42 results on '"Chaoyong He"'
Search Results
2. Exosomes from uterine fluid promote capacitation of human sperm
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Renbin Deng, Zhao Wu, Chaoyong He, Chuncheng Lu, Danpeng He, Xi Li, Zhenling Duan, and Hui Zhao
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Sperm ,Uterine environment ,Extracellular vesicles ,Capacitation ,Human ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Extracellular vesicles (EVs) are membrane-bound vesicles containing various proteins, lipids, and nucleic acids. EVs are found in many body fluids, such as blood and urine. The release of EVs can facilitate intercellular communication through fusion with the plasma membrane or endocytosis into the recipient cell or through internalization of the contents. Recent studies have reported that EVs isolated from human endometrial epithelial cells (EECs) promote sperm fertilization ability. EVs from uterine flushing fluid more closely resemble the physiological condition of the uterus. However, it is unclear whether EVs derived directly from uterine flushing fluid have the same effect on sperm. This study aimed to research the effect of EVs from uterine flushing fluid on sperm. Methods EVs were isolated from the uterine flushing fluid. The presence of EVs was confirmed by nanoparticle tracking analysis (NTA), Western blot, and transmission electron microscopy (TEM). EVs were incubated with human sperm for 2 h and 4 h. The effects of EVs on sperm were evaluated by analyzing acrosome reaction, sperm motility, and reactive oxygen species (ROS). Results The EVs fractions isolated from the uterine fluid were observed in cup-shaped vesicles of different sizes by TEM. All isolated vesicles contained similar numbers of vesicles in the expected size range (30–200 nm) by NTA. CD9 and CD63 were detected in EVs by western blot. Comparing the motility of the two groups incubated sperm motility significantly differed at 4 h. The acrosome reactions were promoted by incubating with EVs significantly. ROS were increased in sperm incubated with EVs. Conclusion Our results showed EVs present in the uterine fluid. Acrosome reactions and ROS levels increased in human sperm incubated with EVs. EVs from uterine fluid can promote the capacitation of human sperm. The increased capacitation after sperm interaction with EVs suggests a possible physiological effect during the transit of the uterus.
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- 2024
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3. MiR-483-5p downregulation alleviates ox-LDL induced endothelial cell injury in atherosclerosis
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Hezhong Zhu, Hui Liang, Zhen Gao, Xiaoqiao Zhang, Qian He, Chaoyong He, Chao Cai, and Jiajuan Chen
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Atherosclerosis ,Endothelial injury ,MiR-483-5p ,Autophagy ,TIMP2 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background In light of the abnormal expression of microRNA (miR-483-5p) in patients with atherosclerosis (AS), its role in vascular endothelial cell injury was explored. And the mechanisms related to autophagy were also elucidated. Methods Human umbilical vein endothelial cells (HUVECs) were given 100 mg/L ox-LDL to induce endothelial injury. Cell transfection was done to regulate miR-483-5p levels. Cell viability and apoptosis were detected. qRT-PCR was employed for the mRNA levels’ detection. Results Autophagic flux impairment of HUVECs was detected after ox-LDL treatment, along with the upregulation of miR-483-5p. Ox-LDL inhibited cell viability and promoted cell apoptosis, but these influences were changed by miR-483-5p downregulation. MiR-483-5p downregulation decreased the mRNA levels of IL-1β, IL-6, ICAM-1 and VCAM-1. 3-MA, the autophagy inhibitor, reversed the beneficial role of miR-483-5p downregulation in ox-LDL-induced HUVECs’ injury. TIMP2 acts as a target gene of miR-483-5p, and was downregulated in HUVEC models. Conclusion MiR-483-5p downregulation alleviated ox-LDL-induced endothelial injury via activating autophagy, this might be related to TIMP2.
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- 2023
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4. Polypyrimidine tract binding protein 1 exacerbates cardiac fibrosis by regulating fatty acid‐binding protein 5
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Zhen Chen, Chaoyong He, Zhen Gao, Yu Li, Qian He, Yiyan Wang, and Chao Cai
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Cardiac fibrosis ,PTBP1 ,Nur77 ,FABP5 ,Cardiac fibroblasts ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims The activation of cardiac fibroblasts (CFs) leads to overproduction of collagens and subsequently cardiac fibrosis. However, the regulatory mechanism of CF function in the process of cardiac fibrosis remains unclear. This work investigated the function of polypyrimidine tract binding protein 1 (PTBP1)/nuclear receptor NR4A1 (Nur77)/fatty acid‐binding protein 5 (FABP5) axis in myocardial fibrosis. Methods and results Cardiac fibrosis was induced in mice suffered left anterior descending ligation. In parallel, neonatal mouse CFs were isolated and stimulated with transforming growth factor‐β1 (TGF‐β1). Cardiac fibrosis was evaluated by Masson's trichrome staining. Expression of PTBP1, Nur77, FABP5, collagen I, and collagen III was measured by quantitative real‐time PCR and western blotting. Proliferation of CFs was assessed by 5‐ethynyl‐2′‐deoxyuridine assay. Molecular interaction was validated by RNA‐binding protein immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assay. PTBP1 was up‐regulated (P
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- 2023
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5. Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect
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Yao Du, Hui Zhang, Xiaoyan Nie, Yajun Qi, Shi Shi, Yingying Han, Wenchen Zhou, Chaoyong He, and Lintao Wang
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STING ,cGAS ,inflammation ,cardiovascular diseases ,therapy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases, metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, collectively termed as sterile inflammatory diseases. In recent years, substantial evidence has revealed that the inflammatory response is closely related to cardiovascular diseases. Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway which is activated by cytoplasmic DNA promotes the activation of interferon regulatory factor 3 (IRF3) or nuclear factor-κB (NF-κB), thus leading to upregulation of the levels of inflammatory factors and interferons (IFNs). Therefore, studying the role of inflammation caused by cGAS-STING pathway in cardiovascular diseases could provide a new therapeutic target for cardiovascular diseases. This review focuses on that cGAS-STING-mediated inflammatory response in the progression of cardiovascular diseases and the prospects of cGAS or STING inhibitors for treatment of cardiovascular diseases.
