Pharmacological research最新文献_第6页

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

The efficacy of sodium-glucose transporter 2 inhibitors in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-08 DOI: 10.1016/j.phrs.2025.107647

Hongsheng Li , Yanli Hou , Wenyong Xin , Lina Ding , Ying Yang , Yikun Zhang , Wenqi Wu , Zhibin Wang , Wenyu Ding

The efficacy of sodium-glucose transporter 2 (SGLT-2) inhibitors for nonalcoholic fatty liver disease (NAFLD) is unclear. Therefore, we conducted a systematic review and meta-analysis to evaluate SGLT-2 inhibitors efficacy for NAFLD treatment. We systematically searched major electronic databases (PubMed, Cochrane Library, Web of Science, Embase) from inception until 11/2023, identifying randomized controlled trials (RCTs) of SGLT-2 inhibitors treatment for patients with NAFLD. The mean differences (MD or SMD) and 95 % confidence intervals (CIs) were calculated via random-effects models. Eleven articles (n = 805 patients with NAFLD) were included in this study. Of these, 408 participants received SGLT-2 inhibitors, while 397 participants were in the control group. SGLT-2 inhibitors significantly reduced liver enzyme levels, including aspartate alanine aminotransferase (ALT) (MD [95 % CI]; −9.31 U/L [-13.41, −5.21], p < 0.00001), aspartate aminotransferase (AST) (MD [95 % CI]; −6.06 U/L [-10.98, −1.15], p = 0.02), and gamma-glutamyltransferase (GGT) (MD [95 % CI]; −11.72 U/L [-15.65, −7.80], p < 0.00001). SGLT-2 inhibitors intervention was also associated with significant reductions in body weight (MD [95 % CI]; −2.72 kg [-3.49, −1.95], p < 0.00001) and BMI (MD [95 % CI]; −1.11 kg/m² [-1.39, −0.82], p < 0.00001) and improvements in glycaemic indices, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). However, no significant changes in total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) were observed. The meta-analysis revealed a beneficial effect of SGLT-2 inhibitors on liver functions and body weight, BMI, TG, HDL-C, and glucose homeostasis in patients with NAFLD, indicating that SGLT-2 inhibitors might be a clinical therapeutic strategy for these patients, especially individuals with concurrent type 2 diabetes mellitus (T2DM).

{"title":"The efficacy of sodium-glucose transporter 2 inhibitors in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis","authors":"Hongsheng Li , Yanli Hou , Wenyong Xin , Lina Ding , Ying Yang , Yikun Zhang , Wenqi Wu , Zhibin Wang , Wenyu Ding","doi":"10.1016/j.phrs.2025.107647","DOIUrl":"10.1016/j.phrs.2025.107647","url":null,"abstract":"<div><div>The efficacy of sodium-glucose transporter 2 (SGLT-2) inhibitors for nonalcoholic fatty liver disease (NAFLD) is unclear. Therefore, we conducted a systematic review and meta-analysis to evaluate SGLT-2 inhibitors efficacy for NAFLD treatment. We systematically searched major electronic databases (PubMed, Cochrane Library, Web of Science, Embase) from inception until 11/2023, identifying randomized controlled trials (RCTs) of SGLT-2 inhibitors treatment for patients with NAFLD. The mean differences (MD or SMD) and 95 % confidence intervals (<em>CIs</em>) were calculated via random-effects models. Eleven articles (n = 805 patients with NAFLD) were included in this study. Of these, 408 participants received SGLT-2 inhibitors, while 397 participants were in the control group. SGLT-2 inhibitors significantly reduced liver enzyme levels, including aspartate alanine aminotransferase (ALT) (MD [95 % <em>CI</em>]; −9.31 U/L [-13.41, −5.21], <em>p</em> < 0.00001), aspartate aminotransferase (AST) (MD [95 % <em>CI</em>]; −6.06 U/L [-10.98, −1.15], <em>p</em> = 0.02), and gamma-glutamyltransferase (GGT) (MD [95 % <em>CI</em>]; −11.72 U/L [-15.65, −7.80], <em>p</em> < 0.00001). SGLT-2 inhibitors intervention was also associated with significant reductions in body weight (MD [95 % <em>CI</em>]; −2.72 kg [-3.49, −1.95], <em>p</em> < 0.00001) and BMI (MD [95 % <em>CI</em>]; −1.11 kg/m<sup>2</sup> [-1.39, −0.82], <em>p</em> < 0.00001) and improvements in glycaemic indices, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). However, no significant changes in total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) were observed. The meta-analysis revealed a beneficial effect of SGLT-2 inhibitors on liver functions and body weight, BMI, TG, HDL-C, and glucose homeostasis in patients with NAFLD, indicating that SGLT-2 inhibitors might be a clinical therapeutic strategy for these patients, especially individuals with concurrent type 2 diabetes mellitus (T2DM).</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107647"},"PeriodicalIF":9.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377290","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 essential role of sphingolipids in TRPC5 ion channel localization and functionality within lipid rafts

