Hemorrhage transformation (HT) is a frequent but maybe fatal complication following the acute ischemic stroke due to the severe damage of blood brain barrier (BBB). Quantitative BBB permeability imaging is...
Background: Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway. Methods: We established a TP-treated IgAN mouse model and produced IgA1-induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3-Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p-p38 MAPK/p38 MAPK following TP treatment. Results: Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1-induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN. Conclusion: TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.
Circular RNA (circRNA) plays a regulatory role in periodontitis. This study explored whether circ_0138959 affected lipopolysaccharide (LPS)-induced pyroptosis in human gingival fibroblasts (HGFs). The periodontal ligament (PDL) tissues and HGFs were derived from patients with periodontitis and healthy volunteers. HGFs treated with LPS were considered to mimic periodontitis
in vitro
. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the mRNA expression levels of circRNAs, miR-527, and caspase-5 (CASP5), and Western blotting assay was used to measure protein expression levels of caspase-1, caspase-4, and cleaved N-terminal gasdermin D (GSDMD-N). Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The concentration of lactate dehydrogenase (LDH), interleukin (IL)-1β, and IL-18 and the pyroptosis rate were determined to evaluate pyroptosis. The interaction between miR-527 and circ_0138959 or CASP5 was verified by dual-luciferase reporter and RNA pull-down assays. Circ_0138959 expression was higher in the PDL tissues of patients with periodontitis than in the healthy group; likewise, circ_0138959 was also upregulated in LPS-treated HGFs. Suppressed circ_0138959 increased cell viability and decreased pyroptosis of HGFs induced by LPS. miR-527 was a target of circ_0138959, and inhibition of miR-527 contributed to the dysfunction of LPS-treated HGFs and reversed the protective effects of downregulated circ_0138959. Additionally, miR-527 targeted CASP5. Increased CASP5 abrogated the effects of overexpressed miR-527 on cell viability and pyroptosis of LPS-treated HGFs. Inhibition of circ_0138959 promoted cell viability and suppressed pyroptosis of HGFs via the miR-527/CASP5 axis. Therefore, knockdown of circ_0138959 may be a promising therapy for periodontitis.
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