作者机构:
[Liqun Lu; Jiangang Cao; Lanfang Li; Linxi Chen] 1 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Learning Key Laboratory for Pharmacoproteomics , University of South China , Hengyang 421001 , China
通讯机构:
[Lanfang Li; Linxi Chen] 1;1 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Learning Key Laboratory for Pharmacoproteomics , University of South China , Hengyang 421001 , China
关键词:
adult;embryo;ligands
摘要:
Apelin is an endogenous ligand of the APJ receptor (also known as Aplnr) which is a G protein-coupled receptor. Elabela (also known as Toddler, Apela), which shares little sequence similarity with Apelin (Fig.1),has been identified as a new endogenous ligand for APJ receptor. Elabela is encoded by AK092578 gene from a region of the human genome which was previously classified as 'non-coding'. Elabela is initially translated into a peptide of 54 amino acids including a secretory signal peptide. However, its mature form only contains 32 amino acids. The Elabela/Aplnr axis mainly acts in embryonic development compared with Apelin/APJ system which has abundant biological functions in different physiological and pathological processes. During zebrafish embryogenesis, Elabela is proved to be indispensable for the proper differentiation of endodermal precursors which guide the overlying cardiac progenitors to the heart-forming region to initiate cardiogenesis. Therefore, loss of Elabela causes severe cardiac dysplasia ranging from a rudimentary heart to no heart, and has little to no blood circulation. Elabela expresses concomitantly with Aplnr before the onset of gastrulation, and loss of Elabela phenocopies the loss of Aplnr during early heart development. However, Apelin is not expressed until midgastrulation and Apelin zebrafish morphants are not presented with overt congenital cardiac anomalies. Thus, the Elabela/Aplnr axis appears to be exclusive for endoderm differentiation and subsequent cardiogenesis (Fig.2).
摘要:
Apelin is the endogenous ligand for the G protein-coupled receptor APJ, and plays important roles in the cardiovascular system. Our previous studies showed that apelin-13 promotes the hypertrophy of H9c2 rat cardiomyocytes through the PI3K-autophagy pathway. The aim of this study was to explore what roles ER stress and autophagy played in apelin-13-induced hypertrophy of cardiomyocytes in vitro. Treatment of H9c2 cells with apelin-13 (0.001–2 μmol/L) dose-dependently increased the production of ROS and the expression levels of NADPH oxidase 4 (NOX4). Knockdown of Nox4 with siRNAs effectively prevented the reduction of GSH/GSSG ratio in apelin-13-treated cells. Furthermore, apelin-13 treatment dose-dependently increased the expression of Bip and CHOP, two ER stress markers, in the cells. Knockdown of APJ or Nox4 with the corresponding siRNAs, or application of NADPH inhibitor DPI blocked apelin-13-induced increases in Bip and CHOP expression. Moreover, apelin-13 treatment increased the formation of autophagosome and ER fragments and the LC3 puncta in the ER of the cells. Knockdown of APJ, Nox4, Bip or CHOP with the corresponding siRNAs, or application of DPI or salubrinal attenuated apelin-13-induced overexpression of LC3-II/I and beclin 1. Finally, knockdown of Nox4, Bip or CHOP with the corresponding siRNAs, or application of salubrinal significantly suppressed apelin-13-induced increases in the cell diameter, volume and protein contents. Our results demonstrate that ER stress-autophagy is involved in apelin-13-induced H9c2 cell hypertrophy.
作者机构:
[Li Lanfang; Zhou Qionglin; Li Xiaoxiao; Chen Linxi] Institute of Pharmacy and Pharmacology, University of South China, Learning Key Laboratory for Pharmacoproteomics;[Li Lanfang; Zhou Qionglin; Li Xiaoxiao; Chen Linxi] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001
通讯机构:
[Linxi Chen] 1
摘要:
The apelin receptor gene, also known as APJ or angiotensin receptor-like 1, was first cloned in 1993. APJ has strong sequence homology with the angiotensin II receptor (AT1); 54% for intrans membrane domains and 31% for the entire sequence. Nevertheless, APJ does not bind with angiotensin II. In 1998, Apelin, the first endogenous ligand for APJ, was identified in bovine stomach extracts. Both apelin and APJ are widely expressed in various tissues including the heart, brain, limbs, retina, liver, lung, skin, kidney, adipose tissue, and so on [1].
