Pharmacological research最新文献_第5页

A comprehensive review of the multifaceted role of cannabinoid receptor type 2 in neurodegenerative and neuropsychiatric disorders

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-18 DOI: 10.1016/j.phrs.2025.107657

María S. García-Gutiérrez , Abraham B. Torregrosa , Francisco Navarrete , Daniela Navarro , Jorge Manzanares

Research carried out during the last 30 years since the first identification of CB2r in 1993 has changed the landscape of this receptor's role and therapeutic utility. Initially, studies focused on elucidating the role of CB2r at the periphery since it was first characterized in spleen and lymphocytes. Later, CB2r was found in the brain not only under pathological conditions but also under basal conditions. It is now known that this receptor is expressed in different brain regions and different cell types, including neurons and microglia. Experimental studies have provided robust evidence that CB2r is involved in the modulation of the immune system, neuroinflammation, oxidative stress and neuroprotection. Besides, CB2r mediated the response to stress, anxiety, and depression. Also, CB2r plays a relevant role in modulating the reinforcing properties of different drugs of abuse, including alcohol, nicotine and cocaine. In this review, we summarize the cumulative knowledge regarding the immunomodulatory, anti-inflammatory, antioxidant, and neuroprotective properties of CB2r against the development of neurodegenerative diseases. Indeed, we cover the anxiolytic and antidepressant potential of CB2r, which raises the therapeutic interest of this receptor in different psychiatric diseases associated with anxiety and depression. Finally, we discuss the involvement of CB2r in the regulation of drug addiction. A better understanding of the properties of CB2r is essential for the pharmacological development of this receptor in different neurodegenerative, psychiatric, and addictive disorders.

{"title":"A comprehensive review of the multifaceted role of cannabinoid receptor type 2 in neurodegenerative and neuropsychiatric disorders","authors":"María S. García-Gutiérrez , Abraham B. Torregrosa , Francisco Navarrete , Daniela Navarro , Jorge Manzanares","doi":"10.1016/j.phrs.2025.107657","DOIUrl":"10.1016/j.phrs.2025.107657","url":null,"abstract":"<div><div>Research carried out during the last 30 years since the first identification of CB2r in 1993 has changed the landscape of this receptor's role and therapeutic utility. Initially, studies focused on elucidating the role of CB2r at the periphery since it was first characterized in spleen and lymphocytes. Later, CB2r was found in the brain not only under pathological conditions but also under basal conditions. It is now known that this receptor is expressed in different brain regions and different cell types, including neurons and microglia. Experimental studies have provided robust evidence that CB2r is involved in the modulation of the immune system, neuroinflammation, oxidative stress and neuroprotection. Besides, CB2r mediated the response to stress, anxiety, and depression. Also, CB2r plays a relevant role in modulating the reinforcing properties of different drugs of abuse, including alcohol, nicotine and cocaine. In this review, we summarize the cumulative knowledge regarding the immunomodulatory, anti-inflammatory, antioxidant, and neuroprotective properties of CB2r against the development of neurodegenerative diseases. Indeed, we cover the anxiolytic and antidepressant potential of CB2r, which raises the therapeutic interest of this receptor in different psychiatric diseases associated with anxiety and depression. Finally, we discuss the involvement of CB2r in the regulation of drug addiction. A better understanding of the properties of CB2r is essential for the pharmacological development of this receptor in different neurodegenerative, psychiatric, and addictive disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107657"},"PeriodicalIF":9.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453157","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}

引用次数: 0

Systematic druggable genome-wide Mendelian randomization to identify therapeutic targets and dominant flora for ulcerative colitis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-18 DOI: 10.1016/j.phrs.2025.107662

