Acta Pharmacologica Sinica最新文献

Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1^+/- mutant mice are resistant to morphine- and methamphetamine-induced conditioned place preference. Given the critical role of learning and memory in drug dependence, we herein explored whether and how Clk1 deficiency affected the cognitive processes in mice. We found that mutant Clk1 mice (Clk1^+/-) exhibited recognition memory impairment in novel object recognition (NOR) and novel arm recognition (NAR) tests. In addition, we observed in Clk1^+/- mutant mice a selective reduction in dendritic spine density in prefrontal cortex (PFC) but not in the hippocampus (HIP). The expression of brain-derived neurotrophic factor (BDNF) was also decreased in PFC but not in HIP. Furthermore, Clk1^+/- mutant mice displayed impairment in the ERK/CREB signaling pathway in PFC that might underlie Clk1^+/- mutation-induced changes in BDNF and dendritic morphology. Administration of antipsychotic drugs aripiprazole (0.3 mg·kg^-1·d^-1, i.p.) or risperidone (1 mg·kg^-1·d^-1, i.p.) for 7 days fully rescued Clk1 mutation-induced recognition memory deficits. This study provides primary evidence highlighting the role of mitochondrial Clk1 in the regulation of recognition memory and presents an informative model for investigating mitochondrial function in learning and memory.

Hypoxia is a common phenomenon in the microenvironment of solid tumors; mitochondria, as the site of cellular oxidative respiration, are among the first organelles to be affected under hypoxic conditions. Mitochondrial cristae organizing protein 19 (MIC19), a core component of the mitochondrial contact site and cristae organizing system (MICOS), is essential for preserving mitochondrial activity. In this study, we investigated the effects of hypoxia on MIC19 and its regulatory mechanisms in non-small cell lung cancer (NSCLC). We showed that the expression levels of MIC19 were significantly increased in NSCLC, which were associated with advanced stages and a poor prognosis in patients with NSCLC. We demonstrated that MIC19 promoted the proliferation and invasion of A549 and PC9 cells in vitro, and MIC19 played a crucial role in maintaining mitochondrial function. We revealed that USP3 mediated the hypoxia-induced upregulation of MIC19 expression in A549 and PC9 cells. In the hypoxic microenvironment, HIF-1α bound to the USP3 promoter region and promoted USP3 expression, which in turn stabilized MIC19 through K48-linked deubiquitination, thereby driving NSCLC progression. The role of MIC19 in NSCLC growth and progression was confirmed in nude mice bearing A549 xenograft tumors in vivo. In conclusion, under hypoxic conditions, USP3 stabilizes MIC19 through deubiquitination, thereby promoting NSCLC progression. This study reveals the HIF1α-USP3-MIC19 axis in NSCLC progression, providing a theoretical basis for future therapeutic strategies.

Neuroinflammation and immune responses mediated by glial cells and immune cells play dual roles in the neural injury and repair of ischemic stroke (IS): glial cells and immune cells primarily have a detrimental role in the acute phase of IS, while they mainly serve a reparative function in the chronic phase. Thus, suppressing neuroinflammation and immune responses driven by glial and immune cells represents a major strategy in the treatment of IS. In this review, we provide an overview of the molecular mechanisms of neuroinflammation and immune responses mediated by glial cells and immune cells at different stages after IS and highlight the roles of different glial cells and immune cells in post-IS neural injury and repair. We also summarize the relevant molecular targets and clinical application challenges for reducing neuroinflammation and immune responses to promote IS repair. Current evidence supports that PD-1/PD-L1, DAPK1, HDAC3-p65-cGAS-STING could be the targets. In addition, we discuss some treatment strategies for reducing neuroinflammation and immune responses such as traditional Chinese medicine (TCM) and natural product therapy, stem cell-based therapy and biomaterials, as well as current clinical trial progress and prospects.

The progression of hepatocellular carcinoma (HCC) is partly driven by reactive oxygen species (ROS)-induced tissue damage and inflammation. Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are key regulators of ROS production, yet the specific role of NOX1 in HCC progression and therapeutic response remain incompletely understood. In this study we investigated the critical role of NOX1 in progression, metastasis and therapeutic sensitivity of HCC, and explored its potential as a therapeutic target. By comprehensive analysis of public databases and validation with in-house clinical specimens, we showed that NOX1 expression was significantly elevated in metastatic HCC that was correlated to poor patient prognosis. Knockdown of NOX1 or pharmacological inhibition with a selective NOX1 inhibitor ML171 significantly reduced ROS production and suppressed HCC cell motility and invasion in vitro. NOX1 inhibition also attenuated HCC metastasis in experimental metastasis mouse model using direct injection of HCC cells, and mitigated CCl₄-induced liver injury and pro-tumorigenic microenvironment in CCl₄-induced chronic liver injury and spontaneous tumor development mouse model. Importantly, we demonstrated that combined sorafenib or radiotherapy with NOX1 inhibition synergistically reduced the metastatic potential of HCC cells and enhanced the therapeutic efficacy. Bioinformatics analysis revealed that NOX1 contributed to HCC metastasis and therapy resistance by modulating ROS homeostasis, cellular antioxidant systems and inflammatory pathways. Taken together, this study elucidates the critical role of NOX1 in HCC pathogenesis, suggesting that NOX1 inhibition represents a promising strategy to overcome resistance and enhance HCC sensitivity to sorafenib and radiotherapy.

