Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α-lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre-treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to tunicamycin. In functional assays, ALA treatment abrogated significantly the tunicamycin-mediated transcriptional activation of ATF6 while it enhanced the insulin-stimulated glucose uptake and Glut4 translocation. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin-induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA-alleviated tunicamycin-induced ER stress. Furthermore, the effect of ALA on insulin-stimulated glucose uptake is significantly reduced in C2C12 and HepG2 cells transfected with DNAJB3 siRNA. In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improves glucose uptake.

Cancer stem cells (CSCs) are a minor subpopulation of tumor cells characterized by self-renewal capacity and stemness features and are responsible for tumor progression and therapy resistance. Several studies have shown that CSCs possess immunomodulatory properties that allow them to evade from immune responses. One of the mechanisms by which CSCs can escape from immune cells recognition and killing is represented by the overexpression of immune checkpoints (ICPs). The observation that cancer patients may still display or acquire resistance to immunotherapy despite targeting the PD-1/PD-L1 axis, highlights the importance of other ICPs as potential mediators of immune resistance. In this review, we summarize the immunomodulatory properties of CSCs and comprehensively discuss the crosstalk between these cells and selected ICPs (i.e., B7-H3, B7-H4, CD200 and CD155, VISTA, TIGIT, CD47, CD70, CEACAMs, and galectins) that are thought to be involved in CSC mediated immune evasion. Open questions regarding the immunological profile of CSCs, especially in relation to ICPs expression and their underlying regulatory mechanisms, are also addressed. Improved immunological profiling of CSCs will contribute to the identification of prognostic and predictive biomarkers for cancer patients and the development of effective therapeutic interventions that may lead to the eradication of malignant tumors.

RNA‐binding proteins (RBPs) play a crucial role in the regulation of posttranscriptional RNA networks, which can undergo dysregulation in many pathological conditions. Human antigen R (HuR) is a highly researched RBP that plays a crucial role as a posttranscriptional regulator. HuR plays a crucial role in the amplification of inflammatory signals by stabilizing the messenger RNA of diverse inflammatory mediators and key molecular players. The noteworthy correlations between HuR and its target molecules, coupled with the remarkable impacts reported on the pathogenesis and advancement of multiple diseases, position HuR as a promising candidate for therapeutic intervention in diverse inflammatory conditions. This review article examines the significance of HuR as a member of the RBP family, its regulatory mechanisms, and its implications in the pathophysiology of inflammation and cardiometabolic illnesses. Our objective is to illuminate potential directions for future research and drug development by conducting a comprehensive analysis of the existing body of research on HuR.