Haiya Ou , Hongshu Huang , Yiqi Xu , Haixiong Lin , Xiaotong Wang

The relationship and mechanism among gut microbiota (GM), metabolites and active ulcerative colitis (UC) are unclear. This study aims to infer the causal relationship between druggable-genes and active UC using Mendelian randomization (MR) and bioinformatics methods. The "microbiota-target" and "microbiota- metabolite" network was constructed to screen the microorganisms and metabolites associated with active UC, and the mechanism of GM, metabolites and active-UC was analyzed. These findings were verified through molecular docking, molecular dynamics (MD) simulations and co-localization analysis. Subsequently, the effects of key GM and targets on mice with UC induced by dextran sulfate sodium (DSS) was investigated. Our findings indicated that four drug targets (IFN-γ, IL24, CXCR6, PRKCZ) are closely associated with the risk of active UC, with IL24 specifically found to be colocalized with UC. These four targets were significantly correlated with differences of immune cell infiltration in active-UC. Faecalibacterium prausnitzii (F. prausnitzii) was predicted to inhibit IFN-γ and promote the remission of active UC. Additionally, seven GM were identified to be associated with the risk of active UC. Molecular docking and MD further confirmed the stable interactions between IFN-γ and metabolites of F. prausnitzii. We also verified the alleviating effect of F. prausnitzii on DSS-induced UC mice. The result indicated that F. prausnitzii can reduce inflammatory cell infiltration and goblet cell death in the colon, lower myeloperoxidase activity, and downregulate IFN-γ expression levels. This study revealed that GM can modify the immune microenvironment of active UC, providing new ideas for the prevention and treatment of UC.

{"title":"Systematic druggable genome-wide Mendelian randomization to identify therapeutic targets and dominant flora for ulcerative colitis","authors":"Haiya Ou , Hongshu Huang , Yiqi Xu , Haixiong Lin , Xiaotong Wang","doi":"10.1016/j.phrs.2025.107662","DOIUrl":"10.1016/j.phrs.2025.107662","url":null,"abstract":"<div><div>The relationship and mechanism among gut microbiota (GM), metabolites and active ulcerative colitis (UC) are unclear. This study aims to infer the causal relationship between druggable-genes and active UC using Mendelian randomization (MR) and bioinformatics methods. The \"microbiota-target\" and \"microbiota- metabolite\" network was constructed to screen the microorganisms and metabolites associated with active UC, and the mechanism of GM, metabolites and active-UC was analyzed. These findings were verified through molecular docking, molecular dynamics (MD) simulations and co-localization analysis. Subsequently, the effects of key GM and targets on mice with UC induced by dextran sulfate sodium (DSS) was investigated. Our findings indicated that four drug targets (IFN-γ, IL24, CXCR6, PRKCZ) are closely associated with the risk of active UC, with IL24 specifically found to be colocalized with UC. These four targets were significantly correlated with differences of immune cell infiltration in active-UC. <em>Faecalibacterium prausnitzii</em> (<em>F. prausnitzii</em>) was predicted to inhibit IFN-γ and promote the remission of active UC. Additionally, seven GM were identified to be associated with the risk of active UC. Molecular docking and MD further confirmed the stable interactions between IFN-γ and metabolites of <em>F. prausnitzii</em>. We also verified the alleviating effect of <em>F. prausnitzii</em> on DSS-induced UC mice. The result indicated that <em>F. prausnitzii</em> can reduce inflammatory cell infiltration and goblet cell death in the colon, lower myeloperoxidase activity, and downregulate IFN-γ expression levels. This study revealed that GM can modify the immune microenvironment of active UC, providing new ideas for the prevention and treatment of UC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107662"},"PeriodicalIF":9.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453160","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}

引用次数: 0

IUPHAR review: Eating disorders, gut microbiota dysbiosis and epigenetic aberrations

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-17 DOI: 10.1016/j.phrs.2025.107653

Shabnam Nohesara , Hamid Mostafavi Abdolmaleky , Giuseppe Pettinato , Ahmad Pirani , Sam Thiagalingam , Jin-Rong Zhou

