Pub Date : 2023-06-27DOI: 10.53941/ijddp.2023.100002
Haishan Xu, J. Duan, J. Tao, Wen Wang, Yunqing Wu, S. Dai, Jun Ren
Article Oxidized LDL Regulates Endothelin-1 and Oxidative Stress in Vascular Endothelial Cells: Role of Extracellular Regulated Kinase1/2 (ERK1/2) Haishan Xu 1,#, Jinhong Duan 1,#, Jun Tao 2, Wen Wang 3, Yunqing Wu 1,^, Shunling Dai 1,*, and Jun Ren 4,5, 1 Faculty of Basic Medicine, Peking Union Medical College, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005 China 2 Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000 China 3 Department of Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China 4 Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China 5 National Clinical Research Center for Interventional Medicine, Shanghai 200032, China # These two authors contributed equally to this work ^ Deceased * Correspondence: daishunling@aliyun.com (Shunling Dai); corresponding author:jren_aldh2@outlook.com (Jun Ren) Abstract: It is perceived that oxidized low density lipoprotein (oxLDL) perturbs endothelial function and fosters endothelin-1 (ET-1) secretion although the underlying mechanism remains elusive. This study was designed to decipher potential mechanisms underscoring oxLDL-evoked regulation of ET-1 and signaling pathways involved in endothelial cells. ET-1 mRNA expression, secretion and promoter function were determined using RT-PCR, enzyme immunometric and luciferase assays, respectively. GO and GSEA bioinformatics analyses depicted differentially expressed genes (DEGs) mainly associated with cell proliferation, cell division, cellular structure, energy supply, and apoptosis in oxLDL-challenged endothelial cells. Incubation of oxLDL overtly increased ROS production, apoptosis, mRNA level, secretion and promoter activity of ET-1 in human umbilical vein endothelial cells (HUVECs), the effects were mitigated by N-Acetyl Cysteine (NAC). Moreover, oxLDL challenge evoked phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) in HUVECs, the effect was reversed by NAC and MEK inhibitor PD98059. NAC and PD98059 nullified oxLDL- induced rises in mRNA expression, secretion and promoter activity of ET-1. Truncation of 5’-flanking sequence of ET-1 (–566 bpLuc to –250 bpLuc) displayed elevated luciferase activity with 24-h oxLDL incubation. Fusion plasmid from –233 and –185 bp Luc drastically dampened luciferase activity in basal and oxLDL-challenged HUVECs. Transfection of reporter construct –250 bp Luc with a 2 bp mutation at AP-1 locus, removed basal and oxLDL- evoked rises in ET-1 promoter activity. Collectively, our findings support that oxLDL evoked activation of ERK1/2 signaling likely through ROS production, en route to upregulation of endothelial transcriptional factor AP-1, resulting in expression and secretion of ET-1.
{"title":"Oxidized LDL Regulates Endothelin-1 and Oxidative Stress in Vascular Endothelial Cells: Role of Extracellular Regulated Kinase1/2 (ERK1/2)","authors":"Haishan Xu, J. Duan, J. Tao, Wen Wang, Yunqing Wu, S. Dai, Jun Ren","doi":"10.53941/ijddp.2023.100002","DOIUrl":"https://doi.org/10.53941/ijddp.2023.100002","url":null,"abstract":"Article Oxidized LDL Regulates Endothelin-1 and Oxidative Stress in Vascular Endothelial Cells: Role of Extracellular Regulated Kinase1/2 (ERK1/2) Haishan Xu 1,#, Jinhong Duan 1,#, Jun Tao 2, Wen Wang 3, Yunqing Wu 1,^, Shunling Dai 1,*, and Jun Ren 4,5, 1 Faculty of Basic Medicine, Peking Union Medical College, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005 China 2 Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000 China 3 Department of Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China 4 Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China 5 National Clinical Research Center for Interventional Medicine, Shanghai 200032, China # These two authors contributed