Pharmacological research最新文献

{"title":"CB1 cannabinoid receptor agonists induce acute respiratory depression in awake mice","authors":"Joshua Watkins ,&nbsp;Petra Aradi ,&nbsp;Rachel Hahn ,&nbsp;Alexandros Makriyannis ,&nbsp;Ken Mackie ,&nbsp;Istvan Katona ,&nbsp;Andrea G. Hohmann","doi":"10.1016/j.phrs.2025.107682","DOIUrl":"10.1016/j.phrs.2025.107682","url":null,"abstract":"<div><div>Recreational use of synthetic cannabinoid agonists (i.e., “spice compounds”) that target the cannabinoid type 1 receptor (CB₁) can cause acute respiratory failure in humans. However, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with the brain respiratory system, based largely upon sparse labeling of CB₁ receptors in the medulla and relative safety suggested by widespread human use. Here we used whole body plethysmography and RNAscope <em>in situ</em> hybridization in mice to reconcile this conflict between conventional wisdom and human data. We examined the respiratory effects of the synthetic CB₁ full agonist CP55,940 and Δ⁹-THC in male and female mice. CP55,940 and Δ⁹-THC potently and dose-dependently suppressed minute ventilation and tidal volume, decreasing measures of respiratory effort (i.e., peak inspiratory and expiratory flow). Both cannabinoids reduced respiratory frequency, decreasing inspiratory and expiratory time while markedly increasing inspiratory and expiratory pause. Respiratory suppressive effects were fully blocked by the CB₁ antagonist AM251, were minimally impacted by the peripherally-restricted CB₁ antagonist AM6545, and occurred at doses lower than those that produce cardinal behavioral signs of CB₁ activation. Using RNAscope <em>in situ</em> hybridization, we also demonstrated extensive coexpression of <em>Cnr1</em> (encoding the CB₁ receptor) and <em>Oprm1</em> (encoding the µ-opioid receptor) mRNA in respiratory cells in the medullary pre-Bötzinger complex, a critical nucleus of respiratory control. Our results show that mRNA for CB₁ is present in respiratory cells in a medullary brain region essential for breathing and demonstrate that cannabinoids produce respiratory suppression via activation of central CB₁ receptors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107682"},"PeriodicalIF":9.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597530","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":"FOXO6: A unique transcription factor in disease regulation and therapeutic potential","authors":"Songzhe Li ,&nbsp;Ting Ye ,&nbsp;Zhitao Hou ,&nbsp;Yuqing Wang ,&nbsp;Zhihua Hao ,&nbsp;Jing Chen","doi":"10.1016/j.phrs.2025.107691","DOIUrl":"10.1016/j.phrs.2025.107691","url":null,"abstract":"<div><div>FOXO6, a unique member of the Forkhead box O (FOXO) transcription factor family, has emerged as a pivotal regulator in various physiological and pathological processes, including apoptosis, oxidative stress, autophagy, cell cycle control, and inflammation. Unlike other FOXO proteins, FOXO6 exhibits distinct regulatory mechanisms, particularly its inability to undergo classical nucleocytoplasmic shuttling. These unique properties suggest that FOXO6 may function through alternative pathways, positioning it as a novel research target. This review provides the first comprehensive review of FOXO6's biological functions and its roles in the progression of multiple diseases, such as cancer, metabolic disorders, neurodegenerative conditions, and cardiovascular dysfunction. We highlight FOXO6's interaction with critical signaling pathways, including PI3K/Akt, PPARγ, and TXNIP, and discuss its contributions to tumor progression, glucose and lipid metabolism, oxidative stress, and neuronal degeneration. Moreover, FOXO6's potential as a therapeutic target is explored, with particular emphasis on its ability to modulate drug resistance and its implications for disease treatment. Despite its promising therapeutic potential, the development of FOXO6-targeted therapies remains challenging due to overlapping functions within the FOXO family and the context-dependent nature of FOXO6's regulatory roles. This review underscores the need for further experimental and clinical studies to elucidate the molecular mechanisms underlying FOXO6's functions and to validate its application in disease prevention and treatment. By systematically analyzing current research, this review aims to provide a foundational reference for future studies on FOXO6, paving the way for novel therapeutic strategies targeting this unique transcription factor.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107691"},"PeriodicalIF":9.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586618","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":"Gut microbiota-derived deoxycholic acid in colorectal cancer therapy: Critical considerations and an extended clinical investigation panorama analysis","authors":"Guomin Zhou,&nbsp;Yu Yang,&nbsp;Jun Leng,&nbsp;Jin Chen,&nbsp;Hangyu Zhou,&nbsp;Rui Ming,&nbsp;Huaiwu Jiang","doi":"10.1016/j.phrs.2025.107683","DOIUrl":"10.1016/j.phrs.2025.107683","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107683"},"PeriodicalIF":9.