The number of endothelial cells (ECs) decreases with aging; consequently, their function is impaired, which is a major cause of the mortality and morbidity of age-related ischemic diseases such as peripheral arterial disease (PAD). Growing evidence suggests that tryptophan metabolism dysfunction has been closely linked to age-related diseases and lifespan regulation across multiple species. In this study, we investigated whether tryptophan metabolism mediated vascular rarefaction and neovascularization impairment in aging. Fasting peripheral blood samples were collected from healthy volunteers, we found that the levels of indoleacrylic acid (IA), a metabolite primarily produced through gut microbial metabolism, were significantly lower in the elderly compared with the young. In both young and elderly PAD patients, lower IA levels were positively correlated with the PAD severity, risk of onset, and cardiovascular outcome, with larger correlation coefficients observed in the elderly patients. We established a hindlimb ischemia mouse model by ligating the femoral artery (FAL). A similar trend was observed between young and aged mice both non- and post-FAL. Supplementing aged mice with IA (50 mg·kg^-1·d^-1, i.g.) for 12 weeks was able to alleviate vascular dysfunction in aged mice. RNA-seq analysis revealed that IA activated the APLNR signaling pathway, alleviated ECs senescence, and enhanced their ability to respond to ischemia. These results provide new insights into the association between IA and vascular dysfunction, laying the theoretical foundation for the potential preventive and therapeutic roles of IA in age-related PAD.

Mechanical hyperalgesia is a primary symptom of clinical pain; there remains a therapeutic challenge for severe mechanical and chronic forms of neuropathic pain. The 34-amino-acid neuropeptide GsMTx4, isolated from Tarantula spatulata, was identified as a selective inhibitor of mechanosensitive channels and shown to reduce mechanical hyperalgesia and neuropathic pain in rats. We previously reported two types (type I and type II) of short peptides derived from GsMTx4 that mimicked the inhibitory action of GsMTx4 on a mechanosensitive BK (SAKca) channel. In this study, we investigated whether these short peptides alleviate mechanical hypersensitivity, a major symptom of neuropathic pain. The synthetic type I peptide 01 (Pept 01) was derived from loop2+loop3 of GsMTx4, whereas type II Pept 02, Pept 03 and, Pept 04 were derived from loop 2 of GsMTx4. Carrageenan-induced inflammatory pain was induced in rats and mice, while the chronic constriction nerve injury (CCI) model was established in rats. We showed that administration of short peptides (270 μg/kg, i.p.) selectively inhibited mechanical pain in rats but failed to impact thermal or cold hyperalgesia. Interestingly, the antihyperalgesic effects of these peptides were comparable to those of morphine; however, they were resistant to the μ-opioid receptor antagonist naloxone and lacked morphine-induced side effects, e.g., tolerance and conditioned place preference (CPP). Among them, Pept 03, which contained only one Trp (Trp1) at the head and an additional Arg (Arg11, corresponding to Arg18 in GsMTx4) at the end of the peptide, most potently alleviated mechanical hyperalgesia. Genetic deletion of the TRPV4 gene in mice mostly abolished the analgesic effect of Pept 03. In oocytes expressing TRPV4 channels, application of Pept 03 or Pept 01 inhibited GSK101- or hypotonicity-activated TRPV4 currents in a dose-dependent manner. These results suggest that TRPV4 channels may serve as a direct target for the short peptides in alleviating mechanical pain. This study identifies several natural toxin-based peptides as promising non-opioid analgesics, paving the way for the development of selective and potent painkillers to treat mechanical pain.