equally to this work ^ Deceased * Correspondence: daishunling@aliyun.com (Shunling Dai); corresponding author:jren_aldh2@outlook.com (Jun Ren) Abstract: It is perceived that oxidized low density lipoprotein (oxLDL) perturbs endothelial function and fosters endothelin-1 (ET-1) secretion although the underlying mechanism remains elusive. This study was designed to decipher potential mechanisms underscoring oxLDL-evoked regulation of ET-1 and signaling pathways involved in endothelial cells. ET-1 mRNA expression, secretion and promoter function were determined using RT-PCR, enzyme immunometric and luciferase assays, respectively. GO and GSEA bioinformatics analyses depicted differentially expressed genes (DEGs) mainly associated with cell proliferation, cell division, cellular structure, energy supply, and apoptosis in oxLDL-challenged endothelial cells. Incubation of oxLDL overtly increased ROS production, apoptosis, mRNA level, secretion and promoter activity of ET-1 in human umbilical vein endothelial cells (HUVECs), the effects were mitigated by N-Acetyl Cysteine (NAC). Moreover, oxLDL challenge evoked phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) in HUVECs, the effect was reversed by NAC and MEK inhibitor PD98059. NAC and PD98059 nullified oxLDL- induced rises in mRNA expression, secretion and promoter activity of ET-1. Truncation of 5’-flanking sequence of ET-1 (–566 bpLuc to –250 bpLuc) displayed elevated luciferase activity with 24-h oxLDL incubation. Fusion plasmid from –233 and –185 bp Luc drastically dampened luciferase activity in basal and oxLDL-challenged HUVECs. Transfection of reporter construct –250 bp Luc with a 2 bp mutation at AP-1 locus, removed basal and oxLDL- evoked rises in ET-1 promoter activity. Collectively, our findings support that oxLDL evoked activation of ERK1/2 signaling likely through ROS production, en route to upregulation of endothelial transcriptional factor AP-1, resulting in expression and secretion of ET-1.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81139244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-27DOI: 10.53941/ijddp.2023.100005
Jiayu Guo, Yan Wang, Haihai Liang, Baofeng Yang
Review Small Leucine Rich Proteoglycan in Fibrotic Diseases: New Frenemies? Jiayu Guo 1,2, Yan Wang 1,2, Haihai Liang 1,2,3,*, and Baofeng Yang 1,2,3,* 1 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases), College of Pharmacy, Harbin Medical University, Harbin 150081, China 2 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150081, China 3 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China * Correspondence: lianghaihai@ems.hrbmu.edu.cn (H.H.L),; yangbf@ems.hrbmu.edu.cn (B.F.Y) Received: 27 April 2023 Accepted: 2 June 2023 Abstract: The human body is a complex organism with self-regulating ability and can cope with external pressures and challenges. To protect the body from damage during exercise or confrontations, beneath the human epidermal layer, the human body has evolved a coverall gown: the extracellular matrix (ECM). ECM provides a suitable space for the survival and activity of cells in the body, and affects the behavior of cells through signal transduction system. Proteoglycans, particularly the small leucine rich proteoglycan (SLRP) family, have been shown to be molecules that play important roles in matrix remodeling and organ fibrosis, such as by affecting ECM components or altering the intracellular environment. But in recent years reports of SLRP families, their manifestations in different organs have not been consistent. Recent studies suggest that proteoglycans entering the blood in a soluble form hold promise as diagnostic biomarkers of organ fibrosis and may provide novel therapeutic strategies for fibrotic diseases. Herein, we discuss and review studies of SLRPs in multi-organ fibrotic diseases.
