Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). As a transcription factor, the Transcript induced in spermiogenesis 40 (Tisp40) has been found to be involved in renal IRI. However, the role of Tisp40 in tubular epithelial cell (TEC) pyroptosis of renal IRI remains unknown. In this study, we investigated effects of Tisp40 on Gasdermin D (GSDMD)-mediated TEC pyroptosis in renal IRI and underlying molecular mechanisms in I/R-induced kidney by hematoxylin and eosin (HE) staining, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay,immunohistochemistry (IHC), reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis in vivo and oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated TCMK-1 cells by lactate dehydrogenase (LDH) release assay, CCK-8 assay,enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, immunofluorescence staining,RT-qPCRand western blot analysis in vitro. We found that the levels of Tisp40 and GSDMD-N expression increased gradually, and peaked at 30 min ischemia/24 h reperfusion in vivo and 24 h OGD/R/6 h reoxygenation in vitro, simultaneously, the levels of TEC pyroptosis and renal injury were correspondingly increased. The data of Pearson's correlation analysis showed that the expression of Tisp40 and GSDMD-N was positively correlated. Furthermore, Tisp40 overexpression aggravated TEC pyroptosis rate and increased the expressions of related proteins, including GSDMD-N, NLRP3, caspase-1, IL-1β, and IL-18 in the OGD/R-stimulated TCMK-1 cell line, whereas the opposite occurred in cells treated with small interfeing RNA (siRNA) targeting Tisp40. Tisp40-deficient mice showed attenuated renal IRI and pyroptosis compared with wild-type mice. In addition, Tisp40 knockout remarkably decreased the levels of GSDMD-N, IL-1β, IL-18, NLRP3, and caspase-1 expression, and alleviated renal pyroptosis induced by I/R. Importantly, Tisp40 overexpression significantly increased TECs pyroptosis via p-p65 activation, however, the effects of Tisp40 overexpression were partially blocked by parthenolide (PTL). Collectively, our findings provide insight into the mechanism of how Tisp40 regulated GSDMD-mediated pyroptosis in renal IRI.

The aim of this study was to investigate the effect of evodiamine (EV) on dexamethasone-induced osteoporosis in zebrafish. Zebrafish larvae were exposed to different concentrations of dexamethasone to obtain the osteoporosis in zebrafish. Calcium, phosphorus, and alizarin red staining determination were performed to evaluate the effects of EV on bone mineralization. Alkaline phosphatase (ALP), hydroxyproline (HP), and tartrate resistant acid phosphatase (TRAP) were also measured by commercial kits. The expression of MMP3-OPN-MAPK pathway in zebrafish was measured by Western blot. RT-PCR was used to determine mRNA levels of MMP3, OPN, and MAPK. EV could significantly increase the content of calcium and phosphorus. The results of alizarin red staining showed that EV could significantly increase the calcium sink of horse fish, increasing the area of bone formation. EV could increase the content of hydroxyproline in zebrafish. EV also increased ALP and TRAP in zebrafish. Western blot and RT-PCR results showed that EV restored the MMP3-OPN-MAPK pathway in zebrafish. In conclusion, we found that EV can alleviate dexamethasone-induced osteoporosis in zebrafish. The mechanism is related to activating MMP3-OPN-MAPK pathway and then activating bone remodeling.

The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03–1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04–1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.