摘要:
Apelin acts as the endogenous ligand of G protein coupled receptors APJ. The apelin/APJ systemis responsible for the occurrence and development of cardiovascular diseases. In recent years, apelin/APJ has been considered to play an important role in cardiac hypertrophy, but whether that role is beneficial or aggravating remains controversial. Apelin/APJ alleviates cardiac hypertrophy which is triggered by angiotensin II, oxidative stress and exercise. However, central administration of apelin induces cardiac hypertrophy. Peripheral administration of apelin also promotes the development of cardiac hypertrophy under non-pathological conditions. Furthermore, our laboratory discovers that apelin/APJ is able to induce hypertrophy of cardiomyocytes in vitro. The exact mechanism of apelin/APJ's dual effects in cardiac hypertrophy requires further study. In this paper, we review the controversies associated with apelin/APJ in cardiac hypertrophy and we elaborate the role of apelin/APJ in cardiac hypertrophy related-diseases including obesity, diabetes, hypertension, myocarditis and myocardial infarction. We conclude that further studies should emphasize more about the relationship between apelin/APJ and pathological hypertrophy especially in clinical patients. Moreover, apelin/APJ can be a promising therapeutic target for cardiac hypertrophy. (C) 2016 Published by Elsevier Ireland Ltd.
作者机构:
[Lu He] Department of Neurosurgery, First Affiliated Hospital, University of South China, Hengyang, 421001, China;[Linxi Chen] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug StudyUniversity of South China, Hengyang, 421001, China;[Lanfang Li] Department of Neurosurgery, First Affiliated Hospital, University of South China, Hengyang, 421001, China. llanfang6@126.com;[Lanfang Li] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug StudyUniversity of South China, Hengyang, 421001, China. llanfang6@126.com
通讯机构:
[Li, Lanfang] D;Department of Neurosurgery, First Affiliated Hospital, University of South China, Hengyang, 421001, China.;Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug StudyUniversity of South China, Hengyang, 421001, China.
关键词:
Crosstalk;Immune;Diseases
摘要:
Recently, Richter et al. [1] revealed the potential functions of the interaction between the serine/threonine kinase Tank-binding kinase 1 (TBK1) and the autophagy receptor optineurin (OPTN). The TBK1-OPTN axis targets damaged mitochondria for degradation via PINK1/parkin-mediated mitophagy [2, 3]. Indeed, TBK1 can phosphorylate OPTN at Ser177, Ser473, or Ser513 to enhance the binding capacity of OPTN with poly-ubiquitin (poly-UB) chains. Conversely, binding of poly-UB chains to OPTN is essential for the efficient recruitment and activation of TBK1 on mitochondria. These processes (Fig. 1) point toward an essential role of TBK1-OPTN signaling in mitochondrial quality control and maintaining cellular homeostasis. Currently, some studies have just focused on the role of the autophagy receptors OPTN, NDP52 (nuclear dot protein 52 kDa; also known as CALCOCO2, calciumbinding and coiled-coil domain 2), TAX1BP1 (Tax1 binding protein 1), and p62/sequestosome (SQSTM1) in damaged mitochondria [4–6]. However, only OPTN promotes auto-phagosome formation around mitochondria via the microtubule-associated protein light chain 3 (MAP1LC3/LC3)-interacting region (LIR) domain and is sufficient to trigger mitophagy.
通讯机构:
[Li, Lanfang] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Learning Key Lab Pharmacoprote, Hengyang 421001, Peoples R China.
摘要:
The G protein-coupled receptor APJ elicits cellular response to diverse extracellular stimulus. Accumulating evidence reveals that APJ receptor plays a prominent role in the cardiomyocyte adapting to hypertrophic stimulation. At present, it remains obscure that the regulatory mechanism of APJ receptor in myocardial hypertrophy. The natural endogenous ligands apelin and Elabela as well as agonists maintain high affinity for the APJ receptor and drive its internalization. Ligand-activated receptor internalization is mainly performed by clathrin-mediated endocytic pathway. Simultaneously, clathrin-mediated endocytosis takes participate in the occurrence and development of cardiac hypertrophy. In this study, we hypothesize that natural ligands and agonists induce the mechanosensitive APJ internalization via clathrin-mediated endocytosis. APJ internalization may contribute to the development of cardiac hypertrophy. The mechanosensitive APJ internalization via clathrin-mediated endocytosis may be a new molecular mechanism of cardiac hypertrophy. (C) 2016 Elsevier Ltd. All rights reserved.
