In this study, MTT assays, apoptosis detection, immunofluorescence, and functional studies were used to elucidate the mechanisms underlying the effects of dihydrotanshinone I (DHT) on gastric cancer cells. Drug target prediction and analysis were conducted to identify potential targets of DHT. MTT assay revealed significant inhibition of AGS and HGC27 cells by DHT. Morphological changes, including nuclear shrinkage and the induction of necrotic cell death, were observed in DHT-treated gastric cancer cells, along with cell cycle arrest at the G2/M phase. Further analysis revealed potential targets of DHT, including PTPN11, which is highly expressed in gastric cancer cells. DHT treatment increased necrosis-related proteins (RIPK1/RIPK3/MLKL) and downregulated cell cycle-related proteins (CDC25C and CDK1) levels in gastric cancer cells. After DHT treatment, PTPN11 protein expression decreased. Furthermore, DHT significantly increased the phosphorylated p38/JNK protein level, with the phosphorylated p38 protein notably enriched in the nucleus. These functional studies indicate that PTPN11 plays a key role in mediating the effects of DHT, including cell cycle regulation and necrosis induction. In conclusion, PTPN11 is a central target through which DHT affects gastric cancer cells, regulating downstream pathways involved in necroptosis (p38/RIPK1/RIPK3/MLKL/JNK) and cell cycle arrest (p38/CDC25C/CDK1).

01 Dec 2024·Molecular Biology Reports

RIPK3 and RIPK1 gene expression in pterygium: unveiling molecular insights into pathogenesis

Article

Author: Divandari, Mahnaz ; Janatabadi, Ali Akbar ; Moghadam, Arezoo Baradaran ; Javadifar, Amin

BACKGROUNDPterygium, characterized by the abnormal proliferation of epithelial cells, matrix remodeling, vascularization, and lesion migration, is a prevalent ocular surface disease involving the growth of fibrovascular tissue on the cornea. Despite the unclear underlying causes of pterygium, numerous investigations have indicated the involvement of cell death pathways in the regulation of cell cycle dynamics. Consequently, the objective of this study was to assess the expression levels of necroptosis markers in individuals diagnosed with pterygium, aiming to shed light on the potential role of necroptosis in the pathogenesis of this condition.METHODSThis study aimed to investigate the expression patterns of receptor-interacting serine/threonine kinase 3 (RIPK3) and receptor-interacting serine/threonine kinase 1 (RIPK1) genes in pterygium tissues. 41 patients undergoing pterygium excision surgery were recruited. Resected pterygium samples and normal conjunctival tissues were collected, and RIPK3 and RIPK1 mRNA levels were measured using quantitative real-time PCR.RESULTSOur findings reveal that the expression of RIPK3 is significantly increased in samples obtained from individuals with pterygium. However, no significant alterations were observed in the expression of RIPK1 in these samples. Results showed significantly higher RIPK3 expression in pterygium tissues compared to controls. Moreover, increased RIPK3 levels correlated negatively with pterygium recurrence rates.CONCLUSIONSThese findings suggest RIPK3 may play a protective role against pterygium recurrence through necroptosis.

01 Nov 2024·Cellular Signalling

Erbin alleviates sepsis-induced cardiomyopathy by inhibiting RIPK1-dependent necroptosis through activating PKA/CREB pathway

Article

Author: Wang, YuXuan ; Zhou, Huimin ; Zuo, Jing ; Liu, Huifan ; Wu, Xiaojing ; Wang, Yanlin ; Gong, Hailong ; Xia, Yun ; Wu, Die ; Yang, Cheng ; Jing, Guoqing ; Song, Xuemin

Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin^-/- mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1β, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.

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