Neuropsychiatry and neurodegenerative disorders (NPDs and NDDs) are often associated with various physiological factors. It is increasingly apparent that signal transducers like G-protein-coupled receptors (GPCRs) are critical in disease progression and constitute an important class of drug targets. Several members of class A, class B, and class C GPCR families, along with their cognate binding partners, are involved in neurotransmission and neuromodulation. The vast information about the different molecular states of these GPCRs with their signaling complexes unravels the understanding of residual specificity in these protein-protein interactions and the dynamicity of transmembrane helices. The atypical mode of interaction of GPCRs with binding partners provides valuable insights for GPCR-conformation-based drug designing. In this review, we highlight the structural features of the serotonin, dopamine, and corticotropin receptors, namely 5-HTR_1A, 5-HTR_1B, 5-HTR_2A, 5-HTR_2B, 5-HTR_2C, 5-HTR₄, 5-HTR₆, 5-HTR₇, D_1-5R, and CRF_1-2R when forming transient complexes with G-proteins and arrestins. The distinct structural characteristics of these receptors explain the underlying molecular mechanism for signaling specificity and related physiological processes. This review also summarizes the importance of these structural insights in developing newer and effective pharmacologically biased drugs that can mediate specific signaling pathways to GPCRs.

Coronary atherosclerosis is a leading cause of morbidity and mortality worldwide and is characterized by complex molecular and cellular mechanisms involving lipid dysregulation, endothelial dysfunction, immune-inflammatory processes, and vascular remodeling. Despite advancements in conventional therapies, including statins and antiplatelet agents, significant residual risk persists, particularly in patients with genetic dyslipidemias, persistent inflammation, or limited access to advanced care. Recent breakthroughs in precision medicine, multiomics technologies, and high-resolution imaging are transforming our approach to cardiovascular risk assessment by enabling refined stratification through single-cell transcriptomics, polygenic risk scoring, and artificial intelligence-powered plaque analysis. This review synthesizes the contemporary understanding of disease mechanisms and emerging therapeutic strategies, highlighting novel interventions targeting PCSK, inflammatory pathways, and vascular regeneration through cell-based therapies. We further explored the transformative potential of CRISPR-Cas9 gene editing for durable lipid lowering, nanotechnology-enabled drug delivery, and gut microbiota modulation targeting metabolites such as trimethylamine N-oxide. Although these innovations promise personalized atherosclerosis management, challenges remain in terms of accessibility, health equity, and clinical implementation. The integration of multimodal data analytics with targeted therapeutics heralds a new era of precision cardiology aimed at reducing the global burden of coronary artery disease.

The endoplasmic reticulum (ER) is a central organelle for protein synthesis and folding, lipid metabolism and calcium signaling, etc. To maintain ER homeostasis, cells employ a specific autophagy process termed ER-phagy (reticulophagy), which depredates ER components via three forms: macro-ER-phagy (involving bulk ER sequestration), micro-ER-phagy (lysosome-direct), and ER-to-lysosome-associated degradation (ERLAD). The identification of specific ER-phagy receptors including FAM134A, FAM134B, FAM134C, TEX264, SEC62, RTN3L, CCPG1, ATL3, CALCOCO1 and others has significantly advanced our understanding of ER quality control mechanisms. In this review we summarize the current knowledge on ER-phagy receptors, and emerging evidence linking ER-phagy dysfunction to various disease pathologies including neurological disorders, cancer, metabolic diseases, cardiovascular diseases, infections and immune disorders. Recent evidence shows that ER-phagy receptors can form novel ER-derived structures, such as ER-tubular bodies (ER-TBs) consisted of ATL3 and RTN3L, which mediate Golgi-bypassing unconventional protein secretion under stress conditions, revealing non-degradative functions of these receptors beyond quality control. Targeting ER-phagy receptors may provide insights into potential therapeutic strategies for diseases associated with this fundamental cellular process.

Janus kinase 2 (JAK2) is an important therapeutic target for various inflammatory diseases, cancers, and rheumatoid arthritis. Therefore, inhibiting JAK2 has become a promising approach for treating these conditions. In this study, molecular descriptors such as Morgan fingerprints, Molecular Access System (MACCS), and PaDEL were calculated and used to develop machine-learning models. Among these models, CatBoost combined with Morgan fingerprints performed the best, achieving an accuracy of 0.94 on the test dataset. This CatBoost model was then used to screen the Korean Chemical Databank (KCB) to identify the most potent JAK2 inhibitors. Computational analyses, including density functional theory (DFT), molecular docking, and molecular dynamics simulations, were carried out to evaluate the performance of the top-ranked molecules. Finally, four compounds were selected for experimental testing, and the results showed that their IC₅₀ values were less than 10 μM. The integration of AI-driven modeling with experimental validation provides a promising strategy for personalized medicine, enabling the development of more precise and effective kinase-targeted therapies while reducing the time and cost required to bring new drugs to clinical trials.