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-07 DOI: 10.1016/j.phrs.2025.107648

Junliang Wan , Zhenying Hu , Huaiyi Zhu , Jingyi Li , Ziyuan Zheng , Zhitao Deng , Junyan Lu , Yu Chen , Gui-Lan Chen , Bo Zeng , Jin Zhang , Jingjing Duan

Sphingolipids are critical components of cellular membranes that play a pivotal role in modulating ion channel function by forming lipid rafts that stabilize and localize these channels. These lipids regulate membrane fluidity and protein-lipid interactions, directly influencing ion channel activity, trafficking, and signaling pathways essential for maintaining cellular homeostasis. Despite their fundamental role, the impact of sphingolipids on ion channel functionality, particularly within the nervous system, remains insufficiently understood. This study addresses this gap by examining the influence of sphingolipids on transient receptor potential canonical 5 (TRPC5), a key brain ion channel involved in sensory transduction and linked to conditions such as obesity, anxiety, and postpartum depression when disrupted. In this study, we demonstrate that TRPC5 is localized within lipid rafts. Inhibition of sphingolipid synthesis through myrioncin (Myr), the sphingomyelin synthase 2 inhibitor Ly93, or D,L-erythro-PDMP hydrochloride (PMDP) significantly disrupts TRPC5 localization at the plasma membrane. Treatment with lipid raft disruptors methyl-β-cyclodextrin (MCD) or sphingomyelin phosphodiesterase 3 (SMPD3), in conjunction with sphingolipid synthesis inhibitors, led to decreased TRPC5-mediated calcium flux and currents. This highlights the critical importance of TRPC5 localization in lipid rafts for its functionality. Furthermore, LC-MS/MS-based sphingolipidomics has shown that a balanced sphingolipid profile is crucial for channel function. Alterations in sphingolipid metabolism, especially the deficiency of sphingomyelin and glycosphingolipids, may primarily disrupt lipid raft structure. Interactions between amino acid residues with phenyl ring side chains and lipids at the inner and outer plasma membrane edges serve as ‘fixators’, anchoring TRPC5 channels within lipid rafts. Given the structural similarities among TRP channels, we propose that sphingolipid metabolic homeostasis may universally influence TRP channel activity, potentially explaining diverse neurological disorder phenotypes associated with sphingolipid metabolism disruptions.