{"title":"Small Leucine Rich Proteoglycan in Fibrotic Diseases: New Frenemies?","authors":"Jiayu Guo, Yan Wang, Haihai Liang, Baofeng Yang","doi":"10.53941/ijddp.2023.100005","DOIUrl":"https://doi.org/10.53941/ijddp.2023.100005","url":null,"abstract":"Review\u0000Small Leucine Rich Proteoglycan in Fibrotic Diseases: New Frenemies?\u0000\u0000Jiayu Guo 1,2, Yan Wang 1,2, Haihai Liang 1,2,3,*, and Baofeng Yang 1,2,3,*\u0000\u0000\u00001 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases), College of Pharmacy, Harbin Medical University, Harbin 150081, China\u00002 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150081, China\u00003 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China\u0000* Correspondence: lianghaihai@ems.hrbmu.edu.cn (H.H.L),; yangbf@ems.hrbmu.edu.cn (B.F.Y)\u0000 \u0000 \u0000Received: 27 April 2023\u0000Accepted: 2 June 2023\u0000 \u0000\u0000Abstract: The human body is a complex organism with self-regulating ability and can cope with external pressures and challenges. To protect the body from damage during exercise or confrontations, beneath the human epidermal layer, the human body has evolved a coverall gown: the extracellular matrix (ECM). ECM provides a suitable space for the survival and activity of cells in the body, and affects the behavior of cells through signal transduction system. Proteoglycans, particularly the small leucine rich proteoglycan (SLRP) family, have been shown to be molecules that play important roles in matrix remodeling and organ fibrosis, such as by affecting ECM components or altering the intracellular environment. But in recent years reports of SLRP families, their manifestations in different organs have not been consistent. Recent studies suggest that proteoglycans entering the blood in a soluble form hold promise as diagnostic biomarkers of organ fibrosis and may provide novel therapeutic strategies for fibrotic diseases. Herein, we discuss and review studies of SLRPs in multi-organ fibrotic diseases.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88511823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Review Recent Advances in Natural Plant-based Treatment of Myocardial Ischemia-reperfusion Injury Peixun Yang 1,3,4, Minxuan Liu 2,3,4, Xiaoxue Fan 3,4, Xinzhuang Zhang 3,4, Liang Cao 3,4, Zhenzhong Wang 3,4, and Wei Xiao 3,4, * 1 Kanion School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue Qixia District, Nanjing 210046, China 2 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue Qixia District, Nanjing 210046, China 3 National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Jiangning Industrial City, Economic and Technological Development Zone of Lianyungang, Lianyungang 222001, China 4 Jiangsu Kanion Pharmaceutical Co Ltd, Jiangning Industrial City, Economic and Technological Development Zone of Lianyungang, Lianyungang 222001, China * Correspondence: xw_kanion@163.com ( Wei Xiao) Received: 23 March 2023 Accepted: 10 May 2023 Abstract: Cardiovascular disease (CDV) is the primary cause of death in the world, and myocardial ischemia (MI) is one of the high-risk CVDs. The myocardial blood supply must be restored as soon as possible to reduce the mortality risk, however, reperfusion itself paradoxically leads to further death of cardiomyocytes and increases the infarct size; this is known as myocardial ischemia/reperfusion injury (MIRI). The pathological mechanism of MIRI is complex, and current research mainly focuses on oxidative stress, dysfunctional mitochondrial energy metabolism, Ca 2+ overload, endoplasmic reticulum stress (ERs) and the inflammatory response. This review briefly summarizes the mechanism of MIRI, and natural plant product (NPP) components proven to ameliorate MIRI and their related signaling pathways. NPPs can alleviate MIRI by regulating oxidative stress, inflammation, ERs, Ca 2+ overload and mitochondrial function maintenance. This review will deepen our understanding of how NPPs reduce MIRI and the future value of NPPs in cardio-protection.
