Pharmacological research最新文献

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Protective effects and mechanisms of quercetin in animal models of hyperuricemia: A systematic review and meta-analysis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-21 DOI: 10.1016/j.phrs.2025.107665

Xueren Bian , Zhihao Ge , Xuannan Chen , Shutian Zhong , Lu Li , Wanfeng Xu , Bo Li , Suhong Chen , Guiyuan Lv

Quercetin, a prevalent natural flavonoid found in various medicinal plants, including Dendrobium officinale Kimura & Migo, has garnered attention for its potential health benefits. However, foundational animal studies investigating the effects of quercetin on lowering uric acid levels remain insufficiently established, and the number of related clinical studies is limited. This scarcity hinders the practical application of quercetin in managing hyperuricemia. We systematically searched for preclinical studies published by December 2024 in nine databases, such as PubMed, Web of Science, and Embase. The results of our meta-analysis showed that, compared with the model group, quercetin not only effectively alleviated the pathological injury of the kidney and liver and improved the renal function indexes in the animal model of hyperuricemia but also played a role in lowering uric acid by modulating multiple signaling pathways such as oxidative stress, lipid metabolism, and transporter proteins. Quercetin showed a more substantial effect in decreasing serum creatinine levels (SMD = −4.29, 95 % CI [−6.48, −2.10], P = 0.0001), blood urea nitrogen levels (SMD = −3.08, 95 % CI [−4.80, −1.35], P = 0.0005), and Up-regulate organic anion transporter 1 mRNA expression levels (SMD = 2.72, 95 %CI [0.45, 4.99], P = 0.02) compared to the positive control group. Sensitivity analyses confirmed the stability of the results, while the subgroup analysis indicates that the treatment course may be the main source of heterogeneity. The results of the Dose-efficacy analysis suggested that quercetin had a more substantial protective effect against hyperuricemia at a gavage dose of 100–200 mg/kg. However, to more accurately assess the effects of quercetin on hyperuricemia, it is essential to conduct additional high-quality, large-scale animal trials to validate our findings.

{"title":"Protective effects and mechanisms of quercetin in animal models of hyperuricemia: A systematic review and meta-analysis","authors":"Xueren Bian , Zhihao Ge , Xuannan Chen , Shutian Zhong , Lu Li , Wanfeng Xu , Bo Li , Suhong Chen , Guiyuan Lv","doi":"10.1016/j.phrs.2025.107665","DOIUrl":"10.1016/j.phrs.2025.107665","url":null,"abstract":"<div><div>Quercetin, a prevalent natural flavonoid found in various medicinal plants, including <em>Dendrobium officinale</em> Kimura & Migo, has garnered attention for its potential health benefits. However, foundational animal studies investigating the effects of quercetin on lowering uric acid levels remain insufficiently established, and the number of related clinical studies is limited. This scarcity hinders the practical application of quercetin in managing hyperuricemia. We systematically searched for preclinical studies published by December 2024 in nine databases, such as PubMed, Web of Science, and Embase. The results of our meta-analysis showed that, compared with the model group, quercetin not only effectively alleviated the pathological injury of the kidney and liver and improved the renal function indexes in the animal model of hyperuricemia but also played a role in lowering uric acid by modulating multiple signaling pathways such as oxidative stress, lipid metabolism, and transporter proteins. Quercetin showed a more substantial effect in decreasing serum creatinine levels (SMD = −4.29, 95 % CI [−6.48, −2.10], <em>P</em> = 0.0001), blood urea nitrogen levels (SMD = −3.08, 95 % CI [−4.80, −1.35], <em>P</em> = 0.0005), and Up-regulate organic anion transporter 1 mRNA expression levels (SMD = 2.72, 95 %CI [0.45, 4.99], <em>P</em> = 0.02) compared to the positive control group. Sensitivity analyses confirmed the stability of the results, while the subgroup analysis indicates that the treatment course may be the main source of heterogeneity. The results of the Dose-efficacy analysis suggested that quercetin had a more substantial protective effect against hyperuricemia at a gavage dose of 100–200 mg/kg. However, to more accurately assess the effects of quercetin on hyperuricemia, it is essential to conduct additional high-quality, large-scale animal trials to validate our findings.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107665"},"PeriodicalIF":9.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474773","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

Decoding TGR5: A comprehensive review of its impact on cerebral diseases

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-21 DOI: 10.1016/j.phrs.2025.107671

