Francisco Alejandro Lagunas-Rangel, Edgars Liepinsh, Robert Fredriksson, Ahmed M. Alsehli, Michael J. Williams, Maija Dambrova, Jörgen Jönsson, Helgi B. Schiöth
Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.
他汀类药物是最重要的药物类别之一。在这篇分析综述中，我们阐明了他汀类药物在靶向（针对 3-羟基-3-甲基戊二酰辅酶 A 还原酶 [HMGCR]）和非靶向效应方面错综复杂的分子机制和毒理学原理。他汀类药物与许多膜激酶（如表皮生长因子受体（EGFR）、erb-b2 受体酪氨酸激酶 2（HER2）和 MET 原癌基因、受体酪氨酸激酶（MET））以及细胞膜激酶（如 SRC 原癌基因、非受体酪氨酸激酶（Src））相互作用，并在纳摩尔浓度下显示出抑制活性。此外，在浓度较高时，它们还与钙 ATP 酶和过氧化物酶体增殖激活受体 α（PPARα/NR1C1）相互作用。他汀类药物与线粒体复合物 III 和 IV 相互作用，抑制辅酶 Q10 的合成也会损害复合物 I 和 II 的功能。他汀类药物是激酶、钙离子 ATP 酶和线粒体复合物的抑制剂，同时激活 PPARα。这些脱靶效应可能是他汀类药物治疗患者出现副作用的原因，包括肌肉骨骼症状和肝脏效应。有趣的是，他汀类药物的某些脱靶效应也可能是产生良好疗效的原因，这与他汀类药物在炎症性疾病和癌症等疾病中的再利用有关。
{"title":"Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases","authors":"Francisco Alejandro Lagunas-Rangel, Edgars Liepinsh, Robert Fredriksson, Ahmed M. Alsehli, Michael J. Williams, Maija Dambrova, Jörgen Jönsson, Helgi B. Schiöth","doi":"10.1111/bph.17309","DOIUrl":"10.1111/bph.17309","url":null,"abstract":"<p>Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 20","pages":"3799-3818"},"PeriodicalIF":6.8,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046362","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}
Hongtao Yu, Peter J. Greasley, Hiddo J. Lambers Heerspink, Philip Ambery, Christine Ahlstrom, Bengt Hamren, Anis A. Khan, David W. Boulton, K. Melissa Hallow
Background and Purpose
Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging.
Approach
We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR).
Background and Key Results
An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR.
Conclusions and Impact
These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.
{"title":"The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial","authors":"Hongtao Yu, Peter J. Greasley, Hiddo J. Lambers Heerspink, Philip Ambery, Christine Ahlstrom, Bengt Hamren, Anis A. Khan, David W. Boulton, K. Melissa Hallow","doi":"10.1111/bph.16504","DOIUrl":"10.1111/bph.16504","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Approach</h3>\u0000 \u0000 <p>We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Key Results</h3>\u0000 \u0000 <p>An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Impact</h3>\u0000 \u0000 <p>These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4693-4707"},"PeriodicalIF":6.8,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003677","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}
Pedro R. J. Almeida, Alexandre M. Periard, Fernanda L. Tana, Renata E. Avila, Larissa B. Milhorato, Katlen M. M. Alcantara, Carolina B. Resende, Angela V. Serufo, Felipe R. Santos, Danielle C. Teixeira, Celso M. Queiroz-Junior, Talita C. M. Fonseca, Barbara L. V. Silva, Vivian V. Costa, Renan P. Souza, Mauro Perretti, Thomas E. N. Jonassen, Mauro M. Teixeira
Introduction
Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19.
Methods
C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg−1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air.
Results
Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1β by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017).
Conclusion
Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.