Eating disorders (EDs) are a heterogeneous class of increasing mental disorders that are characterized by disturbances in eating behaviors, body weight regulation, and associated psychological dysfunctions. These disorders create physiological imbalances that alter the diversity and composition of the gut microbiota. While evidence suggests that EDs can arise from epigenetic aberrations, alterations in gut microbial communities may also contribute to the development and/or persistence of EDs through epigenetic mechanisms. Understanding the interplay among gut microbial communities, epigenetic processes, and the risk of EDs provides opportunities for designing preventive and/or therapeutic interventions through gut microbiome modulation. This review highlights how microbiome-based therapeutics and specific dietary interventions can contribute to improving various subtypes of EDs by modulating gut microbial communities and mitigating epigenetic aberrations. First, we briefly review the literature on links between epigenetic aberrations and the pathophysiology of EDs. Second, we examine the potential role of the gut microbiome in the pathogenesis of EDs through epigenetic mechanisms. Next, we explore the associations between EDs and other psychiatric disorders, and examine the potential roles of the microbiome in their pathogenesis. Finally, we present evidence supporting the potential of microbiome-based therapeutics and specific dietary interventions to improve EDs through epigenetic modifications.

{"title":"IUPHAR review: Eating disorders, gut microbiota dysbiosis and epigenetic aberrations","authors":"Shabnam Nohesara , Hamid Mostafavi Abdolmaleky , Giuseppe Pettinato , Ahmad Pirani , Sam Thiagalingam , Jin-Rong Zhou","doi":"10.1016/j.phrs.2025.107653","DOIUrl":"10.1016/j.phrs.2025.107653","url":null,"abstract":"<div><div>Eating disorders (EDs) are a heterogeneous class of increasing mental disorders that are characterized by disturbances in eating behaviors, body weight regulation, and associated psychological dysfunctions. These disorders create physiological imbalances that alter the diversity and composition of the gut microbiota. While evidence suggests that EDs can arise from epigenetic aberrations, alterations in gut microbial communities may also contribute to the development and/or persistence of EDs through epigenetic mechanisms. Understanding the interplay among gut microbial communities, epigenetic processes, and the risk of EDs provides opportunities for designing preventive and/or therapeutic interventions through gut microbiome modulation. This review highlights how microbiome-based therapeutics and specific dietary interventions can contribute to improving various subtypes of EDs by modulating gut microbial communities and mitigating epigenetic aberrations. First, we briefly review the literature on links between epigenetic aberrations and the pathophysiology of EDs. Second, we examine the potential role of the gut microbiome in the pathogenesis of EDs through epigenetic mechanisms. Next, we explore the associations between EDs and other psychiatric disorders, and examine the potential roles of the microbiome in their pathogenesis. Finally, we present evidence supporting the potential of microbiome-based therapeutics and specific dietary interventions to improve EDs through epigenetic modifications.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107653"},"PeriodicalIF":9.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458920","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}

引用次数: 0

An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT)

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-16 DOI: 10.1016/j.phrs.2025.107660

David Pauck , Daniel Picard , Mara Maue , Kübra Taban , Viktoria Marquardt , Lena Blümel , Jasmin Bartl , Nan Qin , Nadezhda Kubon , Dominik Schöndorf , Frauke-Dorothee Meyer , Johanna Theruvath , Siddhartha Mitra , Martin Hasselblatt , Michael C. Frühwald , Guido Reifenberger , Marc Remke

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the SMARCB1 or, less commonly, the SMARCA4 gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an in vitro high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated in vitro preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies.

{"title":"An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT)","authors":"David Pauck , Daniel Picard , Mara Maue , Kübra Taban , Viktoria Marquardt , Lena Blümel , Jasmin Bartl , Nan Qin , Nadezhda Kubon , Dominik Schöndorf , Frauke-Dorothee Meyer , Johanna Theruvath , Siddhartha Mitra , Martin Hasselblatt , Michael C. Frühwald , Guido Reifenberger , Marc Remke","doi":"10.1016/j.phrs.2025.107660","DOIUrl":"10.1016/j.phrs.2025.107660","url":null,"abstract":"<div><div>Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the <em>SMARCB1</em> or, less commonly, the <em>SMARCA4</em> gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an <em>in vitro</em> high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated <em>in vitro</em> preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our <em>in vitro</em> pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future <em>in vivo</em> and clinical evaluations of novel pharmacological strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107660"},"PeriodicalIF":9.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441609","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}