{"title":"The essential role of sphingolipids in TRPC5 ion channel localization and functionality within lipid rafts","authors":"Junliang Wan , Zhenying Hu , Huaiyi Zhu , Jingyi Li , Ziyuan Zheng , Zhitao Deng , Junyan Lu , Yu Chen , Gui-Lan Chen , Bo Zeng , Jin Zhang , Jingjing Duan","doi":"10.1016/j.phrs.2025.107648","DOIUrl":"10.1016/j.phrs.2025.107648","url":null,"abstract":"<div><div>Sphingolipids are critical components of cellular membranes that play a pivotal role in modulating ion channel function by forming lipid rafts that stabilize and localize these channels. These lipids regulate membrane fluidity and protein-lipid interactions, directly influencing ion channel activity, trafficking, and signaling pathways essential for maintaining cellular homeostasis. Despite their fundamental role, the impact of sphingolipids on ion channel functionality, particularly within the nervous system, remains insufficiently understood. This study addresses this gap by examining the influence of sphingolipids on transient receptor potential canonical 5 (TRPC5), a key brain ion channel involved in sensory transduction and linked to conditions such as obesity, anxiety, and postpartum depression when disrupted. In this study, we demonstrate that TRPC5 is localized within lipid rafts. Inhibition of sphingolipid synthesis through myrioncin (Myr), the sphingomyelin synthase 2 inhibitor Ly93, or D,L-erythro-PDMP hydrochloride (PMDP) significantly disrupts TRPC5 localization at the plasma membrane. Treatment with lipid raft disruptors methyl-<em>β</em>-cyclodextrin (MCD) or sphingomyelin phosphodiesterase 3 (SMPD3), in conjunction with sphingolipid synthesis inhibitors, led to decreased TRPC5-mediated calcium flux and currents. This highlights the critical importance of TRPC5 localization in lipid rafts for its functionality. Furthermore, LC-MS/MS-based sphingolipidomics has shown that a balanced sphingolipid profile is crucial for channel function. Alterations in sphingolipid metabolism, especially the deficiency of sphingomyelin and glycosphingolipids, may primarily disrupt lipid raft structure. Interactions between amino acid residues with phenyl ring side chains and lipids at the inner and outer plasma membrane edges serve as ‘fixators’, anchoring TRPC5 channels within lipid rafts. Given the structural similarities among TRP channels, we propose that sphingolipid metabolic homeostasis may universally influence TRP channel activity, potentially explaining diverse neurological disorder phenotypes associated with sphingolipid metabolism disruptions.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107648"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382925","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

Pharmacological regression of atherosclerotic plaque in patients with type 2 diabetes

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-05 DOI: 10.1016/j.phrs.2025.107635

Loredana Bucciarelli , Daniele Andreini , Giulio Stefanini , Roberta Maria Fiorina , Marco Francone , Federica Catapano , Maria Elena Lunati , Edoardo Conte , Davide Marchetti , Paolo Fiorina

Atherosclerosis of the coronary arteries continues to be one of the major global health burdens and acute coronary syndrome is responsible annually for at least 30 % of all deaths globally. Acute coronary syndrome may be the consequence of thrombus formation after erosion or rupture of obstructive or non-obstructive atherosclerotic plaque. The rupture of plaques is mostly caused by mechanical stress usually called cap fatigue. Vulnerable plaques are characterized by a softer atheromatous core and a thinner fibrous cap, with inflammation and hypercholesterolemia playing a crucial role in the atherothrombotic process. Based on animal studies that extend back to the 1920s, regression of atherosclerotic plaques in humans has just started to be considered and pursued. The idea that the human atherosclerotic plaques could regress at all met an important resistance over the decades; indeed, advanced plaques contain components, such as necrosis, calcification and fibrosis, which are hard to be removed. However, new animal models and imaging technics allowed a more complete and accurate quantitative assessment of plaque volume and are shedding new light on atherosclerosis regression. In this review, we are revisiting the existence of atherosclerosis regression in preclinical and clinical studies, with a focus on the latest mechanistic insights and on the newest pharmacological agents, particularly in patients with diabetes. Interestingly, we suggested that based on literature insights and preclinical studies, a combination of drugs to target hyperglycemia, dyslipidemia and inflammation may be desirable for a fast-track Pharmacological regression of atherosclerotic plaque in patients with type 2 diabetes.