Zehan Zhang , Yifei Zhang , Hongye Peng, Qingqian Yu, Xiangdong Kang, Ying Liu, Yuxiao Zheng, Fafeng Cheng, Xueqian Wang, Feng Li

Currently, unraveling the enigmatic realm of drug targets for cerebral disorders poses a formidable challenge. Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1, is a specific bile acid receptor. Widely distributed across various tissues, TGR5 orchestrates a myriad of biological functions encompassing inflammation, energy metabolism, fatty acid metabolism, immune responses, cellular proliferation, apoptosis, and beyond. Alongside its well-documented implications in liver diseases, obesity, type 2 diabetes, tumors, and cardiovascular diseases, a growing body of evidence accentuates the pivotal role of TGR5 in cerebral diseases. Thus, this comprehensive review aimed to scrutinize the current insights into the pathological mechanisms involving TGR5 in cerebral diseases, while contemplating its potential as a promising therapeutic target for cerebral diseases.

目前，揭开脑部疾病药物靶点的神秘面纱是一项艰巨的挑战。武田G蛋白偶联受体5（TGR5）又称G蛋白偶联胆汁酸受体1，是一种特异性胆汁酸受体。TGR5 广泛分布于各种组织，协调着炎症、能量代谢、脂肪酸代谢、免疫反应、细胞增殖、细胞凋亡等多种生物功能。TGR5在肝脏疾病、肥胖症、2型糖尿病、肿瘤和心血管疾病中的作用已得到充分证实，此外，越来越多的证据表明，TGR5在脑部疾病中发挥着关键作用。因此，这篇综合综述旨在仔细研究 TGR5 在脑部疾病中的病理机制，同时探讨其作为脑部疾病治疗靶点的潜力。

引用次数: 0

SIRT1: A likely key for future therapeutic strategies for pain management

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-20 DOI: 10.1016/j.phrs.2025.107670

Sara Ilari , Saverio Nucera , Lucia Carmela Passacatini , Rosamaria Caminiti , Valeria Mazza , Roberta Macrì , Maria Serra , Federica Scarano , Valentina Malafoglia , Ernesto Palma , Francesca Oppedisano , Jessica Maiuolo , Carlo Tomino , Vincenzo Mollace , Carolina Muscoli

Sirtuin 1 (SIRT1), a NAD+ -dependent histone deacetylase, plays a crucial role in mitigating oxidative stress, regulating inflammation, and maintaining mitochondrial function. Reduced SIRT1 activity has been linked to elevated pro-inflammatory cytokines, mitochondrial dysfunction, and chronic pain, all of which are observed in long COVID pathology. Emerging evidence identifies mitochondrial dysfunction and oxidative stress as central contributors to these symptoms. Increases reactive oxygen species (ROS) such as superoxide, nitric oxide, and peroxynitrite, leading to oxidative damage, chronic inflammation, and central/peripheral sensitization. Nutraceuticals, particularly the polyphenolic fraction of bergamot (BPF), have demonstrated potent antioxidant, anti-inflammatory, and antiviral properties. This study highlights BPF’s ability to modulate SIRT1 activity in a rat model of inflammation and hyperalgesia. It provides novel evidence of SIRT1 nitration within the nucleus as a key event in inflammatory pain pathogenesis. BPF administration preserved SIRT1 activity, reduced oxidative stress markers such as malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG), and minimized post-translational modifications of nuclear proteins, including nitration, acetylation, and carbonylation. Additionally, it alleviated hyperalgesia and allodynia. These findings underscore the therapeutic potential of polyphenols like BPF in reducing oxidative stress and inflammation-driven pain. By activating SIRT1, BPF may provide relief for pain conditions. Further research on SIRT1-targeted therapies is essential to combat inflammation and oxidative stress, preventing chronic conditions and enhancing treatment options.

