammation-induced neurological function and BWC by inhibiting the Mincle/Syk signaling pathway in vivo. The conditioned medium of MSCs co-cultured with IronQ decreased inflammation, the protein expression levels of Mincle, and its downstream targets in LPS-induced BV2 cell line. Conclusions These data suggested that the combined treatment plays a synergistic role in ameliorating the consequences of ICH, including neurologic deficits, brain edema, and inflammatory response through the downregulation of the Mincle/syk signaling pathway.
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