Pharmacological research最新文献

英文中文

From bench to bedside: Developing CRISPR/Cas-based therapy for ocular diseases

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-30 DOI: 10.1016/j.phrs.2025.107638

Qing Zhao , Linxin Wei , Youxin Chen

Vision-threatening disorders, including both hereditary and multifactorial ocular diseases, necessitate innovative therapeutic approaches. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) has emerged as a promising tool for treating ocular diseases through gene editing and expression regulation. This system has contributed to the development of representative disease models, including animal models, organoids, and cell lines, thereby facilitating investigations into the pathogenesis of disease-related genes. Besides, therapeutic applications of CRISPR/Cas have been extensively explored in preclinical in vitro and in vivo studies, targeting various ocular conditions, such as retinitis pigmentosa, Leber congenital amaurosis, Usher syndrome, fundus neovascular diseases, glaucoma, and corneal diseases. Recent advancements have demonstrated the technology's potential to restore cellular homeostasis and alleviate disease phenotypes, thereby prompting a variety of clinical trials. To date, active trials include treatments for primary open angle glaucoma with MYOC mutations, refractory herpetic viral keratitis, CEP290-associated inherited retinal degenerations, neovascular age-related macular degeneration, and retinitis pigmentosa with RHO mutations. However, challenges remain, primarily concerning off-target effects, immunogenicity, ethical considerations, and regulatory particularity. To reach higher safety and efficiency before truly transitioning from bench to bedside, future research should concentrate on improving the specificity and efficacy of Cas proteins, optimizing delivery vectors, and broadening the applicability of therapeutic targets. This review summarizes the application strategies and delivery methods of CRISPR/Cas, discusses recent progress in CRISPR/Cas-based disease models and therapies, and provides an overview of the landscape of clinical trials. Current obstacles and future directions regarding the bench-to-bedside transition are also discussed.

{"title":"From bench to bedside: Developing CRISPR/Cas-based therapy for ocular diseases","authors":"Qing Zhao , Linxin Wei , Youxin Chen","doi":"10.1016/j.phrs.2025.107638","DOIUrl":"10.1016/j.phrs.2025.107638","url":null,"abstract":"<div><div>Vision-threatening disorders, including both hereditary and multifactorial ocular diseases, necessitate innovative therapeutic approaches. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) has emerged as a promising tool for treating ocular diseases through gene editing and expression regulation. This system has contributed to the development of representative disease models, including animal models, organoids, and cell lines, thereby facilitating investigations into the pathogenesis of disease-related genes. Besides, therapeutic applications of CRISPR/Cas have been extensively explored in preclinical in vitro and in vivo studies, targeting various ocular conditions, such as retinitis pigmentosa, Leber congenital amaurosis, Usher syndrome, fundus neovascular diseases, glaucoma, and corneal diseases. Recent advancements have demonstrated the technology's potential to restore cellular homeostasis and alleviate disease phenotypes, thereby prompting a variety of clinical trials. To date, active trials include treatments for primary open angle glaucoma with <em>MYOC</em> mutations, refractory herpetic viral keratitis, <em>CEP290</em>-associated inherited retinal degenerations, neovascular age-related macular degeneration, and retinitis pigmentosa with <em>RHO</em> mutations. However, challenges remain, primarily concerning off-target effects, immunogenicity, ethical considerations, and regulatory particularity. To reach higher safety and efficiency before truly transitioning from bench to bedside, future research should concentrate on improving the specificity and efficacy of Cas proteins, optimizing delivery vectors, and broadening the applicability of therapeutic targets. This review summarizes the application strategies and delivery methods of CRISPR/Cas, discusses recent progress in CRISPR/Cas-based disease models and therapies, and provides an overview of the landscape of clinical trials. Current obstacles and future directions regarding the bench-to-bedside transition are also discussed.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107638"},"PeriodicalIF":9.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075190","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

Effects of natural products on macrophage immunometabolism: A new frontier in the treatment of metabolic diseases

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-30 DOI: 10.1016/j.phrs.2025.107634

Jiani Li , Chen Guo , Xiaofei Yang , Weinan Xie , Wenjing Mi , Chenglong Hua , Cheng Tang , Han Wang

Immunometabolic variations in macrophages critically influence their differentiation into pro-inflammatory or anti-inflammatory phenotypes, thereby contributing to immune homeostasis, defense against infection, and tissue repair. Dysregulation of macrophage immunometabolism has been closely implicated in several metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), hypertension, atherosclerosis, and gout, which positions macrophages as potential therapeutic targets. Recently, several natural products that target macrophage metabolic pathways have shown significant efficacy in managing metabolic diseases; however, a systematic review of these findings has yet to be conducted. This study consolidates natural products with immunoregulatory properties, including flavonoids, phenols, terpenoids, and naphthoquinones, which can alleviate chronic inflammation associated with metabolic disorders by modulating macrophage metabolic pathways, such as aerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO). This review aims to elucidate the metabolic regulation of the immune system, analyze metabolic alterations in macrophage associated with metabolic diseases, and summarize the beneficial roles of natural products in immunometabolism, providing novel insights for the prevention and therapeutic management of metabolic diseases.

