Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

Environmental toxicology of bisphenol A: Mechanistic insights and clinical implications on the neuroendocrine system.

Bisphenol A (BPA) is a widely used environmental estrogen found in a variety of products, including food packaging, canned goods, baby bottle soothers, reusable cups, medical devices, tableware, dental sealants, and other consumer goods. This substance has been found to have detrimental effects on both the environment and human health, particularly on the reproductive, immune, embryonic development, nervous, endocrine, and respiratory systems. This paper aims to provide a comprehensive review of the effects of BPA on the neuroendocrine system, with a primary focus on its impact on the brain, neurons, oligodendrocytes, neural stem cell proliferation, DNA damage, and behavioral development. Additionally, the review explores the clinical implications of BPA, specifically examining its role in the onset and progression of various diseases associated with the neuroendocrine metabolic system. By delving into the mechanistic analysis and clinical implications, this review aims to serve as a valuable resource for studying the impacts of BPA exposure on organisms.

BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases.

Subcellular organelles dysfunction is implicated in various diseases, including metabolic diseases, neurodegenerative diseases, cancer, and cardiovascular diseases. BAM15, a selective mitochondrial uncoupler, has emerged as a promising therapeutic agent due to its ability to enhance mitochondrial respiration and metabolic flexibility. By disrupting the coupling between electron transport and ATP synthesis, BAM15 dissipates the proton gradient, leading to increased mitochondrial respiration and energy expenditure. This review provides a comprehensive overview of BAM15, including its mechanism of action and potential therapeutic applications in diverse disease contexts. BAM15 has shown promise in obesity by increasing energy expenditure and reducing fat accumulation. In diabetes, it improves glycemic control and reverses insulin resistance. Additionally, BAM15 has potential in non-alcoholic fatty liver disease, sepsis, and cardiovascular diseases by mitigating oxidative stress, modulating inflammatory responses, and promoting cardioprotection. The safety profile of BAM15 is encouraging, with minimal adverse effects and remarkable tolerability. However, challenges such as its high lipophilicity and the need for alternative delivery methods need to be addressed. Further research is necessary to fully understand the therapeutic potential of BAM15 and optimize its application in clinical settings.

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling.

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Secreted frizzled-related proteins: A promising therapeutic target for cancer therapy through Wnt signaling inhibition.

The Wnt signaling system is a critical pathway that regulates embryonic development and adult homeostasis. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or Frizzled receptors. SFRPs can act as anti-Wnt agents and suppress cancer growth by blocking the action of Wnt ligands. However, SFRPs are often silenced by promoter methylation in cancer cells, resulting in hyperactivation of the Wnt pathway. Epigenetic modifiers can reverse this silencing and restore SFRPs expression. Despite the potential of SFRPs as a therapeutic target, the effects of SFRPs on tumor development remain unclear. Therefore, a review of the expression of various members of the SFRPs family in different cancers and their potential as therapeutic targets is warranted. This review aims to summarize the current knowledge of SFRPs in cancer, focusing on their expression patterns and their potential as novel therapeutic targets.

Crosstalk between the CBM complex/NF-κB and MAPK/P27 signaling pathways of regulatory T cells contributes to the tumor microenvironment.

Regulatory T cells (Tregs), which execute their immunosuppressive functions by multiple mechanisms, have been verified to contribute to the tumor microenvironment (TME). Numerous studies have shown that the activation of the CBM complex/NF-κB signaling pathway results in the expression of hypoxia-inducible factor-1 (HIF-1α) and interleukin-6 (IL-6), which initiate the TME formation. HIF-1α and IL-6 promote regulatory T cells (Tregs) proliferation and migration through the MAPK/CDK4/6/Rb and STAT3/SIAH2/P27 signaling pathways, respectively. IL-6 also promotes the production of HIF-1α and enhances the self-regulation of Tregs in the process of tumor microenvironment (TME) formation. In this review, we discuss how the crosstalk between the CARMA1-BCL10-MALT1 signalosome complex (CBM complex)/NF-κB and MAPK/P27 signaling pathways contributes to the formation of the TME, which may provide evidence for potential therapeutic targets in the treatment of solid tumors.

Mutation of PD-1 immune receptor tyrosine-based switch motif (ITSM) enhances the antitumor activity of cytotoxic T cells.

BACKGROUND: Programmed cell death protein 1 (PD-1), as an immune checkpoint cell membrane receptor, negatively regulates T cell activation via its immune receptor, the tyrosine-based switch motif (ITSM). The purpose of this research was to evaluate the antitumor activity T cells with the ITSM mutation of PD-1 on non-small cell lung cancer (NSCLC) in vitro and in vivo. METHODS: In this study, the tyrosine of ITSM in cytotoxic T cells was mutated using the adenine base editor (ABE)-xCas9 system to evaluate its effect on the antitumor activity of T cells against NSCLC. RESULTS: Results showed that the PD-1-deficient T cells enhanced the death of the cocultured NSCLC cells compared with the normal T cells and saline solution. PD-1-deficient T cells also changed the interleukin 2(IL-2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion of T cells compared with those of the normal T cells. The effectiveness of ITSM mutation in enhancing the antitumor activity of PD-1-deficient T cells was verified in vivo by using a mouse xenograft model. The xenografted mice treated with PD-1-deficient T cells demonstrated repressed tumor growth of the NSCLC cells compared with those treated with normal T cells and saline solution. CONCLUSIONS: The mutation of ITSM in cytotoxic T cell via the ABE-xCas9 system can significantly enhance the antitumor activity of T cells.