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577350","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":"Choline metabolism in ischemic stroke: An underappreciated \"two-edged sword\"","authors":"Mengchen Yu ,&nbsp;Guohao Liu ,&nbsp;Wenbo Chen ,&nbsp;Yanmei Qiu ,&nbsp;Nanlin You ,&nbsp;Sui Chen ,&nbsp;Zhaosheng Wei ,&nbsp;Longxin Ji ,&nbsp;Mengtao Han ,&nbsp;Zhen Qin ,&nbsp;Tao Sun ,&nbsp;Donghai Wang","doi":"10.1016/j.phrs.2025.107685","DOIUrl":"10.1016/j.phrs.2025.107685","url":null,"abstract":"<div><div>Ischemic stroke (IS) is an important cause of death and disability worldwide, but the molecular mechanisms involved are not fully understood. In this context, choline metabolism plays an increasingly important role in IS due to its multifaceted mechanisms involving neuroprotection, neuroregeneration, inflammatory response, immune regulation, and long-term health effects. With the deepening of the research on choline and its metabolites, such as trimethylamine-N-oxide (TMAO), scientists have gradually realized its key role in the occurrence, development and potential treatment of IS. This review summarizes the importance of choline in neuroprotection and long-term disease management, highlighting the complexity of choline metabolism affecting cerebrovascular health through gut microbes. Although choline and its metabolites exhibit a protective effect, excessive intake and increases in some metabolites may confer risk, suggesting the need to carefully balance dietary choline intake. The purpose of this review is to integrate the existing research results and provide a theoretical basis for further exploring the mechanism, prognosis evaluation and clinical intervention of choline metabolism in ischemic IS, hoping to provide a new perspective and enlightenment for the formulation of effective stroke prevention and treatment strategies, and promote a comprehensive understanding of heart and brain health and optimize intervention methods.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107685"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562065","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":"Leveraging HER2-targeted biparatopic antibodies in solid tumors","authors":"Xinlin Liu ,&nbsp;Xinyi Fan ,&nbsp;Xiang Gao ,&nbsp;Weiyu Hu ,&nbsp;Peng Sun","doi":"10.1016/j.phrs.2025.107687","DOIUrl":"10.1016/j.phrs.2025.107687","url":null,"abstract":"<div><div>Biparatopic antibodies (bpAbs), which target non-overlapping epitopes on the same antigen, offer unique mechanisms of action and therapeutic applications that surpass those of conventional monospecific antibodies. These distinctive properties have positioned bpAbs as effective therapeutic agents in the treatment of cancer and infectious diseases, especially in cases where current treatments face limitations. Among these, HER2-targeted bpAbs have shown significant improvements in survival outcomes for patients with solid tumors that depend on HER2 signaling. However, a comprehensive understanding of their clinical impact, mechanisms of action, and limitations in therapeutic use remains lacking. Here, we review and contrast the clinical performance of the well-established HER2-targeted bpAbs in current use, with a focus on their mechanisms of action, associated limitations, and potential combination strategies. We also highlight emerging investigational bpAbs-based agents that have shown promise in the treatment of HER2-positive solid cancers. These advancements may lead to enhanced therapeutic options and potentially broaden the scope of bpAbs in cancer therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107687"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586620","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":"Low LDL-cholesterol drives the risk of bleeding in patients treated with aspirin: A 15-year study in a real-world large population","authors":"Valentina Trimarco ,&nbsp;Raffaele Izzo ,&nbsp;Daniela Pacella ,&nbsp;Fahimeh Varzideh ,&nbsp;Maria Virginia Manzi ,&nbsp;Paola Gallo ,&nbsp;Giuseppe Giugliano ,&nbsp;Roberto Piccinocchi ,&nbsp;Giovanni Esposito ,&nbsp;Gaetano Piccinocchi ,&nbsp;Luca Bardi ,&nbsp;Carmine Morisco ,&nbsp;Francesco Rozza ,&nbsp;Maria Lembo ,&nbsp;Bruno Trimarco ,&nbsp;Gaetano Santulli","doi":"10.1016/j.phrs.2025.107688","DOIUrl":"10.1016/j.phrs.2025.107688","url":null,"abstract":"<div><div>We aimed to investigate the link between LDL cholesterol (LDL-C) levels and hemorrhage risk over an extended period, both in subjects taking aspirin and in individuals not receiving any antiplatelet agent. We calculated the predicted adjusted relative hazard of bleeding by LDL-C concentration for the whole cohort and the aspirin-treated subgroup. The study included 39,784 individuals with a mean follow-up of 14.9 years, totaling over 500,000 patient-years. Across the cohort, 