{"title":"Recent Advances in Natural Plant-based Treatment of Myocardial Ischemia-reperfusion Injury","authors":"Peixun Yang, Minxuan Liu, Xiaoxue Fan, Xinzhuang Zhang, Liang Cao, Zhenzhong Wang, W. Xiao","doi":"10.53941/ijddp.2023.100003","DOIUrl":"https://doi.org/10.53941/ijddp.2023.100003","url":null,"abstract":"Review\u0000Recent Advances in Natural Plant-based Treatment of Myocardial Ischemia-reperfusion Injury\u0000\u0000Peixun Yang 1,3,4, Minxuan Liu 2,3,4, Xiaoxue Fan 3,4, Xinzhuang Zhang 3,4, Liang Cao 3,4, Zhenzhong Wang 3,4, and Wei Xiao 3,4, *\u0000\u0000\u00001 Kanion School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue Qixia District, Nanjing 210046, China\u00002 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue Qixia District, Nanjing 210046, China\u00003 National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Jiangning Industrial City, Economic and Technological Development Zone of Lianyungang, Lianyungang 222001, China\u00004 Jiangsu Kanion Pharmaceutical Co Ltd, Jiangning Industrial City, Economic and Technological Development Zone of Lianyungang, Lianyungang 222001, China\u0000* Correspondence: xw_kanion@163.com ( Wei Xiao)\u0000 \u0000 \u0000Received: 23 March 2023\u0000Accepted: 10 May 2023\u0000 \u0000\u0000Abstract: Cardiovascular disease (CDV) is the primary cause of death in the world, and myocardial ischemia (MI) is one of the high-risk CVDs. The myocardial blood supply must be restored as soon as possible to reduce the mortality risk, however, reperfusion itself paradoxically leads to further death of cardiomyocytes and increases the infarct size; this is known as myocardial ischemia/reperfusion injury (MIRI). The pathological mechanism of MIRI is complex, and current research mainly focuses on oxidative stress, dysfunctional mitochondrial energy metabolism, Ca 2+ overload, endoplasmic reticulum stress (ERs) and the inflammatory response. This review briefly summarizes the mechanism of MIRI, and natural plant product (NPP) components proven to ameliorate MIRI and their related signaling pathways. NPPs can alleviate MIRI by regulating oxidative stress, inflammation, ERs, Ca 2+ overload and mitochondrial function maintenance. This review will deepen our understanding of how NPPs reduce MIRI and the future value of NPPs in cardio-protection.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87771300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Review Pathophysiological Mechanisms and Pharmaceutical Interventions of Myocardial Infarction with Depression Mingyang Xu 1, Yinxiang Wei 2, Zhenhui Wang 1, Yaohui Wang 2, Xiaoming Zhong 3,*, and Qiying Chen 4,* 1 School of medicine, Henan University, Kaifeng 475000, China. 2 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China. 3 Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng 475000, China. 4 Department of Cardiology, Huashan Hospital, Fudan University, Shanghai 200040, China. * Correspondence: Xiaoming Zhong (zxm10020202@126.com); Qiying Chen (chenqiying@huashan.org.cn) Received: 23 March 2023 Accepted: 10 May 2023 Abstract: The strong association between acute myocardial infarction (AMI) and major depression disorder（MDD）is a universally accepted. Patients with AMI complicated by MDD often have poor prognosis. Most early studies focused on how AMI leads to MDD, but there are few reports on depression-induced AMI. In terms of mechanism, inflammation, the hypothalamic-pituitary-adrenal axis (HPA axis) and brain-gut axis may be involved in the occurrence and development of MDD after AMI. The inflammatory injury, abnormal sympathetic and vagal nerve activity, HPA axis overactivation, overeating and some therapeutic medicine administration in patients with MDD can also be risk factors for AMI. Both behavioral and pharmaceutical interventions are important for the treatment of AMI with MDD. More drugs are being developed and tested. At present, there are still many issues, needing to be addressed, in the diagnosis, pathogenesis, intervention strategies and therapeutic drugs for AMI with MDD. To aid clinical diagnosis and treatment, this review classifies the existing studies on AMI complicated with MDD, and also includes some of our considerations.
{"title":"Pathophysiological Mechanisms and Pharmaceutical Interventions of Myocardial Infarction with Depression","authors":"Mingyang Xu, Yinxiang Wei, Zhenhui Wang, Yaohui Wang, Xiaoming Zhong, Qiying Chen","doi":"10.53941/ijddp.2023.100004","DOIUrl":"https://doi.org/10.53941/ijddp.2023.100004","url":null,"abstract":"Review\u0000Pathophysiological Mechanisms and Pharmaceutical Interventions of Myocardial Infarction with Depression\u0000\u0000Mingyang Xu 1, Yinxiang Wei 2, Zhenhui Wang 1, Yaohui Wang 2, Xiaoming Zhong 3,*, and Qiying Chen 4,*\u0000\u0000\u00001 School of medicine, Henan University, Kaifeng 475000, China.\u00002 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China.\u00003 Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng 475000, China.\u00004 Department of Cardiology, Huashan Hospital, Fudan University, Shanghai 200040, China.