引用次数: 0

Lactobacillus vaginalis alleviates DSS induced colitis by regulating the gut microbiota and increasing the production of 3-indoleacrylic acid

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-16 DOI: 10.1016/j.phrs.2025.107663

Zhuoya Wang , Tian Liu , Li Liu , Jian Xie , Furui Tang , Yimin Pi , Yuchun Zhong , Zhidong He , Wenming Zhang , Cihua Zheng

Ulcerative colitis (UC) is a chronic inflammatory disorder, and its incidence is experiencing an upward trend worldwide. UC can result in gut microbiota dysbiosis, impaired intestinal epithelial barrier, and systemic inflammation, for all of which there is presently no definitive treatment available. Lactobacillus is known to regulate gut microbiota and related metabolites to intervene in the development of UC. The objective of this study was to explore the underlying mechanism through which a novel probiotic, Lactobacillus vaginalis, alleviates DSS-induced colitis. Specifically, L. vaginalis were found to ameliorate the DSS-induced UC phenotype, restore intestinal microbiota balance and intestinal barrier function, and elevate the levels of 3-indoleacrylic acid (IAA) in mouse feces. Furthermore, fecal microbiota transplantation and fecal filtrate transplantation provide additional evidence that L. vaginalis alleviate DSS-induced colitis through metabolic products. Additionally, IAA has been shown to alleviate DSS-induced colitis symptoms, decrease inflammatory responses, and enhance intestinal barrier function. Finally, our findings confirm that L. vaginal and metabolites possess the capability to regulate the immune microenvironment in mice with colitis. And the RNA-seq analysis suggests that L. vaginal may play a pivotal role in alleviating colitis by modulating the PPAR signaling pathway. In conclusion, our findings suggest that oral administration of L. vaginalis alleviates DSS induced colonic inflammation by increasing the levels of IAA. L. vaginalis, as an emerging probiotic, provides a potential therapeutic strategy for clinical UC.

{"title":"Lactobacillus vaginalis alleviates DSS induced colitis by regulating the gut microbiota and increasing the production of 3-indoleacrylic acid","authors":"Zhuoya Wang , Tian Liu , Li Liu , Jian Xie , Furui Tang , Yimin Pi , Yuchun Zhong , Zhidong He , Wenming Zhang , Cihua Zheng","doi":"10.1016/j.phrs.2025.107663","DOIUrl":"10.1016/j.phrs.2025.107663","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic inflammatory disorder, and its incidence is experiencing an upward trend worldwide. UC can result in gut microbiota dysbiosis, impaired intestinal epithelial barrier, and systemic inflammation, for all of which there is presently no definitive treatment available. <em>Lactobacillus</em> is known to regulate gut microbiota and related metabolites to intervene in the development of UC. The objective of this study was to explore the underlying mechanism through which a novel probiotic, <em>Lactobacillus vaginalis</em>, alleviates DSS-induced colitis. Specifically, <em>L. vaginalis</em> were found to ameliorate the DSS-induced UC phenotype, restore intestinal microbiota balance and intestinal barrier function, and elevate the levels of 3-indoleacrylic acid (IAA) in mouse feces. Furthermore, fecal microbiota transplantation and fecal filtrate transplantation provide additional evidence that <em>L. vaginalis</em> alleviate DSS-induced colitis through metabolic products. Additionally, IAA has been shown to alleviate DSS-induced colitis symptoms, decrease inflammatory responses, and enhance intestinal barrier function. Finally, our findings confirm that <em>L. vaginal</em> and metabolites possess the capability to regulate the immune microenvironment in mice with colitis. And the RNA-seq analysis suggests that <em>L. vaginal</em> may play a pivotal role in alleviating colitis by modulating the PPAR signaling pathway. In conclusion, our findings suggest that oral administration of <em>L. vaginalis</em> alleviates DSS induced colonic inflammation by increasing the levels of IAA. <em>L. vaginalis</em>, as an emerging probiotic, provides a potential therapeutic strategy for clinical UC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107663"},"PeriodicalIF":9.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441611","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}

