BAP1's function as a tumor suppressor is strongly suggested by these findings, in conjunction with substantial evidence of its participation in numerous cancer-related biological activities. Nonetheless, the ways in which BAP1 functions as a tumor suppressor are only now being unraveled. BAP1's roles in maintaining genome stability and apoptosis have become increasingly important areas of recent research, highlighting it as a compelling candidate for critical mechanistic factors. This paper focuses on genome stability, elaborating on the cellular and molecular functions of BAP1 in DNA repair and replication. These processes are vital for genome integrity, and we then discuss the implications for BAP1-associated cancers and potential therapeutic strategies. We also delineate certain unresolved issues and prospective future research paths.
Cellular condensates and membrane-less organelles, arising from liquid-liquid phase separation (LLPS), are mediated by RNA-binding proteins (RBPs) harboring low-sequence-complexity domains, thereby fulfilling biological functions. Yet, the anomalous phase shift of these proteins leads to the formation of insoluble clumps. Pathological aggregates serve as a defining characteristic of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Aggregate formation by ALS-linked RPBs is governed by molecular mechanisms that are largely unknown. This review considers emerging studies that explore the diverse post-translational modifications (PTMs) associated with protein aggregation processes. Our introductory focus is on several RNA-binding proteins (RBPs) associated with ALS, which develop aggregates as a consequence of phase separation. Consequently, our research has identified a novel PTM central to the phase separation phenomena within the pathogenesis of fused-in-sarcoma (FUS)-linked ALS. We hypothesize a molecular pathway for LLPS-mediated glutathionylation in FUS-linked amyotrophic lateral sclerosis. To enhance our grasp of ALS pathogenesis and expedite the development of therapeutic interventions, this review thoroughly explores the key molecular mechanisms of PTM-driven LLPS aggregate formation.
Biological processes practically all involve proteases, highlighting their crucial roles in both health and disease. Disruption of protease function is a pivotal event in the initiation and advancement of cancer. Although research initially highlighted proteases' influence on invasion and metastasis, subsequent studies revealed their crucial role in all facets of cancer development and progression, directly through proteolytic action and indirectly through governing cellular signaling and functions. In the last two decades, a new subfamily of serine proteases, known as type II transmembrane serine proteases (TTSPs), has been discovered. Tumors frequently overexpress TTSPs, potentially indicating development and progression; these TTSPs thus represent a possible molecular target for anticancer therapies. TMPRSS4, a serine protease situated within cell membranes (transmembrane), and part of the TTSP family, exhibits increased activity in pancreatic, colorectal, gastric, lung, thyroid, prostate, and various other cancers. Elevated TMPRSS4 levels frequently indicate a less favorable patient outcome. The extensive expression of TMPRSS4 in different forms of cancer has prompted intensive anticancer research focusing on this target. This review provides a comprehensive overview of the current understanding of TMPRSS4's expression, regulation, clinical impact, and involvement in pathological processes, particularly cancer. Medications for opioid use disorder It also provides a general overview of the epithelial-mesenchymal transition and the technical aspects of TTSPs.
Proliferating cancer cells are substantially supported in their survival and proliferation by glutamine. The TCA cycle mediates glutamine's function as a carbon source for lipid and metabolite synthesis, and concurrently supplies nitrogen for amino acid and nucleotide biosynthesis. Numerous studies, spanning the period up to the present, have investigated the role of glutamine metabolism in cancer, thereby establishing a scientific rationale for targeting glutamine metabolism in cancer therapy. This review elucidates the series of mechanisms involved in glutamine metabolism, ranging from its initial transport to its influence on redox homeostasis, while also highlighting its potential as a therapeutic target in cancer. Furthermore, we analyze the mechanisms by which cancer cells develop resistance to agents targeting glutamine metabolism, and we investigate approaches to counteract these mechanisms. Finally, we scrutinize the consequences of glutamine blockage within the tumor microenvironment, and explore strategies to improve the utility of glutamine blockers as anti-cancer therapies.
