摘要：
Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases. However, the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear. In this study, rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) for five weeks. The mobility of rats was evaluated by forced swimming test, while their cognitive capabilities were evaluated by Y-maze test. Expression of sortilin, alpha-synuclein, p-JUN, and c-JUN proteins in the substantia nigra were detected by western blot analysis. In addition, immunofluorescence staining of sortilin and alpha-synuclein was performed to detect expression in the substantia nigra. The results showed that, compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg) + CPA co-treated rats, motor and memory abilities were reduced, surface expression of sortin and alpha-synuclein in dopaminergic neurons was reduced, and total sortilin and total alpha-synuclein were increased in CPA-treated rats. MN9D cells were incubated with 500 nM CPA alone or in combination with 10 muM SP600125 (JNK inhibitor) for 48 hours. Quantitative real-time polymerase chain reaction analysis of sortilin and alpha-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone, but the combination of CPA and SP600125 could inhibit this expression. Predictions made using Jasper, PROMO, and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents. A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction. After sortilin expression was inhibited by sh-SORT1, expression of p-JUN and c-JUN was detected by western blot analysis. Long-term adenosine A1 receptor activation levels upregulated alpha-synuclein expression at the post-transcriptional level by affecting sortilin expression. The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind to alpha-synuclein. Co-immunoprecipitation revealed an interaction between sortilin and alpha-synuclein in MN9D cells. Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression and alpha-synuclein accumulation, and dramatically improved host cognition and kineticism. This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan (approval No. AUP#20070090) in March 2007 and the Animals Ethics Committee of University of South China (approval No. LL0387-USC) in June 2017.
作者机构：
[Lingzhi Wang; Jinyong Jiang; Linxi Chen] Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China;[Qun Zhou] Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
通讯机构：
[Linxi Chen; Jinyong Jiang] I;Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China , Hengyang 421001, China
关键词：
aging;iron;mitochondria
摘要：
A recent study by Hughes et al. [1] showed that cysteine-mediated iron deficiency is the main cause of aging-related mitochondrial dysfunction. They also uncovered that aging-induced vacuolar/lysosomal de-acidification participates in the cysteine-mediated iron deficiency, implying that the de-acidifying lysosome triggers vacuolar/lysosomal dysfunction and iron deficiency, further leading to mitochondrial dysfunction. Previous studies showed that iron and lysosomal-mitochondrial crosstalk are the two important mechanisms that lysosome regulates aging, and it is well known that iron plays a pivotal role in various cell metabolic activities [2,3]. Accumulating evidence shows that there is a close relationship between lysosome and mitochondria, yet little is known about the exact role of them. The discovery that iron deficiency mediates lysosomal-mitochondrial crosstalk has presented a new therapeutic avenue for managing aging and aging-related diseases.
作者机构：
[Yiyuan Yang; Lanfang Li; Kai Zhang; Linxi Chen] Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
通讯机构：
[Li, L.] I;Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
摘要：
Cardiomyocytes, also known as myocardial fibers, are the muscle cells which form the heart tissue. Previous studies have indicated that fetal mammalian cardiomyocytes maintain the regeneration capacity, which promotes the fetal heart growth. Regardless of environment insults including nutrient deprivation, changes of blood flow, along with mechanical and volume loading [1], embryonic mammalian cardiac muscle cells are also related to robust proliferation response. Similarly, the hearts of 1-day-old neonatal mice could also be fully regenerated after surgical resection of the left ventricular apex or myocardial infarction (MI) [2]. Intriguingly, studies have also shown that certain fish, such as adult zebrafish, or urodele amphibians retain an observable capacity for regeneration [3]. In response to cardiac damage, zebrafish exhibits complete regeneration primarily due to the proliferation of cardiomyocytes. Nevertheless, the mouse heart loses this potential in the first week after birth. Tragically, it has been demonstrated that the adult mammalian cardiomyocyte unable to proliferate (Fig. 1A). Adult heart is considered as a terminally differentiated organ [4] that has limited capacity for cardiomyogenesis. Therefore, patients suffering from cardiovascular failure are unable to repair the heart and survive after MI or other heart diseases. Therefore, finding a feasible approach to stimulate adult mammalian cardiomyocyte proliferation is beneficial for the treatment of MI and other heart diseases.