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- 2022
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6. A long noncoding RNA GTF2IRD2P1 suppresses cell proliferation in bladder cancer by inhibiting the Wnt/β‑catenin signaling pathway
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Zhuo Huang, Hongbin Gao, Liangliang Qing, Biao Wang, Chaoyong He, Ning Luo, Chuncheng Lu, Shipeng Fan, Peng Gu, and Hui Zhao
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Bladder cancer ,Long noncoding RNA ,Cell cycle ,Proliferation ,Signaling pathway ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background There is growing evidence that long non-coding RNAs (LncRNAs) are key in the development of a variety of human tumors. However, the role of lncRNA GTF2IRD2P1 has not been well studied in cancer. The impact of GTF2IRD2P1 on the biological function and clinical relevance in bladder cancer is largely unknown. This study aimed to investigate the biological role of GTF2IRD2P1 in bladder evolution and carcinogenesis. Methods We used bioinformatics to obtain the lncRNA GTF2IRD2P1 from bladder urothelial carcinoma (BLCA) in The Cancer Genome Atlas (TCGA) database. The expression of lncRNA GTF2IRD2P1 was detected by qRT-PCR. The CCK8 assay and flow cytometry were used to detect the lncRNA GTF2IRD2P1 function on the proliferation of bladder cancer cells. A western blot was used to calculate the protein level of cell cycle proteins and Wnt signaling pathway proteins. The effect of lncRNA GTF2IRD2P1 on tumorigenesis of bladder cancer was confirmed by a xenograft nude mouse model. Results GTF2IRD2P1 expression was found to be lower in both human bladder cancer tissues and cell lines (UM-UC-3, RT4, and 5637), and elevated in T24 compared to the corresponding normal controls. GTF2IRD2P1 expression was also enhanced after transfection of UM-UC-3 cells with the overexpression vector. Meanwhile, overexpression of GTF2IRD2P1 inhibited the proliferation of UM-UC-3 and prolonged the cell cycle. The silencing of GTF2IRD2P1 significantly increased the proliferation and shortened the cell cycle of T24 cells and induced Wnt signaling activity to promote the progression of bladder cancer. Similarly, the transplanted tumor nude mouse model demonstrated that silencing GTF2IRD2P1 strengthens the progression of bladder cancer by targeting the Wnt signaling pathway.
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- 2022
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7. Chronic Stress-Induced Gene Changes In Vitro and In Vivo: Potential Biomarkers Associated With Depression and Cancer Based on circRNA- and lncRNA-Associated ceRNA Networks
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Ting Zhou, Mingming Li, Zhijun Xiao, Jian Cai, Weiwei Zhao, Jingjing Duan, Zhen Yang, Zhijun Guo, Yitian Chen, Weijia Cai, Piaopiao Huang, Chaoyong He, and Feng Xu
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ceRNA network ,circRNA ,lncRNA ,depression ,cancer ,microarray analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) have been considered as biomarkers or regulators in many diseases. However, the exact role of circRNA- or lncRNA-mediated competing endogenous RNA (ceRNA) networks in the modulation of depression pathogenesis-relevant processes is not clear. In this study, we profiled whole transcriptome in depression patients’ blood samples via microarray analysis. As a result, a total of 340 circRNAs, 398 lncRNAs, 206 miRNAs, and 92 mRNAs were differentially expressed between the depression and control groups. Then, we constructed ceRNA networks according to the differentially expressed genes (DEGs). Using bioinformatics analysis, 89 pairs of circRNA-ceRNA and 49 pairs of lncRNA-ceRNA networks were obtained. Since depression is a broad and heterogeneous condition that is known as promoter for many chronic diseases including cancer, so we further dug out 28 circRNAs, 61 lncRNAs, 26 miRNAs, and 29 mRNAs that are associated with cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the DEGs were significantly enriched in cancer-related signaling pathways such as MAPK, Wnt, IL-17, Ras, and PI3K-Akt. Genes involved in the above pathways such as S100A9, GATA2, SRFP5, SLC45A3, NTRK1, FRZB, has_circ_0014221, has_circ_0014220, and has_circ_0087100 were dysregulated in various cancer cell lines by stress hormones induced. HDC, GATA2, SLC45A3, and NTRK1 were downregulated in tumor-bearing mice subjected to chronic unpredictable mild stress (CUMS). LncRNA-mediated ceRNA network validation showed that overexpression of miR-4530 declined HDC level. Our findings highlight the potential circRNA- and lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of depression and as potential biomarkers in depression cancer comorbidity through the pathways of IL-17 or histidine metabolism.
