Pharmacological research最新文献

{"title":"Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects","authors":"Hao-wen Lin ,&nbsp;Shi-pian Li ,&nbsp;Jia-xin Wen ,&nbsp;Jia-xuan Zhang ,&nbsp;Bi-meng Zhang ,&nbsp;Yong-jun Wang ,&nbsp;Xue-jun Cui ,&nbsp;Min Yao","doi":"10.1016/j.phrs.2025.108074","DOIUrl":"10.1016/j.phrs.2025.108074","url":null,"abstract":"<div><div>Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from <em>Panax notoginseng</em> (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108074"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800202","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":"Response letter to Chi-Tung Lu et al.’s Comment on “Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China”","authors":"Yu Zhang,&nbsp;Yingjie Wang","doi":"10.1016/j.phrs.2026.108086","DOIUrl":"10.1016/j.phrs.2026.108086","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108086"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918201","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":"Study on epigenetic regulatory mechanism of MBD4 with a germline loss-of-function mutation (rs140693) responsible for retinoblastoma chemoresistance via the cell cycle and apoptotic pathways","authors":"Li Zhang ,&nbsp;Wenping Song ,&nbsp;Junting Wang ,&nbsp;Yelin Zhao ,&nbsp;Chenyu Yuan ,&nbsp;Zhilong Ruan ,&nbsp;Jiaqi Chen ,&nbsp;Junyang Zhao ,&nbsp;Hongjuan Yao ,&nbsp;Hebing Chen ,&nbsp;Chengyue Zhang ,&nbsp;Liang Li","doi":"10.1016/j.phrs.2026.108098","DOIUrl":"10.1016/j.phrs.2026.108098","url":null,"abstract":"<div><div>Recurrence of high-risk advanced retinoblastoma (RB) is still a major obstacle even after enucleation due to resistance to adjuvant chemotherapy, especially in China. To identify any germline alterations or candidate genes associated with RB prognosis, we obtained whole-exome sequencing (WES) and reduced-representation bisulfite sequencing (RRBS) profiles by using patient peripheral blood samples, followed by clinical validation and functional characterization. For follow-up studies, we selected 17 candidate genes from the WES and RRBS analyses. Among them, <em>MBD4</em>, which carries a germline loss-of-function mutation (rs140693), was identified for further clinical replication. MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. There were marked decreases in the expression of 5 related genes plus increased DNA methylation in their promoters in Y79 (MBD4^-/-) cells, along with even more significant effects after carboplatin treatment. MBD4 affected the transcription and expression of its downstream genes, such as FADD and P21, via MBDCap-PCR, ChIP<img>qPCR, and reporter gene assays. Moreover, the germline mutation was responsible for MBD4 instability with attenuated binding to USP7, thereby leading to impaired drug sensitivity. It was confirmed by the reinstated susceptibility of Y79 (MBD4^-/-) cells after MBD4-WT was restored. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108098"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980180","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":"Corrigendum to “TREX1 activators: A novel therapeutic strategy for rheumatoid arthritis management via cfDNA clearance” [Pharmacol. Res. 218 (2025) 107817]","authors":"Yuping Wang ,&nbsp;Weidan Luo ,&nbsp;Wanyu Wu ,&nbsp;Chang Chen ,&nbsp;Bo Qin ,&nbsp;Xiongfei Xu ,&nbsp;Yulin Xu ,&nbsp;Jianghuiyi Zeng ,&nbsp;Linna Wang ,&nbsp;Jiujie Yang ,&nbsp;Jerome P.L. Ng ,&nbsp;Wuyan Zheng ,&nbsp;Xiaoyun Yun ,&nbsp;Jie Zhou ,&nbsp;Baixiong Huang ,&nbsp;Betty Yuen-Kwan Law ,&nbsp;Vincent Kam-Wai Wong","doi":"10.1016/j.phrs.2026.108093","DOIUrl":"10.1016/j.phrs.2026.108093","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108093"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966740","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":"PHGDH as a therapeutic node: Natural modulators from TCM, degradation pathways, and emerging TPD strategies","authors":"Song-Song Shi ,&nbsp;Yu-Dan Du ,&nbsp;Si-Yi Chen ,&nbsp;Wen Zhang ,&nbsp;Guo-Wu Rao ,&nbsp;Quan Zheng","doi":"10.1016/j.phrs.2025.108079","DOIUrl":"10.1016/j.phrs.2025.108079","url":null,"abstract":"<div><div>Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108079"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834543","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":"IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes","authors":"Andrew J. Elmendorf ,&nbsp;Mostafa Yousefian ,&nbsp;Il-Man Kim ,&nbsp;J. Andrew Hardaway ,&nbsp;Kirk Habegger ,&nbsp;Jonathan N. Flak","doi":"10.1016/j.phrs.2025.108077","DOIUrl":"10.1016/j.phrs.2025.108077","url":null,"abstract":"<div><div>The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108077"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889625","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":"Evaluation