引用次数: 0

Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-12 DOI: 10.1016/j.phrs.2025.107652

Silvia Pelucchi , Lorenzo Da Dalt , Giulia De Cesare , Ramona Stringhi , Laura D’Andrea , Filippo La Greca , Clara Cambria , Lina Vandermeulen , Elisa Zianni , Stefano Musardo , Silvia Roda , Fabrizia Bonacina , Sofia Nasini , Maria Giovanna Lupo , Nicola Ferri , Stefano Comai , Fabrizio Gardoni , Flavia Antonucci , Diego Scheggia , Monica Di Luca , Elena Marcello

PCSK9 promotes the degradation of the low-density lipoprotein receptors and its inhibition by monoclonal antibodies or gene silencing approaches results in the reduction of plasma cholesterol levels coupled to that of cardiovascular events. Notably, while the liver is the primary source of circulating PCSK9, this protein is also abundantly expressed in the brain. However, its specific functions in the brain remain poorly understood. Here, we demonstrate that neuron-specific PCSK9 knockout mice exhibit impaired cognitive function, driven by alterations in hippocampal synapse morphology and synaptic plasticity mechanisms, coupled to spatial memory deficits. Among PCSK9 targets, we identified ApoER2 as the primary mediator of PCSK9-dependent effects on synaptic function. In neuronal cultures, PCSK9 downregulation affects ApoER2 synaptic membrane localization and lipid droplets abundance. In conclusion, our results highlight the critical role of neuronal PCSK9 in modulating synaptic ApoER2 and reveal the detrimental effects of its deficiency on synaptic function and cognitive performance. Our results shed light on the complex biology of PCSK9, crucial for evaluating side effects of PCSK9 inhibition and for developing new therapies targeting PCSK9 for brain disorders.

{"title":"Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization","authors":"Silvia Pelucchi , Lorenzo Da Dalt , Giulia De Cesare , Ramona Stringhi , Laura D’Andrea , Filippo La Greca , Clara Cambria , Lina Vandermeulen , Elisa Zianni , Stefano Musardo , Silvia Roda , Fabrizia Bonacina , Sofia Nasini , Maria Giovanna Lupo , Nicola Ferri , Stefano Comai , Fabrizio Gardoni , Flavia Antonucci , Diego Scheggia , Monica Di Luca , Elena Marcello","doi":"10.1016/j.phrs.2025.107652","DOIUrl":"10.1016/j.phrs.2025.107652","url":null,"abstract":"<div><div>PCSK9 promotes the degradation of the low-density lipoprotein receptors and its inhibition by monoclonal antibodies or gene silencing approaches results in the reduction of plasma cholesterol levels coupled to that of cardiovascular events. Notably, while the liver is the primary source of circulating PCSK9, this protein is also abundantly expressed in the brain. However, its specific functions in the brain remain poorly understood. Here, we demonstrate that neuron-specific PCSK9 knockout mice exhibit impaired cognitive function, driven by alterations in hippocampal synapse morphology and synaptic plasticity mechanisms, coupled to spatial memory deficits. Among PCSK9 targets, we identified ApoER2 as the primary mediator of PCSK9-dependent effects on synaptic function. In neuronal cultures, PCSK9 downregulation affects ApoER2 synaptic membrane localization and lipid droplets abundance. In conclusion, our results highlight the critical role of neuronal PCSK9 in modulating synaptic ApoER2 and reveal the detrimental effects of its deficiency on synaptic function and cognitive performance. Our results shed light on the complex biology of PCSK9, crucial for evaluating side effects of PCSK9 inhibition and for developing new therapies targeting PCSK9 for brain disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107652"},"PeriodicalIF":9.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426049","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}

引用次数: 0

Quality and composition control of complex TCM preparations through a novel “Herbs-in vivo Compounds-Targets-Pathways” network methodology: The case of Lianhuaqingwen capsules

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-12 DOI: 10.1016/j.phrs.2025.107650

