Pharmacological research最新文献

{"title":"Identification of the TRPA1 cannabinoid-binding site","authors":"Tala Amawi ,&nbsp;Alaa Nmarneh ,&nbsp;Gilad Noy ,&nbsp;Mariana Ghantous ,&nbsp;Masha Y. Niv ,&nbsp;Antonella Di Pizio ,&nbsp;Avi Priel","doi":"10.1016/j.phrs.2024.107444","DOIUrl":"10.1016/j.phrs.2024.107444","url":null,"abstract":"<div><div>Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood. The principal phytocannabinoids, the psychoactive Δ⁹-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors. Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies. Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations. Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107444"},"PeriodicalIF":9.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378169","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":"Harnessing natural inhibitors of protein synthesis for cancer therapy: A comprehensive review","authors":"Liqin Liu,&nbsp;Zhihui Li,&nbsp;Wenshuang Wu","doi":"10.1016/j.phrs.2024.107449","DOIUrl":"10.1016/j.phrs.2024.107449","url":null,"abstract":"<div><div>Cancer treatment remains a formidable challenge in modern medicine, necessitating a nuanced understanding of its molecular underpinnings and the identification of novel therapeutic modalities. Among the intricate web of cellular pathways implicated in oncogenesis, protein synthesis has emerged as a fundamental process warranting meticulous investigation. This review elucidates the multifaceted role of protein synthesis pathways in tumor initiation and progression, highlighting the potential of targeting key nodes within these pathways as viable therapeutic strategies. Natural products have long served as a source of bioactive compounds with therapeutic potential owing to their structural diversity and evolutionary honing. Within this framework, we provide a thorough examination of natural inhibitors of protein synthesis as promising candidates for cancer therapy, drawing upon recent advancements and mechanistic insights. By synthesizing current evidence and elucidating key challenges and opportunities, this review aims to galvanize further research into the development of natural product-based anticancer therapeutics, thereby advancing the clinical armamentarium against malignancies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107449"},"PeriodicalIF":9.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378168","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":"β-asarone protects against age-related motor decline via activation of SKN-1/Nrf2 and subsequent induction of GST-4","authors":"Ming Lei ,&nbsp;Jiayu Wu ,&nbsp;Yanheng Tan ,&nbsp;Yang Shi ,&nbsp;Wuyan Yang ,&nbsp;Haijun Tu ,&nbsp;Weihong Tan","doi":"10.1016/j.phrs.2024.107450","DOIUrl":"10.1016/j.phrs.2024.107450","url":null,"abstract":"<div><div>Decelerating motor decline is important for promoting healthy aging in the elderly population. <em>Acorus tatarinowii</em> Schott is a traditional Chinese medicine that contains β-asarone as a pharmacologically active constituent. We found that β-asarone can decelerate motor decline in various age groups of <em>Caenorhabditis elegans</em>, while concurrently prolonging their lifespan and modulating synaptic transmission. To understand the mechanisms of its efficacy in motor improvement, we investigated and discovered that mitochondrial fragmentation, a marker for aging, is delayed after β-asarone treatment. Moreover, their efficacy is blocked by dysfunctional mitochondria. Corresponding to their role in regulating mitochondrial homeostasis, we found that SKN-1/Nrf2 and GST-4 are critical in the β-asarone treatment, and they appear to be activated via the insulin/IGF-1 signaling pathway. Well-developed intestinal microvilli are required for this process. Our study demonstrates the efficacy and mechanism of β-asarone treatment in age-related motor decline, contributing to the discovery of drugs for achieving healthy aging.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107450"},"PeriodicalIF":9.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375738","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":"Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin","authors":"Alexander P. Young,&nbsp;Eileen M. Denovan-Wright","doi":"10.1016/j.phrs.2024.107443","DOIUrl":"10.1016/j.phrs.2024.107443","url":null,"abstract":"<div><div>Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington’s disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. ST<em>Hdh</em>^Q7/Q7 and ST<em>Hdh</em>^Q111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that ST<em>Hdh</em>^Q111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was required to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107443"},"PeriodicalIF":9.