{"title":"Effects of a pro-resolving drug in COVID-19: preclinical studies to a randomized, placebo-controlled, phase Ib/IIa trial in hospitalized patients","authors":"Pedro R. J. Almeida, Alexandre M. Periard, Fernanda L. Tana, Renata E. Avila, Larissa B. Milhorato, Katlen M. M. Alcantara, Carolina B. Resende, Angela V. Serufo, Felipe R. Santos, Danielle C. Teixeira, Celso M. Queiroz-Junior, Talita C. M. Fonseca, Barbara L. V. Silva, Vivian V. Costa, Renan P. Souza, Mauro Perretti, Thomas E. N. Jonassen, Mauro M. Teixeira","doi":"10.1111/bph.17322","DOIUrl":"10.1111/bph.17322","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg<sup>−1</sup>, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO<sub>2</sub> ≥ 93% in ambient air.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1β by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (<i>P</i> = 0.017).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4750-4765"},"PeriodicalIF":6.8,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cheng Peng, Elizabeth A. Vecchio, Anh T. N. Nguyen, Mia De Seram, Ruby Tang, Peter Keov, Owen L. Woodman, Yung-Chih Chen, Jonathan Baell, Lauren T. May, Peishen Zhao, Rebecca H. Ritchie, Cheng Xue Qin
Background
There is increasing interest in developing FPR2 agonists (compound 43, ACT-389949 and BMS-986235) as potential pro-resolving therapeutics, with ACT-389949 and BMS-986235 having entered phase I clinical development. FPR2 activation leads to diverse downstream outputs. ACT-389949 was observed to cause rapid tachyphylaxis, while BMS-986235 and compound 43 induced cardioprotective effects in preclinical models. We aim to characterise the differences in ligand-receptor engagement and downstream signalling and trafficking bias profile.
Experimental Approach
Concentration-response curves to G protein dissociation, β-arrestin recruitment, receptor trafficking and second messenger signalling were generated using FPR2 ligands (BMS-986235, ACT-389949, compound 43 and WKYMVm), in HEK293A cells. Log(τ/KA) was obtained from the operational model for bias analysis using WKYMVm as a reference ligand. Docking of FPR2 ligands into the active FPR2 cryoEM structure (PDBID: 7T6S) was performed using ICM pro software.
Key Results
Bias analysis revealed that WKYMVm and ACT-389949 shared a very similar bias profile. In comparison, BMS-986235 and compound 43 displayed approximately 5- to 50-fold bias away from β-arrestin recruitment and trafficking pathways, while being 35- to 60-fold biased towards cAMP inhibition and pERK1/2. Molecular docking predicted key amino acid interactions at the FPR2 shared between WKYMVm and ACT-389949, but not with BMS-986235 and compound 43.
Conclusion and Implications
In vitro characterisation demonstrated that WKYMVm and ACT-389949 differ from BMS-986235 and compound 43 in their signalling and protein coupling profile. This observation may be explained by differences in the ligand-receptor interactions. In vitro characterisation provided significant insights into identifying the desired bias profile for FPR2-based pharmacotherapy.
{"title":"Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists","authors":"Cheng Peng, Elizabeth A. Vecchio, Anh T. N. Nguyen, Mia De Seram, Ruby Tang, Peter Keov, Owen L. Woodman, Yung-Chih Chen, Jonathan Baell, Lauren T. May, Peishen Zhao, Rebecca H. Ritchie, Cheng Xue Qin","doi":"10.1111/bph.17310","DOIUrl":"10.1111/bph.17310","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>There is increasing interest in developing FPR2 agonists (compound 43, ACT-389949 and BMS-986235) as potential pro-resolving therapeutics, with ACT-389949 and BMS-986235 having entered phase I clinical development. FPR2 activation leads to diverse downstream outputs. ACT-389949 was observed to cause rapid tachyphylaxis, while BMS-986235 and compound 43 induced cardioprotective effects in preclinical models. We aim to characterise the differences in ligand-receptor engagement and downstream signalling and trafficking bias profile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Concentration-response curves to G protein dissociation, <i>β</i>-arrestin recruitment, receptor trafficking and second messenger signalling were generated using FPR2 ligands (BMS-986235, ACT-389949, compound 43 and WKYMVm), in HEK293A cells. Log(<i>τ</i>/K<sub>A</sub>) was obtained from the operational model for bias analysis using WKYMVm as a reference ligand. Docking of FPR2 ligands into the active FPR2 cryoEM structure (PDBID: 7T6S) was performed using ICM pro software.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Bias analysis revealed that WKYMVm and ACT-389949 shared a very similar bias profile. In comparison, BMS-986235 and compound 43 displayed approximately 5- to 50-fold bias away from <i>β</i>-arrestin recruitment and trafficking pathways, while being 35- to 60-fold biased towards cAMP inhibition and pERK1/2. Molecular docking predicted key amino acid interactions at the FPR2 shared between WKYMVm and ACT-389949, but not with BMS-986235 and compound 43.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p><i>In vitro</i> characterisation demonstrated that WKYMVm and ACT-389949 differ from BMS-986235 and compound 43 in their signalling and protein coupling profile. This observation may be explained by differences in the ligand-receptor interactions. <i>In vitro</i> characterisation provided significant insights into identifying the desired bias profile for FPR2-based pharmacotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4677-4692"},"PeriodicalIF":6.8,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999427","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}
Xinyi Qiao, Ke Zheng, Lei Ye, Jin Yang, Rong Cui, Yuanyuan Shan, Xiaoheng Li, Huitao Li, Qiqi Zhu, Zhiguang Zhao, Ren-shan Ge, Yiyan Wang
Background and Purpose
Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer.
