Pub Date : 2024-09-01Epub Date: 2024-07-04DOI: 10.1007/s12012-024-09887-w
Russell Hunter, Thomas Wilson, Selita Lucas, David Scieszka, Barry Bleske, Andrew Ottens, Ryan Ashley, Carolyn Pace, Nancy Kanagy, Matthew Campen
The contribution of air pollution-induced cardiopulmonary damage on the development of hypertensive disorders of pregnancy and other adverse outcomes of pregnancy has gained increased attention as epidemiological data continue to highlight spatiotemporal pregnancy trends related to air pollution exposure. However clinical mechanistic data surrounding gestational complications remain sparse, necessitating the need for the use of animal models to study these types of complications of pregnancy. The current study seeks to examine the real-time effects of mid-gestational ozone exposure on maternal blood pressure and body temperature through the use of radiotelemetry in a rat model. The exposure resulted in acute depression of heart rate and core body temperature as compared to control animals. Ozone-exposed animals also presented with a slight but significant increase in arterial blood pressure which was perpetuated until term. The data presented here illustrates the feasibility of murine models to assess cardiovascular complications caused by inhaled toxicants during the window of pregnancy.
{"title":"Characterization of Mild Delayed Gestational Hypertension in Rats Following Ozone Exposure.","authors":"Russell Hunter, Thomas Wilson, Selita Lucas, David Scieszka, Barry Bleske, Andrew Ottens, Ryan Ashley, Carolyn Pace, Nancy Kanagy, Matthew Campen","doi":"10.1007/s12012-024-09887-w","DOIUrl":"10.1007/s12012-024-09887-w","url":null,"abstract":"<p><p>The contribution of air pollution-induced cardiopulmonary damage on the development of hypertensive disorders of pregnancy and other adverse outcomes of pregnancy has gained increased attention as epidemiological data continue to highlight spatiotemporal pregnancy trends related to air pollution exposure. However clinical mechanistic data surrounding gestational complications remain sparse, necessitating the need for the use of animal models to study these types of complications of pregnancy. The current study seeks to examine the real-time effects of mid-gestational ozone exposure on maternal blood pressure and body temperature through the use of radiotelemetry in a rat model. The exposure resulted in acute depression of heart rate and core body temperature as compared to control animals. Ozone-exposed animals also presented with a slight but significant increase in arterial blood pressure which was perpetuated until term. The data presented here illustrates the feasibility of murine models to assess cardiovascular complications caused by inhaled toxicants during the window of pregnancy.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-24DOI: 10.1007/s12012-024-09894-x
Reda A Ali, Eatemad A Awadalla, Amal S Hamed, Dalia Elzahraa F Mostafa
Cadmium (Cd) is a dangerous heavy metal that is non-degradable in the environment. Many organs can accumulate Cd and adversely affect organ function and health. Cd is considered as a teratogenic and embryotoxic agent. This study aims to evaluate the teratogenicity of Cd at concentrations lesser than the permissible and its effects on the heart during chick embryogenesis. Fertilized eggs of the chick Gallus domesticus were divided into; control, saline injected and four experimental groups injected with single doses of 5, 25, 50 or 75 µM of CdCl2. Histological observations of the heart before hatching and the cardiomyocytes after hatching were recorded. Morphometric measurements of heart chambers were achieved at 3, 4 and 6 days of incubation. Electrocardiograph and respiratory rate were recorded at tenth day. Different cardiac problems had been brought on by Cd. In comparison to controls, the heart looked much larger, and in certain cases, growth retardation was seen. Degeneration in heart walls and malformations of dorsal aorta were noticed. Morphometrically, the width and wall thickness of heart chambers showed significant changes. Heart beats and respiratory rate significantly decreased compared to control. The cardiotoxic effect of Cd on heart compartments structure and function was dose dependent. One of Cd toxicity is its ability to induce cellular oxidative stress. The heart in particular is sensitive to oxidative stress. Cardiac oxidative stress might intensify heart failure and promote disease progression. Calcium is one of the components that is needed for normal heart work. Cd might interfere with calcium metabolism by removing it from the body.