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372499","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":"Influence of statin potency and liposolubility on Alzheimer’s disease patients: A population-based study","authors":"Mar García-Zamora ,&nbsp;Gemma García–Lluch ,&nbsp;Lucrecia Moreno ,&nbsp;Juan Pardo ,&nbsp;Consuelo Cháfer – Pericás","doi":"10.1016/j.phrs.2024.107446","DOIUrl":"10.1016/j.phrs.2024.107446","url":null,"abstract":"<div><div>Although Alzheimer’s disease (AD) cause is still unknown, there are several known risk factors, such as dyslipidemia. Statins are the most prescribed lipid-modifying therapies. Recent research has suggested a relationship between statins and AD, nevertheless, their ability to prevent AD is still unclear. Therefore, this cross-sectional study aimed to examine the relationship between statin use and anti-AD drug prescription. For that purpose, a database containing information on medications prescribed to patients aged 50 years or older (n = 233183) between 2018 and 2020 was used. Defined daily doses (DDDs) were calculated according to the ATC/DDD index 2023. Statistical analyses, with logistic regression and cumulative incidence, were carried out to assess statins and anti-AD drug consumption. As a result, a total of 47852 patients aged more than 70 years who were prescribed at least one antihypertensive, antidiabetic or lipid-modifying agent were included in the study. Of these, 45345 patients were classified within the cardiovascular risk group and 2483 were classified as patients with only hyperlipidemia. Patients using low-potency or hydrophilic statins had lower odds of anti-AD usage when compared to high-potency or lipophilic statins, respectively. Similarly, rosuvastatin and pitavastatin had lower odds of anti-AD medication intake when compared to atorvastatin. Finally, pitavastatin DDDs were prone to lower the odds of anti-AD medication usage when compared to rosuvastatin. In conclusion, a potential association between statins and the intake of AD medication has been observed. Specifically, low-potency (pitavastatin) and hydrophilic (rosuvastatin) statins were associated with less use of anti-AD medication.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107446"},"PeriodicalIF":9.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372498","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":"Revisiting the nature and pharmacodynamics of tacrolimus metabolites","authors":"Rudy Mevizou ,&nbsp;Hassan Aouad ,&nbsp;François-Ludovic Sauvage ,&nbsp;Hélène Arnion ,&nbsp;Emilie Pinault ,&nbsp;Jean-Sébastien Bernard ,&nbsp;Gildas Bertho ,&nbsp;Nicolas Giraud ,&nbsp;Rodolphe Alves de Sousa ,&nbsp;Adolfo Lopez-Noriega ,&nbsp;Florent Di Meo ,&nbsp;Mélanie Campana ,&nbsp;Pierre Marquet","doi":"10.1016/j.phrs.2024.107438","DOIUrl":"10.1016/j.phrs.2024.107438","url":null,"abstract":"<div><div>The toxicity of tacrolimus metabolites and their potential pharmacodynamic (PD) interactions with tacrolimus might respectively explain the surprising combination of higher toxicity and lower efficacy of tacrolimus despite normal blood concentrations, described in extensive metabolizers. To evaluate such interactions, we produced tacrolimus metabolites <em>in vitro</em> and characterized them by high resolution mass spectrometry (HRMS, for all) and nuclear magnetic resonance (NMR, for the most abundant, M-I). We quantified tacrolimus metabolites and checked their structure in patient whole blood and peripheral blood mononuclear cells (PBMC). We explored the interactions of M-I with tacrolimus <em>in silico</em>, <em>in vitro</em> and <em>ex vivo</em>. <em>In vitro</em> metabolization produced isoforms of tacrolimus and of its metabolites M-I and M-III, whose HRMS fragmentation suggested an open-ring structure. M-I and M-III open-ring isomers were also observed in patient blood. By contrast, NMR could not detect these open-ring forms. Transplant patients expressing CYP3A5 exhibited higher M-I/TAC ratios in blood and PBMC than non-expressers. Molecular Dynamics simulations showed that: all possible tacrolimus metabolites and isomers bind FKPB12; and the hypothetical open-ring structures induce looser binding between FKBP12 and calcineurins, leading to lower CN inhibition. <em>In vitro</em>, tacrolimus bound FKPB12 with more affinity than purified M-I, and the pool of tacrolimus metabolites and purified M-I had only weak inhibitory activity on IL2 secretion and not at all on NFAT nuclear translocation. M-I showed no competitive effect with tacrolimus on either test. Finally, M-I or the metabolite pool did not significantly interact with tacrolimus MLR suppression, thus eliminating a pharmacodynamic interaction.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107438"},"PeriodicalIF":9.