作者机构：
[向花花; 肖正午; 周晶; 彭华; 张宏全; 周琛; 郭紫芬] Institute of Pharmacy and Pharmacology, University of South China, Cooperative Innovation Center for Molecular Target New Drug Study of Hunan Province, Hengyang, Hunan 421001, China
通讯机构：
[Guo, Z.] I;Institute of Pharmacy and Pharmacology, University of South China, Cooperative Innovation Center for Molecular Target New Drug Study of Hunan Province, Hengyang, Hunan, China
作者机构：
[向花花; 郭紫芬; 周晶; 张宏全; 彭华; 龚咏晴] Institute of Pharmacy and Pharmacology, Hunan Provincial Cooperative Innovation Center for Molecular Target New Drug Research, University of South China, Hengyang, Hunan 421001, China. Email: guozifen@aliyun.com;[董巍檑] Department of Obstetrics and Gynecology, the First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China
通讯机构：
[Xiang, Huahua] I;Institute of Pharmacy and Pharmacology, Hunan Provincial Cooperative Innovation Center for Molecular Target New Drug Research, University of South China, Hengyang, Hunan 421001, China. Email:
摘要：
Truttmann MC et al.[1] recently reported that AMPylation of heat shock protein 70 (HSP70) family of chaperones participates in altering the aggregation properties and maintaining protein homeostasis (proteostasis), thereby playing a vital role in the development of neurodegenerative diseases (NDs). NDs are commonly manifested by protein aggregates, which exert harmful effects on proteostasis. Interestingly, it has been observed that AMPylation of heat shock proteins (HSPs) can maintain proteostasis by inhibiting the formation of protein aggregates. As previous studies only indicate that HSPs could regulate proteostasis, such a novel discovery further demonstrates the involvement of HSP70 AMPylation in the regulation of protein aggregation and the maintenance of proteostasis. Therefore, AMPylation can be considered to possess a therapeutic potential to target certain physiological processes related to proteostasis, such as age-related diseases.
作者机构：
[李洁] The First People's Hospital of Chenzhou, Chenzhou, 423000, China;[秦旭平] Institute of Drug and Pharmacology, University of South China, Hengyang, 421001, China;[周楠] Medical College, Xi'an Jiaotong University, Xi'an, 710061, China;[林杰; 陈根] The First People's Hospital of Chenzhou, Chenzhou, 423000, China, Institute of Drug and Pharmacology, University of South China, Hengyang, 421001, China
通讯机构：
[Li, J.] T;The First People's Hospital of ChenzhouChina
关键词：
TLR4单克隆抗体;轻度氧化修饰低密度脂蛋白;炎症;肠系膜动脉;内皮依赖性舒张
摘要：
目的探讨预先使用TLR4单克隆抗体(TLR4mAb)对轻度氧化修饰低密度脂蛋白(mmLDL)诱发小鼠肠系膜动脉内皮依赖性舒张功能损伤的影响及作用机制。方法实验分为:空白对照组、mmLDL处理组、TLR4mAb干预组。采用ELISA方法测定血浆中白细胞介素(IL)-1β和肿瘤坏死因子(TNF)-α的浓度水平,微血管张力描记技术测定血管内皮依赖性舒张功能, Western blot技术和RT-PCR技术分别考察血管组织蛋白表达量和mRNA表达水平,透射电镜观察肠系膜动脉内皮细胞超显微结构。结果TLR4mAb剂量依赖性改善mmLDL损伤血管内皮依赖性舒张功能的损伤作用,显著上调KCa3.1-通道、KCa 2.3-通道蛋白表达和下调炎症因子TNF-α和IL-1β表达。TLR4mAb改善mmLDL损伤血管内皮细胞及内皮依赖性舒张功能,可能与其竞争性拮抗mmLDL激活TLR4信号转导通路及其下游的NF-κBp65和p-38MAPK通路有关。结论预先使用TLR4mAb可以减轻mmLDL所诱发的内皮细胞损伤和内皮依赖性舒张功能降低,以及抑制炎症因子的过度表达,调控TLR4通路及其下游的NF-κBp65和p-38MAPK通路可能是预防治疗心血管疾病的有效靶点。 <&wdkj&>OBJECTIVE To investigate the effect and mechanism of TLR4 monoclonal antibody (TLR4mAb) on mmLDL induced impairment of endothelium-dependent vasodilatation in mouse mesenteric artery. METHODS The experiment established three groups of normal saline group,mmLDL treatment group and TLR4mAb intervention group. The concentration of IL-1β and TNF-α in plasma was determined by enzyme-linked immunosorbent assay (ELISA) . Measurement of endothelium-dependent vasodilatation was achieved by microvascular tension mapping. Western blot and RT-PCR were used to investigate the expression level of protein and mRNA expressions