{"title":"Pharmacological regression of atherosclerotic plaque in patients with type 2 diabetes","authors":"Loredana Bucciarelli , Daniele Andreini , Giulio Stefanini , Roberta Maria Fiorina , Marco Francone , Federica Catapano , Maria Elena Lunati , Edoardo Conte , Davide Marchetti , Paolo Fiorina","doi":"10.1016/j.phrs.2025.107635","DOIUrl":"10.1016/j.phrs.2025.107635","url":null,"abstract":"<div><div>Atherosclerosis of the coronary arteries continues to be one of the major global health burdens and acute coronary syndrome is responsible annually for at least 30 % of all deaths globally. Acute coronary syndrome may be the consequence of thrombus formation after erosion or rupture of obstructive or non-obstructive atherosclerotic plaque. The rupture of plaques is mostly caused by mechanical stress usually called cap fatigue. Vulnerable plaques are characterized by a softer atheromatous core and a thinner fibrous cap, with inflammation and hypercholesterolemia playing a crucial role in the atherothrombotic process. Based on animal studies that extend back to the 1920s, regression of atherosclerotic plaques in humans has just started to be considered and pursued. The idea that the human atherosclerotic plaques could regress at all met an important resistance over the decades; indeed, advanced plaques contain components, such as necrosis, calcification and fibrosis, which are hard to be removed. However, new animal models and imaging technics allowed a more complete and accurate quantitative assessment of plaque volume and are shedding new light on atherosclerosis regression. In this review, we are revisiting the existence of atherosclerosis regression in preclinical and clinical studies, with a focus on the latest mechanistic insights and on the newest pharmacological agents, particularly in patients with diabetes. Interestingly, we suggested that based on literature insights and preclinical studies, a combination of drugs to target hyperglycemia, dyslipidemia and inflammation may be desirable for a fast-track Pharmacological regression of atherosclerotic plaque in patients with type 2 diabetes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107635"},"PeriodicalIF":9.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348348","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

Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-03 DOI: 10.1016/j.phrs.2025.107643

Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li

Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

{"title":"Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells","authors":"Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li","doi":"10.1016/j.phrs.2025.107643","DOIUrl":"10.1016/j.phrs.2025.107643","url":null,"abstract":"<div><div>Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107643"},"PeriodicalIF":9.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256321","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

Butyrate-engineered yeast activates Nppa and Sgcg genes and reduces radiation-induced heart damage via the gut-heart axis

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-03 DOI: 10.1016/j.phrs.2025.107642

Jiahao Wu , Kaihua Ji , Guangbo Kang , Manman Zhang , Jigang Wang , Lina Wang , Mengxue Gao , Xiaoxiao Jia , Xinran Lu , Yan Wang , Xinran Gao , Yufei Guo , Zhixin Zhu , Qinghua Wang , Zhenyu Zhao , Qiang Liu , He Huang

Radiotherapy is a method of treating cancer through radiation aimed at killing cancer cells or inhibiting their growth. However, radiotherapy has numerous side effects because it kills tumors while causing damage to normal cells or tissues. The literature shows that radiation can cause damage to heart tissue. This study found that engineered yeast that produced butyrate can maintain small intestinal barrier function by recovering GPR109A to reduce intestinal damage caused by abdominal irradiation in mice. We unexpectedly found that engineered yeast could mitigate irradiation-induced heart damage via the gut-heart axis. Mechanistically, engineered yeast enhanced taurine and nicotinamide metabolism by increasing the relative abundance of Akkermansia and Lachnospiraceae_NK4A136; then, yeast modulated cardiac function by activating the Sgcg and Nppa genes to attenuate cardiac damage induced by abdominal irradiation. Finally, we confirmed that engineered yeast mitigated cardiac damage caused by total body irradiation, which protected other vital organs through the intestinal tract. This study has a profound impact on cancer treatment, the emergence of engineered yeast will alleviate radiotherapy side effects and benefit patients.

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引用次数: 0

A comprehensive review on the plant sources, pharmacological activities and pharmacokinetic characteristics of Syringaresinol 丁香皂苷醇的植物来源、药理活性及药动学研究综述。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2024.107572

Lei Zhang, Yuqing Tian, Lingling Zhang, Huanyu Zhang, Jinghua Yang, Yi Wang, Na Lu, Wei Guo, Liang Wang