作者机构:
Institute of Cardiovascular Disease, University of South China, Key Laboratory for Arteriosclerology of Hunan Province;[Li Lanfang] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study;[Li Lanfang; Xu Jin; Chen Linxi] Hunan Province Learning Key Laboratory for Pharmacoproteomics, Hengyang, 421001;Institute of Pharmacy and Pharmacology, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study;Institute of Cardiovascular Disease, University of South China, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, 421001
通讯机构:
[Linxi Chen *] 2;[Zhisheng Jiang *] 1
关键词:
Receptor-mediated;reticulophagy;diseases
摘要:
Autophagy is a highly conserved self-digestion process raging from lower eukaryotes to mammals. Autophagy involves in the degradation of misfolded protein aggregates and damaged organelles, which are subsequently reused. Upon autophagy is initiated, a membrane structure termed the phagophore, the precursor of autophagosome, gradually expands and engulfs misfolded protein or damaged organelles and delivers them to the vacuole/lysosome for degradation. Autophagy contributes to the process of survival and death. Basic autophagy is essential for maintaining cellular homeostasis. During normal physiology, specialized cellular function requires the regulation of autophagy by scavenging misfolded protein or damaged organelles. However, excessive and dysregulated autophagy may induce apoptosis and even cell death due to enzymes leaking from lysosomes [1].
作者机构:
[Yu Guo; Li-xian Shen; Hai-yan Li; Ke Min; Lan-fang Li; Cui-yun Yu; Xing Zheng] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China;[Yan-feng Lu] Department of Pharmacy, the Second Hospital of Zhuzhou City, Zhuzhou 412100, China
摘要:
Objective To prepare, characterize and evaluate the antioxidant activity of rutin-liposome(RL). Methods Liposomes of rutin were prepared by film dispersion method and the encapsulation efficiency(EE) was determined by RP-HPLC. Human umbilical vein endothelial cells(HUVECs) were injuried by H2O2 and treated with either free aqueous rutin or the RL delivery systems. The viability of HUVECs was determined by MTT and ELISA. Results The drug delivery system showed uniform rutin loaded nanoparticles with average particle size of(147.20 ± 1.42) nm, polydispersity index of(0.191 ± 0.003) nm, Zeta potential of(-20.0 ± 1.0) mV, and the drug EE was closed to 90.0%. The antioxidant effect of the drug delivery system to H2O2-damaged HUVECs showed that RL could increase injury cells viability compared to free aqueous rutin, which was accompanied with an obvious decrease in malondialdehyde(MDA), lactate dehydrogenase(LDH) while increase the level of nitrogen oxide(NOS). Conclusion The nanostructured RL is improved on the antioxidant effect and may be treating the different diseases caused by free radicals.
期刊:
Journal of Pharmacy and Pharmacology,2016年68(6):751-761 ISSN:0022-3573
通讯作者:
Tang Guotao
作者机构:
[Huang Rongbin] First Peoples Hosp Xiangtan City, Xiangtan, Peoples R China.;[Deng Xiangping; Xiang Lei; Cao Xuan; Li Lanfang; Tang Guotao; Liu Ying; Yu Cuiyun] Univ South China, Learning Key Lab Pharmacoprote, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.;[Chen Yanming] Mu Dan Jiang You Bo Pharmacert Co Ltd, Mudanjiang, Peoples R China.
通讯机构:
[Tang Guotao] U;Univ South China, Learning Key Lab Pharmacoprote, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.
关键词:
benzoic-imine bond;pH-sensitive;micelle;drug delivery system
摘要:
Apelin is an endogenous ligand of the apelin receptor(APJ),a seven-transmembrane G protein-coupled receptor.Apelin and APJ exist in a variety of tissues,with special status in the heart,lung and tumors.Furthermore,many research shows that the apelin/APJ system exerts a broad range of activities that affect kidney systems.This review we summarize the role of apelin/APJ system on renal fibrosis,renal ischemia/reperfusion injury and diabetic nephropathy,polycystic kidney disease,hemodialysis.It was found that the level expression of apelin m RNA in the inner stripe of kidney outer medulla was the highest,and the region is significantly correlated with water and sodium balance.In UUO mice model,intraperitoneal injection of Apelin can reduceα-SMA,the expression of TGF-1 and its receptor,and between renal stromal components also significantly decreased.These results show that Apelin can reduce the deposition of ECM and improve renal interstitial fibrosis.In renal ischemia/reperfusion injury studies show that apelin-13 can significantly reduce the damage induced by renal tubularlesions,renal cell death and the normal renal function is not completely lead to large damage.But in diabetic nephropathy,Apelin-APJ system can promote or slow DN disease progression is controversial,still needs further research.Analysis the receiver operating characteristic curve found that in the process of identifying ADPKD disease apelin and copeptin shows good receiver operating characteristic curve(ROC),cox proportional hazards regression model also showed apelin can predict on the progress of kidney disease.In hemodialysis patients the apelin levels and PTH levels were positively correlated,it could prompt apelin can protect bone dialysis patients.Apelin also can reduce Pit-1 inhibition of vascular smooth muscle cell osteoblast calcification and thus improve the aortic calcification,so Apelin may have a potential role in the treatment of vascular calcification in CKD.In kidney disease conditions,Apelin/APJ system plays a variety of biological functions,because of the Apelin protective on kidney,Apelin/APJ may be a potential material for the treatment of chronic kidney disease.