\u0000* Correspondence: Xiaoming Zhong (zxm10020202@126.com); Qiying Chen (chenqiying@huashan.org.cn)\u0000 \u0000 \u0000Received: 23 March 2023\u0000Accepted: 10 May 2023\u0000 \u0000\u0000Abstract: The strong association between acute myocardial infarction (AMI) and major depression disorder（MDD）is a universally accepted. Patients with AMI complicated by MDD often have poor prognosis. Most early studies focused on how AMI leads to MDD, but there are few reports on depression-induced AMI. In terms of mechanism, inflammation, the hypothalamic-pituitary-adrenal axis (HPA axis) and brain-gut axis may be involved in the occurrence and development of MDD after AMI. The inflammatory injury, abnormal sympathetic and vagal nerve activity, HPA axis overactivation, overeating and some therapeutic medicine administration in patients with MDD can also be risk factors for AMI. Both behavioral and pharmaceutical interventions are important for the treatment of AMI with MDD. More drugs are being developed and tested. At present, there are still many issues, needing to be addressed, in the diagnosis, pathogenesis, intervention strategies and therapeutic drugs for AMI with MDD. To aid clinical diagnosis and treatment, this review classifies the existing studies on AMI complicated with MDD, and also includes some of our considerations.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85964398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-27DOI: 10.53941/ijddp.2023.100001
Z. S. Rana, Reena Suman, Shobi Veleri, Pradeep Punnakkal
Review Mechanism of Anti-seizure Medications and Emerging Trends in Epilepsy Treatment Zubin Singh Rana 1, Reena Suman 1, Shobi Veleri 2, and Pradeep Punnakkal 1, * 1 Department of Biophysics, Postgraduate Institute of Medical Education and Research Chandigarh, 160012, India 2 Drug Safety Division, ICMR-National Institute of Nutrition, Hyderabad, 500007, India. * Correspondence: p.pradeep@pgimer.edu.in Received: 28 November 2022 Accepted: 24 January 2023 Abstract: About one percent of the world’s population is affected by epilepsy. Epilepsy-induced psychiatric co-morbidity and mortality impose a huge burden on patients, their families, and society. Anti-seizure medications (ASMs) are drugs used to control seizures in patients with epilepsy. Epilepsy constitutes a spectrum of disorders, with various underlying causes. Hence, finding the right drug to control seizures with minimal side effects is a difficult task for clinicians. Besides controlling seizures, many ASMs have off-target effects that result in unwanted side effects. Compared to first and second-generation drugs, third-generation drugs have shown better tolerance. Even though the target of many ASMs is known, their mechanism of action is not well understood. The main mechanism behind epilepsy is defined as an imbalance in the excitatory-to-inhibitory ratio in neurotransmission. So, the key target of ASMs is the ion channels controlling the intrinsic property of neurons like sodium channels, potassium channels, and calcium channels, the excitatory synaptic transmission via glutamate receptors, and the inhibitory synaptic transmission by GABA receptors. Here we review the role of ion channels in epilepsy, and how the ASMs act on them for seizure control.
{"title":"Mechanism of Anti-seizure Medications and Emerging Trends in Epilepsy Treatment","authors":"Z. S. Rana, Reena Suman, Shobi Veleri, Pradeep Punnakkal","doi":"10.53941/ijddp.2023.100001","DOIUrl":"https://doi.org/10.53941/ijddp.2023.100001","url":null,"abstract":"Review\u0000Mechanism of Anti-seizure Medications and Emerging Trends in Epilepsy Treatment\u0000\u0000Zubin Singh Rana 1, Reena Suman 1, Shobi Veleri 2, and Pradeep Punnakkal 1, *\u0000\u0000\u00001 Department of Biophysics, Postgraduate Institute of Medical Education and Research Chandigarh, 160012, India\u00002 Drug Safety Division, ICMR-National Institute of Nutrition, Hyderabad, 500007, India.\u0000* Correspondence: p.pradeep@pgimer.edu.in\u0000 \u0000 \u0000Received: 28 November 2022\u0000Accepted: 24 January 2023\u0000 \u0000\u0000Abstract: About one percent of the world’s population is affected by epilepsy. Epilepsy-induced psychiatric co-morbidity and mortality impose a huge burden on patients, their families, and society. Anti-seizure medications (ASMs) are drugs used to control seizures in patients with epilepsy. Epilepsy constitutes a spectrum of disorders, with various underlying causes. Hence, finding the right drug to control seizures with minimal side effects is a difficult task for clinicians. Besides controlling seizures, many ASMs have off-target effects that result