{"title":"Effects of natural products on macrophage immunometabolism: A new frontier in the treatment of metabolic diseases","authors":"Jiani Li , Chen Guo , Xiaofei Yang , Weinan Xie , Wenjing Mi , Chenglong Hua , Cheng Tang , Han Wang","doi":"10.1016/j.phrs.2025.107634","DOIUrl":"10.1016/j.phrs.2025.107634","url":null,"abstract":"<div><div>Immunometabolic variations in macrophages critically influence their differentiation into pro-inflammatory or anti-inflammatory phenotypes, thereby contributing to immune homeostasis, defense against infection, and tissue repair. Dysregulation of macrophage immunometabolism has been closely implicated in several metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), hypertension, atherosclerosis, and gout, which positions macrophages as potential therapeutic targets. Recently, several natural products that target macrophage metabolic pathways have shown significant efficacy in managing metabolic diseases; however, a systematic review of these findings has yet to be conducted. This study consolidates natural products with immunoregulatory properties, including flavonoids, phenols, terpenoids, and naphthoquinones, which can alleviate chronic inflammation associated with metabolic disorders by modulating macrophage metabolic pathways, such as aerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO). This review aims to elucidate the metabolic regulation of the immune system, analyze metabolic alterations in macrophage associated with metabolic diseases, and summarize the beneficial roles of natural products in immunometabolism, providing novel insights for the prevention and therapeutic management of metabolic diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107634"},"PeriodicalIF":9.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075188","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

Toward an immunology-based classification of pain disorders?

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-28 DOI: 10.1016/j.phrs.2025.107631

A H C Rosenström, M F Bjurström

引用次数: 0

Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-28 DOI: 10.1016/j.phrs.2025.107628

Baijin Xia , Huolun Feng , Xinmiao Jiang , Jialing Guo , Keming Lin , Wenxing Zhang , Fan Xing , Lixue Cao , Yong Li , Hui Zhang , Xu Zhang , Wenyu Li , Fei Yu

T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other hand, although direct Granzyme B (GrB) administration can effectively induce tumor cell apoptosis, it lacks universal tumor targeting and efficient cellular entry mechanisms. To address these limitations, we developed a novel nanoparticle-based therapy for the precise targeting of TCL tumor cells and the delivery of GrB. We fused nanobody (Nb) targeting CD30 and CD5 with GrB and coupled them to human ferritin (h-HFn) using the Gv/Sd system, creating a novel therapeutic nanoparticle named BiCD30/5-GF, which specifically targets CD30 and CD5 receptors on TCL tumor cells. The Nb-GrB conjugation enhances tumor targeting, while a Gv/Sd linker coupled to h-HFn further improves cellular transport and targeting. Additionally, the multimerization of GrB enhances its effectiveness. These nanoparticles demonstrated superior binding affinity and cytotoxicity in vitro compared to conventional treatments. In vivo studies on tumor-bearing mice showed significant tumor suppression and prolonged survival following treatment with BiCD30/5-GF nanoparticles. We also extended similar nanoparticle strategies for gastric cancer therapy, targeting FGFR4-expressing tumor cells. Our findings highlight the potential of engineered nanoparticles as effective and targeted therapeutic agents across various tumor types, offering promising prospects for clinical translation in cancer treatment.