The global health care systems and public health strategies faced a significant strain during the past three years due to the SARS-CoV-2 pandemic. The primary cause of death from SARS-CoV-2 infection was the onset of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Subsequently, a considerable number of people who survived SARS-CoV-2 infection, including those with ALI/ARDS, face multiple, inflammation-induced lung complications, leading to long-term disabilities and even death. The lung-bone axis describes the link between diseases of the lungs (COPD, asthma, and cystic fibrosis) and bone disorders, including osteopenia and osteoporosis. Consequently, to reveal the mechanistic basis, we examined the role of ALI in shaping bone characteristics in mice. In vivo, the phenomenon of enhanced bone resorption and trabecular bone loss was witnessed in LPS-induced ALI mice. Furthermore, serum and bone marrow levels of chemokine (C-C motif) ligand 12 (CCL12) were elevated. Eliminating CCL12 throughout the living body, or conditionally eliminating CCR2 in bone marrow stromal cells (BMSCs), suppressed bone resorption and eradicated trabecular bone loss in ALI mice. Cell-based bioassay The study further demonstrated the capability of CCL12 to induce bone resorption through the stimulation of RANKL production in bone marrow stromal cells, the CCR2/Jak2/STAT4 pathway being paramount in this mechanism. Our findings shed light on the progression of ALI, and establish a roadmap for future studies to discover novel treatment targets to address bone loss due to inflammation-induced lung damage.
Senescence, a defining characteristic of aging, plays a role in age-related diseases. Consequently, the strategy of targeting senescence is broadly considered a viable approach for influencing the processes of aging and ARDs. We present regorafenib, a multiple receptor tyrosine kinase inhibitor, as an identified senescent cell attenuation agent in this report. From a systematic screening of an FDA-approved drug library, we isolated regorafenib. Sub-lethal doses of regorafenib effectively reduced the phenotypic manifestations of PIX knockdown- and doxorubicin-induced senescence, as well as replicative senescence, within IMR-90 cells; this included cell cycle arrest and an augmentation of SA-Gal staining, along with heightened senescence-associated secretory phenotypes, notably an increase in interleukin-6 (IL-6) and interleukin-8 (IL-8) release. find more Following this finding, the lungs of mice treated with regorafenib exhibited a diminished pace of PIX depletion-induced senescence progression. Regorafenib's effect on growth differentiation factor 15 and plasminogen activator inhibitor-1, as observed in proteomics studies of various senescent cell types, points to a shared mechanistic pathway. Phosphorylation array analyses of receptors and kinases identified platelet-derived growth factor receptor and discoidin domain receptor 2 as additional regorafenib targets, further demonstrating the involvement of AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling cascades. Subsequently, regorafenib treatment led to a reduction in senescence and an enhancement in the resolution of porcine pancreatic elastase-induced emphysema in mice. These findings suggest regorafenib as a novel senomorphic agent, potentially efficacious in managing pulmonary emphysema.
High-frequency hearing loss, initially symmetrical and later progressive, eventually impacting all frequencies, often emerges in later life and is a symptom of pathogenic variations within the KCNQ4 gene. To discern the impact of KCNQ4 variations on auditory function, we scrutinized whole-exome and genome sequencing data from individuals exhibiting hearing impairment and those with unidentified auditory phenotypes. Among nine hearing loss patients, seven missense variants and a single deletion variant were detected within the KCNQ4 gene; furthermore, fourteen missense variants were found in a Korean population experiencing hearing loss of unknown etiology. The p.R420W and p.R447W genetic variants were found within both study populations. To understand the influence of these variations on KCNQ4 function, we used whole-cell patch-clamp analysis, combined with a study of their expression levels. Excluding the p.G435Afs*61 KCNQ4 variant, every other KCNQ4 variant presented normal expression patterns similar to those of the wild-type KCNQ4. In patients with hearing loss, the p.R331Q, p.R331W, p.G435Afs*61, and p.S691G variants displayed potassium (K+) current density measurements that were either lower than or equivalent to that observed with the previously reported pathogenic p.L47P variant. The p.S185W and p.R216H variations caused the activation voltage to move toward more hyperpolarized potentials. The channel function of KCNQ4 proteins, including p.S185W, p.R216H, p.V672M, and p.S691G, was rejuvenated by the application of KCNQ activators, retigabine or zinc pyrithione. Conversely, the p.G435Afs*61 KCNQ4 protein's activity was only partially recovered by treatment with the chemical chaperone sodium butyrate. Additionally, the predicted structures from AlphaFold2 displayed dysfunctional pore configurations, which corresponded with the data from patch-clamp recordings.