in unwanted side effects. Compared to first and second-generation drugs, third-generation drugs have shown better tolerance. Even though the target of many ASMs is known, their mechanism of action is not well understood. The main mechanism behind epilepsy is defined as an imbalance in the excitatory-to-inhibitory ratio in neurotransmission. So, the key target of ASMs is the ion channels controlling the intrinsic property of neurons like sodium channels, potassium channels, and calcium channels, the excitatory synaptic transmission via glutamate receptors, and the inhibitory synaptic transmission by GABA receptors. Here we review the role of ion channels in epilepsy, and how the ASMs act on them for seizure control.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73923511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-01Epub Date: 2023-01-11DOI: 10.53941/ijddp.0201003
Antoinette Holland, Molly Enrick, Arianna Diaz, Liya Yin
microRNA-21 (miR-21) serves a multitude of functions at the molecular level through its regulation of messenger RNA. Previous research has sparked interest in the role of miR-21 as a potential therapeutic target in cardiovascular diseases. miR-21 expression contributes to the differentiation, proliferation, and maturation of many cell types, such as fibroblasts, endothelial cells, cardiomyocytes, and endothelial progenitor cells. The function of miR-21 depends upon its expression level in the specific cell types and downstream targets, which determine cell fate. Under pathological conditions, the expression level of miR-21 is altered, leading to abnormal gene regulation of downstream signaling and cardiovascular diseases such as hypertension, cardiac hypertrophy and fibrosis, atherosclerosis, and heart failure. Agomirs or antagomirs can be introduced into the respective tissue type to reverse or stop the progression of the disease. Exosomes in the extracellular vesicles, which mediate many cellular events with high biocompatibility, have a high potential of efficiently delivering miR-21 to their targeted cells. The critical role of miR-21 in cardiovascular disease (CVD) is indisputable, but there are controversial reports on the function of miR-21 in the same disease. This discrepancy sparks interest in better understanding the role of miR-21 in different tissues under different stages of various diseases and the mechanism of how miR-21 inhibitors work.
{"title":"Is miR-21 A Therapeutic Target in Cardiovascular Disease?","authors":"Antoinette Holland, Molly Enrick, Arianna Diaz, Liya Yin","doi":"10.53941/ijddp.0201003","DOIUrl":"10.53941/ijddp.0201003","url":null,"abstract":"<p><p>microRNA-21 (miR-21) serves a multitude of functions at the molecular level through its regulation of messenger RNA. Previous research has sparked interest in the role of miR-21 as a potential therapeutic target in cardiovascular diseases. miR-21 expression contributes to the differentiation, proliferation, and maturation of many cell types, such as fibroblasts, endothelial cells, cardiomyocytes, and endothelial progenitor cells. The function of miR-21 depends upon its expression level in the specific cell types and downstream targets, which determine cell fate. Under pathological conditions, the expression level of miR-21 is altered, leading to abnormal gene regulation of downstream signaling and cardiovascular diseases such as hypertension, cardiac hypertrophy and fibrosis, atherosclerosis, and heart failure. Agomirs or antagomirs can be introduced into the respective tissue type to reverse or stop the progression of the disease. Exosomes in the extracellular vesicles, which mediate many cellular events with high biocompatibility, have a high potential of efficiently delivering miR-21 to their targeted cells. The critical role of miR-21 in cardiovascular disease (CVD) is indisputable, but there are controversial reports on the function of miR-21 in the same disease. This discrepancy sparks interest in better understanding the role of miR-21 in different tissues under different stages of various diseases and the mechanism of how miR-21 inhibitors work.</p>","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41169497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Editorial New Tale of Metformin in Cardio-Oncology Xin Wang , Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M139PT Manchester, UK. * Correspondence: xin.wang@manchester.ac.uk