Syringaresinol, a phytochemical constituent belonging to lignan, is formed from two sinapyl alcohol units linked via a β-β linkage, which can be found in a wide variety of cereals and medicinal plants. Medical researches revealed that Syringaresinol possesses a broad spectrum of biological activities, including anti-inflammatory, anti-oxidation, anticancer, antibacterial, antiviral, neuroprotection, and vasodilation effects. These pharmacological properties lay the foundation for its use in treating various diseases such as inflammatory diseases, neurodegenerative disorders, diabetes and its complication, skin disorders, cancer, cardiovascular, and cerebrovascular diseases. As the demand for natural therapeutics increases, Syringaresinol has garnered significant attention for its pharmacological properties. Despite the extensive literature that highlights the various biological activities of this molecule, the underlying mechanisms and the interrelationships between these activities are rarely addressed from a comprehensive perspective. Moreover, no thorough comprehensive summary and evaluation of Syringaresinol has been conducted to offer recommendations for potential future clinical trials and therapeutic applications of this bioactive compound. Thus, a comprehensive review on Syringaresinol is essential to advance scientific understanding, assess its therapeutic applications, ensure safety, and guide future research efforts. This will ultimately contribute to its potential integration into clinical practice and public health. This study aims to provide a comprehensive overview of Syringaresinol on its sources and biological activities to provide insights into its therapeutic potential, and to provide a basis for high-quality studies to determine the clinical efficacy of this compound. Additionally, we explored the pharmacokinetics, toxicology, and drug development aspects of Syringaresinol to guide future research efforts. The review also discussed the limitations of current research on Syringaresinol and put forward some new perspectives and challenges, which laid a solid foundation for further study on clinical application and new drug development of Syringaresinol in the future.

丁香皂苷醇是木脂素的一种植物化学成分，由两个丁香醇单元通过β-β键连接而成，可以在各种谷物和药用植物中发现。医学研究表明丁香甲醇具有广泛的生物活性，包括抗炎、抗氧化、抗癌、抗菌、抗病毒、神经保护和血管舒张作用。这些药理特性为其用于治疗各种疾病，如炎症性疾病、神经退行性疾病、糖尿病及其并发症、皮肤病、癌症、心脑血管疾病奠定了基础。随着对天然疗法需求的增加，丁香甲醇因其药理特性而引起了人们的极大关注。尽管大量文献强调了该分子的各种生物活性，但其潜在机制和这些活性之间的相互关系很少从全面的角度加以解决。此外，目前还没有对丁香皂苷醇进行全面的总结和评价，为今后的临床试验和治疗应用提供建议。因此，对丁香甲醇进行全面的综述对于促进科学认识、评估其治疗应用、确保安全性和指导未来的研究工作至关重要。这最终将有助于将其纳入临床实践和公共卫生。本研究旨在全面综述丁香甲醇的来源及生物活性，深入了解其治疗潜力，为确定其临床疗效的高质量研究提供依据。此外，我们还探讨了丁香甲醇的药代动力学、毒理学和药物开发方面的问题，以指导未来的研究工作。本文还讨论了丁香甲醇目前研究的局限性，并提出了一些新的研究方向和挑战，为今后进一步研究丁香甲醇的临床应用和新药开发奠定了坚实的基础。

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引用次数: 0

Ginsenoside Rg1: A bioactive therapeutic agent for diverse liver diseases 人参皂苷Rg1：多种肝脏疾病的生物活性治疗剂。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2024.107571

Mingyu Wu , Ke Li , Jiabin Wu , Xianyi Ding , Xiaotong Ma , Wenhong Wang , Weihua Xiao

Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (Panax ginseng C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(S)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.

多种肝病具有诊断晚、进展快的特点，已成为威胁人类健康的主要疾病之一。为了延缓从良性组织病变到实质性器官损伤的转变，科学家们逐渐将植物中提取的天然化合物作为肝病学领域的补充疗法。人参（Panax Ginseng C. a . Meyer）是一种滋补的传统中草药，天然产物人参皂苷Rg1 （G-Rg1）是一种生物活性较高的20(S)-原人参三醇皂苷。鉴于这些信息，本文旨在总结和讨论G-Rg1在多种肝脏疾病调节中的代谢机制以及提高其生物利用度的措施。G-Rg1作为一种具有多靶点药理作用的中药单体，在缓解酒精性肝病、非酒精性脂肪性肝病、肝纤维化、病毒性肝炎等方面具有显著的治疗效果，其作用机制主要是通过抑制细胞凋亡、增强内源性抗炎抗氧化机制、激活免疫反应、调节外排转运信号等。改善肝脏因脂质沉积、炎症、氧化应激、肝毒性产物积累等引起的病理改变。但G-Rg1生物利用度差的问题必须克服，才能提高其临床应用价值。综上所述，关注G-Rg1的保肝作用将为开发针对肝脏疾病的天然中药资源及其药物提供新的思路。

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引用次数: 0