{"title":"Cardiotoxicity of Cadmium and Its Effects on Heart Efficiency During Early and Late Chick Embryogenesis.","authors":"Reda A Ali, Eatemad A Awadalla, Amal S Hamed, Dalia Elzahraa F Mostafa","doi":"10.1007/s12012-024-09894-x","DOIUrl":"10.1007/s12012-024-09894-x","url":null,"abstract":"<p><p>Cadmium (Cd) is a dangerous heavy metal that is non-degradable in the environment. Many organs can accumulate Cd and adversely affect organ function and health. Cd is considered as a teratogenic and embryotoxic agent. This study aims to evaluate the teratogenicity of Cd at concentrations lesser than the permissible and its effects on the heart during chick embryogenesis. Fertilized eggs of the chick Gallus domesticus were divided into; control, saline injected and four experimental groups injected with single doses of 5, 25, 50 or 75 µM of CdCl<sub>2</sub>. Histological observations of the heart before hatching and the cardiomyocytes after hatching were recorded. Morphometric measurements of heart chambers were achieved at 3, 4 and 6 days of incubation. Electrocardiograph and respiratory rate were recorded at tenth day. Different cardiac problems had been brought on by Cd. In comparison to controls, the heart looked much larger, and in certain cases, growth retardation was seen. Degeneration in heart walls and malformations of dorsal aorta were noticed. Morphometrically, the width and wall thickness of heart chambers showed significant changes. Heart beats and respiratory rate significantly decreased compared to control. The cardiotoxic effect of Cd on heart compartments structure and function was dose dependent. One of Cd toxicity is its ability to induce cellular oxidative stress. The heart in particular is sensitive to oxidative stress. Cardiac oxidative stress might intensify heart failure and promote disease progression. Calcium is one of the components that is needed for normal heart work. Cd might interfere with calcium metabolism by removing it from the body.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 μg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.
{"title":"Activation AMPK in Hypothalamic Paraventricular Nucleus Improves Renovascular Hypertension Through ERK1/2-NF-κB Pathway.","authors":"Li-Yan Fu, Yu Yang, Rui-Juan Li, Abdoulaye Issotina Zibrila, Hua Tian, Xiu-Yue Jia, Jin-An Qiao, Jin-Min Wu, Jie Qi, Xiao-Jing Yu, Yu-Ming Kang","doi":"10.1007/s12012-024-09888-9","DOIUrl":"10.1007/s12012-024-09888-9","url":null,"abstract":"<p><p>Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 μg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-16DOI: 10.1007/s12012-024-09896-9
Mohammad Shabani, Saleh Khezri, Ahmad Salimi
The hallmark of aluminum phosphide (AlP) poisoning is heart failure in victims which is associated with reactive oxygen species (ROS), mitochondrial dysfunction, oxidative stress, alteration in antioxidant defense system and depletion of ATP in cardiomyocytes. In the present study, we hypothesized that the injection of isolated mitochondria into blood or mitochondrial transplantation can likely create a primary target for phosphine released from AlP and inhibit AlP-induced mortality and cardiotoxicity in rat. Male, Wistar, healthy and adult rats were randomly divided into 5 groups as control, AlP (12.5 mg/kg, orally), AlP + mitochondria (125 µg/kg), AlP + mitochondria (250 µg/kg) and mitochondria (250 µg/kg) alone. Functional and intact mitochondria isolated from rat heart and transplantation was carried out via tail vein, 30 min after exposure to AlP. Survival rate, histopathological alterations, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters were monitored and analyzed during 30 days. We found that injection of healthy mitochondria into blood at concentrations of 125 and 250 125 µg/ml significantly increased the survival of rats up to 40% and 56.25% respectively, during 30 days. Moreover, we observed that mitochondria injection into blood decreased histopathological damages, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters. To our knowledge, the current study is the first report in the literature that demonstrated good therapeutic effects of mitochondrial transplantation in AlP-induced mortality and cardiotoxicity. The findings of the present study suggests that injection of exogenous mitochondria into blood could be an effective therapeutic strategy in treating AlP poisoning.