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- 2021
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8. Activation of STING Pathway Contributed to Cisplatin-Induced Cardiac Dysfunction via Promoting the Activation of TNF-α-AP-1 Signal Pathway
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Lintao Wang, Suya Zhang, Jibo Han, Xiaoyan Nie, Yajun Qi, Yingying Han, Xiong Chen, and Chaoyong He
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stimulator of interferon genes ,cisplatin ,tumor necrosis factor-α ,activator protein 1 ,cardiotoxicity ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Cardiovascular complications are a well-documented limitation of conventional cancer chemotherapy. As a notable side effect of cisplatin, cardiotoxicity represents a major obstacle to the treatment of cancer. Recently, it has been reported that cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway was associated with the occurrence and development of cardiovascular diseases. However, the effect of STING on cardiac damage caused by cisplatin remains unclear. In this study, cisplatin was shown to activate the cGAS-STING signaling pathway, and deficiency of STING attenuated cisplatin-induced cardiotoxicity in vivo and in vitro. Mechanistically, the STING-TNF-α-AP-1 axis contributed to cisplatin-induced cardiotoxicity by triggering cardiomyocyte apoptosis. In conclusion, our results indicated that STING might be a critical regulator of cisplatin-induced cardiotoxicity and be considered as a potential therapeutic target for preventing the progression of chemotherapy-associated cardiovascular complications.
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- 2021
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9. Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis
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Eva M Buhl, Sonja Djudjaj, Barbara M Klinkhammer, Katja Ermert, Victor G Puelles, Maja T Lindenmeyer, Clemens D Cohen, Chaoyong He, Erawan Borkham‐Kamphorst, Ralf Weiskirchen, Bernd Denecke, Panuwat Trairatphisan, Julio Saez‐Rodriguez, Tobias B Huber, Lorin E Olson, Jürgen Floege, and Peter Boor
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anemia ,chronic kidney disease ,fibroblasts ,PDGFR ,progression ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Kidney fibrosis is characterized by expansion and activation of platelet‐derived growth factor receptor‐β (PDGFR‐β)‐positive mesenchymal cells. To study the consequences of PDGFR‐β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR‐β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR‐β activation resembled those found in patients. In conclusion, PDGFR‐β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.
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- 2020
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10. Wnt/β-Catenin Signaling in Liver Cancers
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Wenhui Wang, Ron Smits, Haiping Hao, and Chaoyong He
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liver cancer ,precancerous lesion ,HCC ,CCA ,HB ,Wnt/β-catenin signaling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.
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- 2019
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11. Single-cell analysis reveals Cxcl14+ progenitor fibroblast accumulation in regenerating diabetic wound treated by hydrogel-delivering carbon monoxide
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Ya Li, Sun Lu, Ranxi Chen, Yuyun Liang, Hexu Zhang, Chaoyong He, Bi Shi, Sophie Petropoulos, Cheng Zhao, and LIYANG SHI
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Non-healing skin wound is a problematic complication associated with diabetes. Therapeutic gases delivered by biomaterials have demonstrated powerful wound healing capabilities, but the mechanisms by which they promote skin regeneration remain unclear. Here, we demonstrated the benefit of a carbon monoxide-releasing hyaluronan hydrogel (CO@HAG) in promoting diabetic wound healing and investigated the regeneration mechanism through single-cell transcriptomic analysis. The presented CO@HAG demonstrated wound microenvironment responsive gas releasing properties and significantly accelerated diabetic wound healing process. In CO@HAG-treated regenerating wound, a new cluster of Cxcl14+ fibroblast with progenitor properties was found to be accumulated and wound macrophages of pro-inflammatory feature decreased while their anti-inflammatory property increased. Moreover, TGF-β signal between pro-inflammatory (M1) macrophage and Cxcl14+ fibroblast was attenuated, which may result in Cxcl14+ fibroblast enrichment. Our study provides a novel hydrogel-mediated gas therapy method for diabetic wound and new insights into the underlying mechanisms by which gas-releasing biomaterials facilitate skin regeneration.
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- 2023
12. Balasubramide derivative 3C attenuates atherosclerosis in apolipoprotein E-deficient mice: role of AMPK-STAT1-STING signaling pathway
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Yuanlong Hou, Chaoyong He, Hansen Lin, Dong-Cheng Cai, Tao Pang, Hongxia Liu, and Jing Wang
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Apolipoprotein E ,AMPK ,Male ,Aging ,Apolipoprotein B ,Mice, Knockout, ApoE ,Drug Evaluation, Preclinical ,Inflammation ,Pharmacology ,AMP-Activated Protein Kinases ,Mice ,STAT1 ,medicine ,Macrophage ,Animals ,Humans ,Protein kinase A ,Aorta ,biology ,Chemistry ,Membrane Proteins ,Cell Biology ,Atherosclerosis ,(+)-balasubramide derivative 3C ,Disease Models, Animal ,RAW 264.7 Cells ,STAT1 Transcription Factor ,Stimulator of interferon genes ,biology.protein ,medicine.symptom ,Signal transduction ,Heterocyclic Compounds, 3-Ring ,Injections, Intraperitoneal ,Research Paper ,STING ,Signal Transduction - Abstract
We previously reported the neuroprotective effects of (+)-balasubramide derived compound 3C, but its action on atherosclerosis in vivo remains unknown. The study was designed to investigate the potential effects of 3C on atherogenesis and explore the possible underlying mechanisms. 3C ameliorated high-fat diet-induced body weight gain, hyperlipidemia, and atherosclerotic plaque burden in apolipoprotein E-deficient (ApoE-/-) mice after 10 weeks of treatment. 3C suppressed the expression of genes involved in triglyceride synthesis in liver. 3C prevented aortic inflammation as evidenced by reduction of adhesive molecule levels and macrophage infiltration. Mechanistic studies revealed that activation of AMP-activated protein kinase (AMPK) is central to the athero-protective effects of 3C. Increased AMPK activity by 3C resulted in suppressing interferon-γ (IFN-γ) induced activation of signal transducer and activator of transcription-1 (STAT1) and stimulator of interferon genes (STING) signaling pathways and downstream pro-inflammatory markers. Moreover, 3C inhibited ox-LDL triggered lipid accumulation and IFN-γ induced phenotypic switch toward M1 macrophage in RAW 264.7 cells. Our present data suggest that 3C prevents atherosclerosis via pleiotropic effects, including amelioration of lipid profiles, vascular inflammation and macrophage pro-inflammatory phenotype. 3C has the potential to be developed as a promising drug for atherosclerosis and related cardiovascular disease.