Experimental Approach
NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses.
Key Results
Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 μM vs. 35.45 μM) and DU145 (IC50, 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3.
Conclusion and Implications
NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.
背景和目的：前列腺癌仍然是全球主要的公共卫生负担。Polo like kinase 4（PLK4）在细胞周期调控和肿瘤进展中起着关键作用，因此已成为前列腺癌的一个有希望的治疗靶点。本研究旨在开发和鉴定新型姜黄素类似物 NL13，将其作为一种潜在的前列腺癌治疗剂和 PLK4 抑制剂：实验方法：合成 NL13，并在前列腺癌细胞和小鼠异种移植模型中评估其效果。基因组筛选和分子建模确定 PLK4 为主要靶点。通过细胞周期、细胞凋亡、基因和蛋白质分析探讨了抗增殖和促凋亡机制：与姜黄素相比，NL13在抑制PC3（IC50，3.51 μM vs. 35.45 μM）和DU145（IC50，2.53 μM vs. 29.35 μM）前列腺癌细胞活力和PLK4激酶活性（2.32 μM vs. 246.88 μM）方面表现出更强的效力。NL13通过下调CCNB1/CDK1诱导G2/M细胞周期停滞，并通过caspase-9/caspase-3裂解引发细胞凋亡。这些效应由 PLK4 抑制介导，从而导致 AKT 信号通路失活。在小鼠体内，NL13能显著抑制肿瘤生长，并调节与体外研究结果一致的分子标记物，包括降低p-AKT和增加裂解的caspase-9/3：NL13是一种新型PLK4靶向姜黄素类似物，通过破坏PLK4-AKT-CNB1/CDK1和细胞凋亡通路，对前列腺癌具有良好的抗癌作用。NL13 是一种很有前景的前列腺癌治疗新药。
{"title":"NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models","authors":"Xinyi Qiao, Ke Zheng, Lei Ye, Jin Yang, Rong Cui, Yuanyuan Shan, Xiaoheng Li, Huitao Li, Qiqi Zhu, Zhiguang Zhao, Ren-shan Ge, Yiyan Wang","doi":"10.1111/bph.16501","DOIUrl":"10.1111/bph.16501","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC<sub>50</sub>, 3.51 μM vs. 35.45 μM) and DU145 (IC<sub>50</sub>, 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with <i>in vitro</i> findings, including decreased p-AKT and increased cleaved caspase-9/3.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4658-4676"},"PeriodicalIF":6.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ian Sayers, Dhruma Thakker, Charlotte Billington, Stefan Kreideweiss, Marc A. Grundl, Thierry Bouyssou, Sven Thamm, Sebastian Kreuz, Ian P. Hall
Background and Purpose
Toll-like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important regulator of signalling by toll-like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling.
Experimental Approach
We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways.
Key Results
We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor-α (TNF-α) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase-dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)-induced airway inflammation in wild-type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7/8 stimulation in human lung tissue studied ex vivo.
Conclusion and Implications
These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.
