Pharmacological research最新文献

{"title":"The interplay of aging, sleep dysregulation, and mitochondrial dysfunction in metabolic and neurodegenerative diseases","authors":"Kuo-Jen Lin , I-Hung Shao , Yu-Hsiang Lin","doi":"10.1016/j.phrs.2025.107614","DOIUrl":"10.1016/j.phrs.2025.107614","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107614"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009570","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":"Stem Cell Revolutions: An alliance for Parkinson’s disease driven by European Commission consortia","authors":"Elena Cattaneo , Dario Besusso","doi":"10.1016/j.phrs.2024.107569","DOIUrl":"10.1016/j.phrs.2024.107569","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107569"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922484","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":"Efficacy and safety of SHR8554 on postoperative pain in subjects with moderate to severe acute pain following orthopedic surgery: A multicenter, randomized, double-blind, dose-explored, active-controlled, phase II/III clinical trial","authors":"Yanhua Zhao ,&nbsp;Zhisheng Lu ,&nbsp;Xuesong Song ,&nbsp;Haihui Xie ,&nbsp;Xungang Xiao ,&nbsp;Guonian Wang ,&nbsp;Qi Zhou ,&nbsp;Qingmei Zhang ,&nbsp;Liang Liu ,&nbsp;Zhijian Lan ,&nbsp;Ning Bai ,&nbsp;Haiyan Wang ,&nbsp;Zhihao Pan ,&nbsp;Liang Dong ,&nbsp;Xianzhong Lin ,&nbsp;Gang Chen ,&nbsp;Qinghui Wang ,&nbsp;Jiangtao Dong ,&nbsp;Jia Deng ,&nbsp;Yongshan Nan ,&nbsp;Xiyao Gu","doi":"10.1016/j.phrs.2025.107576","DOIUrl":"10.1016/j.phrs.2025.107576","url":null,"abstract":"<div><div>Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID₂₄). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID₂₄ compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and −19.8 (p &lt; 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery.</div></div><div><h3>Trial Registration</h3><div>Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107576"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927737","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 ion homeostasis in metabolic diseases: Molecular mechanisms and targeted therapies","authors":"Yanjiao Zhang ,&nbsp;Kaile Ma ,&nbsp;Xinyi Fang ,&nbsp;Yuxin Zhang ,&nbsp;Runyu Miao ,&nbsp;Huifang Guan ,&nbsp;Jiaxing Tian","doi":"10.1016/j.phrs.2025.107579","DOIUrl":"10.1016/j.phrs.2025.107579","url":null,"abstract":"<div><div>The incidence of metabolic diseases—hypertension, diabetes, obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and atherosclerosis—is increasing annually, imposing a significant burden on both human health and the social economy. The occurrence and development of these diseases are closely related to the disruption of ion homeostasis, which is crucial for maintaining cellular functions and metabolic equilibrium. However, the specific mechanism of ion homeostasis in metabolic diseases is still unclear. This article reviews the role of ion homeostasis in the pathogenesis of metabolic diseases and assesses its potential as a therapeutic target. Furthermore, the article explores pharmacological strategies that target ion channels and transporters, including existing drugs and emerging drugs under development. Lastly, the article discusses the development direction of future therapeutic strategies, including the possibility of gene therapy targeting specific ion channels and personalized therapy using novel biomarkers. In summary, targeting ion homeostasis provides a new perspective and potential therapeutic approach for the treatment of metabolic diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107579"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932543","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":"Expanding perspectives on the relationship between statin potency and lipophilicity in Alzheimer's disease management","authors":"Yixiang Hu,&nbsp;Shixuan Peng,&nbsp;Can Xiao","doi":"10.1016/j.phrs.2025.107594","DOIUrl":"10.1016/j.phrs.2025.107594","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107594"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971873","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 insights on antidiabetic therapies: Differential impacts of SGLT2i, GLP-1, and insulin","authors":"Yu-Hsiang Lin,&nbsp;Kuo-Hsuan Chang,&nbsp;Yu-Jen Lu","doi":"10.1016/j.phrs.2025.107610","DOIUrl":"10.1016/j.phrs.2025.107610","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107610"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009632","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":"Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection","authors":"Michaela Dvorakova ,&nbsp;Ken Mackie ,&nbsp;Alex Straiker","doi":"10.1016/j.phrs.2025.107606","DOIUrl":"10.1016/j.phrs.2025.107606","url":null,"abstract":"<div><div>Δ⁹-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity – depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activation-dependent desensitization. Cultured autaptic hippocampal neurons express all of these, illustrating the rich functional and temporal heterogeneity of CB1 at a single set of synapses. Here we report that coincident activation of muscarinic acetylcholine receptors and elicitation of DSE in autaptic hippocampal neurons results in a substantial (∼40 %) and temporally precise inhibition of excitatory transmission lasting ∼10 minutes. Its induction is blocked by CB1 and muscarinic M3/M5 receptor antagonists and is absent in CB1 receptor knockout neurons. Notably, once it is established, inhibition is reversed by a CB1, but not a muscarinic, antagonist, suggesting that the inhibition occurs via persistent activation of CB1 receptors. We refer to this inhibition as muscarinic cannabinoid suppression of excitation (MCSE). MCSE can be mimicked by coapplication of muscarinic and cannabinoid agonists and requires Ca²⁺-release from internal stores. As such, MCSE represents a novel and targeted form of coincidence detection – important for many modes of learning and memory -- between cannabinoid and muscarinic signaling systems that elicits a medium-duration depression of synaptic signaling. Given the known roles of muscarinic and cannabinoid receptors in the hippocampus, MCSE may be important in the modulation of hippocampal signaling at the site of septal inputs, with potential implications for learning and memory, epilepsy and addiction.