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- 2021
13. Time-Resolved Acetaldehyde-Based Accessibility Profiling Maps Ligand–Target Interactions
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Ning Wan, Hui Ye, Langlang Lv, Yang Tian, Haiping Hao, Nian Wang, Qiuyu Bao, and Chaoyong He
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RNase P ,Lysine ,Quantitative proteomics ,Acetaldehyde ,Ligands ,010402 general chemistry ,Proteomics ,01 natural sciences ,Mass Spectrometry ,Peptide Library ,Tandem Mass Spectrometry ,Structural Biology ,Humans ,Binding site ,Spectroscopy ,Ligand ,Chemistry ,010401 analytical chemistry ,Selected reaction monitoring ,Proteins ,Hep G2 Cells ,Ribonuclease, Pancreatic ,Affinities ,0104 chemical sciences ,Molecular Docking Simulation ,Biochemistry - Abstract
Elucidating ligand-protein interactions is important in understanding the biochemical machinery for given proteins. Previously, formaldehyde (FH)-based labeling has been employed to obtain such structural knowledge, since reactive residues that participate in ligand-target interactions display reduced accessibility to FH-labeling reagents, and thus can be identified by quantitative proteomics. Although being rapid and efficient for probing proteinaceous lysine accessibility, here, we report an acetaldehyde (AcH)-labeling approach that complements with FH for probing ligand-target interactions. AcH labeling examines lysine accessibility at a more moderate reaction speed and hence delivers a cleaner reaction when compared to that of FH. The subsequent application of AcH to label RNase A without and with ligands has assisted to assign lysines involved in ligand-RNase A binding by detecting the time-dependent changes in accessibility profiles. We further employed multiple reaction monitoring (MRM) to quantify these ligand-binding-responsive sites when a variety of potential ligands were queried. We noted that the time-resolved abundance changes of these peptides can sensitively determine the ligand-binding sites and differentiate binding affinities among these ligands, which was confirmed by native mass spectrometry (MS) and molecular docking. Lastly, we demonstrated that the binding sites can be recognized by monitoring the chemical accessibility of these responsive peptides in cell lysates. Together, we believe that the proposed combined use of AcH-based lysine accessibility profiling, native MS, and MRM screening is a powerful toolbox in characterizing ligand-target interactions, mapping topography, and interrogating affinities and holds promise for future applications in a complex cellular environment.
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- 2020
14. Sgi-52 Participate in Sperm Selection and Clearance in Macrophages
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Chaoyong He, Jiankai Li, Zhao Wu, Chuncheng Lu, Zhou Huang, Ning Luo, Shipeng Fan, Jihong Shen, Xiaodong Liu, and Hui Zhao
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- 2022
15. Regulation of thermogenesis in Brown and Beige Adipose Tissues
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Chaoyong He
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medicine.medical_specialty ,Endocrinology ,Internal medicine ,medicine ,General Earth and Planetary Sciences ,Adipose tissue ,Biology ,Thermogenesis ,General Environmental Science - Published
- 2020
16. Hyaluronic Acid‐Guided Cerasome Nano‐Agents for Simultaneous Imaging and Treatment of Advanced Atherosclerosis
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Qian Ma, Sijing Wu, Ling Yang, Yaohua Wei, Chaoyong He, Wenshan Wang, Yingxin Zhao, Zhijian Wang, Shiwei Yang, Dongmei Shi, Yuyang Liu, Zhiming Zhou, Jiefang Sun, and Yujie Zhou
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General Chemical Engineering ,General Engineering ,General Physics and Astronomy ,Medicine (miscellaneous) ,General Materials Science ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
Early noninvasive screening and regression therapy for vulnerable atherosclerotic plaques remain challenging. In this study, it is aimed to develop a new approach for the active targeting of atherosclerotic plaques with nano-agents to aid imaging and treatment. Biocompatible hyaluronic acid (HA)-guided cerasomes are generated to selectively target CD44-positive cells within the plaque in in vitro studies and in vivo testing in Apoe
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- 2022
17. Chronic Stress-Induced Gene Changes In Vitro and In Vivo: Potential Biomarkers Associated With Depression and Cancer Based on circRNA- and lncRNA-Associated ceRNA Networks
- Author
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Weijia Cai, Zhen Yang, Weiwei Zhao, Piaopiao Huang, Yitian Chen, Zhijun Guo, Chaoyong He, Zhijun Xiao, Jingjing Duan, Feng Xu, Mingming Li, Jian Cai, and Ting Zhou
- Subjects
ceRNA network ,Cancer Research ,Competing endogenous RNA ,Microarray analysis techniques ,Wnt signaling pathway ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Computational biology ,Biology ,Transcriptome ,lncRNA ,Oncology ,Frzb ,depression ,microRNA ,cancer ,circRNA ,microarray analysis ,KEGG ,Gene ,RC254-282 ,Original Research - Abstract
Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) have been considered as biomarkers or regulators in many diseases. However, the exact role of circRNA- or lncRNA-mediated competing endogenous RNA (ceRNA) networks in the modulation of depression pathogenesis-relevant processes is not clear. In this study, we profiled whole transcriptome in depression patients’ blood samples via microarray analysis. As a result, a total of 340 circRNAs, 398 lncRNAs, 206 miRNAs, and 92 mRNAs were differentially expressed between the depression and control groups. Then, we constructed ceRNA networks according to the differentially expressed genes (DEGs). Using bioinformatics analysis, 89 pairs of circRNA-ceRNA and 49 pairs of lncRNA-ceRNA networks were obtained. Since depression is a broad and heterogeneous condition that is known as promoter for many chronic diseases including cancer, so we further dug out 28 circRNAs, 61 lncRNAs, 26 miRNAs, and 29 mRNAs that are associated with cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the DEGs were significantly enriched in cancer-related signaling pathways such as MAPK, Wnt, IL-17, Ras, and PI3K-Akt. Genes involved in the above pathways such as S100A9, GATA2, SRFP5, SLC45A3, NTRK1, FRZB, has_circ_0014221, has_circ_0014220, and has_circ_0087100 were dysregulated in various cancer cell lines by stress hormones induced. HDC, GATA2, SLC45A3, and NTRK1 were downregulated in tumor-bearing mice subjected to chronic unpredictable mild stress (CUMS). LncRNA-mediated ceRNA network validation showed that overexpression of miR-4530 declined HDC level. Our findings highlight the potential circRNA- and lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of depression and as potential biomarkers in depression cancer comorbidity through the pathways of IL-17 or histidine metabolism.