{"title":"SIRT1: A likely key for future therapeutic strategies for pain management","authors":"Sara Ilari , Saverio Nucera , Lucia Carmela Passacatini , Rosamaria Caminiti , Valeria Mazza , Roberta Macrì , Maria Serra , Federica Scarano , Valentina Malafoglia , Ernesto Palma , Francesca Oppedisano , Jessica Maiuolo , Carlo Tomino , Vincenzo Mollace , Carolina Muscoli","doi":"10.1016/j.phrs.2025.107670","DOIUrl":"10.1016/j.phrs.2025.107670","url":null,"abstract":"<div><div>Sirtuin 1 (SIRT1), a NAD+ -dependent histone deacetylase, plays a crucial role in mitigating oxidative stress, regulating inflammation, and maintaining mitochondrial function. Reduced SIRT1 activity has been linked to elevated pro-inflammatory cytokines, mitochondrial dysfunction, and chronic pain, all of which are observed in long COVID pathology. Emerging evidence identifies mitochondrial dysfunction and oxidative stress as central contributors to these symptoms. Increases reactive oxygen species (ROS) such as superoxide, nitric oxide, and peroxynitrite, leading to oxidative damage, chronic inflammation, and central/peripheral sensitization. Nutraceuticals, particularly the polyphenolic fraction of bergamot (BPF), have demonstrated potent antioxidant, anti-inflammatory, and antiviral properties. This study highlights BPF’s ability to modulate SIRT1 activity in a rat model of inflammation and hyperalgesia. It provides novel evidence of SIRT1 nitration within the nucleus as a key event in inflammatory pain pathogenesis. BPF administration preserved SIRT1 activity, reduced oxidative stress markers such as malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG), and minimized post-translational modifications of nuclear proteins, including nitration, acetylation, and carbonylation. Additionally, it alleviated hyperalgesia and allodynia. These findings underscore the therapeutic potential of polyphenols like BPF in reducing oxidative stress and inflammation-driven pain. By activating SIRT1, BPF may provide relief for pain conditions. Further research on SIRT1-targeted therapies is essential to combat inflammation and oxidative stress, preventing chronic conditions and enhancing treatment options.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107670"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453159","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

Strategies for ectopic expression of specific genes to enhance CAR-T cell tumoricidal capacity: How far are we from the clinical practice?

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-20 DOI: 10.1016/j.phrs.2025.107656

Yuning Wang , Peiwen Ma , Jiatong Ding , Shujun Xing , Yale Jiang, Jiawei Zhou, Hanqing He, Caie Wang, Shuhang Wang, Ning Li

引用次数: 0

Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-19 DOI: 10.1016/j.phrs.2025.107664

Jianhua Zhang , Xujie Liu , Xian Jin , Xudong Mao , Xueli Xu , Xing Zhang , Ke Shang , Yuan Xu , Yanhuan Zhang , Guofeng Meng , Ming Yue , Guoqing Cai , Song Yang , Jinyu Huang , Jianwu Fang , Ling Pan , Lei Jiang , Stella Shi , Jianyong Shou

Germline mutations of CIDEB, a lipid droplets (LDs)-associated protein, confer protection against various liver diseases in humans. It remains to be determined whether liver-specific inhibition of CIDEB will bring clinical benefits. We aim to establish pharmacological proof of concept by testing GalNAc-conjugated Cideb surrogate siRNAs in respective animal models of obesity and MASH and to develop siRNA drug candidates for clinical investigations. Surrogate siRNAs targeting mouse Cideb were designed and evaluated via a panel of assays. Concurrently, humanized CIDEB knock-in mice were generated as a research tool to facilitate human therapeutic siRNA discovery. In vivo administration of the surrogate siRNAs was conducted in the diet-induced obesity (DIO) model and CDAA-HFD model of MASH. In the DIO model, Cideb knockdown led to significant reductions of serum total cholesterol (TC) and triglyceride (TG) levels, a significant decrease in hepatic macro-steatosis and notable weight loss. In the CDAA-HFD model, Cideb siRNA treatment significantly reduced liver TC and TG levels. Furthermore, remarkable reductions of hepatic steatosis and the composite NAS score were observed with a concomitant amelioration of liver fibrosis. Transcriptome analyses revealed that integrin pathways may contribute to the major pharmacological activities upon Cideb inactivation beyond lipid metabolism. CIDEB exhibits significant potential as a therapeutic target for the treatment of MASH. Liver-targeting siRNA candidates are under development for therapeutic hypothesis testing in humans.