磷化铝(AlP)中毒的特征是受害者心力衰竭,这与活性氧(ROS)、线粒体功能障碍、氧化应激、抗氧化防御系统的改变以及心肌细胞中 ATP 的耗竭有关。在本研究中,我们假设向血液中注入分离的线粒体或线粒体移植可能会成为 AlP 释放的磷化氢的主要靶点,并抑制 AlP 引起的大鼠死亡和心脏毒性。健康成年雄性 Wistar 大鼠被随机分为 5 组,分别为对照组、AlP 组(12.5 毫克/千克,口服)、AlP + 线粒体组(125 微克/千克)、AlP + 线粒体组(250 微克/千克)和单独线粒体组(250 微克/千克)。从大鼠心脏中分离出功能完整的线粒体,并在接触 AlP 30 分钟后通过尾静脉进行移植。在 30 天内对存活率、组织病理学改变、心脏生化指标、氧化应激和线粒体毒性参数进行了监测和分析。我们发现,向血液中注射浓度为 125 和 250 125 µg/ml 的健康线粒体可显著提高大鼠的存活率,30 天内存活率分别达到 40% 和 56.25%。此外,我们还观察到,向血液中注入线粒体可减少组织病理学损伤、心脏生化指标、氧化应激和线粒体毒性参数。据我们所知,本研究是文献中首次报道线粒体移植对 AlP 引起的死亡和心脏毒性有良好的治疗效果。本研究结果表明,向血液中注入外源性线粒体可能是治疗 AlP 中毒的一种有效治疗策略。
{"title":"Mitotherapy with Fresh Isolated Cardiac Mitochondria Via Injection Into Blood Reduces Aluminum Phosphide-Induced Mortality and Protects Cardiac Tissue Against Oxidative Stress and Mitochondrial Damages.","authors":"Mohammad Shabani, Saleh Khezri, Ahmad Salimi","doi":"10.1007/s12012-024-09896-9","DOIUrl":"10.1007/s12012-024-09896-9","url":null,"abstract":"<p><p>The hallmark of aluminum phosphide (AlP) poisoning is heart failure in victims which is associated with reactive oxygen species (ROS), mitochondrial dysfunction, oxidative stress, alteration in antioxidant defense system and depletion of ATP in cardiomyocytes. In the present study, we hypothesized that the injection of isolated mitochondria into blood or mitochondrial transplantation can likely create a primary target for phosphine released from AlP and inhibit AlP-induced mortality and cardiotoxicity in rat. Male, Wistar, healthy and adult rats were randomly divided into 5 groups as control, AlP (12.5 mg/kg, orally), AlP + mitochondria (125 µg/kg), AlP + mitochondria (250 µg/kg) and mitochondria (250 µg/kg) alone. Functional and intact mitochondria isolated from rat heart and transplantation was carried out via tail vein, 30 min after exposure to AlP. Survival rate, histopathological alterations, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters were monitored and analyzed during 30 days. We found that injection of healthy mitochondria into blood at concentrations of 125 and 250 125 µg/ml significantly increased the survival of rats up to 40% and 56.25% respectively, during 30 days. Moreover, we observed that mitochondria injection into blood decreased histopathological damages, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters. To our knowledge, the current study is the first report in the literature that demonstrated good therapeutic effects of mitochondrial transplantation in AlP-induced mortality and cardiotoxicity. The findings of the present study suggests that injection of exogenous mitochondria into blood could be an effective therapeutic strategy in treating AlP poisoning.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-14DOI: 10.1007/s12012-024-09879-w
Sol Guerra-Ojeda, Patricia Marchio, Andrea Suarez, Martin Aldasoro, Soraya L Valles, Patricia Genoves, Jose M Vila, Maria D Mauricio
Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.
左旋咪唑是一种仅限于兽医使用的抗蠕虫药物,但目前在欧洲国家被检测出是使用最广泛的可卡因切割剂。掺杂左旋咪唑的可卡因与急性肾损伤有关,其特征是肾小球滤过率下降,这涉及肾血流量减少,但有关左旋咪唑改变肾血管反应的数据很少。我们从健康兔子身上分离出肾动脉,在器官浴中记录等长张力并进行蛋白质分析。我们提供的证据表明,左旋咪唑可作为一种非选择性α肾上腺素能受体阻断剂,并下调α1肾上腺素受体的表达,从而调节肾动脉张力,具体取决于其浓度。此外,左旋咪唑会损害乙酰胆碱诱导的内皮依赖性松弛,但不会改变内皮一氧化氮合酶(eNOS)的表达。然而,暴露于超氧化物歧化酶(SOD)可部分防止左旋咪唑对乙酰胆碱诱导的内皮松弛的损害。这种反应与 SOD1 的下调和 NADPH 氧化酶 4(Nox4)的上调相一致,表明内皮 NO 的损失是由于局部氧化应激增加所致。我们的研究结果表明,左旋咪唑可干扰肾血流和对血管扩张刺激的协调反应,这可能会加重使用可卡因的有害后果。
{"title":"Levamisole Impairs Vascular Function by Blocking α-Adrenergic Receptors and Reducing NO Bioavailability in Rabbit Renal Artery.","authors":"Sol Guerra-Ojeda, Patricia Marchio, Andrea Suarez, Martin Aldasoro, Soraya L Valles, Patricia Genoves, Jose M Vila, Maria D Mauricio","doi":"10.1007/s12012-024-09879-w","DOIUrl":"10.1007/s12012-024-09879-w","url":null,"abstract":"<p><p>Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α<sub>1</sub>-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-25DOI: 10.1007/s12012-024-09878-x
Anatoly Soloviev, Vadym Sydorenko
Oxidative stress results from the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in quantities exceeding the potential activity of the body's antioxidant system and is one of the risk factors for the development of vascular dysfunction in diabetes and exposure to ionizing radiation. Being the secondary products of normal aerobic metabolism in living organisms, ROS and RNS act as signaling molecules that play an important role in the regulation of vital organism functions. Meanwhile, in high concentrations, these compounds are toxic and disrupt various metabolic pathways. The various stress factors (hyperglycemia, gamma-irradiation, etc.) trigger free oxygen and nitrogen radicals accumulation in cells that are capable to damage almost all cellular components including ion channels and transporters such as Na+/K+-ATPase, BKCa, and TRP channels. Vascular dysfunctions are governed by interaction of ROS and RNS. For example, the reaction of ROS with NO produces peroxynitrite (ONOO-), which not only oxidizes DNA, cellular proteins, and lipids, but also disrupts important signaling pathways that regulate the cation channel functions in the vascular endothelium. Further increasing in ROS levels and formation of ONOO- leads to reduced NO bioavailability and causes endothelial dysfunction. Thus, imbalance of ROS and RNS and their affect on membrane ion channels plays an important role in the pathogenesis of vascular dysfunction associated with various disorders.