- Published
- 2021
18. The semenogelin I-derived peptide SgI-52 in seminal plasma participates in sperm selection and clearance by macrophages
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Chaoyong, He, Jiankai, Li, Zhao, Wu, Chuncheng, Lu, Zhuo, Huang, Ning, Luo, Shipeng, Fan, Jihong, Shen, Xiaodong, Liu, and Hui, Zhao
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Male ,Cellular and Molecular Neuroscience ,Adenosine Triphosphate ,Endocrinology ,Semen ,Physiology ,Macrophages ,Sperm Motility ,Humans ,Female ,Peptides ,Spermatozoa ,Biochemistry - Abstract
Macrophages can phagocytose sperm, especially damaged spermatozoa, in the female genital tract. The semenogelin I-derived peptide SgI-52 in seminal plasma exhibits seminal plasma motility inhibitor (SPMI) activity and can inhibit sperm motility. This raises the question of the role played by SPMIs in macrophage-mediated phagocytosis of sperm. We speculated that SgI-52 promotes sperm clearance by macrophages. Therefore, we investigated the phagocytosis of sperm in different states using this peptide.SgI-52 was fluorescently labeled, and its binding site for sperm was observed. The ability of macrophages to phagocytose sperm was observed using fluorescence confocal microscopy. Spermatozoa from different sources were co-cultured with SgI-52 in BWW medium for 4 and 22 h to compare the differences in their phagocytosis by macrophages. Sperm motility, induced acrosome reaction, mitochondrial membrane potential, and ATP content were examined after incubation with SgI-52.SgI-52 could bind to spermatozoa in different states, mainly to the tail, and then spread to the acrosome. This effect was more pronounced in demembranated spermatozoa. SgI-52 promoted phagocytosis of spermatozoa by macrophages, decreased the mitochondrial membrane potential, and increased the average ATP content of spermatozoa (P 0.05).We found for the first time that SgI-52 can bind to spermatozoa in different states and promote their phagocytosis by macrophages. Therefore, we speculate that SgI-52 is involved in the screening of sperm in the female reproductive tract and has potential value in improving assisted reproductive technology.
- Published
- 2022
19. A novel affinity peptide-antibody sandwich electrochemical biosensor for PSA based on the signal amplification of MnO
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Jing, Zheng, Hui, Zhao, Guobao, Ning, Weijie, Sun, Li, Wang, Huan, Liang, Hanbin, Xu, Chaoyong, He, and Can-Peng, Li
- Subjects
Immunoassay ,Male ,Manganese Compounds ,Limit of Detection ,Humans ,Metal Nanoparticles ,Oxides ,Biosensing Techniques ,Electrochemical Techniques ,Gold ,Prostate-Specific Antigen ,Peptides ,Metal-Organic Frameworks - Abstract
This work describes a novel affinity peptide-antibody sandwich electrochemical strategy for the ultrasensitive detection of prostate-specific antigen (PSA). Herein, polydopamine-coated boron-doped carbon nitride (Au@PDA@BCN) was synthesized and used as a sensing platform to anchor gold nanoparticles and immobilize primary antibody. Meanwhile, AuPt metallic nanoparticle and manganese dioxide (MnO
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- 2021
20. Signal transducer and transcriptional activation 1 protects against pressure overload-induced cardiac hypertrophy
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Chaoyong He, Yuanyuan Tong, Li Gao, Hongxia Liu, and Changlin Zhen
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0301 basic medicine ,Dynamins ,Cardiomegaly ,Biochemistry ,Mitochondria, Heart ,Muscle hypertrophy ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fibrosis ,Genetics ,Medicine ,Animals ,Uncoupling Protein 2 ,STAT1 ,Molecular Biology ,Pressure overload ,Mice, Knockout ,biology ,business.industry ,medicine.disease ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,STAT1 Transcription Factor ,Apoptosis ,Knockout mouse ,cardiovascular system ,biology.protein ,Mitochondrial fission ,Signal transduction ,business ,030217 neurology & neurosurgery ,Biotechnology ,Signal Transduction - Abstract
Signal transducers and transcriptional activation 1 (Stat1) is a member of the STATs family, and its role in various biological responses, including cell proliferation, differentiation, migration, apoptosis, and immune regulation has been extensively studied. We aimed to investigate its role in pathological cardiac hypertrophy, which is currently poorly understood. Experiments using H9C2 cardiomyocytes, Stat1, and IfngR cardiomyocyte-specific knockout mice revealed that Stat1 had a protective effect on cardiac hypertrophy. Using transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice, we analyzed the degree of hypertrophy using echocardiography, pathology, and at the molecular level. Mice lacking Stat1 had more pronounced cardiac hypertrophy and fibrosis than wild-type TAC mice. Analysis of the molecular mechanisms suggested that Stat1 downregulated the mRNA levels of hypertrophy and fibrosis markers to inhibit cardiac hypertrophy, and promotes mitochondrial fission through the Ucp2/P-Drp1 pathway, enhancing mitochondrial function, and increasing compensatory myocardial ATP production in the compensatory phase for cardiac hypertrophy inhibition. Overall, this comprehensive analysis revealed that Stat1 inhibits cardiac hypertrophy by downregulating hypertrophic and fibrotic marker genes and enhancing the mitochondrial function to enhance cardiomyocyte function through the Ucp2/P-Drp1 signaling pathway.