{"title":"Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs","authors":"Ian Sayers, Dhruma Thakker, Charlotte Billington, Stefan Kreideweiss, Marc A. Grundl, Thierry Bouyssou, Sven Thamm, Sebastian Kreuz, Ian P. Hall","doi":"10.1111/bph.16509","DOIUrl":"10.1111/bph.16509","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Toll-like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important regulator of signalling by toll-like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor-α (TNF-α) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase-dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)-induced airway inflammation in wild-type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7/8 stimulation in human lung tissue studied ex vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4647-4657"},"PeriodicalIF":6.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975085","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}
Xin Wang, Angelo A. Izzo, Andreas Papapetropoulos, Steve P. H. Alexander, Miriam Cortese-Krott, Dave A. Kendall, Kirill A. Martemyanov, Claudio Mauro, Reynold A. Panettieri Jr, Hemal H. Patel, Rainer Schulz, Barbara Stefanska, Gary J. Stephens, Mauro M. Teixeira, Nathalie Vergnolle, Péter Ferdinandy
Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare.
{"title":"Natural product pharmacology: the British Journal of Pharmacology perspective","authors":"Xin Wang, Angelo A. Izzo, Andreas Papapetropoulos, Steve P. H. Alexander, Miriam Cortese-Krott, Dave A. Kendall, Kirill A. Martemyanov, Claudio Mauro, Reynold A. Panettieri Jr, Hemal H. Patel, Rainer Schulz, Barbara Stefanska, Gary J. Stephens, Mauro M. Teixeira, Nathalie Vergnolle, Péter Ferdinandy","doi":"10.1111/bph.17300","DOIUrl":"10.1111/bph.17300","url":null,"abstract":"<p>Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 <i>British Journal of Pharmacology</i> (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 19","pages":"3547-3555"},"PeriodicalIF":6.8,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916113","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}
Sun Ruixin, Liu Yifan, Sun Yansha, Zhou Min, Dong Yiwei, Hu Xiaoli, Shi Bizhi, Jiang Hua, Li Zonghai
Background and Purpose
Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs.
Experimental Approach
In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo.
Key Results
Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-β dependent manner.
Conclusion and Implications
The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.
{"title":"Dual targeting chimeric antigen receptor cells enhance antitumour activity by overcoming T cell exhaustion in pancreatic cancer","authors":"Sun Ruixin, Liu Yifan, Sun Yansha, Zhou Min, Dong Yiwei, Hu Xiaoli, Shi Bizhi, Jiang Hua, Li Zonghai","doi":"10.1111/bph.16505","DOIUrl":"10.1111/bph.16505","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8<sup>+</sup> T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-β dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4628-4646"},"PeriodicalIF":6.8,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amit Kumar, Zoe F. Mark, Morgan P. Carbajal, Dhemerson Souza DeLima, Nicolas Chamberlain, Joseph Walzer, Mona Ruban, Ravishankar Chandrasekaran, Nirav Daphtary, Minara Aliyeva, Matthew E. Poynter, Yvonne M. W. Janssen-Heininger, Jason H. Bates, John F. Alcorn, Clemente J. Britto, Charles S. Dela Cruz, Anil G. Jegga, Vikas Anathy
Background and Purpose
Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral–fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling.
Experimental Approach
A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model.
Key Results
The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1.
Conclusion and Implications
The PDIA3–SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.
{"title":"The protein disulfide isomerase A3 and osteopontin axis promotes influenza-induced lung remodelling","authors":"Amit Kumar, Zoe F. Mark, Morgan P. Carbajal, Dhemerson Souza DeLima, Nicolas Chamberlain, Joseph Walzer, Mona Ruban, Ravishankar Chandrasekaran, Nirav Daphtary, Minara Aliyeva, Matthew E. Poynter, Yvonne M. W. Janssen-Heininger, Jason H. Bates, John F. Alcorn, Clemente J. Britto, Charles S. Dela Cruz, Anil G. Jegga, Vikas Anathy","doi":"10.1111/bph.16511","DOIUrl":"10.1111/bph.16511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral–fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The PDIA3–SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4610-4627"},"PeriodicalIF":6.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905999","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}
Huanyu Ding, Minchun Jiang, Andrew M Chan, Yin Xia, Ronald C W Ma, Xiaoqiang Yao, Li Wang, Yu Huang
Background and purpose: Previous studies have shown that Src can regulate inflammation and tumour progression. However, the mechanisms by which Src regulates the inflammatory response of vascular endothelium and atherogenesis are currently poorly understood. This study aimed to investigate the role of Src in endothelial inflammation and atherogenesis, as well as the underlying mechanisms.