{"title":"Oxidative and Nitrous Stress Underlies Vascular Malfunction Induced by Ionizing Radiation and Diabetes.","authors":"Anatoly Soloviev, Vadym Sydorenko","doi":"10.1007/s12012-024-09878-x","DOIUrl":"10.1007/s12012-024-09878-x","url":null,"abstract":"<p><p>Oxidative stress results from the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in quantities exceeding the potential activity of the body's antioxidant system and is one of the risk factors for the development of vascular dysfunction in diabetes and exposure to ionizing radiation. Being the secondary products of normal aerobic metabolism in living organisms, ROS and RNS act as signaling molecules that play an important role in the regulation of vital organism functions. Meanwhile, in high concentrations, these compounds are toxic and disrupt various metabolic pathways. The various stress factors (hyperglycemia, gamma-irradiation, etc.) trigger free oxygen and nitrogen radicals accumulation in cells that are capable to damage almost all cellular components including ion channels and transporters such as Na<sup>+</sup>/K<sup>+</sup>-ATPase, BK<sub>Ca</sub>, and TRP channels. Vascular dysfunctions are governed by interaction of ROS and RNS. For example, the reaction of ROS with NO produces peroxynitrite (ONOO<sup>-</sup>), which not only oxidizes DNA, cellular proteins, and lipids, but also disrupts important signaling pathways that regulate the cation channel functions in the vascular endothelium. Further increasing in ROS levels and formation of ONOO<sup>-</sup> leads to reduced NO bioavailability and causes endothelial dysfunction. Thus, imbalance of ROS and RNS and their affect on membrane ion channels plays an important role in the pathogenesis of vascular dysfunction associated with various disorders.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1007/s12012-024-09868-z
Aleksandra Żórawik, Wojciech Hajdusianek, Agnieszka Kusnerż, Iwona Markiewicz-Górka, Aleksandra Jaremków, Helena Martynowicz, Krystyna Pawlas, Grzegorz Mazur, Rafał Poręba, Paweł Gać
Exposure to tobacco smoke (ETS) is one of the main risk factors for cardiovascular disease (CVD). Renalase is a protein that may play a role in the pathogenesis of CVD. The aim of the study was to assess the relationship between ETS and serum renalase concentration. A group of 109 patients was recruited for this study (49.7 ± 14.7 years). In accordance with the questionnaire, patients were divided into the following subgroups: subgroup A- declaring themselves active smokers (n = 36), subgroup B- declaring themselves non-smokers and exposed to environmental tobacco smoke (n = 35), subgroup C- declaring themselves non-smokers and not exposed to environmental tobacco smoke (n = 38). The same patients were divided based on cotinine concentration into the following subgroups: subgroup D- active smokers (n = 42), subgroup E- non-smokers exposed to environmental tobacco smoke (n = 66), and subgroup F- non-smokers not exposed to environmental tobacco smoke (n = 1). Serum cotinine concentration and serum renalase concentration were measured using ELISA tests. Serum renalase concentration was statistically significantly higher in subgroup C than in subgroups A and B and in subgroup E and F than in D. There was a negative correlation between serum cotinine concentration and serum renalase concentration (r = -0.41, p < 0.05). Regression analysis showed that higher BMI, higher diastolic blood pressure, coronary artery disease and higher serum cotinine concentration are independent risk factors of lower serum renalase concentration. The questionnaire method of assessing exposure to tobacco smoke was characterized by high sensitivity, but only moderate specificity, especially in terms of assessing environmental exposure to tobacco smoke. In summary, the study showed an independent relationship between exposure to tobacco smoke and lower serum renalase concentration.