Simian Chen , Hui Qi , Chunyan Zhu , Yiheng Zhao , Bo Jiao , Yun Tan , Yuexin Yang , Tongxing Wang , Yunlong Hou , Binxin Dai , Dandan Zhang , Hairong Zhang , Junyu Zhang , Xiaojuan Jiang , Xiaodan Guo , Xiaoyu Qian , Caixia Yuan , Xue Bai , Jiayun Chen , Suping Wang , Caisheng Wu

Lianhuaqingwen (LHQW) capsules, a Chinese patent medicine composed of 13 herbal ingredients, are widely used for respiratory diseases. However, the complex composition of LHQW poses challenges in assessing its quality and consistency. In this study, a comprehensive network of LHQW was constructed by integrating Digital RNA with pertUrbation of Genes (DRUG)-seq, RNA sequencing, and pharmacodynamic data. This approach enables rapid and systematic screening of compounds in LHQW that exhibit high-exposure in vivo and significant activity potential, serving as potential quality control markers. Specifically, DRUG-seq was employed to evaluate gene expression alterations in peripheral blood mononuclear cells derived from healthy volunteers. Ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS) identified 505 compounds in LHQW-treated rats. Additionally, absorption, distribution, metabolism, and excretion (ADME) profiles were plotted for 27 primary components of LHQW. Furthermore, an HPLC-MS/MS method quantified 46 compounds from LHQW, with 15 of them identified as potential quality markers with high exposure levels. These markers exhibited significant inhibitory effects on lipopolysaccharide (LPS)-induced pneumonia in mice, with mechanisms predicted by RNA-seq and verified by RT-qPCR. In summary, this study successfully constructed an "Herbs- in vivo Compounds-targets-pathways" network, offering novel insights into the mechanisms of LHQW and establishing a foundation for enhancing quality control measures.

{"title":"Quality and composition control of complex TCM preparations through a novel “Herbs-in vivo Compounds-Targets-Pathways” network methodology: The case of Lianhuaqingwen capsules","authors":"Simian Chen , Hui Qi , Chunyan Zhu , Yiheng Zhao , Bo Jiao , Yun Tan , Yuexin Yang , Tongxing Wang , Yunlong Hou , Binxin Dai , Dandan Zhang , Hairong Zhang , Junyu Zhang , Xiaojuan Jiang , Xiaodan Guo , Xiaoyu Qian , Caixia Yuan , Xue Bai , Jiayun Chen , Suping Wang , Caisheng Wu","doi":"10.1016/j.phrs.2025.107650","DOIUrl":"10.1016/j.phrs.2025.107650","url":null,"abstract":"<div><div>Lianhuaqingwen (LHQW) capsules, a Chinese patent medicine composed of 13 herbal ingredients, are widely used for respiratory diseases. However, the complex composition of LHQW poses challenges in assessing its quality and consistency. In this study, a comprehensive network of LHQW was constructed by integrating Digital RNA with pertUrbation of Genes (DRUG)-seq, RNA sequencing, and pharmacodynamic data. This approach enables rapid and systematic screening of compounds in LHQW that exhibit high-exposure <em>in vivo</em> and significant activity potential, serving as potential quality control markers. Specifically, DRUG-seq was employed to evaluate gene expression alterations in peripheral blood mononuclear cells derived from healthy volunteers. Ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS) identified 505 compounds in LHQW-treated rats. Additionally, absorption, distribution, metabolism, and excretion (ADME) profiles were plotted for 27 primary components of LHQW. Furthermore, an HPLC-MS/MS method quantified 46 compounds from LHQW, with 15 of them identified as potential quality markers with high exposure levels. These markers exhibited significant inhibitory effects on lipopolysaccharide (LPS)-induced pneumonia in mice, with mechanisms predicted by RNA-seq and verified by RT-qPCR. In summary, this study successfully constructed an \"Herbs- <em>in vivo</em> Compounds-targets-pathways\" network, offering novel insights into the mechanisms of LHQW and establishing a foundation for enhancing quality control measures.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107650"},"PeriodicalIF":9.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414770","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}

引用次数: 0

Gut microbiome-derived indole-3-carboxaldehyde regulates stress vulnerability in chronic restraint stress by activating aryl hydrocarbon receptors