{"title":"Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy","authors":"Baijin Xia , Huolun Feng , Xinmiao Jiang , Jialing Guo , Keming Lin , Wenxing Zhang , Fan Xing , Lixue Cao , Yong Li , Hui Zhang , Xu Zhang , Wenyu Li , Fei Yu","doi":"10.1016/j.phrs.2025.107628","DOIUrl":"10.1016/j.phrs.2025.107628","url":null,"abstract":"<div><div>T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other hand, although direct Granzyme B (GrB) administration can effectively induce tumor cell apoptosis, it lacks universal tumor targeting and efficient cellular entry mechanisms. To address these limitations, we developed a novel nanoparticle-based therapy for the precise targeting of TCL tumor cells and the delivery of GrB. We fused nanobody (Nb) targeting CD30 and CD5 with <strong>G</strong>rB and coupled them to human ferritin (h-H<strong>F</strong>n) using the Gv/Sd system, creating a novel therapeutic nanoparticle named BiCD30/5-<strong>GF,</strong> which specifically targets CD30 and CD5 receptors on TCL tumor cells. The Nb-GrB conjugation enhances tumor targeting, while a Gv/Sd linker coupled to h-HFn further improves cellular transport and targeting. Additionally, the multimerization of GrB enhances its effectiveness. These nanoparticles demonstrated superior binding affinity and cytotoxicity in vitro compared to conventional treatments. In vivo studies on tumor-bearing mice showed significant tumor suppression and prolonged survival following treatment with BiCD30/5-GF nanoparticles. We also extended similar nanoparticle strategies for gastric cancer therapy, targeting FGFR4-expressing tumor cells. Our findings highlight the potential of engineered nanoparticles as effective and targeted therapeutic agents across various tumor types, offering promising prospects for clinical translation in cancer treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107628"},"PeriodicalIF":9.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067264","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: Drug repurposing in Schizophrenia – An updated review of clinical trials

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-28 DOI: 10.1016/j.phrs.2025.107633

Jihan K. Zaki , Jakub Tomasik , Sabine Bahn

There is an urgent need for mechanistically novel and more efficacious treatments for schizophrenia, especially those targeting negative and cognitive symptoms with a more favorable side-effect profile. Drug repurposing—the process of identifying new therapeutic uses for already approved compounds—offers a promising approach to overcoming the lengthy, costly, and high-risk process of traditional CNS drug discovery. This review aims to update our previous findings on the clinical drug repurposing pipeline in schizophrenia. We examined studies conducted between 2018 and 2024, identifying 61 trials evaluating 40 unique repurposed drug candidates. These encompassed a broad range of pharmacological mechanisms, including immunomodulation, cognitive enhancement, and hormonal, metabolic, and neurotransmitter modulation. A notable development is the combination of the muscarinic modulators xanomeline, a compound with antipsychotic properties, and trospium, included to mitigate peripheral side effects, now approved by the FDA as the first antipsychotic drug in decades with a fundamentally novel mechanism of action. Moving beyond the traditional dopaminergic paradigm of schizophrenia, such findings highlight opportunities to improve treatment-resistant symptoms and alleviate adverse effects. Overall, the evolving drug repurposing landscape illustrates a significant shift in the rationale for schizophrenia drug development, highlighting the potential of in silico strategies, biomarker-based patient stratification, and personalized treatments that align with underlying pathophysiological processes.

{"title":"IUPHAR review: Drug repurposing in Schizophrenia – An updated review of clinical trials","authors":"Jihan K. Zaki , Jakub Tomasik , Sabine Bahn","doi":"10.1016/j.phrs.2025.107633","DOIUrl":"10.1016/j.phrs.2025.107633","url":null,"abstract":"<div><div>There is an urgent need for mechanistically novel and more efficacious treatments for schizophrenia, especially those targeting negative and cognitive symptoms with a more favorable side-effect profile. Drug repurposing—the process of identifying new therapeutic uses for already approved compounds—offers a promising approach to overcoming the lengthy, costly, and high-risk process of traditional CNS drug discovery. This review aims to update our previous findings on the clinical drug repurposing pipeline in schizophrenia. We examined studies conducted between 2018 and 2024, identifying 61 trials evaluating 40 unique repurposed drug candidates. These encompassed a broad range of pharmacological mechanisms, including immunomodulation, cognitive enhancement, and hormonal, metabolic, and neurotransmitter modulation. A notable development is the combination of the muscarinic modulators xanomeline, a compound with antipsychotic properties, and trospium, included to mitigate peripheral side effects, now approved by the FDA as the first antipsychotic drug in decades with a fundamentally novel mechanism of action. Moving beyond the traditional dopaminergic paradigm of schizophrenia, such findings highlight opportunities to improve treatment-resistant symptoms and alleviate adverse effects. Overall, the evolving drug repurposing landscape illustrates a significant shift in the rationale for schizophrenia drug development, highlighting the potential of <em>in silico</em> strategies, biomarker-based patient stratification, and personalized treatments that align with underlying pathophysiological processes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107633"},"PeriodicalIF":9.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067268","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

Targeted gut microbiome therapy: Applications and prospects of probiotics, fecal microbiota transplantation and natural products in the management of type 2 diabetes