接触烟草烟雾(ETS)是心血管疾病(CVD)的主要风险因素之一。肾酶是一种可能在心血管疾病发病机制中发挥作用的蛋白质。本研究旨在评估 ETS 与血清肾酶浓度之间的关系。本研究共招募了 109 名患者(49.7 ± 14.7 岁)。根据调查问卷,患者被分为以下几个亚组:A 亚组--自称积极吸烟者(36 人);B 亚组--自称不吸烟且暴露于环境烟草烟雾(35 人);C 亚组--自称不吸烟且未暴露于环境烟草烟雾(38 人)。同样的患者根据可替宁浓度被分为以下亚组:D亚组--活跃吸烟者(n = 42),E亚组--未接触环境烟草烟雾的非吸烟者(n = 66),F亚组--未接触环境烟草烟雾的非吸烟者(n = 1)。血清可替宁浓度和血清肾酶浓度采用酶联免疫吸附试验进行测定。据统计,C 亚组的血清肾酶浓度明显高于 A 和 B 亚组,E 和 F 亚组的血清肾酶浓度明显高于 D 亚组。
{"title":"Relation Between Exposure to Tobacco Smoke Assessed by Serum Cotinine Concentration and Questionnaire Method, and Serum Renalase Concentration-the Importance of the Coexistence of Arterial Hypertension and Other Cardiovascular Diseases.","authors":"Aleksandra Żórawik, Wojciech Hajdusianek, Agnieszka Kusnerż, Iwona Markiewicz-Górka, Aleksandra Jaremków, Helena Martynowicz, Krystyna Pawlas, Grzegorz Mazur, Rafał Poręba, Paweł Gać","doi":"10.1007/s12012-024-09868-z","DOIUrl":"10.1007/s12012-024-09868-z","url":null,"abstract":"<p><p>Exposure to tobacco smoke (ETS) is one of the main risk factors for cardiovascular disease (CVD). Renalase is a protein that may play a role in the pathogenesis of CVD. The aim of the study was to assess the relationship between ETS and serum renalase concentration. A group of 109 patients was recruited for this study (49.7 ± 14.7 years). In accordance with the questionnaire, patients were divided into the following subgroups: subgroup A- declaring themselves active smokers (n = 36), subgroup B- declaring themselves non-smokers and exposed to environmental tobacco smoke (n = 35), subgroup C- declaring themselves non-smokers and not exposed to environmental tobacco smoke (n = 38). The same patients were divided based on cotinine concentration into the following subgroups: subgroup D- active smokers (n = 42), subgroup E- non-smokers exposed to environmental tobacco smoke (n = 66), and subgroup F- non-smokers not exposed to environmental tobacco smoke (n = 1). Serum cotinine concentration and serum renalase concentration were measured using ELISA tests. Serum renalase concentration was statistically significantly higher in subgroup C than in subgroups A and B and in subgroup E and F than in D. There was a negative correlation between serum cotinine concentration and serum renalase concentration (r = -0.41, p < 0.05). Regression analysis showed that higher BMI, higher diastolic blood pressure, coronary artery disease and higher serum cotinine concentration are independent risk factors of lower serum renalase concentration. The questionnaire method of assessing exposure to tobacco smoke was characterized by high sensitivity, but only moderate specificity, especially in terms of assessing environmental exposure to tobacco smoke. In summary, the study showed an independent relationship between exposure to tobacco smoke and lower serum renalase concentration.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cognitive impairment is a commonly observed complication following myocardial infarction; however, the underlying mechanisms are still not well understood. The most recent research suggests that extracellular signal-regulated kinase (ERK) plays a critical role in the development and occurrence of cognitive dysfunction-related diseases. This study aims to explore whether the ERK inhibitor U0126 targets the ERK/Signal Transducer and Activator of Transcription 1 (STAT1) pathway to ameliorate cognitive impairment after myocardial infarction. To establish a mouse model of myocardial infarction, we utilized various techniques including Echocardiography, Hematoxylin-eosin (HE) staining, Elisa, Open field test, Elevated plus maze test, and Western blot analysis to assess mouse cardiac function, cognitive function, and signal transduction pathways. For further investigation into the mechanisms of cognitive function and signal transduction, we administered the ERK inhibitor U0126 via intraperitoneal injection. Reduced total distance and activity range were observed in mice subjected to myocardial infarction during the open field test, along with decreased exploration of the open arms in the elevated plus maze test. However, U0126 treatment exhibited a significant improvement in cognitive decline, indicating a protective effect through the inhibition of the ERK/STAT1 signaling pathway. Hence, this study highlights the involvement of the ERK/STAT1 pathway in regulating cognitive dysfunction following myocardial infarction and establishes U0126 as a promising therapeutic target.