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-12 DOI: 10.1016/j.phrs.2025.107654

Congcong Chen , Qiang Xiao , Zhaoyi Wen , Fenfang Gong , Huang Zhan , Jian Liu , Hui Li , Yukun Jiao

Chronic stress constitutes a major precipitating factor for Major Depressive Disorder (MDD), and comprehending individual differences in stress responses is crucial for the development of effective intervention strategies for MDD. Recent studies indicate that an individual's vulnerability to chronic stress is closely associated with gut microbiota composition, but the underlying mechanisms remain unclear. This study aims to investigate whether the gut microbiota and its metabolites can serve as gut-brain signaling molecules and explores how the gut microbiota affects stress sensitivity. Here, we showed that gut microbiome-derived indole-3-carboxaldehyde (I3C) can act as a gut-brain signaling molecule that links tryptophan metabolism by gut microbes to stress vulnerability in the host. First, we identified a specific reduction in gut microbiome-derived I3C levels in the hippocampus and colon through untargeted and targeted metabolomic analyses. Then, the study of gut microbiota suggested that the relative abundance of lactobacillus was reduced significantly in stress-susceptible rats, whereas fecal microbiota transplantation regulates stress vulnerability. Furthermore, supplementation with I3C and the representative I3C-producing strain, Lactobacillus reuteri, was shown to alleviate depression-like behaviors induced by chronic stress. Further research confirms that I3C can inhibit neuroinflammation and promote hippocampal neurogenesis through the aryl hydrocarbon receptors (AhR) signal pathway, thereby mitigating the host's susceptibility to stress. In conclusion, our findings elucidate that the gut microbiome-derived-I3C can help buffer the host's stress through the AhR/SOCS2/NF-κB/NLRP3 pathway, providing a gut-brain signaling basis for emotional behavior.

{"title":"Gut microbiome-derived indole-3-carboxaldehyde regulates stress vulnerability in chronic restraint stress by activating aryl hydrocarbon receptors","authors":"Congcong Chen , Qiang Xiao , Zhaoyi Wen , Fenfang Gong , Huang Zhan , Jian Liu , Hui Li , Yukun Jiao","doi":"10.1016/j.phrs.2025.107654","DOIUrl":"10.1016/j.phrs.2025.107654","url":null,"abstract":"<div><div>Chronic stress constitutes a major precipitating factor for Major Depressive Disorder (MDD), and comprehending individual differences in stress responses is crucial for the development of effective intervention strategies for MDD. Recent studies indicate that an individual's vulnerability to chronic stress is closely associated with gut microbiota composition, but the underlying mechanisms remain unclear. This study aims to investigate whether the gut microbiota and its metabolites can serve as gut-brain signaling molecules and explores how the gut microbiota affects stress sensitivity. Here, we showed that gut microbiome-derived indole-3-carboxaldehyde (I3C) can act as a gut-brain signaling molecule that links tryptophan metabolism by gut microbes to stress vulnerability in the host. First, we identified a specific reduction in gut microbiome-derived I3C levels in the hippocampus and colon through untargeted and targeted metabolomic analyses. Then, the study of gut microbiota suggested that the relative abundance of <em>lactobacillus</em> was reduced significantly in stress-susceptible rats, whereas fecal microbiota transplantation regulates stress vulnerability. Furthermore, supplementation with I3C and the representative I3C-producing strain, <em>Lactobacillus reuteri</em>, was shown to alleviate depression-like behaviors induced by chronic stress. Further research confirms that I3C can inhibit neuroinflammation and promote hippocampal neurogenesis through the aryl hydrocarbon receptors (AhR) signal pathway, thereby mitigating the host's susceptibility to stress. In conclusion, our findings elucidate that the gut microbiome-derived-I3C can help buffer the host's stress through the AhR/SOCS2/NF-κB/NLRP3 pathway, providing a gut-brain signaling basis for emotional behavior.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107654"},"PeriodicalIF":9.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394383","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}

引用次数: 0

The role of HIF-1α in hypoxic metabolic reprogramming in osteoarthritis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-11 DOI: 10.1016/j.phrs.2025.107649

