Pharmacological research最新文献

{"title":"Gut microbiota reshapes the TNBC immune microenvironment: Emerging immunotherapeutic strategies","authors":"Mingyao Huang ,&nbsp;Yikai Zhang ,&nbsp;Zhaoji Chen ,&nbsp;Xin Yu ,&nbsp;Shiping Luo ,&nbsp;Xueqiang Peng ,&nbsp;Xuexin Li","doi":"10.1016/j.phrs.2025.107726","DOIUrl":"10.1016/j.phrs.2025.107726","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. The gut microbiota, a diverse community of microorganisms in the gastrointestinal tract, plays a crucial role in regulating immune responses through the gut-immune axis. Recent studies have highlighted its significant impact on TNBC progression and the efficacy of immunotherapies. This review examines the interactions between gut microbiota and the immune system in TNBC, focusing on key immune cells and pathways involved in tumor immunity. It also explores microbiota modulation strategies, including probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, as potential methods to enhance immunotherapeutic outcomes. Understanding these mechanisms offers promising avenues for improving treatment efficacy and patient prognosis in TNBC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107726"},"PeriodicalIF":9.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting USP47 enhances the efficacy of KRAS inhibitor in KRASG12C mutated non-small cell lung cancer by controlling deubiquitination of c-Myc","authors":"Hyungkyung Shin ,&nbsp;SuA Hwang ,&nbsp;Jeong Hyun Jeong ,&nbsp;Sang Chul Shin ,&nbsp;Yeonji Oh ,&nbsp;Jinhyeok Kim ,&nbsp;Inah Hwang ,&nbsp;Eunice EunKyeong Kim ,&nbsp;Hyunah Choo ,&nbsp;Eun Joo Song","doi":"10.1016/j.phrs.2025.107722","DOIUrl":"10.1016/j.phrs.2025.107722","url":null,"abstract":"<div><div>FDA-approved KRAS^G12C inhibitors, like Sotorasib, target G12C-mutated KRAS in NSCLC. However, issues with insensitivity and drug resistance have emerged, requiring the development of new combination therapies to overcome these limitations. USP47 has been identified as a regulator of cancer-related signaling pathways such as Wnt, Hippo, and p53. However, its role in the KRAS signaling pathway remains largely unexplored and USP47 inhibitors are less developed than those targeting its homolog, USP7. Here, we identify USP47 as a novel therapeutic target in KRAS^G12C-mutated NSCLC and report K-552, a selective USP47 inhibitor, as a potential treatment strategy. We demonstrate that USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, thereby promoting NSCLC cell proliferation. Additionally, the compound K-552, a USP47 inhibitor identified through virtual screening, effectively destabilizes c-Myc and inhibits KRAS^G12C-mutated NSCLC cell proliferation. Furthermore, USP47 inhibition—either by siRNA knockdown or K-552 treatment—enhances the efficacy of Sotorasib <em>in vitro</em> and <em>in vivo</em>. Together, our findings establish USP47 as a promising therapeutic target in KRAS^G12C-mutated NSCLC and introduce K-552 as a USP47 inhibitor with potential for combination therapy with KRAS^G12C inhibitors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107722"},"PeriodicalIF":9.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold atmospheric plasma control metabolic syndromes via targeting fat mass and obesity-associated protein","authors":"Xiaofeng Dai ,&nbsp;Shuo Feng ,&nbsp;Tian Li","doi":"10.1016/j.phrs.2025.107720","DOIUrl":"10.1016/j.phrs.2025.107720","url":null,"abstract":"<div><div>Both obesity and metabolic disorders are global medical problems. Driven by prolonged inflammation, obesity increases the risk of developing metabolic syndromes such as fatty liver, diabetes, cardiovascular diseases and cancers. The fat mass and obesity-associated protein (FTO) is an m⁶A demethylase, elevated activity of which is known to promote the pathogenesis of many metabolic disorders, leading to the establishment of various FTO inhibitors. By combing through intrinsic connections among obesity and the four primary metabolic problems, we attribute their shared pathological cause to prolonged inflammation. By reviewing the roles of FTO in promoting these disorders and the current status of existing FTO inhibitors in treating these syndromes, we underpinned the paramount potential of resolving these clinical issues by targeting FTO and the urgent need of establishing novel FTO inhibitors with maximized efficacy and minimized side effect. Cold atmospheric plasma (CAP) is the fourth state of matter with demonstrated efficacy in treating various diseases associated with chronic inflammation. By introducing the medical characteristics of CAP, we proposed it as a possible solution to unresolved issues of current FTO inhibitors given its anti-inflammation feature and demonstrated clinical safety. We also emphasized the need of intensive investigations in exploring the feasibility of using CAP in treating obesity and associated metabolic syndromes that might function through targeting FTO.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107720"},"PeriodicalIF":9.