3380 bleeding events were reported, with a higher incidence in patients with LDL-C &lt; 70 mg/dL compared to those with LDL-C ≥ 70 mg/dL (9.9 % vs 8.4 %). In aspirin-treated patients, multivariable analysis revealed that hemorrhagic events were significantly associated with aging, male sex, body mass index, hypertension, and LDL-C &lt; 70 mg/dL. These patients had a significantly lower event-free survival probability if their LDL-C was &lt; 70 mg/dL compared to ≥ 70 mg/dL. Low LDL-C values were a significant risk factor (HR &gt;1) while higher LDL-C values were protective (HR &lt;1). A stepwise increase of 10 mg/dL in LDL-C from &lt; 30 to ≥ 200 mg/dL was associated with a decreasing trend for bleeding events in both the entire cohort and the aspirin-treated subgroup. This is the first report specifically addressing the relationship between LDL-C levels and bleeding risk in a population receiving low-intensity antithrombotic therapy. Our data demonstrate that in patients taking aspirin, LDL-C levels below 70 mg/dL significantly increase the risk of bleeding, with major implications for long-term cardiovascular risk management.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107688"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586621","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":"Phytosterols and phytostanols in context: From physiology and pathophysiology to food supplementation and clinical practice","authors":"Massimiliano Ruscica ,&nbsp;Wann Jia Loh ,&nbsp;Cesare R. Sirtori ,&nbsp;Gerald F. Watts","doi":"10.1016/j.phrs.2025.107681","DOIUrl":"10.1016/j.phrs.2025.107681","url":null,"abstract":"<div><div>Phytosterols and phytostanols are two classes of sterol derivatives naturally synthesised in plants, but not in humans. Structurally, phytosterols and phytostanols have a sterane ring in common, but phytostanols do not have a double bond between carbons 5 and 6. The therapeutic potential of phytosterols and phytostanols supplementation in cholesterol reduction is the main reason for its wide usage in an expansive food matrix, including milk, yoghurt, margarine, mayonnaise, chocolate, tartare, chips, esterification with omega-3, and recently, as a successful nutraceutical among athletes is its fortification with whey protein. The heterogeneous effect of phytosterols and phytostanols in cholesterol lowering appears to be related to whether the individuals’ inherent physiologic tendencies to “hyper-synthesise” cholesterol in the liver or “hyperabsorb” cholesterol via the small intestine. Individuals who are ‘hypersynthesizers” of cholesterol tend to have a good reduction in plasma low-density lipoprotein cholesterol (LDLc) in response to statin therapy. Conversely, “hyper-absorbers” of cholesterol show a greater LDLc lowering in response to phytosterols or phytostanols. The ratios of cholestanol to cholesterol and lathosterol to cholesterol are good biomarkers of intestinal absorption of cholesterol and hepatic cholesterol synthesis. Animal data and human observational data suggest that phytosterols and phytostanols may have anti-atherosclerotic activities, e.g. reduction of the formation of nitric oxide, antagonism to the formation of LDL aggregates and plaque formation. The absence of cardiovascular outcome trials using phytosterol or phytostanol supplementation, makes it difficult to confirm a wider use in clinical practice, especially with the rapidly expanding list of effective and safe lipid-lowering medications.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107681"},"PeriodicalIF":9.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573639","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":"Antagonising Yin Yang 1 ameliorates the symptoms of lupus nephritis via modulating T lymphocyte signaling-correspondence","authors":"Szu-Yu Huang,&nbsp;An-An Ku,&nbsp;Wen-Chun Lo,&nbsp;Su-Boon Yong,&nbsp;Chin-Yuan Yii","doi":"10.1016/j.phrs.2025.107680","DOIUrl":"10.1016/j.phrs.2025.107680","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107680"},"PeriodicalIF":9.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571476","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 EVA1B in breast cancer: New avenues for precision oncology","authors":"Jui-Hu Hsiao,&nbsp;Chen-Yueh Wen,&nbsp;Su-Boon Yong,&nbsp;Chin-Yuan Yii,&nbsp;Chia-Jung Li","doi":"10.1016/j.phrs.2025.107684","DOIUrl":"10.1016/j.phrs.2025.107684","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107684"},"PeriodicalIF":9.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562066","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":"Toward an immunology-based classification of pain disorders?","authors":"A.H.C. Rosenström,&nbsp;M.F. Bjurström","doi":"10.1016/j.phrs.2025.107631","DOIUrl":"10.1016/j.phrs.2025.107631","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107631"},"PeriodicalIF":9.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067273","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}