Jie Zhang , Peng Gao , Wei-Rong Chang , Jia-Yi Song , Fang-Yu An , Yu-Jie Wang , Zhi-Pan Xiao , Hua Jin , Xu-Hui Zhang , Chun-Lu Yan

The joint dysfunction caused by osteoarthritis (OA) is increasingly becoming a major challenge in global healthcare, and there is currently no effective strategy to prevent the progression of OA. Therefore, better elucidating the relevant mechanisms of OA occurrence and development will provide theoretical basis for formulating new prevention and control strategies. Due to long-term exposure of cartilage tissue to the hypoxic microenvironment of joints, metabolic reprogramming changes occur. Hypoxia-inducible factor-1alpha (HIF-1α), as a core gene regulating hypoxia response in vivo, plays an important regulatory role in the hypoxic metabolism of chondrocytes. HIF-1α adapts to the hypoxic microenvironment by regulating metabolic reprogramming changes such as glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, and lipid metabolism in OA chondrocytes. In addition, HIF-1α also regulates macrophage polarization and synovial inflammation, chondrocytes degeneration and extracellular matrix (ECM) degradation, subchondral bone remodeling and angiogenesis in the hypoxic microenvironment of OA, and affects the pathophysiological progression of OA. Consequently, the regulation of chondrocytes metabolic reprogramming by HIF-1α has become an important therapeutic target for OA. Therefore, this article reviews the mechanism of hypoxia affecting chondrocyte metabolic reprogramming, focusing on the regulatory mechanism of HIF-1α on chondrocyte metabolic reprogramming, and summarizes potential effective ingredients or targets targeting chondrocyte metabolic reprogramming, in order to provide more beneficial basis for the prevention and treatment of clinical OA and the development of effective drugs.

{"title":"The role of HIF-1α in hypoxic metabolic reprogramming in osteoarthritis","authors":"Jie Zhang , Peng Gao , Wei-Rong Chang , Jia-Yi Song , Fang-Yu An , Yu-Jie Wang , Zhi-Pan Xiao , Hua Jin , Xu-Hui Zhang , Chun-Lu Yan","doi":"10.1016/j.phrs.2025.107649","DOIUrl":"10.1016/j.phrs.2025.107649","url":null,"abstract":"<div><div>The joint dysfunction caused by osteoarthritis (OA) is increasingly becoming a major challenge in global healthcare, and there is currently no effective strategy to prevent the progression of OA. Therefore, better elucidating the relevant mechanisms of OA occurrence and development will provide theoretical basis for formulating new prevention and control strategies. Due to long-term exposure of cartilage tissue to the hypoxic microenvironment of joints, metabolic reprogramming changes occur. Hypoxia-inducible factor-1alpha (HIF-1α), as a core gene regulating hypoxia response in vivo, plays an important regulatory role in the hypoxic metabolism of chondrocytes. HIF-1α adapts to the hypoxic microenvironment by regulating metabolic reprogramming changes such as glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, and lipid metabolism in OA chondrocytes. In addition, HIF-1α also regulates macrophage polarization and synovial inflammation, chondrocytes degeneration and extracellular matrix (ECM) degradation, subchondral bone remodeling and angiogenesis in the hypoxic microenvironment of OA, and affects the pathophysiological progression of OA. Consequently, the regulation of chondrocytes metabolic reprogramming by HIF-1α has become an important therapeutic target for OA. Therefore, this article reviews the mechanism of hypoxia affecting chondrocyte metabolic reprogramming, focusing on the regulatory mechanism of HIF-1α on chondrocyte metabolic reprogramming, and summarizes potential effective ingredients or targets targeting chondrocyte metabolic reprogramming, in order to provide more beneficial basis for the prevention and treatment of clinical OA and the development of effective drugs.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107649"},"PeriodicalIF":9.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414774","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}

引用次数: 0

Targeting TIPARP in ischemic stroke: A promising therapeutic strategy and future directions

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-11 DOI: 10.1016/j.phrs.2025.107651

Yinuo Pan, Xiande Ma

引用次数: 0