- Published
- 2020
21. Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis
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Chaoyong He, Maja T. Lindenmeyer, Clemens D. Cohen, Julio Saez-Rodriguez, Eva Miriam Buhl, Katja Ermert, Panuwat Trairatphisan, Bernd Denecke, Ralf Weiskirchen, Jürgen Floege, Tobias B. Huber, Victor G. Puelles, Sonja Djudjaj, Barbara M. Klinkhammer, Erawan Borkham-Kamphorst, Lorin E. Olson, and Peter Boor
- Subjects
0301 basic medicine ,Medicine (General) ,PDGFR ,Urogenital System ,QH426-470 ,Article ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,Growth factor receptor ,Fibrosis ,fibroblasts ,Genetics ,medicine ,Renal fibrosis ,ddc:610 ,biology ,business.industry ,Mesenchymal stem cell ,Articles ,medicine.disease ,anemia ,Obstructive Nephropathy ,3. Good health ,030104 developmental biology ,Erythropoietin ,Cancer research ,biology.protein ,Molecular Medicine ,progression ,business ,chronic kidney disease ,030217 neurology & neurosurgery ,Platelet-derived growth factor receptor ,medicine.drug ,Kidney disease - Abstract
Kidney fibrosis is characterized by expansion and activation of platelet‐derived growth factor receptor‐β (PDGFR‐β)‐positive mesenchymal cells. To study the consequences of PDGFR‐β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR‐β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR‐β activation resembled those found in patients. In conclusion, PDGFR‐β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression., Kidney fibrosis is the common pathological process of chronic kidney diseases (CKD), a major global health problem. Using a newly developed murine model of primary fibrosis and analyses of patient samples, this study demonstrated the important role of PDGFR‐β signaling in driving renal fibrosis.
- Published
- 2020
22. WITHDRAWN: Smooth muscle cell-specific knockout of interferon gamma (IFN-γ) receptor attenuates intimal hyperplasia via STAT1-KLF4 activation
- Author
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Lu He, Hongxia Liu, Chaoyong He, Kun Gao, Jing Wang, and Xin-Wei Li
- Subjects
0301 basic medicine ,Neointima ,Neointimal hyperplasia ,Intimal hyperplasia ,Vascular smooth muscle ,Chemistry ,General Medicine ,musculoskeletal system ,medicine.disease ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,Restenosis ,KLF4 ,cardiovascular system ,Cancer research ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor - Abstract
Background Intimal hyperplasia is a main contributor to in-stent restenosis. Previous researches have shown that interferon-gamma (IFN-γ), a pleiotropic pro-inflammatory factor, plays a pathological role in intimal hyperplasia. However, the specific role and molecular mechanism of vascular smooth muscle cells (VSMCs)-derived IFN-γ receptor in intimal hyperplasia remains unknown. Methods We examined the distribution of IFN-γ receptor in human restenosis arteries. Then, the role of IFN-γ receptor in intimal hyperplasia was detected using VSMC-specific IFN-γ receptor-knock out carotid ligation injury models. We performed immunostaining, transwell assay and EdU staining to identify the role of IFN-γ in VSMCs proliferation and migration. The effect of IFN-γ on VSMCs phenotype switching was also investigated. Finally, we evaluated whether the mechanism of IFN-γ on intimal hyperplasia is STAT1-KLF4 dependent. Results The distribution of IFN-γ receptor in human restenosis arteries with VSMC-rich neointima is eventually upregulated. Specific deletion of IFN-γ receptor exhibits thinner intima and lesser proliferating VSMCs. In vitro, treatment with IFN-γ promotes human aortic VSMC (HAVSMCs) proliferation and migration, whereas specifically knock out IFN-γ receptor results in the opposite effect. Deficiency of IFN-γ receptor regulates VSMCs phenotypic switching, such as upregulated contractile markers and downregulated proliferation markers. Mechanistic studies suggest that ablation of IFN-γ receptor prevents VSMCs proliferation, migration and dedifferentiation via STAT1-KLF4 activation. Conclusion These results reveal that knockout of VSMC-derived IFN-γ receptor potentiates neointimal hyperplasia by preventing VSMCs proliferation, migration and dedifferentiation. Our finding implies that targeting IFN-γ-STAT1-KLF4 signaling could provide a new therapeutic strategy to attenuate vessel restenosis.
