The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.
HHcy aggravated DSS-induced colitis by stimulating IL-17 expression via the p38/cPLA2/COX2/PGE2 signalling pathway. The folate supplementation may represent a novel approach to treating the chronic intestinal inflammation of IBD exacerbated by HHcy.
Objectives
The present study was designed to investigate the effects of microRNA‐21 (miR‐21) on orthodontic tooth movement.
Methods
The orthodontic tooth movement model was established in C57BL/6 and miR‐21−/− mice with or without implantation of activated T cells. Histological and histomorphometrical analyses were performed by hematoxylin–eosin staining. Tartrate‐resistant acid phosphate staining was used to analyze the osteoclast numbers during tooth movement. Enzyme‐linked immunosorbent assay, reverse transcription polymerase chain reaction, and immunohistochemistry analysis were used to examine the expression of RANKL and OPG.
Results
In miR‐21−/− mice, the distance of tooth movement was retarded, the osteoclast number was decreased, and serum RANKL expression was strongly reduced. MiR‐21 promoted the secretion of RANKL from activated T cells. Furthermore, activated T cells could partially rescue the decreased orthodontic tooth movement distance in miR‐21−/− mice. MiR‐21 was shown to promote orthodontic tooth movement by modulating the RANKL/OPG balance in T cells.
Conclusions
The impact of miR‐21 on tooth movement was better elucidated, furthering our understanding of its role and clinical applications in orthodontics.
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