in vascular tissues. In addition,ultra-structure of mesenteric artery endothelial cells was observed by transmission electron microscope. RESULTS TLR4mAb could improve the damage of mmLDL induced impairment of endothelium-dependent vasodilatation in a dose-dependent manner. Besides,TLR4mAb obviously up-regulated protein expressions in KCa 3.1-channel and KCa 2.3-channel,and down-regulated the expression of inflammatory factors TNF-α and IL-1β. Furthermore,the improvement of mmLDL impaired vascular endothelial cells and endothelium-dependent vasodilatation might be correlated with its competitive antagonism of mmLDL-activated TLR4 signal transduction pathway and its downstream NF-κBp65 and p-38 MAPK pathway. CONCLUSION Administration of TLR4mAb in advance can alleviate the impairment of endothelial cells and the decrease of endothelium-dependent vasodilatation induced by mmLDL,and inhibit the overexpression of inflammatory factors. Regulation of TLR4 pathway as well as its downstream NF-κBp65 and P-38 MAPK pathways may be effective targets for the prevention and treatment of cardiovascular diseases.
作者机构：
[Yao P.; Cao J.] Affiliated Nanhua Hospital of University of South China, Hengyang, 421002, China;[Zhao H.; Chen L.] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drugs Study, University of South China, Hengyang, 421001, China
通讯机构：
[Cao, J.] A;Affiliated Nanhua Hospital of University of South China, Hengyang, China
摘要：
Pancreatitis, the pancreas digestion itself as well as its surroundings, is a potentially fatal disease involved in severe public health care burdens [1]. It is broadly classified into acute and chronic pancreatitis. The incidence of acute pancreatitis is 13–45 cases per 100,000 persons each year worldwide. Compared with acute pancreatitis, chronic pancreatitis, although lower in prevalence than acute pancreatitis, has profound effects on the patient’s quality of life. It has long been recognized that the pancreas is prominently sensitive to mechanical injury, which in turn triggers the occurrence of pancreatitis. For instance, gallstones are the most common cause for acute pancreatitis and the increased pressure within the gland could be responsible for gallstone pancreatitis [2]. In addition, endoscopic retrograde cholangiopancreatography (ERCP) carries a risk of post- ERCP pancreatitis. And it is believed that the acute pancreatitis induced by ERCP is due to the increased intraductal pressure [3]. Furthermore, in the process of surgery, manipulation of the pancreas can trigger acute pancreatitis, which is complicating postoperative recovery [4]. Therefore, it is widely believed that the pancreas itself is sensitive to mechanical forces.
作者机构：
[贺庆芝; 吴移谋; 罗晓清; 贺梦婷; 王昕] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study Center, University of South China, Hengyang, 421001, China;[钟光明] The University of Texas Health Science Center at San Antonio, San Antonio, 78229, United States
通讯机构：
[He, Q.] H;Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study Center, University of South China, Hengyang, China
作者机构：
Institute of Pharmacy & Pharmacology,Hunan Province Cooperative innovation Center for Molecular Target New Druge Study,University of South China, Hengyang, 421101;Institute of Chemistry & Chemical Engineering,University of South China, Hengyang, 421101;[刘鼎; 成林; 郭玉; 刘运美] Institute of Pharmacy & Pharmacology,Hunan Province Cooperative innovation Center for Molecular Target New Druge Study,University of South China, Hengyang, 421101;[何军] Institute of Chemistry & Chemical Engineering,University of South China, Hengyang, 421101