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-26 DOI: 10.1016/j.phrs.2025.107625

Luqi Qin, Bei Fan, Yixia Zhou, Jiahuan Zheng, Rao Diao, Fengzhong Wang, Jiameng Liu

Type 2 diabetes mellitus (T2DM) is considered as one of the most pressing public health challenges worldwide. Studies have shown significant differences in the gut microbiota between healthy individuals and T2DM patients, suggesting that gut microorganisms may play a key role in the onset and progression of T2DM. This review systematically summarizes the relationship between gut microbiota and T2DM, and explores the mechanisms through which gut microorganisms may alleviate T2DM. Additionally, it evaluates the potential of probiotics, fecal microbiota transplantation (FMT)/virome transplantation (FVT), and natural products in modulating gut microbiota to treat T2DM. Although existing studies have suggested that these interventions may delay or even halt the progression of T2DM, most research remained limited to animal models and observational clinical studies, with a lack of high-quality clinical data. This has led to an imbalance between theoretical research and clinical application. Although some studies have explored the regulatory role of the gut virome on the gut microbiota, research in this area remains in its early stages. Based on these current studies, future research should be focused on large-scale, long-term clinical studies and further investigation on the potential role of the gut virome in T2DM. In conclusion, this review aims to summarize the current evidence and explore the applications of gut microbiota in T2DM treatment, as well as providing recommendations for further investigation in this field.

{"title":"Targeted gut microbiome therapy: Applications and prospects of probiotics, fecal microbiota transplantation and natural products in the management of type 2 diabetes","authors":"Luqi Qin, Bei Fan, Yixia Zhou, Jiahuan Zheng, Rao Diao, Fengzhong Wang, Jiameng Liu","doi":"10.1016/j.phrs.2025.107625","DOIUrl":"10.1016/j.phrs.2025.107625","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) is considered as one of the most pressing public health challenges worldwide. Studies have shown significant differences in the gut microbiota between healthy individuals and T2DM patients, suggesting that gut microorganisms may play a key role in the onset and progression of T2DM. This review systematically summarizes the relationship between gut microbiota and T2DM, and explores the mechanisms through which gut microorganisms may alleviate T2DM. Additionally, it evaluates the potential of probiotics, fecal microbiota transplantation (FMT)/virome transplantation (FVT), and natural products in modulating gut microbiota to treat T2DM. Although existing studies have suggested that these interventions may delay or even halt the progression of T2DM, most research remained limited to animal models and observational clinical studies, with a lack of high-quality clinical data. This has led to an imbalance between theoretical research and clinical application. Although some studies have explored the regulatory role of the gut virome on the gut microbiota, research in this area remains in its early stages. Based on these current studies, future research should be focused on large-scale, long-term clinical studies and further investigation on the potential role of the gut virome in T2DM. In conclusion, this review aims to summarize the current evidence and explore the applications of gut microbiota in T2DM treatment, as well as providing recommendations for further investigation in this field.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107625"},"PeriodicalIF":9.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059331","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

Gene armoring: A way to enhance CAR-T cell function.

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-25 DOI: 10.1016/j.phrs.2025.107622

Yuxin Chen, Lulu Han, Ying Cai, Shuxin Huang, Meng Wang, Huizhong Li, Junnian Zheng, Bo Ma, Gang Wang

引用次数: 0

Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-25 DOI: 10.1016/j.phrs.2025.107623

Yanshan Chen , Yuanxing Zhi , Hailin Zhong , Liang Ma , Xinpei Gu , Yijing Cai , Jingjing Huang , Xin Yi , Xiaoyan Wu , Ken Kin Lam Yung , Pingzheng Zhou

Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases.

{"title":"Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation","authors":"Yanshan Chen , Yuanxing Zhi , Hailin Zhong , Liang Ma , Xinpei Gu , Yijing Cai , Jingjing Huang , Xin Yi , Xiaoyan Wu , Ken Kin Lam Yung , Pingzheng Zhou","doi":"10.1016/j.phrs.2025.107623","DOIUrl":"10.1016/j.phrs.2025.107623","url":null,"abstract":"<div><div>Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107623"},"PeriodicalIF":9.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053089","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

PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-22 DOI: 10.1016/j.phrs.2025.107624

Anella Saviano , Bonita Apta , Samantha Tull , Laleh Pezhman , Areeba Fatima , Mustafa Sevim , Antonio Mete , Myriam Chimen , Anna Schettino , Noemi Marigliano , Helen M. McGettrick , Asif J. Iqbal , Francesco Maione , G. Ed Rainger

PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here, we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. These peptidomimetics regulate T-cell trafficking in vitro and reduce T-cell, neutrophil and macrophage numbers in the inflamed peritoneal cavity in vivo. In a plaque psoriasis model, topical administration reduced disease severity, inflammation and immune cell infiltration, while regulating cytokine release in macrophages and fibroblasts, as well as keratinocyte proliferation. Th1 and Th17 cell abundance, along with their cytokines, was reduced in secondary lymphoid organs. This expanded functional repertoire of PEPITEM and its derivatives provides innovative tools for countering immune and stromal cell-induced pathology in IMIDs. Moreover, by identifying significantly smaller tripeptide pharmacophores of 14 amino acid PEPITEM, we may be able to deliver substantial financial advantages in synthesis and formulation. The order of magnitude increase in efficacy observed for some peptidomimetics may deliver agents with enhanced pharmacological characteristics compared to the parent PEPITEM sequence. Taken together with other reports on the efficacy of PEPITEM, this study paves the way for the development and translation of a novel class of anti-inflammatory agents which may have utility in a broad range of autoimmune and chronic inflammatory diseases.

{"title":"PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis","authors":"Anella Saviano , Bonita Apta , Samantha Tull , Laleh Pezhman , Areeba Fatima , Mustafa Sevim , Antonio Mete , Myriam Chimen , Anna Schettino , Noemi Marigliano , Helen M. McGettrick , Asif J. Iqbal , Francesco Maione , G. Ed Rainger","doi":"10.1016/j.phrs.2025.107624","DOIUrl":"10.1016/j.phrs.2025.107624","url":null,"abstract":"<div><div>PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here, we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. These peptidomimetics regulate T-cell trafficking <em>in vitro</em> and reduce T-cell, neutrophil and macrophage numbers in the inflamed peritoneal cavity <em>in vivo</em>. In a plaque psoriasis model, topical administration reduced disease severity, inflammation and immune cell infiltration, while regulating cytokine release in macrophages and fibroblasts, as well as keratinocyte proliferation. Th1 and Th17 cell abundance, along with their cytokines, was reduced in secondary lymphoid organs. This expanded functional repertoire of PEPITEM and its derivatives provides innovative tools for countering immune and stromal cell-induced pathology in IMIDs. Moreover, by identifying significantly smaller tripeptide pharmacophores of 14 amino acid PEPITEM, we may be able to deliver substantial financial advantages in synthesis and formulation. The order of magnitude increase in efficacy observed for some peptidomimetics may deliver agents with enhanced pharmacological characteristics compared to the parent PEPITEM sequence. Taken together with other reports on the efficacy of PEPITEM, this study paves the way for the development and translation of a novel class of anti-inflammatory agents which may have utility in a broad range of autoimmune and chronic inflammatory diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107624"},"PeriodicalIF":9.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040872","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: Alpha6-containing GABAA receptors – Novel targets for the treatment of schizophrenia

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-21 DOI: 10.1016/j.phrs.2025.107613

Lih-Chu Chiou , Werner Sieghart

α6-containing GABA_A receptors (α6GABA_ARs) are strongly expressed in cerebellar granule cells and are of central importance for cerebellar functions. The cerebellum not only is involved in regulation of motor activity, but also in regulation of thought, cognition, emotion, language, and social behavior. Activation of α6GABA_ARs enhances the precision of sensory inputs, enables rapid and coordinated movement and adequate responses to the environment, and protects the brain from information overflow. The cerebellum has strong connections to multiple brain regions via closed loop circuits and is also extensively connected with the dopamine system in the prefrontal cortex, that initiates the execution of behavior. Patients suffering from schizophrenia exhibit an impaired structure and function of the cerebellum and an impaired GABAergic transmission at α6GABA_ARs. This also impairs the function of the dopamine system, can explain a variety of schizophrenia symptoms observed, and might be one of the pathophysiological causes of schizophrenia. Enhancing GABAergic transmission at α6GABA_ARs should thus reduce the symptoms of schizophrenia. This recently has been confirmed by demonstrating that positive allosteric modulators with high selectivity for α6GABA_ARs can reduce positive and negative symptoms and cognitive impairment of schizophrenia in several animal models of this disorder. So far, the beneficial actions of these modulators have been demonstrated in animal models of neuropsychiatric disorders, only. Future human studies have to investigate the safety and possible side effects of these modulators and to clarify, to which extent individual symptoms of schizophrenia can be reduced by these drugs in patients during acute and chronic dosing.

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