摘要:
The G-protein-coupled receptor APJ and its endogenous ligand apelin are widely expressed in many peripheral tissues and central nervous system, including adipose tissue, skeletal muscles and hypothalamus. Apelin/APJ system, involved in numerous physiological functions like angiogenesis, fluid homeostasis and energy metabolism regulation, is notably implicated in the development of different pathologies such as diabetes and its complications. Increasing evidence suggests that apelin regulates insulin sensitivity, stimulates glucose utilization and enhances brown adipogenesis in different tissues associated with diabetes. Moreover, apelin is also involved in the regulation of diabetic complications via binding to APJ receptor. Apelin improves diabetes-induced kidney hypertrophia, normalizes obesity-associated cardiac hypertrophy and negatively promotes retinal angiogenesis in diabetic retinopathy. In this review, we provide a comprehensive overview about the role of apelin/APJ system in different tissues related with diabetes. Furthermore, we describe the pathogenesis of diabetic complications associated with apelin/APJ system. Finally, agonists and antagonists targeted to APJ receptor are described in the literature. Thus, we highlight apelin/APJ system as a novel therapeutic target for pharmacological intervention in treating diabetes and its complications.
作者机构:
[Hong Zhao] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study, University of South China, Hengyang 421001, China;[Pingbo Yao] Intensive Care Units of the Affiliated Nanhua Hospital, University of South China, Hengyang 421002, China;[Lanfang Li; Linxi Chen] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study, University of South China, Hengyang 421001, China llfwjl@126.com lxchen6@126.com
通讯机构:
[Lanfang Li; Linxi Chen] 1;1 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study , University of South China , Hengyang 421001 , China
关键词:
Apelin;mechanism;polarization
摘要:
Cellular polarization is common to many types of cells, such as vascular endothelial cells (ECs), macrophages, and epithelial cells [1]. An individual cell has opposite sides and the directions of imaginary axes connecting opposite sides are highly coordinated. This coordination of the polarization axes is essential for the function of organs, named planar cell polarity (PCP) [2]. It occurs when cell organelles, cytoskeleton, and/or adhesion complexes display unidirectional organization along an axis. The ECs are continuously exposed to shear stress, and they directly exhibit profound morphological adaptations, such as planar cell polarization, elongation, and alignment of microtubules. In addition, the state of cell junctions and dynamic rearrangements of cytoskeleton are important for the establishment of flow-induced EC polarization, which is a significant determinant of maintaining vascular homeostasis.
作者机构:
[Lanfang Li; Di Wu] Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China;[Linxi Chen] Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China lxchen6@126.com
通讯机构:
[Linxi Chen *] I;Institute of Pharmacy and Pharmacology , University of South China , Hengyang 421001 , China
关键词:
应激性疾病;肿瘤转移;治疗;通道;敏感;癌症患者;转移过程;肿瘤细胞
摘要:
Cancer metastasis is a process that cancer cells deviate from the primary site and spread to the other areas to form new colonies, which is the leading cause of death in cancer patients. During metastatic progression, circulating cancer cells lodge within the microvasculature of end organs, where most of them die from mechanical deformation. However, cancer cells can survive from mechanical deformation by unknown mechanisms. Recently, Furlow et al. identified a mutation truncated form of pannexin-1 (Panx-1), PANX1~(1–89), which was significantly enriched in highly metastatic cancer cells. PANX1~(1–89) augmented Panx-1 channel-mediated adenosine triphosphate (ATP) release and enhanced the efficiency of metastasis by promoting metastatic breast cancer cells survival during physical deformation. Additionally, carbenoxolone (CBX), a Panx-1 inhibitor, was proved to reduce the efficiency of breast cancer metastasis. These results suggested that Panx-1 is one of the molecular bases for metastatic cell survival in microvasculature-induced biomechanical trauma.