- Published
- 2021
23. STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ
- Author
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Bojie Dai, Longbiao Yao, Jang Kim, Shayna C. Medley, Chaoyong He, Danielle Eppard, Yair Pincu, Lorin E. Olson, Chengyi Sun, Timothy M. Griffin, Hae Ryong Kwon, William L. Berry, and Hiromi Sakashita
- Subjects
Male ,0301 basic medicine ,PDGFRB ,medicine.disease_cause ,Bone and Bones ,Muscle, Smooth, Vascular ,Receptor tyrosine kinase ,Receptor, Platelet-Derived Growth Factor beta ,Mice ,03 medical and health sciences ,Genetics ,medicine ,Animals ,STAT1 ,Receptor ,Aorta ,Growth Disorders ,Skin ,Inflammation ,Mice, Knockout ,Mutation ,Hyperplasia ,biology ,Fibroblasts ,Fibrosis ,Phenotype ,STAT1 Transcription Factor ,030104 developmental biology ,Adipose Tissue ,Immunology ,NIH 3T3 Cells ,STAT protein ,biology.protein ,Cancer research ,Female ,Interferons ,Atrophy ,Platelet-derived growth factor receptor ,Signal Transduction ,Research Paper ,Developmental Biology - Abstract
Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb+/D849V mice with Stat1 knockout (Stat1−/−Pdgfrb+/D849V) are rescued from autoinflammation and have improved life span compared with Stat1+/−Pdgfrb+/D849V mice. Furthermore, PDGFRβ–STAT1 signaling suppresses PDGFRβ itself. Thus, Stat1−/−Pdgfrb+/D849V fibroblasts exhibit increased PDGFRβ signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1+/−Pdgfrb+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRβ signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.
- Published
- 2017
24. Wnt/β-Catenin Signaling in Liver Cancers
- Author
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Ron Smits, Wenhui Wang, Haiping Hao, Chaoyong He, and Gastroenterology & Hepatology
- Subjects
0301 basic medicine ,Cancer Research ,Hepatoblastoma ,HB ,Wnt β catenin signaling ,Review ,lcsh:RC254-282 ,Pathogenesis ,liver cancer ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,medicine ,HCC ,CCA ,business.industry ,Wnt signaling pathway ,Cancer ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,precancerous lesion ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Signal transduction ,Liver cancer ,business ,Wnt/β-catenin signaling - Abstract
Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.
- Published
- 2019
25. AMPK Suppresses Vascular Inflammation In Vivo by Inhibiting Signal Transducer and Activator of Transcription-1
- Author
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Benoit Viollet, Ming-Hui Zou, Hongliang Li, Chaoyong He, and Zhonglin Xie
- Subjects
Vasculitis ,Small interfering RNA ,Complications ,MAP Kinase Signaling System ,Endocrinology, Diabetes and Metabolism ,Inflammation ,Aorta, Thoracic ,AMP-Activated Protein Kinases ,Muscle, Smooth, Vascular ,Proinflammatory cytokine ,Interferon-gamma ,Random Allocation ,Internal Medicine ,medicine ,Animals ,Humans ,STAT1 ,Phosphorylation ,Cells, Cultured ,Mice, Knockout ,biology ,Chemistry ,Activator (genetics) ,Angiotensin II ,Anti-Inflammatory Agents, Non-Steroidal ,AMPK ,Dual Specificity Phosphatase 1 ,Recombinant Proteins ,Cell biology ,Enzyme Activation ,Mice, Inbred C57BL ,STAT1 Transcription Factor ,STAT protein ,biology.protein ,RNA Interference ,medicine.symptom ,Protein Processing, Post-Translational - Abstract
Activation of AMPK suppresses inflammation, but the underlying mechanisms remain poorly understood. This study was designed to characterize the molecular mechanisms by which AMPK suppresses vascular inflammation. In cultured human aortic smooth muscle cells, pharmacologic or genetic activation of AMPK inhibited the signal transducer and activator of transcription-1 (STAT1), while inhibition of AMPK had opposite effects. Deletion of AMPKα1 or AMPKα2 resulted in activation of STAT1 and in increases in proinflammatory mediators, both of which were attenuated by administration of STAT1 small interfering RNA or fludarabine, a selective STAT1 inhibitor. Moreover, AMPK activation attenuated the proinflammatory actions induced by STAT1 activators such as interferon-γ and angiotensin II (AngII). Mechanistically, we found that AMPK activation increased, whereas AMPK inhibition decreased, the levels of mitogen-activated protein kinase phosphatase-1 (MKP-1), an inducible nuclear phosphatase, by regulating proteasome-dependent degradation of MKP-1. Gene silencing of MKP-1 increased STAT1 phosphorylation and prevented 5-aminoimidazole-4-carboxyamide ribonucleoside–reduced STAT1 phosphorylation. Finally, we found that infusion of AngII caused a more severe inflammatory response in AMPKα2 knockout mouse aortas, all of which were suppressed by chronic administration of fludarabine. We conclude that AMPK activation suppresses STAT1 signaling and inhibits vascular inflammation through the upregulation of MKP-1.