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic imbalance and brain tumors: The interlinking metabolic pathways and therapeutic actions of antidiabetic drugs","authors":"Young-Kook Kim ,&nbsp;Juhyun Song","doi":"10.1016/j.phrs.2025.107719","DOIUrl":"10.1016/j.phrs.2025.107719","url":null,"abstract":"<div><div>Brain tumors are complex, heterogeneous malignancies, often associated with significant morbidity and mortality. Emerging evidence suggests the important role of metabolic syndrome, such as that observed in diabetes mellitus, in the progression of brain tumors. Several studies indicated that hyperglycemia, insulin resistance, oxidative stress, and altered adipokine profiles influence tumor growth, proliferation, and treatment resistance. Intriguingly, antidiabetic drugs (e.g., metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and thiazolidinediones) have shown promise as adjunctive or repurposed agents in managing brain tumors. Metformin can impair tumor cell proliferation, enhance treatment sensitivity, and modify the tumor microenvironment by activating AMP-activated protein kinase (AMPK) and inhibiting mammalian target of rapamycin (mTOR) signaling pathways. DPP-4 inhibitors and GLP-1 receptor agonists can target both metabolic and inflammatory aspects of brain tumors, while thiazolidinediones may induce apoptosis in tumor cells and synergize with other therapeutics. Consequently, further studies and clinical trials are needed to confirm the efficacy, safety, and utility of metabolic interventions in treating brain tumors. Here, we review the evidence for the metabolic interconnections between metabolic diseases and brain tumors and multiple actions of anti-diabetes drugs in brain tumors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107719"},"PeriodicalIF":9.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PAR2 deficiency impairs antitumor immunity and attenuates anti-PD1 efficacy in colorectal cancer","authors":"Zilin Liu ,&nbsp;Xuehui Jiang ,&nbsp;Ziliang Ke ,&nbsp;Weihong Wang ,&nbsp;Jianqiang Tang ,&nbsp;Yun Dai","doi":"10.1016/j.phrs.2025.107721","DOIUrl":"10.1016/j.phrs.2025.107721","url":null,"abstract":"<div><div>A T cell-inflamed tumor microenvironment is predictive of better prognosis and clinical response to immunotherapy. Proteinase-activated receptor 2 (PAR2), a member of G-protein coupled receptors is involved in inflammatory process and the progression of various cancers. However, the role of PAR2 in modulating the tumor microenvironment remains unclear. Here, we found that PAR2 high-expression was associated with a favorable prognosis in patients with colorectal cancer. Intriguingly, PAR2 expression in human colorectal cancer was mainly confined to tumor cells and was significantly associated with CD8⁺ T cell infiltration. Tumor-intrinsic PAR2 deficiency blunted antitumor immune responses to promote tumor growth and attenuated the therapeutic efficacy of anti-PD1 in a mouse model of colon cancer. Tumors with downregulated PAR2 showed decreased CD8⁺ T cell infiltration and impaired effector function. Mechanistically, PAR2 activation in tumor cells induced CXCL9 and CXCL10 production via PI3K/AKT/mTOR signaling, thereby enhancing CD8⁺ T cell recruitment in the tumor microenvironment. In addition, PAR2 was essential for dendritic cell activation and differentiation towards conventional type 1 subset. PAR2 deficiency in dendritic cells markedly impaired their ability to prime CD8⁺ T cells and control tumor growth in vivo. Thus, our findings identify new roles for PAR2 in promoting antitumor immunity and provide a promising target to improve immunotherapy efficacy in colorectal cancer.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107721"},"PeriodicalIF":9.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional mechanisms of anxiety and depression in Parkinson’s disease: Integrating neuroimaging, neurocircuits, and molecular pathways","authors":"Jihu Zhao ,&nbsp;Huafang Jia ,&nbsp;Pengju Ma ,&nbsp;Deyuan Zhu ,&nbsp;Yibin Fang","doi":"10.1016/j.phrs.2025.107717","DOIUrl":"10.1016/j.phrs.2025.107717","url":null,"abstract":"<div><div>Anxiety and depression are common non-motor symptoms of Parkinson’s disease (PD) that significantly affect patients’ quality of life. In recent years, our understanding of PD has advanced through multifaceted studies on the pathological mechanisms associated with anxiety and depression in PD. These classic psychiatric symptoms involve complex pathophysiology, with both distinct features and connections to the mechanisms underlying the aetiology of PD. Furthermore, the co-occurrence of anxiety and depression in PD blurs the boundaries between them. Therefore, a comprehensive summary of the pathogenic mechanisms associated with anxiety and depression will aid in better addressing the emergence of these classic psychiatric symptoms in PD. This article integrates neuroanatomical, neural projection, neurotransmitter, neuroinflammatory, brain-gut axis, neurotrophic, hypothalamic-pituitary-adrenal axis, and genetic perspectives to provide a comprehensive description of the core pathological alterations underlying anxiety and depression in PD, aiming to provide an up-to-date perspective and broader therapeutic prospects for PD patients suffering from anxiety or depression.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107717"},"PeriodicalIF":9.