{"title":"Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH","authors":"Jianhua Zhang , Xujie Liu , Xian Jin , Xudong Mao , Xueli Xu , Xing Zhang , Ke Shang , Yuan Xu , Yanhuan Zhang , Guofeng Meng , Ming Yue , Guoqing Cai , Song Yang , Jinyu Huang , Jianwu Fang , Ling Pan , Lei Jiang , Stella Shi , Jianyong Shou","doi":"10.1016/j.phrs.2025.107664","DOIUrl":"10.1016/j.phrs.2025.107664","url":null,"abstract":"<div><div>Germline mutations of CIDEB, a lipid droplets (LDs)-associated protein, confer protection against various liver diseases in humans. It remains to be determined whether liver-specific inhibition of CIDEB will bring clinical benefits. We aim to establish pharmacological proof of concept by testing GalNAc-conjugated <em>Cideb</em> surrogate siRNAs in respective animal models of obesity and MASH and to develop siRNA drug candidates for clinical investigations. Surrogate siRNAs targeting mouse <em>Cideb</em> were designed and evaluated via a panel of assays. Concurrently, humanized <em>CIDEB</em> knock-in mice were generated as a research tool to facilitate human therapeutic siRNA discovery. <em>In vivo</em> administration of the surrogate siRNAs was conducted in the diet-induced obesity (DIO) model and CDAA-HFD model of MASH. In the DIO model, <em>Cideb</em> knockdown led to significant reductions of serum total cholesterol (TC) and triglyceride (TG) levels, a significant decrease in hepatic macro-steatosis and notable weight loss. In the CDAA-HFD model, <em>Cideb</em> siRNA treatment significantly reduced liver TC and TG levels. Furthermore, remarkable reductions of hepatic steatosis and the composite NAS score were observed with a concomitant amelioration of liver fibrosis. Transcriptome analyses revealed that integrin pathways may contribute to the major pharmacological activities upon <em>Cideb</em> inactivation beyond lipid metabolism. CIDEB exhibits significant potential as a therapeutic target for the treatment of MASH. Liver-targeting siRNA candidates are under development for therapeutic hypothesis testing in humans.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107664"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472811","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

A panel of altered blood oxysterols in patients with mild cognitive impairment: A novel combined diagnostic marker

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-19 DOI: 10.1016/j.phrs.2025.107661

Yu An , Yuandi Xi , Tao Wang , Mengwei Ju , Wenjing Feng , Zhiting Guo , Xuejing Sun , Kexin Yang , Chengyan Qi , Rong Xiao

Perturbed cholesterol metabolism may play an important role in the development of dementia and its preclinical stage, mild cognitive impairment (MCI). Oxysterols, the metabolites generated during cholesterol oxidation, also appear to be risk factors for MCI. Therefore, we aimed to investigate if the metabolic profile of blood oxysterols could be used to characterize MCI risk. This cross-sectional study incorporated 501 participants—253 patients with MCI and 248 cognitively normal controls. Serum levels of 22 free oxysterols were measured, and a set of 27 oxysterol-related gene polymorphisms was genotyped. Five [27-hydroxycholesterol (27-OHC), 27-OHC periphery-derived metabolite 3β-hydroxy-5-cholestenoic acid (27-CA) and brain-derived metabolite 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), 4β-hydroxycholesterol (4β-OHC); 4α-hydroxycholesterol (4α-OHC)] of the twenty-two oxysterols detected in serum significantly differed between the patients with MCI and controls, greatly distinguishing patients with MCI from control individuals (AUC=0.834, 95 % CI: 0.804–0.866). Association analyses demonstrated significant correlations between these candidate oxysterol biomarkers with younger age, higher blood lipids, worse cognitive performance, and higher monounsaturated fatty acid intake. This panel of serum free oxysterols as candidate serum oxysterol biomarkers for MCI highlighted the essential role of 27-OHC in the pathogenesis of early dementia prevention. (The study registered in the Chinese Clinical Trial Registry as ChiCTR-OOC-17011882)

{"title":"A panel of altered blood oxysterols in patients with mild cognitive impairment: A novel combined diagnostic marker","authors":"Yu An , Yuandi Xi , Tao Wang , Mengwei Ju , Wenjing Feng , Zhiting Guo , Xuejing Sun , Kexin Yang , Chengyan Qi , Rong Xiao","doi":"10.1016/j.phrs.2025.107661","DOIUrl":"10.1016/j.phrs.2025.107661","url":null,"abstract":"<div><div>Perturbed cholesterol metabolism may play an important role in the development of dementia and its preclinical stage, mild cognitive impairment (MCI). Oxysterols, the metabolites generated during cholesterol oxidation, also appear to be risk factors for MCI. Therefore, we aimed to investigate if the metabolic profile of blood oxysterols could be used to characterize MCI risk. This cross-sectional study incorporated 501 participants—253 patients with MCI and 248 cognitively normal controls. Serum levels of 22 free oxysterols were measured, and a set of 27 oxysterol-related gene polymorphisms was genotyped. Five [27-hydroxycholesterol (27-OHC), 27-OHC periphery-derived metabolite 3β-hydroxy-5-cholestenoic acid (27-CA) and brain-derived metabolite 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), 4β-hydroxycholesterol (4β-OHC); 4α-hydroxycholesterol (4α-OHC)] of the twenty-two oxysterols detected in serum significantly differed between the patients with MCI and controls, greatly distinguishing patients with MCI from control individuals (AUC=0.834, 95 % CI: 0.804–0.866). Association analyses demonstrated significant correlations between these candidate oxysterol biomarkers with younger age, higher blood lipids, worse cognitive performance, and higher monounsaturated fatty acid intake. This panel of serum free oxysterols as candidate serum oxysterol biomarkers for MCI highlighted the essential role of 27-OHC in the pathogenesis of early dementia prevention. (The study registered in the Chinese Clinical Trial Registry as ChiCTR-OOC-17011882)</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107661"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465197","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

Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-19 DOI: 10.1016/j.phrs.2025.107658

Yiwei Zhang , Qi Kong , Junfen Fan , Haiping Zhao

Interleukin-2 (IL-2), the first cloned cytokine, is a multifunctional molecule with diverse cellular origins. As a pivotal T-cell growth factor, IL-2 is crucial for T-cell proliferation and the generation of effector and memory cells. Besides, IL-2 and its receptor (IL-2R) are expressed in various cell types within the brain and have been implicated in the pathogenesis of several neurological disorders. In conditions characterized by primary or secondary inflammatory processes, such as multiple sclerosis, Alzheimer’s disease, ischemic stroke, and encephalitis, IL-2/IL-2R expression exhibits region- and subtype-specific and variations associated with disease stages in plasma, cerebrospinal fluid (CSF), and brain tissues. These variations highlight the potential of IL-2/IL-2R as promising diagnostic and prognostic biomarkers, as well as therapeutic targets. This review provides a comprehensive summary of the roles, expression patterns, and regulatory mechanisms of IL-2/IL-2R in immune-mediated disorders of the central nervous system (CNS), with particular emphasis on the impact of genetic polymorphisms in IL-2 and IL-2R subunits on disease susceptibility and progression. In addition, the research advances in IL-2/IL-2R-targeted therapies are also discussed, offering novel insights into the immunotherapeutic strategies for CNS diseases.

{"title":"Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system","authors":"Yiwei Zhang , Qi Kong , Junfen Fan , Haiping Zhao","doi":"10.1016/j.phrs.2025.107658","DOIUrl":"10.1016/j.phrs.2025.107658","url":null,"abstract":"<div><div>Interleukin-2 (IL-2), the first cloned cytokine, is a multifunctional molecule with diverse cellular origins. As a pivotal T-cell growth factor, IL-2 is crucial for T-cell proliferation and the generation of effector and memory cells. Besides, IL-2 and its receptor (IL-2R) are expressed in various cell types within the brain and have been implicated in the pathogenesis of several neurological disorders. In conditions characterized by primary or secondary inflammatory processes, such as multiple sclerosis, Alzheimer’s disease, ischemic stroke, and encephalitis, IL-2/IL-2R expression exhibits region- and subtype-specific and variations associated with disease stages in plasma, cerebrospinal fluid (CSF), and brain tissues. These variations highlight the potential of IL-2/IL-2R as promising diagnostic and prognostic biomarkers, as well as therapeutic targets. This review provides a comprehensive summary of the roles, expression patterns, and regulatory mechanisms of IL-2/IL-2R in immune-mediated disorders of the central nervous system (CNS), with particular emphasis on the impact of genetic polymorphisms in IL-2 and IL-2R subunits on disease susceptibility and progression. In addition, the research advances in IL-2/IL-2R-targeted therapies are also discussed, offering novel insights into the immunotherapeutic strategies for CNS diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107658"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468801","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

TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-19 DOI: 10.1016/j.phrs.2025.107655

Abeer F. Alharbi , John Parrington

The lysosomal two-pore channel 2 (TPC2) modulates intracellular calcium (Ca^2 +) signaling and has been implicated in inflammatory, cardiovascular, and neurodegenerative conditions, as well as cancer and viral infections. Despite its potential as a drug target, TPC2 is still in the early stages of therapeutic development. The major challenges include achieving high target specificity without inducing unintended effects on other endolysosomal channels and on the crosstalk between TPC2 and other intracellular and extracellular Ca²⁺ channels. Recent advancements in the structural analysis of TPC2, along with the development of TPC2 agonists and inhibitors, have significantly expanded our understanding of its mechanistic contributions to disease. This review highlights potential TPC2-based therapies for cancer, inflammation, and neurological disorders, emphasizing the need for further research to develop targeted TPC2 modulators and fully elucidate the molecular mechanisms of TPC2.