Experimental approach: Real-time quantitative PCR was used to measure the mRNA levels of inflammatory genes. The phosphorylation and localization of proteins were examined using western blotting and immunofluorescence, respectively. The level of p-Src Y416 in mouse endothelium was directly determined using en face staining. Endothelial-specific knockdown of Src was achieved by tail vein injection of AAV-sgSrc in ApoE-/-; Cas9LSL/LSL; Cdh5-cre mice. Atherosclerosis was induced by partial ligation of the carotid artery.
Key results: Oscillatory shear stress (OSS) promotes the phosphorylation of Src at Y416 in endothelial cells, and Piezo1 is required for this regulatory process. Overexpression of constitutively active Src promotes endothelial inflammation, as well as phosphorylation of Stat3 (at Y705) and its nuclear translocation. Endothelial inflammation induced by OSS was abolished by the Src inhibitor dasatinib or si-Src. Dasatinib, when administered orally, reduced endothelial inflammation and plaque formation in ApoE-/- mice induced by partial carotid artery ligation. Additionally, plaque formation was decreased in the ligated left carotid artery of mice with endothelial-specific Src knockdown.
Conclusion and implications: Disturbed flow promotes endothelial inflammation and atherogenesis through the Piezo1-Src-Stat3 pathway. Therefore, inhibiting Src in endothelial cells could be a promising therapeutic strategy to treat atherogenesis.
{"title":"Targeting the tyrosine kinase Src in endothelium attenuates inflammation and atherogenesis induced by disturbed flow.","authors":"Huanyu Ding, Minchun Jiang, Andrew M Chan, Yin Xia, Ronald C W Ma, Xiaoqiang Yao, Li Wang, Yu Huang","doi":"10.1111/bph.17307","DOIUrl":"https://doi.org/10.1111/bph.17307","url":null,"abstract":"<p><strong>Background and purpose: </strong>Previous studies have shown that Src can regulate inflammation and tumour progression. However, the mechanisms by which Src regulates the inflammatory response of vascular endothelium and atherogenesis are currently poorly understood. This study aimed to investigate the role of Src in endothelial inflammation and atherogenesis, as well as the underlying mechanisms.</p><p><strong>Experimental approach: </strong>Real-time quantitative PCR was used to measure the mRNA levels of inflammatory genes. The phosphorylation and localization of proteins were examined using western blotting and immunofluorescence, respectively. The level of p-Src Y416 in mouse endothelium was directly determined using en face staining. Endothelial-specific knockdown of Src was achieved by tail vein injection of AAV-sgSrc in ApoE<sup>-/-</sup>; Cas9<sup>LSL/LSL</sup>; Cdh5-cre mice. Atherosclerosis was induced by partial ligation of the carotid artery.</p><p><strong>Key results: </strong>Oscillatory shear stress (OSS) promotes the phosphorylation of Src at Y416 in endothelial cells, and Piezo1 is required for this regulatory process. Overexpression of constitutively active Src promotes endothelial inflammation, as well as phosphorylation of Stat3 (at Y705) and its nuclear translocation. Endothelial inflammation induced by OSS was abolished by the Src inhibitor dasatinib or si-Src. Dasatinib, when administered orally, reduced endothelial inflammation and plaque formation in ApoE<sup>-/-</sup> mice induced by partial carotid artery ligation. Additionally, plaque formation was decreased in the ligated left carotid artery of mice with endothelial-specific Src knockdown.</p><p><strong>Conclusion and implications: </strong>Disturbed flow promotes endothelial inflammation and atherogenesis through the Piezo1-Src-Stat3 pathway. Therefore, inhibiting Src in endothelial cells could be a promising therapeutic strategy to treat atherogenesis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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