认知功能障碍是心肌梗死后常见的并发症,但其潜在机制仍不十分清楚。最新研究表明,细胞外信号调节激酶(ERK)在认知功能障碍相关疾病的发生和发展中起着关键作用。本研究旨在探讨ERK抑制剂U0126是否能靶向ERK/信号转导和转录激活因子1(STAT1)通路,以改善心肌梗死后的认知障碍。为了建立心肌梗死小鼠模型,我们采用了各种技术,包括超声心动图、血栓素-伊红(HE)染色、Elisa、开阔地试验、高架迷宫试验和 Western 印迹分析,以评估小鼠的心脏功能、认知功能和信号转导通路。为了进一步研究认知功能和信号转导的机制,我们通过腹腔注射ERK抑制剂U0126。我们观察到,心肌梗死小鼠在开阔地测试中的总距离和活动范围都有所减少,同时在高架加迷宫测试中对开阔臂的探索也有所减少。然而,U0126治疗可显著改善认知能力的下降,这表明它通过抑制ERK/STAT1信号通路起到了保护作用。因此,这项研究强调了ERK/STAT1通路参与调节心肌梗死后的认知功能障碍,并将U0126确立为一个有前景的治疗靶点。
{"title":"Inhibition of Extracellular Signal-Regulated Kinase Activity Improves Cognitive Function in Mice Subjected to Myocardial Infarction.","authors":"Yibo Yin, Xin Li, Xiaoxua Zhang, Xinru Yuan, Xingji You, Jingxiang Wu","doi":"10.1007/s12012-024-09877-y","DOIUrl":"10.1007/s12012-024-09877-y","url":null,"abstract":"<p><p>Cognitive impairment is a commonly observed complication following myocardial infarction; however, the underlying mechanisms are still not well understood. The most recent research suggests that extracellular signal-regulated kinase (ERK) plays a critical role in the development and occurrence of cognitive dysfunction-related diseases. This study aims to explore whether the ERK inhibitor U0126 targets the ERK/Signal Transducer and Activator of Transcription 1 (STAT1) pathway to ameliorate cognitive impairment after myocardial infarction. To establish a mouse model of myocardial infarction, we utilized various techniques including Echocardiography, Hematoxylin-eosin (HE) staining, Elisa, Open field test, Elevated plus maze test, and Western blot analysis to assess mouse cardiac function, cognitive function, and signal transduction pathways. For further investigation into the mechanisms of cognitive function and signal transduction, we administered the ERK inhibitor U0126 via intraperitoneal injection. Reduced total distance and activity range were observed in mice subjected to myocardial infarction during the open field test, along with decreased exploration of the open arms in the elevated plus maze test. However, U0126 treatment exhibited a significant improvement in cognitive decline, indicating a protective effect through the inhibition of the ERK/STAT1 signaling pathway. Hence, this study highlights the involvement of the ERK/STAT1 pathway in regulating cognitive dysfunction following myocardial infarction and establishes U0126 as a promising therapeutic target.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aims to investigate the potential role of CYP2D6*10 (c.100 C>T) gene polymorphism in renal function injury among hypertensive patients without elevated cystatin C. A cohort of hypertensive patients without elevated cystatin C was enrolled between 2021 and 2024 in the Fourth Affiliated Hospital of Soochow University, and their peripheral venous blood was used for total RNA extraction and CYP2D6*10 genotype analysis. Based on kidney injury status, patients were categorized into two groups, hypertensive patients with kidney injury (n = 94) and those without (n = 893). General characteristics such as age, gender and hyperlipemia were compared between the two groups. Multiple genotype models were investigated between the two groups, including allele models, dominant models, recessive models, co-dominant models, and super-dominant models. The results revealed that in the co-dominant gene model (CC vs. CT vs. TT), the risk of hypertension combined with renal injury was lower with the CT genotype compared to the CC genotype (Odds Ratio (OR) = 0.55, 95% Confidence Interval (CI) = 0.32-0.93, p = 0.02). In the overdominance model (CC + TT vs. CT), the risk of hypertension and renal injury in CC and CT genotypes was 0.42 times lower than that in the CT genotype (OR = 0.42, 95% CI = 0.27-0.64, p < 0.001). This study proposes CYP2D610 gene polymorphism as a potential predictor of renal function injury in hypertensive patients with normal cystatin C levels.
