Pharmacological research最新文献

{"title":"Mitochondrial insights on antidiabetic therapies: Differential impacts of SGLT2i, GLP-1, and insulin","authors":"Yu-Hsiang Lin, Kuo-Hsuan Chang, 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}

{"title":"The roles of cannabis potency and gender in cannabis dependence and anxiety in recent cannabis users with trauma exposure histories","authors":"T. Snooks ,&nbsp;S.H. Stewart ,&nbsp;P. Romero-Sanchiz ,&nbsp;S. DeGrace ,&nbsp;S.P. Barrett ,&nbsp;H.C.R. Bernusky ,&nbsp;P.G. Tibbo","doi":"10.1016/j.phrs.2025.107586","DOIUrl":"10.1016/j.phrs.2025.107586","url":null,"abstract":"<div><div>Over the past 20 years, levels of Δ9-tetrahydrocannabinol (THC) in cannabis have significantly increased, while levels of cannabidiol (CBD) have increased much less in comparison. Cannabis with higher THC potency (commonly assessed via THC:CBD ratio) may increase the risk for cannabis dependence and trigger/exacerbate anxiety. However, few studies of cannabis potency effects on cannabis dependence and anxiety have examined gender moderation. Additionally, there are issues with how cannabis potency is calculated via the THC:CBD ratio that may contribute to inconsistencies in the literature. N = 202 (55.8 % women) recent cannabis users (<u>&gt;</u>1 g in the past month) with trauma histories – a group at high risk for anxiety and cannabis dependence – completed an online survey including a self-report measure of THC and CBD levels in participants’ typically-used cannabis product. Cannabis potency was calculated as THC:CBD ratio (THC%/CBD%) and as relative THC proportion (THC%/[THC%+CBD%]). Cannabis dependence and anxiety levels were self-reported on the Cannabis Use Disorder Identification Test-Revised (CUDIT-R) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Consistent with prior findings in the general population, cannabis potency was significantly positively correlated with cannabis dependence, <em>p</em> = .002, and anxiety levels, <em>p</em> = .020, but only when assessed via THC proportion and not THC:CBD ratio. Consistent with prior research, women reported significantly higher anxiety levels but also unexpectedly, higher THC:CBD ratios, than men. No significant gender differences were found in the associations of either potency measure with either outcome variable. Results are consistent with recent reports of gender convergence in cannabis use prevalence. Additionally, these results identify relative THC proportion as a superior predictor of adverse cannabis and anxiety outcomes than the THC:CBD ratio in both men and women.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107586"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009578","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":"Phenolic acids from Anisopus mannii modulates phosphofructokinase 1 to improve glycemic control in patients with type 2 diabetes: A double-blind, randomized, clinical trial","authors":"Peter U. Amadi ,&nbsp;Justice O. Osuoha ,&nbsp;Chidi N. Ekweogu ,&nbsp;Suha J. Jarad ,&nbsp;Esienanwan E. Efiong ,&nbsp;Prince C. Odika ,&nbsp;Chioma Ejiofor ,&nbsp;Oluchi Aloy-Amadi ,&nbsp;Govind S. Gill ,&nbsp;Chiamaka W. Adumekwe ,&nbsp;Ailun Gaowa ,&nbsp;Dawei Zhang ,&nbsp;Barbora de Courten ,&nbsp;Emmanuel N. Agomuo","doi":"10.1016/j.phrs.2025.107602","DOIUrl":"10.1016/j.phrs.2025.107602","url":null,"abstract":"<div><div>Phenolic acid-rich fraction from <em>Anisopus mannii</em> (PhAM) contains abundance of ferulic acid, gallic acid, protocatechuic acid, and syringic acid. Among other glycolytic enzymes, in vitro, PhAM counteracted the binding of sodium orthovanadate to phosphofructokinase 1 (PFK-1), improving its activities. In a rat model of diet-induced diabetes, PhAM monotherapy reduced HbA1c by an average of 0.63 % and fasting plasma glucose by 25 mg/dl. This herb rescued β-cells from streptozotocin-mediated destruction, thereby improving glycemic control. Supported by the preclinical trial, eighty-five patients with type 2 diabetes (T2D) receiving first-line medications were enrolled in a double-blind, randomized, placebo-controlled trial with a 90 % power level. Patients were randomized into a placebo group or either of the following two treatment groups: oral administration of 12 mg or 20 mg/kg body weight of PhAM once every 48 h for 6 months. Both treatments were well tolerated. At the endpoint, more than 70 % of patients achieved a 0.5 – 2.0 decrease in HbA1c levels and a &gt; 20 mg/dl decrease in fasting blood glucose, meeting the pre-specified primary outcome. 