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107606"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009639","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":"The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells","authors":"Minghao Sui ,&nbsp;Tiantian Liu ,&nbsp;Xuanli Song ,&nbsp;Ji Li ,&nbsp;Han Ding ,&nbsp;Yuqian Liu ,&nbsp;Xinyu Wang ,&nbsp;Huimin Liu ,&nbsp;Yuchan Xue ,&nbsp;Jianni Qi ,&nbsp;Miao Zhang ,&nbsp;Songbo Zhao ,&nbsp;Qiang Zhu","doi":"10.1016/j.phrs.2025.107619","DOIUrl":"10.1016/j.phrs.2025.107619","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cells have encouraging results in the treatment of hematological malignancies. However, CAR-T therapy still faces numerous challenges against solid tumors, such as hepatocellular carcinoma (HCC), owing to heterogeneous antigen expression in tumor cells, limited persistence of CAR-T cells, etc. Therefore, to treat HCC more effectively, we connected the molecular receptor NKBB to a second-generation glypican-3 (GPC3) CAR to construct GC3328z-NKBB CAR-T cells, which have double specific targets of GPC3 and NKG2DLs (natural killer group 2, member D ligands), dual co-stimulation of CD28 and 41BB, and a single CD3ζ chain. Our study showed that the molecular receptor NKBB conferred GPC3 CAR-T cells with enhanced migration and infiltration abilities towards HCC, higher central memory T (T_CM) cell proportion and proliferation capacity, and reduced exhaustion level. GC3328z-NKBB CAR-T cells exhibited improved cytotoxicity against HCC cells and prolonged persistence. The cathepsin L/interleukin-17 (CTSL/IL-17) axis contributed to the superior anti-HCC activity of GC3328z-NKBB CAR-T cells. Overall, the molecular receptor NKBB significantly increased the persistence of GPC3 CAR-T cells, and GC3328z-NKBB CAR-T cells possessed potent anti-HCC activity in mice, providing a new strategy for the potential improvement of adoptive T cell therapy in the treatment of HCC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107619"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024319","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":"Promising LOX proteins for cartilage-targeting osteoarthritis therapy","authors":"Luca Morici ,&nbsp;Eric Allémann ,&nbsp;Olivier Jordan ,&nbsp;Ines Nikolić","doi":"10.1016/j.phrs.2025.107627","DOIUrl":"10.1016/j.phrs.2025.107627","url":null,"abstract":"<div><div>Osteoarthritis (OA) is the most affected joint disease worldwide, touching millions of people every year. It is caused by a progressive degeneration of articular cartilage, causing pain and limited mobility. Among the pathways involved in cartilage homeostasis, “LOX” proteins (referring to three distinct protein families, very often confused in the literature) play a prominent role. The lipoxygenase enzyme family is involved in the inflammatory process of OA by inducing the production of several pro-inflammatory leukotrienes. Lectin-like oxidized low-density lipoprotein family are receptors located at the surface of chondrocytes, which interact with their ligand, ox-LDL, activating several catabolic pathways involved in OA pathophysiology. Finally, lysyl oxidase and lysyl oxidase-like are enzymes expressed intracellularly (in chondrocytes' cytoplasm) involved in elastin biosynthesis and collagen cross-linking in cartilage extracellular matrix. EMA and FDA have not yet approved any drug targeting the LOX proteins. In particular, today lysyl oxidase-like 2 is considered as a new promising target for OA modifying therapy. This review clarifies the main roles of different LOX proteins involved in the progression of OA. Potential LOX inhibitoion strategies for drug development in advanced OA therapy, particularly for local intraarticular delivery, were listed and discussed for each target type. This review, therefore, proposes promising strategies for future drug development in OA treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107627"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059320","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 protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models","authors":"Ling Xiong ,&nbsp;Dustin Beyer ,&nbsp;Na Liu ,&nbsp;Tina Lehmann ,&nbsp;Sophie Neugebauer ,&nbsp;Sascha Schaeuble ,&nbsp;Oliver Sommerfeld ,&nbsp;Philipp Ernst ,&nbsp;Carl-Magnus Svensson ,&nbsp;Sandor Nietzsche ,&nbsp;Sebastian Scholl ,&nbsp;Tony Bruns ,&nbsp;Nikolaus Gaßler ,&nbsp;Markus H. Gräler ,&nbsp;Marc Thilo Figge ,&nbsp;Gianni Panagiotou ,&nbsp;Michael Bauer ,&nbsp;Adrian T. Press","doi":"10.1016/j.phrs.2025.107581","DOIUrl":"10.1016/j.phrs.2025.107581","url":null,"abstract":"<div><div>Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host’s response or ability to clear the pathogen, highlighting PKCα’s vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107581"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034014","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}