本研究旨在探讨CYP2D6*10(c.100 C>T)基因多态性在无胱抑素C升高的高血压患者肾功能损伤中的潜在作用。2021年至2024年期间,苏州大学附属第四医院招募了一批无胱抑素C升高的高血压患者,用他们的外周静脉血进行总RNA提取和CYP2D6*10基因型分析。根据肾损伤状况,患者被分为两组,即有肾损伤的高血压患者(94 人)和无肾损伤的高血压患者(893 人)。两组患者的年龄、性别和高脂血症等一般特征进行了比较。研究了两组患者的多种基因型模式,包括等位基因模式、显性模式、隐性模式、共显性模式和超显性模式。结果显示,在共显性基因模型(CC vs. CT vs. TT)中,CT 基因型与 CC 基因型相比,高血压合并肾损伤的风险更低(Odds Ratio (OR) = 0.55, 95% Confidence Interval (CI) = 0.32-0.93, p = 0.02)。在超显性模型(CC + TT vs. CT)中,CC 和 CT 基因型患高血压和肾损伤的风险比 CT 基因型低 0.42 倍(OR = 0.42,95% CI = 0.27-0.64,P = 0.02)。
{"title":"The potential Role of CYP2D6*10(c.100 C>T) Gene Polymorphism in Kidney Injury of Patients with Hypertension Complicated with Non-Elevated Cystatin C.","authors":"Yufeng Jiang, Kuangyi Wang, Xiaofei Mei, Yafeng Zhou","doi":"10.1007/s12012-024-09880-3","DOIUrl":"10.1007/s12012-024-09880-3","url":null,"abstract":"<p><p>This study aims to investigate the potential role of CYP2D6*10 (c.100 C>T) gene polymorphism in renal function injury among hypertensive patients without elevated cystatin C. A cohort of hypertensive patients without elevated cystatin C was enrolled between 2021 and 2024 in the Fourth Affiliated Hospital of Soochow University, and their peripheral venous blood was used for total RNA extraction and CYP2D6*10 genotype analysis. Based on kidney injury status, patients were categorized into two groups, hypertensive patients with kidney injury (n = 94) and those without (n = 893). General characteristics such as age, gender and hyperlipemia were compared between the two groups. Multiple genotype models were investigated between the two groups, including allele models, dominant models, recessive models, co-dominant models, and super-dominant models. The results revealed that in the co-dominant gene model (CC vs. CT vs. TT), the risk of hypertension combined with renal injury was lower with the CT genotype compared to the CC genotype (Odds Ratio (OR) = 0.55, 95% Confidence Interval (CI) = 0.32-0.93, p = 0.02). In the overdominance model (CC + TT vs. CT), the risk of hypertension and renal injury in CC and CT genotypes was 0.42 times lower than that in the CT genotype (OR = 0.42, 95% CI = 0.27-0.64, p < 0.001). This study proposes CYP2D610 gene polymorphism as a potential predictor of renal function injury in hypertensive patients with normal cystatin C levels.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-01DOI: 10.1007/s12012-024-09881-2
Caojian Zuo, Lidong Cai, Ya Li, Chencheng Ding, Guiying Liu, Changmei Zhang, Hexiang Wang, Yang Zhang, Mingyue Ji
Radix Paeoniae Rubra. (Chishao, RPR) and Cortex Moutan. (Mudanpi, CM) are a pair of traditional Chinese medicines that play an important role in the treatment of atherosclerosis (AS). The main objective of this study was to identify potential synergetic function and underlying mechanisms of RPR-CM in the treatment of AS. The main active ingredients, targets of RPR-CM and AS-related genes were obtained from public databases. A Venn diagram was utilized to screen the common targets of RPR-CM in treating AS. The protein-protein interaction network was established based on STRING database. Biological functions and pathways of potential targets were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Cytoscape was used to construct the drug-compound-target-signal pathway network. Molecular docking was performed to verify the binding ability of the bioactive ingredients and the target proteins. The endothelial inflammation model was constructed with human umbilical vein endothelial cells stimulated with ox-LDL, and the function of RPR-CM in treating AS was verified by CCK-8 assay, enzyme-linked immunosorbent assay, and qPCR. In this study, 12 active components and 401 potential target genes of RPR-CM were identified, among which quercetin, kaempferol and baicalein were considered to be the main active components. A total of 1903 AS-related genes were identified through public databases and four GEO datasets (GSE57691, GSE72633, GSE6088 and GSE199819). There are 113 common target genes of RPR-CM in treating AS. PPI network analysis identified 17 genes in cluster 1 as the core targets. Bioinformatics analysis showed that RPR-CM in AS treatment was associated with multiple downstream biological processes and signal pathways. PTGS2, JUN, CASP3, TNF, IL1B, IL6, FOS, STAT1 were identified as the core targets of RPR-CM, and molecular docking showed that the main bioactive components of RPR-CM had good binding ability with the core targets. RPR-CM extract significantly inhibited the levels of inflammatory factors TNF-α, IL-6, IL-1β, MCP-1, VCAM-1 and ICAM-1 in HUVECs, and inhibited endothelial inflammation. This study revealed the active ingredients of RPR-CM, and identified the key downstream targets and signaling pathways in the treatment of AS, providing theoretical basis for the application of RPR-CM in prevention and treatment of AS.
