Pharmacological research最新文献

The transient receptor potential melastatin 2 (TRPM2) ion channel is a redox-sensitive, non-specific cation channel that plays a vital role in the regulation of Ca²⁺ homeostasis and cellular functions in response to oxidative stress. However, aberrant expression of TRPM2 is associated with various pathological conditions. Overexpression of TRPM2 promotes cell survival in multiple malignancies, including neuroblastoma, lung, prostate, stomach, and pancreatic cancers. TRPM2 also mediates different neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, and contributes to ischemia/reperfusion (I/R) injuries. This review provides a comprehensive summary of the pathophysiological significance of TRPM2, covering the structural features, regulation, and oxidative stress signaling, with a major focus on the mechanistic pathways that link TRPM2 to these diseases. We discuss the therapeutic potential of TRPM2, its long non-coding antisense RNA (TRPM2-AS), and provide a comprehensive overview of currently available TRPM2 inhibitors, including adenosine diphosphate ribose (ADPR) analogs, small molecules, and peptides. This review covers an in-depth analysis of the structural activity relationships (SAR), pharmacokinetic (PK) properties of these TRPM2 inhibitors, detailing their preclinical efficacy studies, and outlining their shortcomings. Overall, we conclude that TRPM2 represents a promising drug target for effective therapies in several major disease indications.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major dose-limiting complication of chemotherapy, in which pyroptosis is considered a key pathological mechanism. The natural stilbene compound pterostilbene (PTE) has demonstrated cardioprotective potential, but its role in DOX-induced pyroptosis remains unclear. This study, using both in vitro H9C2 cardiomyocyte and in vivo C57BL/6 mouse models of DIC, confirmed that PTE effectively inhibits DOX-induced cardiomyocyte pyroptosis and alleviates cardiac injury. Mechanistically, DOX activates the IL-6/STAT3 signaling pathway, promoting the nuclear translocation of phosphorylated STAT3 (pSTAT3). CUT&Tag and dual-luciferase reporter assays further revealed that activated STAT3 directly binds to the core promoter regions of the caspase-3 and Gasdermin E (GSDME) genes, thereby upregulating their expression at the transcriptional level and ultimately activating the caspase-3/GSDME-mediated pyroptosis pathway. PTE effectively blocks this pyroptotic execution pathway by inhibiting the activation of the IL-6/STAT3 pathway. Furthermore, this study elucidated a critical interaction between cardiomyocytes and immune cells: GSDME-mediated cardiomyocyte pyroptosis releases various soluble factors, with IL-6 being a key cytokine that drives the polarization of macrophages toward the pro-inflammatory M1 phenotype, thereby amplifying the myocardial inflammatory response. By inhibiting cardiomyocyte pyroptosis, particularly by reducing IL-6 release, PTE effectively interrupts this "cardiomyocyte pyroptosis-M1 macrophage polarization" vicious cycle and restores myocardial homeostasis. In summary, our research elucidates a signaling cascade driving DOX-induced cardiotoxicity: IL-6/STAT3-caspase-3/GSDME. We confirmed that PTE is an effective inhibitor of this pathway, not only directly protecting cardiomyocytes but also suppressing the subsequent pyroptosis-driven inflammatory response, thereby highlighting its significant therapeutic potential in mitigating DIC.

Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer's disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ''double-edged sword'' characteristic across different disease stages or tissue contexts-exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.

Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), diabetes, and their multi-organ complications, are characterized by high prevalence, systemic involvement, and a lack of effective reversal strategies. Their pathological core involves energy metabolism imbalance, chronic inflammation, and multi-tissue injury. In recent years, Sterile Alpha and TIR Motif Containing 1 (SARM1), an NAD⁺ hydrolyzing signaling molecule, has been repositioned from a single executor of axonal degeneration to a cross system metabolic regulatory node. By depleting NAD⁺, disrupting mitochondrial homeostasis, and modulating neuroimmune signaling, SARM1 predominantly exerts pro-injury effects in obesity, NAFLD, cardiac disorders, and peripheral neuropathies. However, in specific cell types, such as hepatic stellate cells, its interaction dependent activity can suppress fibrosis, revealing a striking context dependent duality. Despite these findings, a systematic understanding of SARM1's cell-type-specific regulation, tissue heterogeneity and long-term intervention safety in metabolic diseases remains limited, thereby constraining its translational potential. This review outlines the structural characteristics and activation mechanisms of SARM1 and, for the first time, discusses its context-dependent roles in metabolic diseases. It also summarizes emerging pharmacological intervention strategies, including small-molecule inhibitors, natural product modulators, and agonists, aiming to provide a theoretical basis for precise interventions in metabolic diseases and to inspire novel therapeutic approaches.

Pain is a frequently reported long lasting symptom among older adults, often associated with age-related conditions such as osteoarthritis, neuropathies, and musculoskeletal degeneration. In a normal inflammatory condition, the release of pro-inflammatory mediators and the concomitant local vasodilation increases capillary permeability leading to the sensation of pain and hyperalgesia. In a physiologically balanced system, removal of the noxious stimulus allows gradual reduction in inflammation and pain. However, in ageing individuals, the inflammatory response is frequently dysregulated due to immunosenescence, leading to impaired resolution mechanisms, sustained production of pro-inflammatory mediators, and chronic low-grade inflammation-commonly referred to as "inflammaging." This persistent inflammatory condition contributes to the development and maintenance of chronic pain states in the elderly. In this context, the present review explores the role of the endocannabinoid system (ECS) in modulating pain and inflammation during ageing. Particular attention is given to the therapeutic potential of phytocannabinoids derived from Cannabis sativa L., including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and their interactions with cannabinoid receptors. The synergistic effects of phytocannabinoids with other bioactive plant constituents, such as terpenes and flavonoids-commonly known as the "entourage effect"-are also discussed as a means to enhance analgesic efficacy. Furthermore, this review examines how advanced drug delivery platforms, particularly nano-carriers, can address the limitations of conventional cannabis-based formulations by improving bioavailability, pharmacokinetic stability, and targeted delivery, ultimately optimizing the therapeutic application of cannabinoids in managing age-related pain.

Histone lactylation is associated with neurological disorders and the state of reactive microglia. However, the impact of elevated lactate levels, generated through glycolysis under hypoxic conditions, on the status and functionality of reactive microglia in the context of ischemic stroke (IS) remains inadequately understood. Immunofluorescence, Western blot and co-immunoprecipitation were performed to identify the histone lactylation modification sites in microglia after IS. CUT&Tag and RNA sequencing data were used to clarify the target genes of H4K5la in microglia after cerebral ischemia. The influence of H4K5la on microglial functions was assessed through Nile Red staining, ELISA, free fatty acid assays, and energy metabolism kits. TTC, behavioral observation, HE and Nissl staining were used to study the impact of exogenous lactate on IS outcomes. Immunofluorescence, Western blot, co-immunoprecipitation, ELISA and qPCR were conducted to explore the upstream regulator of H4K5la and pro-inflammatory gene expression in microglia following IS.H4K5 lactylation level was elevated in microglia and boosted transcription of immunometabolic genes such as HK1, Fads2, and Pla2g4a. This was linked to higher ECAR, lower OCR, impaired FAO, and a reduced ATP/ADP ratio, resulting in more lipid accumulation and increased pro-inflammatory cytokine expression after IS. Exogenous lactate also increased H4K5la levels, indicating that glycolysis-driven lactate enhances histone lactylation. GCN5 was an upstream regulatory factor in modulating microglia histone lactylation and subsequent immune metabolism gene expression after IS. This study reveals the role and mechanism of H4K5la in microglia immunometabolic dysfunction, identifying a new therapeutic target for IS treatment.