Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Thromboembolic Events Associated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Pharmacovigilance Analysis of the US FDA Adverse Event Reporting System (FAERS) Database.

BACKGROUND AND OBJECTIVES: Although thromboembolic events (TEEs) have been reported with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), their association remains largely unknown. In this study, we aimed to provide a comprehensive review of TEEs associated with EGFR-TKIs. METHODS: We collected EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib) adverse reaction reports from 2015 Q1 to 2023 Q1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to identify thromboembolic adverse events associated with EGFR-TKIs by comparing them with the overall FAERS database according to the reporting odds ratio (ROR). Associated factors were explored using univariate logistic regression. RESULTS: We identified 1068 reports of TEEs associated with EGFR-TKIs (1.24% accounts for all TEEs). Affected patients were females (49.72%) and those older than 65 years (41.20%). The reported TEE case fatality was 30.24%. The median time to onset (TTO) of all cases was 39 days [interquartile range (IQR) 11-161], and the median TTO of fatalities [31 days (IQR 10-116)] was significantly shorter than that of non-fatal cases [46 days (IQR 12-186)]. CONCLUSION: This study yielded three key findings. Firstly, EGFR-TKIs seem to exhibit prothrombotic effects, elevating the risk of TEEs. Secondly, the clinical outcomes of TEEs associated with EGFR-TKIs were poor. Thirdly, most TEEs occurred within the initial 3 months, and fatal cases occurred earlier than non-fatal cases.

Salidroside inhibits chronic myeloid leukemia cell proliferation and induces apoptosis by regulating the miR-140-5p/wnt5a/ß-catenin axis.

Salidroside, an active ingredient of Rhodiola rosea, exhibits antitumor effects in various types of cancer. However, the role of salidroside in chronic myeloid leukemia (CML) has not been elucidated. In the presents study, cell viability was assessed by CCK-8 assay, while apoptosis was detected by flow cytometry. Reverse transcription-quantitative PCR analysis was used to examine the expression levels of miR-140-5p in human CML cell lines. The expression levels of apoptosis and cell cycle-associated proteins and of the wnt5a/ß-catenin signaling pathway were determined by western blot analysis. Bioinformatic analysis and luciferase reporter assays were employed to investigate the association between miR-140-5p and wnt5a. The results revealed that exposure of CML cells to salidroside (80 µM) inhibited cell proliferation and promoted apoptosis. In addition, salidroside treatment led to the upregulation of miR-140-5p expression. Furthermore, the inhibition of wnt5a/ß-catenin signaling pathway and the pro-apoptotic effects induced by salidroside were attenuated by miR-140-5p silencing. Notably, wnt5a was revealed to be a direct target of miR-140-5p. The present findings indicated that salidroside exerted anti-CML effects through regulating miR-140-5p by suppressing the wnt5a/ß-catenin signaling pathway. The present study provided evidence of the therapeutic role of salidroside in CML.