摘要:
Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy.
作者机构:
[Xu Jin; Lu Liqun; Li Lanfang] Institute of Pharmacy and Pharmacology, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study;[Xu Jin; Lu Liqun; Li Lanfang] Learning Key Laboratory for Pharmacoproteomics, Hengyang, 421001
通讯机构:
[Lanfang Li *] H
关键词:
promising;therapy target;inflammatory
摘要:
NLRP3 inflammasome is a multi-protein complex that is critical for the activation of caspases-1, maturation, and secretion of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. NLRP3 has three parts: an amino-terminal pyrin domain (PYD), a central nucleotide-binding domain (NBD), and a C-terminal leucinerich repeat (LRR). The interactions among NLRP3, the adapter apoptosis-associated speck-like protein (ASC), and pro-caspase-1 are closely associated with the formation of NLRP3 inflammasome. Under the pathological conditions, the NLRP3-activating stimuli contribute to the inflammasome assembly and activation of the NLRP3 inflammasome, which consists of NLRP3 oligomerization of ASC and activation of caspase-1. This process leads to the secretion and maturation of IL-1β and IL-18, which eventually triggers cell damage and death. NLRP3 inflammasome is involved in the initiation and development of several pathophysiological events, such as gout, atherosclerosis, Type 2 diabetes, metabolic syndrome, agerelated macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease.
作者机构:
Institute of Pharmacy and Pharmacology,Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study,University of South China
会议名称:
2016年中国药学大会暨第十六届中国药师周
会议时间:
2016-12-08
会议地点:
中国北京
会议论文集名称:
2016年中国药学大会暨第十六届中国药师周论文集
关键词:
Apelin;VSMC;Proliferation and anti-apoptotic;Migration;Contraction and relaxation;Calcification;Cardiovascular diseases;Hypertension;Atherosclerosis
摘要:
Apelin is endogenous ligand of APJ which is an orphan G protein-coupled receptor. Apelin/APJ has a variety of biological effects about cells. Apelin treatment can increase endothelial cell proliferation and inhibits thrombin and collagen but not ADP and TXA2-induced platelet aggregation in vitro. As for vascular smooth muscle cell(VSMC), an integral part of the vascular wall, takes part in normal physiological processes. VSMC dysfunction is linked to the progression of various cardiovascular diseases such as atherosclerosis and hypertension. This review offers a molecular insight into the effect of apelin in regulation of proliferation and anti-apoptotic, migration, contraction and relaxation, calcification of VSMC. What is more, apelin is a promising target for managing VSMC-related disease. This review demonstrates that apelin/APJ system plays a very important role in regulating VSMCs. Proliferation: Our Laboratory first time founds that apelin enhances VSMC proliferation by PI3 K/Akt signaling transduction pathway and the regulation of cyclin D1. Anti-apoptotic: PI3 K/Akt signaling transduction pathway is a key role in treatment strategies of tumors, which involves the regulation of cellular functions, including proliferation, differentiation, apoptosis, migration and glucose transport. Further research shows that apelin suppresses serum deprivation-induced human VSMCs apoptosis. Migration: Through PI3 K/Akt signaling transduction pathway, apelin also protects VSMC from apoptosis and promote VSMC migration. The proliferation and migration of VSMCs may have effect on atherosclerosis and apelin may hopefully lead to treatment of cardiovascular diseases. Contraction and relaxation: Hypertension is a kind of cardiovascular diseases which is characterized by arterial hypertension. The emergence of apelin as an important regulator in vasodilatation has attracted increasing attention on the molecular mechanisms of nitric oxide-dependent pathways. But on the contrary, apelin-13 aggravates hypertension after damage of the vascular endothelium. The true function of apelin in regulate blood pressure is already a controversial subject, which may controls the contraction by VSMCS and relaxation of these vessels by endothelial cells. Calcification: Apelin plays a role of protecting cardiovascular system by restrain the calcification of vessel smooth muscle cells. Above all, suggests that apelin/APJ system plays a pivotal role in VSMC including proliferation and anti-apoptotic, migration and VSM including contraction and relaxation, calcification. It might be a potential new approach for treating cardiovascular diseases.