of in vitro antiviral activity against different SARS-CoV-2 variants of a protease PROTAC degrader","authors":"Mirko G. Liturri,&nbsp;A. Bergna,&nbsp;A. Lai,&nbsp;C. Della Ventura,&nbsp;A. Gabrieli,&nbsp;I. Seravalli,&nbsp;S. Ciofi-Baffoni,&nbsp;E. Lenci,&nbsp;A. Trabocchi,&nbsp;S. Rusconi","doi":"10.1016/j.phrs.2025.108063","DOIUrl":"10.1016/j.phrs.2025.108063","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108063"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738627","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":"Discovery, development, and characterization of potent and selective USP11 inhibitors","authors":"Forum Kayastha ,&nbsp;Noah B. Herrington ,&nbsp;Anirban Roychowdhury ,&nbsp;Nahid M. Nanaji ,&nbsp;Won Sok Lee ,&nbsp;Glen E. Kellogg ,&nbsp;Bandish Kapadia ,&nbsp;Ronald B. Gartenhaus","doi":"10.1016/j.phrs.2025.108075","DOIUrl":"10.1016/j.phrs.2025.108075","url":null,"abstract":"<div><div>Deubiquitinases (DUBs) have long been viewed through the narrow lens of enzymatic catalysis, but emerging evidence reveals their non-catalytic domains as master regulators of oncogenic signaling. USP11, a structurally modular DUB, exemplifies this duality: beyond its canonical role in DNA repair, USP11 scaffolds key translational effectors such as eIF4B, sustaining the expression of pro-survival oncogenes in aggressive lymphomas. Here, we unveil RBF4 and RBF11, first-in-class, non-catalytic USP11 inhibitors discovered through pharmacophore-guided virtual screening anchored on the UBL domain interface. These small molecules selectively bind USP11 without disrupting its catalytic activity yet interrupt critical interactions essential for eIF4B stabilization and oncogenic translation. Mechanistically, USP11 inhibition collapses MYC-driven translational networks, destabilizes DNA repair factors, rewires calcium homeostasis, and induces a post-transcriptional apoptotic program while sparing non-malignant cells. RBF4, chemically identical to the FDA-approved anti-arrhythmic agent Dronedarone, exhibits potent antitumor efficacy in orthotopic EμMyc lymphoma models, suppressing tumor growth, metastatic spread, and ascites formation with no overt toxicity. Transcriptomic analyses reveal broad rewiring of EMT, immune, and metabolic programs, underscoring USP11’s role as a nodal regulator of tumor cell identity and plasticity. These findings establish the UBL domain of USP11 as a druggable scaffold, redefining DUBs not merely as enzymes but as structural signaling platforms. RBF4 emerges as a clinically actionable prototype for dismantling USP11-driven oncogenic circuits, illuminating a new therapeutic axis in lymphoid malignancies and beyond.</div></div><div><h3>One sentence summary</h3><div>Potent, selective USP11 inhibitors exhibit anti-tumor activity.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108075"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857383","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":"Potential of cyclodipeptides in combating oxidative stress in chronic diseases","authors":"Hamsaletchumi Rajan ,&nbsp;Bey-Hing Goh ,&nbsp;Yatinesh Kumari ,&nbsp;Lai Ti Gew ,&nbsp;Hooi-Leng Ser","doi":"10.1016/j.phrs.2025.108076","DOIUrl":"10.1016/j.phrs.2025.108076","url":null,"abstract":"<div><div>Oxidative stress results from an imbalance between free radicals—such as reactive oxygen species (ROS) and reactive nitrogen species (RNS)—and the body’s antioxidant defenses. This imbalance contributes to the progression of diseases affecting the nervous, cardiovascular, and respiratory systems. Cyclodipeptides (CDPs) have exhibited significant antioxidant, cytoprotective, and neuroprotective properties, making them promising candidates for mitigating oxidative damage. Their ability to modulate oxidative stress pathways highlights their potential as therapeutic agents in oxidative damage-related diseases. This review discusses the role of free radicals in oxidative stress before exploring the importance of different types of CDPs in counteracting oxidative damage in various diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108076"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810840","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":"Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives","authors":"Yudan Zhao ,&nbsp;Hongyuan Lu ,&nbsp;Xiaowen Jiang","doi":"10.1016/j.phrs.2025.108082","DOIUrl":"10.1016/j.phrs.2025.108082","url":null,"abstract":"<div><div>With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108082"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912657","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}