引用次数: 0

The landscape of ATF3 in tumors: Metabolism, expression regulation, therapy approach, and open concerns

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-19 DOI: 10.1016/j.phrs.2025.107666

Xu Zhao , Chao Chen , Hui Qiu , Jing Liu , Nan Shao , Mengmeng Guo , Yuanye Jiang , Juanjuan Zhao , Lin Xu

Cellular stress response is a pivotal process in tumor development and therapy. Activating transcription factor 3 (ATF3), a representative stress-responsive protein, plays pleiotropic roles in various biological processes. Over the past decade, studies have described not only the general role of ATF3 in tumor metabolism but also the complexity of ATF3 expression regulation and its associated modifications, including phosphorylation, ubiquitination, SUMOylation, and NEDDylation. Interestingly, beyond being a transcription factor, ATF3 can act as a modifier to control the ubiquitination of target molecules, such as p53, to exert its function in tumors. These advances in uncovering ATF3 biological function have yielded new insights into the cellular stress response during tumor development and will be instrumental in developing novel interventions. In this review, we update the role of ATF3 as a nexus in amino acid metabolism, lipid metabolism, glycometabolism, and other metabolic pathways in tumors; delineate the underlying mechanisms involving DNA level regulation, epigenetic regulation, and post-translational modifications of ATF3; and summarize the progression of tumor mono/combination therapies related to ATF3. In particular, we discuss the challenges that need to be addressed to provide a new conceptual framework for further understanding the potential therapeutic value of ATF3 in ongoing clinical trials.

{"title":"The landscape of ATF3 in tumors: Metabolism, expression regulation, therapy approach, and open concerns","authors":"Xu Zhao , Chao Chen , Hui Qiu , Jing Liu , Nan Shao , Mengmeng Guo , Yuanye Jiang , Juanjuan Zhao , Lin Xu","doi":"10.1016/j.phrs.2025.107666","DOIUrl":"10.1016/j.phrs.2025.107666","url":null,"abstract":"<div><div>Cellular stress response is a pivotal process in tumor development and therapy. Activating transcription factor 3 (ATF3), a representative stress-responsive protein, plays pleiotropic roles in various biological processes. Over the past decade, studies have described not only the general role of ATF3 in tumor metabolism but also the complexity of ATF3 expression regulation and its associated modifications, including phosphorylation, ubiquitination, SUMOylation, and NEDDylation. Interestingly, beyond being a transcription factor, ATF3 can act as a modifier to control the ubiquitination of target molecules, such as p53, to exert its function in tumors. These advances in uncovering ATF3 biological function have yielded new insights into the cellular stress response during tumor development and will be instrumental in developing novel interventions. In this review, we update the role of ATF3 as a nexus in amino acid metabolism, lipid metabolism, glycometabolism, and other metabolic pathways in tumors; delineate the underlying mechanisms involving DNA level regulation, epigenetic regulation, and post-translational modifications of ATF3; and summarize the progression of tumor mono/combination therapies related to ATF3. In particular, we discuss the challenges that need to be addressed to provide a new conceptual framework for further understanding the potential therapeutic value of ATF3 in ongoing clinical trials.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107666"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468804","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

RNA aptamer-mediated RNA nanotechnology for potential treatment of cardiopulmonary diseases

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-18 DOI: 10.1016/j.phrs.2025.107659

Boyu Xia , Nargis Shaheen , Huilong Chen , Jing Zhao , Peixuan Guo , Yutong Zhao

Ribonucleic acid (RNA) aptamers are single-stranded RNAs that bind to target proteins or other molecules with high specificity and affinity, modulating biological functions through distinct mechanisms. These aptamers can act n as antagonists to block pathological interactions, agonists to activate signaling pathways, or delivery vehicles for therapeutic cargos such as siRNAs and miRNAs. The advances in RNA nanotechnology further enhances the versatility of RNA aptamers, offering scalable platforms for engineering. In this review, we have summarized recent developments in RNA aptamer-mediated RNA nanotechnology and provide an overview of its potential in treating cardiovascular and respiratory disorders, including atherosclerosis, acute coronary syndromes, heart failure, lung cancer, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), acute lung injury, viral respiratory infections, and pulmonary fibrosis. By integrating aptamer technologies with innovative delivery systems, RNA aptamers hold the potential to revolutionize the treatment landscape for cardiopulmonary diseases.

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