{"title":"New Tale of Metformin in Cardio-Oncology","authors":"X. Wang","doi":"10.53941/ijddp.0201001","DOIUrl":"https://doi.org/10.53941/ijddp.0201001","url":null,"abstract":"Editorial\u0000New Tale of Metformin in Cardio-Oncology\u0000\u0000Xin Wang ,\u0000\u0000\u0000Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M139PT Manchester, UK.\u0000* Correspondence: xin.wang@manchester.ac.uk\u0000","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73491682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Zi, S. Abraham, A. D’Souza, D. Hutchings, S. Prehar, Xin Wang, E. Cartwright
Review A Minimally Invasive Approach for Cardiac Electrophysiology Studies in Mice Min Zi , * , Sabu Abraham , Alicia D'souza , David Hutchings , Sukhpal Prehar , Xin Wang , and Elizabeth J Cartwright Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom * Correspondence: min.zi@manchester.ac.uk Received: 6 January 2023 Accepted: 9 February 2023 Published: 25 March 2023 Abstract: Atrial fibrillation and ventricular tachycardia are commonly seen in clinic. Different approaches have been developed to investigate underlying mechanisms. Transvenous approach (TA) is widely used for studies but has several drawbacks. We therefore developed a novel minimally invasive approach (MIA) for mechanistic studies. Study included 27 male C57BL/6J mice, 19 for MIA and 8 for TA. Under general anaesthesia, ECG was recorded. A key hole was made on the right first intercostal space by separating the intercostal muscles, followed by the exposure of the superior vena cava and the top of the atrium. An EPR-800 catheter was inserted vertically, perpendicular to the chest, for atrial pacing and flatly over the ventricles for ventricular pacing. Burst S1–S1 and decremental S1–S2 pacing protocols were performed to evaluate SA recovery time (SNRT), the atrioventricular node effective refractory period (AVN-ERP), Wenckebach period, ventricular ERP, and arrhythmia susceptibility. MIA was successfully performed in all 19 mice without any complications. One mouse died during TA due to venous rupture. Compared MIA with TA, surgical time were significantly shorter (P<0.0001). Wenckebach period was shorter as well (P<0.05). No difference was found in baseline sinus cycle length, SNRT, correct SNRT, AVN-ERP, ventricular ERP, and arrhythmia susceptibility (all P>0.05). The novel MIA outplays TA by providing similar outcomes of PES but consuming less time, demanding less surgical expertise, and reducing the potential of surgical complications. Given the minimal tissue injury, it also provides great potential as a recovery procedure for longitudinal study.
{"title":"A Minimally Invasive Approach for Cardiac Electrophysiology Studies in Mice","authors":"M. Zi, S. Abraham, A. D’Souza, D. Hutchings, S. Prehar, Xin Wang, E. Cartwright","doi":"10.53941/ijddp.0201006","DOIUrl":"https://doi.org/10.53941/ijddp.0201006","url":null,"abstract":"Review\u0000A Minimally Invasive Approach for Cardiac Electrophysiology Studies in Mice\u0000\u0000Min Zi , * , Sabu Abraham , Alicia D'souza , David Hutchings , Sukhpal Prehar , Xin Wang , and Elizabeth J Cartwright\u0000\u0000\u0000Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom\u0000* Correspondence: min.zi@manchester.ac.uk\u0000 \u0000 \u0000Received: 6 January 2023\u0000Accepted: 9 February 2023\u0000Published: 25 March 2023\u0000 \u0000\u0000Abstract: Atrial fibrillation and ventricular tachycardia are commonly seen in clinic. Different approaches have been developed to investigate underlying mechanisms. Transvenous approach (TA) is widely used for studies but has several drawbacks. We therefore developed a novel minimally invasive approach (MIA) for mechanistic studies. Study included 27 male C57BL/6J mice, 19 for MIA and 8 for TA. Under general anaesthesia, ECG was recorded. A key hole was made on the right first intercostal space by separating the intercostal muscles, followed by the exposure of the superior vena cava and the top of the atrium. An EPR-800 catheter was inserted vertically, perpendicular to the chest, for atrial pacing and flatly over the ventricles for ventricular pacing. Burst S1–S1 and decremental S1–S2 pacing protocols were performed to evaluate SA recovery time (SNRT), the atrioventricular node effective refractory period (AVN-ERP), Wenckebach period, ventricular ERP, and arrhythmia susceptibility. MIA was successfully performed in all 19 mice without any complications. One mouse died during TA due to venous rupture. Compared MIA with TA, surgical time were significantly shorter (P<0.0001). Wenckebach period was shorter as well (P<0.05). No difference was found in baseline sinus cycle length, SNRT, correct SNRT, AVN-ERP, ventricular ERP, and arrhythmia susceptibility (all P>0.05). The novel MIA outplays TA by providing similar outcomes of PES but consuming less time, demanding less surgical expertise, and reducing the potential of surgical complications. Given the minimal tissue injury, it also provides great potential as a recovery procedure for longitudinal study.