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356862","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":"Type 2 diabetes mellitus and neurodegenerative disorders: The mitochondrial connection","authors":"Isabella R. Baduini ,&nbsp;Jose E. Castro Vildosola ,&nbsp;Sheida Kavehmoghaddam ,&nbsp;Fatmanur Kiliç ,&nbsp;S. Aiman Nadeem ,&nbsp;Juan J. Nizama ,&nbsp;Marietta A. Rowand ,&nbsp;Dileep Annapureddy ,&nbsp;Chris-Ann Bryan ,&nbsp;Lisa H. Do ,&nbsp;Samuel Hsiao ,&nbsp;Sai A. Jonnalagadda ,&nbsp;Akhila Kasturi ,&nbsp;Nikhila Mandava ,&nbsp;Sachin Muppavaram ,&nbsp;Bryan Ramirez ,&nbsp;Aleece Siner ,&nbsp;Christina N. Suoto ,&nbsp;Nasira Tamajal ,&nbsp;Ernest R. Scoma ,&nbsp;Maria E. Solesio","doi":"10.1016/j.phrs.2024.107439","DOIUrl":"10.1016/j.phrs.2024.107439","url":null,"abstract":"<div><div>The incidence of type 2 diabetes mellitus (T2DM) has increased in our society in recent decades as the population ages, and this trend is not expected to revert. This is the same for the incidence of the main neurodegenerative disorders, including the two most common ones, which are, Alzheimer’s and Parkinson’s disease. Currently, no pharmacological therapies have been developed to revert or cure any of these pathologies. Interestingly, in recent years, an increased number of studies have shown a high co-morbidity between T2DM and neurodegeneration, as well as some common molecular pathways that are affected in both types of diseases. For example, while the etiopathology of T2DM and neurodegenerative disorders is highly complex, mitochondrial dysfunction has been broadly described in the early steps of both diseases; accordingly, this dysfunction has emerged as a plausible molecular link between them. In fact, the prominent role played by mitochondria in the mammalian metabolism of glucose places the physiology of the organelle in a central position to regulate many cellular processes that are affected in both T2DM and neurodegenerative disorders. In this collaborative review, we critically describe the relationship between T2DM and neurodegeneration; making a special emphasis on the mitochondrial mechanisms that could link these diseases. A better understanding of the role of mitochondria on the etiopathology of T2DM and neurodegeneration could pave the way for the development of new pharmacological therapies focused on the regulation of the physiology of the organelle. These therapies could, ultimately, contribute to increase healthspan.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107439"},"PeriodicalIF":9.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366170","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":"Commentary on “Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke”","authors":"Raja Kannan","doi":"10.1016/j.phrs.2024.107440","DOIUrl":"10.1016/j.phrs.2024.107440","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107440"},"PeriodicalIF":9.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366161","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":"Deciphering the multifaceted roles and clinical implications of 2-hydroxyglutarate in cancer","authors":"Jie Hao ,&nbsp;Ziyi Huang ,&nbsp;Siyue Zhang ,&nbsp;Kefan Song ,&nbsp;Juncheng Wang ,&nbsp;Chao Gao ,&nbsp;Zhiqing Fang ,&nbsp;Ning Zhang","doi":"10.1016/j.phrs.2024.107437","DOIUrl":"10.1016/j.phrs.2024.107437","url":null,"abstract":"<div><div>Increasing evidence indicates that 2-hydroxyglutarate (2HG) is an oncometabolite that drives tumour formation and progression. Due to mutations in isocitrate dehydrogenase (IDH) and the dysregulation of other enzymes, 2HG accumulates significantly in tumour cells. Due to its structural similarity to α-ketoglutarate (αKG), accumulated 2HG leads to the competitive inhibition of αKG-dependent dioxygenases (αKGDs), such as KDMs, TETs, and EGLNs. This inhibition results in epigenetic alterations in both tumour cells and the tumour microenvironment. This review comprehensively discusses the metabolic pathways of 2HG and the subsequent pathways influenced by elevated 2HG levels. We will delve into the molecular mechanisms by which 2HG exerts its oncogenic effects, particularly focusing on epigenetic modifications. This review will also explore the various methods available for the detection of 2HG, emphasising both current techniques and emerging technologies. Furthermore, 2HG shows promise as a biomarker for clinical diagnosis and treatment. By integrating these perspectives, this review aims to provide a comprehensive overview of the current understanding of 2HG in cancer biology, highlight the importance of ongoing research, and discuss future directions for translating these findings into clinical applications.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107437"},"PeriodicalIF":9.1,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351732","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":"Tissue Kallikrein supplementation in ischemic phase protects the neurovascular unit and attenuates reperfusion-induced injury in ischemic stroke","authors":"Xiao Ran ,&nbsp;Tingting Xu ,&nbsp;Hang Ruan ,&nbsp;Xiaochuan Wang ,&nbsp;Qin Zhang","doi":"10.1016/j.phrs.2024.107435","DOIUrl":"10.1016/j.phrs.2024.107435","url":null,"abstract":"<div><div>Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107435"},"PeriodicalIF":9.1,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351744","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}