66 % of patients treated with 20 mg PhAM achieved the &lt; 7 % HbA1c and HOMA-IR of &gt; 1.0 goal. respectively. Our study shows that PhAM can supplement first-line medications to achieve target glycemic control within 6 months.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107602"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009612","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":"A systematic review of Aspilia africana (Pers.) C.D. adams traditional medicinal uses, phytoconstituents, bioactivities, and toxicities","authors":"Roggers Gang ,&nbsp;Denis Okello ,&nbsp;Yeongjun Ban ,&nbsp;Youngmin Kang","doi":"10.1016/j.phrs.2025.107590","DOIUrl":"10.1016/j.phrs.2025.107590","url":null,"abstract":"<div><div><em>Aspilia africana</em> (Pers.) C. D. Adams, popularly referred to as wild sunflower, has been used for generations across several African communities to treat various diseases, including malaria, wounds, osteoporosis, diabetes mellitus, gastric ulcers, measles, tuberculosis, stomach ache, rheumatic pains, and gonorrhea. This study aimed to systematically and critically compile data on the traditional medicinal uses, phytochemistry, bioactivities, botanical descriptions, and toxicities of <em>A. africana.</em> Relevant research findings were retrieved and organized from various databases, including PubMed and ScienceDirect, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. To date, 149 phytochemicals have been identified from various <em>A. africana</em> parts and they primarily belong to the classes of terpenoids, lipids, hydrocarbons, phenolics, and esters. The extracts and bioactive phytochemicals of <em>A. africana</em> have revealed several pharmacological properties, including antimalarial, anticancer, wound healing, anti-inflammatory, antidiabetic, and antimicrobial activities. However, the major components responsible for these bioactivities and their mechanisms of action in some diseases have not yet been clearly identified. Additionally, toxicity and clinical trial data for <em>A. africana</em> are limited with most toxicological assessments being acute in nature. Therefore, further research on the mechanisms of action of the pure bioactive phytochemicals and toxicity of <em>A. africana</em> are necessary to better understand its efficacy and safety. Taken together, this study provides comprehensive information on the traditional medicinal uses, phytochemistry, bioactivities, and toxicity of <em>A. africana</em>, and a reference for future studies, relevant to the development of therapeutic products.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107590"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952931","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 and epigenetic regulation of macrophage polarization in atherosclerosis: Molecular mechanisms and targeted therapies","authors":"Pinglian Yang ,&nbsp;Xiaoling Rong ,&nbsp;Zhechang Gao ,&nbsp;Jiaojiao Wang ,&nbsp;Zhiping Liu","doi":"10.1016/j.phrs.2025.107588","DOIUrl":"10.1016/j.phrs.2025.107588","url":null,"abstract":"<div><div>Atherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding RNA, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107588"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952939","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":"Erratum to the ‘Long non-coding RNAs-sphingolipid metabolism nexus: Potential targets for cancer treatment’ Pharmacol. Res. 210 (December) (2024) 107539","authors":"Yan Chen ,&nbsp;Jing Dai ,&nbsp;Peng Chen ,&nbsp;Quan Dai ,&nbsp;Ya Chen ,&nbsp;Yuying Li ,&nbsp;Man Lu ,&nbsp;Shugang Qin ,&nbsp;Qiuju Wang","doi":"10.1016/j.phrs.2025.107629","DOIUrl":"10.1016/j.phrs.2025.107629","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107629"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059309","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}