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87208815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Review Controlled and Targeted Drug Delivery Using Smart Nanovectors Abou Bakr M. Salama 1,2, Yasmin Y. Salem 1,2, and Tamer M. A. Mohamed 1,3,4,5,6, * 1 Institute of Molecular Cardiology, Department of Medicine, University of Louisville, KY 40208, U.S.A. 2 Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt. 3 Envirome Institute, Centre for Cardiometabolic Sciences, Department of Medicine, University of Louisville, KY 40208, U.S.A. 4 Department of Bioengineering, Speed School of Engineering, University of Louisville, KY 40208, U.S.A. 5 Department of Pharmacology and Toxicology, University of Louisville, KY 40208, U.S.A. 6 Institute of Cardiovascular Sciences, University of Manchester M13 9PL, U.K. * Correspondence: tamer.mohamed@louisville.edu Received: 28 January 2023 Accepted: 23 February 2023 Published: 20 March 2023 Abstract: The conventional drug delivery systems have several limitations, such as the high frequency of administration, several off-target effects, and the need for tissue specificity. Recently, smart drug shuttles have emerged, and the nano applications provided a new opportunity for advancing the drug delivery system to become tissue targeted and decrease the frequency of administration. The recent development of nanovectors as drug carriers has gone through several steps of evolution that ended with the development of logic-embedded nanovectors. Here, we summarize the different types of nanovectors and their applications in various clinical situations, and finally, we spot the light on the future of this area of research.
{"title":"Controlled and Targeted Drug Delivery Using Smart Nanovectors","authors":"","doi":"10.53941/ijddp.0201010","DOIUrl":"https://doi.org/10.53941/ijddp.0201010","url":null,"abstract":"Review\u0000Controlled and Targeted Drug Delivery Using Smart Nanovectors\u0000\u0000Abou Bakr M. Salama 1,2, Yasmin Y. Salem 1,2, and Tamer M. A. Mohamed 1,3,4,5,6, *\u0000\u0000\u00001 Institute of Molecular Cardiology, Department of Medicine, University of Louisville, KY 40208, U.S.A.\u00002 Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.\u00003 Envirome Institute, Centre for Cardiometabolic Sciences, Department of Medicine, University of Louisville, KY 40208, U.S.A.\u00004 Department of Bioengineering, Speed School of Engineering, University of Louisville, KY 40208, U.S.A.\u00005 Department of Pharmacology and Toxicology, University of Louisville, KY 40208, U.S.A.\u00006 Institute of Cardiovascular Sciences, University of Manchester M13 9PL, U.K.\u0000* Correspondence: tamer.mohamed@louisville.edu\u0000 \u0000 \u0000Received: 28 January 2023\u0000Accepted: 23 February 2023\u0000Published: 20 March 2023\u0000 \u0000\u0000Abstract: The conventional drug delivery systems have several limitations, such as the high frequency of administration, several off-target effects, and the need for tissue specificity. Recently, smart drug shuttles have emerged, and the nano applications provided a new opportunity for advancing the drug delivery system to become tissue targeted and decrease the frequency of administration. The recent development of nanovectors as drug carriers has gone through several steps of evolution that ended with the development of logic-embedded nanovectors. Here, we summarize the different types of nanovectors and their applications in various clinical situations, and finally, we spot the light on the future of this area of research.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75071371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.
{"title":"Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death.","authors":"Jennifer Van, Younghee Hahn, Brett Silverstein, Cairong Li, Fei Cai, Jia Wei, Lokesh Katiki, Puja Mehta, Katherine Livatova, Jaclyn DelPozzo, Tamayo Kobayashi, Yuan Huang, Satoru Kobayashi, Qiangrong Liang","doi":"10.53941/ijddp.0201004","DOIUrl":"10.53941/ijddp.0201004","url":null,"abstract":"<p><p>The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.</p>","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91156558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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