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IUPHAR review: Computational Psychiatry 2.0. A new tool for supporting combination therapy of psychopharmacology with neuromodulation in schizophrenia","authors":"Hugo Geerts","doi":"10.1016/j.phrs.2025.107718","DOIUrl":"10.1016/j.phrs.2025.107718","url":null,"abstract":"<div><div>Recent clinical trial successes in schizophrenia with non-dopaminergic agents have rejuvenated the field after a long period of unsuccesfull attempts. At the same time, non-invasive neurostimulation has been increasingly applied in other mental health disorders while a few studies have been performed in schizophrenia. The time has arrived to consider combining psychotherapy with neuromodulation. However, a systematic approach to optimize trial designs is needed. “Computational Psychiatry” has been defined as computational neuroscience modeling using biophysically and anatomically realistic representations of key brain areas based on neuroimaging data and biological knowledge. In this position paper, we will expand this concept to include modeling drug exposure and pharmacology in combination with non-invasive neuromodulation. This computational approach can be used to optimize the impact of psychotherapy and active neuromodulation. This computational platform generates a new in silico biomarker, the “information bandwidth”, that might be related to clinical outcomes in schizophrenia. This is based on the assumption that the information processing capacity of the human brain can be represented by a measure of the entropy that quantifies the level of uncertainty associated with the brain processes. Previously we have shown that this readout in a computational neuroscience model of the closed cortical-striatal-thalamocortical loop is highly correlated with clinical changes in positive symptoms after antipsychotic treatment. In this paper we will present a strategy on how this expanded Computational Psychiatry approach can support optimization of clinical trial design combining neuromodulation with psychopharmacology, as well as the understanding and mitigating of the placebo response.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107718"},"PeriodicalIF":9.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial quality control: A promising target of traditional Chinese medicine in the treatment of cardiovascular disease","authors":"Deng Pan ,&nbsp;Pengfei Chen ,&nbsp;He Zhang ,&nbsp;Qian Zhao ,&nbsp;Wei Fang ,&nbsp;Siyan Ji ,&nbsp;Tielong Chen","doi":"10.1016/j.phrs.2025.107712","DOIUrl":"10.1016/j.phrs.2025.107712","url":null,"abstract":"<div><div>Cardiovascular disease remains the leading cause of death globally, and drugs for new targets are urgently needed. Mitochondria are the primary sources of cellular energy, play crucial roles in regulating cellular homeostasis, and are tightly associated with pathological processes in cardiovascular disease. In response to physiological signals and external stimuli in cardiovascular disease, mitochondrial quality control, which mainly includes mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, is initiated to meet cellular requirements and maintain cellular homeostasis. Traditional Chinese Medicine (TCM) has been shown to have pharmacological effects on alleviating cardiac injury in various cardiovascular diseases, including myocardial ischemia/reperfusion, myocardial infarction, and heart failure, by regulating mitochondrial quality control. Recently, several molecular mechanisms of TCM in the treatment of cardiovascular disease have been elucidated. However, mitochondrial quality control by TCM for treating cardiovascular disease has not been investigated. In this review, we aim to decipher the pharmacological effects and molecular mechanisms of TCM in regulating mitochondrial quality in various cardiovascular diseases. We also present our perspectives regarding future research in this field.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107712"},"PeriodicalIF":9.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “CBX4 regulation of senescence and associated diseases: Molecular pathways and mechanisms” [Pharmacol. Res. 215 (2025) 107705]","authors":"Qianxing Hu ,&nbsp;Linming Su ,&nbsp;Wanli Zhao ,&nbsp;Yinuo Jin ,&nbsp;Liang Jin ,&nbsp;Yue Yang ,&nbsp;Fangfang Zhang","doi":"10.1016/j.phrs.2025.107715","DOIUrl":"10.1016/j.phrs.2025.107715","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107715"},"PeriodicalIF":9.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lack of IFN-γ response of human uterine myometrium-derived MSCs significantly improve multiple IBD parameters compared to bone marrow MSCs: Implications for anti-TNFα-refractory patients","authors":"Li-Tzu Wang ,&nbsp;Hsiu-Huan Wang ,&nbsp;Shih-Sheng Jiang ,&nbsp;Chia-Chih Chang ,&nbsp;Pei-Ju Hsu ,&nbsp;Ko-Jiunn Liu ,&nbsp;Huey-Kang Sytwu ,&nbsp;B. Linju Yen ,&nbsp;Men-Luh Yen","doi":"10.1016/j.phrs.2025.107716","DOIUrl":"10.1016/j.phrs.2025.107716","url":null,"abstract":"<div><div>The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-γ and IL-17A-secreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-γ receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-γ responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC source-specific therapeutic mechanisms is crucial for optimizing clinical therapies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107716"},"PeriodicalIF":9.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}