赤芍(赤芍)和牡丹皮(Cortex Moutan.(牡丹皮)是一对传统中药,在治疗动脉粥样硬化(AS)方面发挥着重要作用。本研究的主要目的是确定 RPR-CM 在治疗 AS 方面的潜在协同功能和内在机制。研究人员从公共数据库中获取了 RPR-CM 的主要活性成分、靶点和 AS 相关基因。利用维恩图筛选 RPR-CM 治疗强直性脊柱炎的共同靶点。基于 STRING 数据库建立了蛋白质-蛋白质相互作用网络。通过基因本体论(Gene Ontology)和京都基因组百科全书(Kyoto Encyclopedia of Genes and Genomes)的富集分析,分析了潜在靶点的生物学功能和通路。使用 Cytoscape 构建了药物-化合物-靶点-信号通路网络。通过分子对接验证了生物活性成分与靶蛋白的结合能力。用人脐静脉内皮细胞在 ox-LDL 刺激下构建了内皮炎症模型,并通过 CCK-8 检测法、酶联免疫吸附法和 qPCR 验证了 RPR-CM 治疗强直性脊柱炎的功能。本研究鉴定了 RPR-CM 的 12 种活性成分和 401 个潜在靶基因,其中槲皮素、山柰酚和黄芩苷被认为是主要的活性成分。通过公共数据库和四个 GEO 数据集(GSE57691、GSE72633、GSE6088 和 GSE199819)共鉴定出 1903 个 AS 相关基因。RPR-CM在治疗强直性脊柱炎方面有113个共同的靶基因。PPI网络分析发现第1群组中有17个基因是核心靶点。生物信息学分析表明,RPR-CM在强直性脊柱炎治疗中与多个下游生物过程和信号通路相关。PTGS2、JUN、CASP3、TNF、IL1B、IL6、FOS、STAT1被确定为RPR-CM的核心靶点,分子对接显示RPR-CM的主要生物活性成分与核心靶点具有良好的结合能力。RPR-CM提取物能明显抑制HUVECs中炎症因子TNF-α、IL-6、IL-1β、MCP-1、VCAM-1和ICAM-1的水平,抑制内皮炎症。该研究揭示了RPR-CM的活性成分,确定了其治疗强直性脊柱炎的关键下游靶点和信号通路,为RPR-CM在强直性脊柱炎预防和治疗中的应用提供了理论依据。
{"title":"The Molecular Mechanism of Radix Paeoniae Rubra.-Cortex Moutan. Herb Pair in the Treatment of Atherosclerosis: A Work Based on Network Pharmacology and In Vitro Experiments.","authors":"Caojian Zuo, Lidong Cai, Ya Li, Chencheng Ding, Guiying Liu, Changmei Zhang, Hexiang Wang, Yang Zhang, Mingyue Ji","doi":"10.1007/s12012-024-09881-2","DOIUrl":"10.1007/s12012-024-09881-2","url":null,"abstract":"<p><p>Radix Paeoniae Rubra. (Chishao, RPR) and Cortex Moutan. (Mudanpi, CM) are a pair of traditional Chinese medicines that play an important role in the treatment of atherosclerosis (AS). The main objective of this study was to identify potential synergetic function and underlying mechanisms of RPR-CM in the treatment of AS. The main active ingredients, targets of RPR-CM and AS-related genes were obtained from public databases. A Venn diagram was utilized to screen the common targets of RPR-CM in treating AS. The protein-protein interaction network was established based on STRING database. Biological functions and pathways of potential targets were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Cytoscape was used to construct the drug-compound-target-signal pathway network. Molecular docking was performed to verify the binding ability of the bioactive ingredients and the target proteins. The endothelial inflammation model was constructed with human umbilical vein endothelial cells stimulated with ox-LDL, and the function of RPR-CM in treating AS was verified by CCK-8 assay, enzyme-linked immunosorbent assay, and qPCR. In this study, 12 active components and 401 potential target genes of RPR-CM were identified, among which quercetin, kaempferol and baicalein were considered to be the main active components. A total of 1903 AS-related genes were identified through public databases and four GEO datasets (GSE57691, GSE72633, GSE6088 and GSE199819). There are 113 common target genes of RPR-CM in treating AS. PPI network analysis identified 17 genes in cluster 1 as the core targets. Bioinformatics analysis showed that RPR-CM in AS treatment was associated with multiple downstream biological processes and signal pathways. PTGS2, JUN, CASP3, TNF, IL1B, IL6, FOS, STAT1 were identified as the core targets of RPR-CM, and molecular docking showed that the main bioactive components of RPR-CM had good binding ability with the core targets. RPR-CM extract significantly inhibited the levels of inflammatory factors TNF-α, IL-6, IL-1β, MCP-1, VCAM-1 and ICAM-1 in HUVECs, and inhibited endothelial inflammation. This study revealed the active ingredients of RPR-CM, and identified the key downstream targets and signaling pathways in the treatment of AS, providing theoretical basis for the application of RPR-CM in prevention and treatment of AS.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}