- Published
- 2015
26. Dissociation of Bcl-2–Beclin1 Complex by Activated AMPK Enhances Cardiac Autophagy and Protects Against Cardiomyocyte Apoptosis in Diabetes
- Author
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Hongliang Li, Ming-Hui Zou, Chaoyong He, Huaiping Zhu, and Zhonglin Xie
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Complications ,Diabetic Cardiomyopathies ,MAP Kinase Kinase 4 ,Endocrinology, Diabetes and Metabolism ,Cardiomyopathy ,Apoptosis ,Mice, Transgenic ,030204 cardiovascular system & hematology ,Biology ,Cell Line ,Diabetes Mellitus, Experimental ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetic cardiomyopathy ,Autophagy ,Internal Medicine ,medicine ,Animals ,Myocyte ,Myocytes, Cardiac ,Protein kinase A ,Original Research ,030304 developmental biology ,0303 health sciences ,Kinase ,Adenylate Kinase ,AMPK ,medicine.disease ,Friend murine leukemia virus ,Rats ,3. Good health ,Cell biology ,Glucose ,Endocrinology ,Proto-Oncogene Proteins c-bcl-2 ,cardiovascular system ,Beclin-1 ,Apoptosis Regulatory Proteins - Abstract
Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose–treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)–B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1–Bcl-2 signaling and disrupted the Beclin1–Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose–induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1–Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis.
- Published
- 2013
27. PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis
- Author
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Chaoyong He, Myron E. Hinsdale, Taishan Hu, Florea Lupu, Lorin E. Olson, Renu Virmani, and Shayna C. Medley
- Subjects
medicine.medical_specialty ,Vascular smooth muscle ,medicine.medical_treatment ,Blotting, Western ,Hypercholesterolemia ,Myocytes, Smooth Muscle ,General Physics and Astronomy ,Context (language use) ,Inflammation ,Real-Time Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Muscle, Smooth, Vascular ,Article ,Receptor, Platelet-Derived Growth Factor beta ,Mice ,Apolipoproteins E ,Microscopy, Electron, Transmission ,Internal medicine ,Adventitia ,medicine ,Animals ,Immunoprecipitation ,Gene Knock-In Techniques ,Triglycerides ,Mice, Knockout ,Multidisciplinary ,biology ,Growth factor ,General Chemistry ,Atherosclerosis ,Flow Cytometry ,Plaque, Atherosclerotic ,medicine.anatomical_structure ,Endocrinology ,Cholesterol ,STAT1 Transcription Factor ,Receptors, LDL ,Chemokine secretion ,LDL receptor ,Cancer research ,biology.protein ,cardiovascular system ,medicine.symptom ,Chemokines ,Platelet-derived growth factor receptor ,Signal Transduction - Abstract
Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in the context of atherosclerosis. Here we present a new mouse model of atherosclerosis with an activating mutation in PDGFRβ. Increased PDGFRβ signalling induces chemokine secretion and leads to leukocyte accumulation in the adventitia and media of the aorta. Furthermore, PDGFRβ(D849V) amplifies and accelerates atherosclerosis in hypercholesterolemic ApoE(-/-) or Ldlr(-/-) mice. Intriguingly, increased PDGFRβ signalling promotes advanced plaque formation at novel sites in the thoracic aorta and coronary arteries. However, deletion of the PDGFRβ-activated transcription factor STAT1 in VSMCs alleviates inflammation of the arterial wall and reduces plaque burden. These results demonstrate that PDGFRβ pathway activation has a profound effect on vascular disease and support the conclusion that inflammation in the outer arterial layers is a driving process for atherosclerosis.
- Published
- 2014
28. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice
- Author
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Zhonglin Xie, Mingjiang Xu, Chaoyong He, Jiyeon Lee, and Hongliang Li
- Subjects
Male ,Physiology ,Endocrinology, Diabetes and Metabolism ,FOXO1 ,Cell Cycle Proteins ,AMP-Activated Protein Kinases ,Mice ,Random Allocation ,AMP-activated protein kinase ,Sirtuin 1 ,Nicotinamide Phosphoribosyltransferase ,biology ,Forkhead Box Protein O1 ,Reverse Transcriptase Polymerase Chain Reaction ,food and beverages ,Forkhead Transcription Factors ,Mitochondrial Turnover ,Articles ,Glucose clamp technique ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Leucine ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,medicine.medical_specialty ,Blotting, Western ,DNA, Mitochondrial ,Insulin resistance ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Obesity ,nutritional and metabolic diseases ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Gene Expression Regulation ,Dietary Supplements ,biology.protein ,Glucose Clamp Technique ,Trans-Activators ,RNA ,Insulin Resistance ,Dyslipidemia ,Transcription Factors - Abstract
Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD+levels, which decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1α and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity.
- Published
- 2012
29. 7-Ketocholesterol induces autophagy in vascular smooth muscle cells through Nox4 and Atg4B
- Author
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Chaoyong He, Yun-Zheng Le, Qilong Wang, Zhonglin Xie, Huaiping Zhu, Wencheng Zhang, Imoh Okon, and Hongliang Li
- Subjects
Male ,Programmed cell death ,Vascular smooth muscle ,Myocytes, Smooth Muscle ,Autophagy-Related Proteins ,Apoptosis ,Muscle, Smooth, Vascular ,Pathology and Forensic Medicine ,Mice ,Autophagy ,Myocyte ,Animals ,Humans ,Enzyme Inhibitors ,Ketocholesterols ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Sirolimus ,Reactive oxygen species ,NADPH oxidase ,biology ,Cell Death ,NADPH Oxidases ,Cardiovascular Agents ,Regular Article ,Free Radical Scavengers ,Hydrogen Peroxide ,Atherosclerosis ,Cell biology ,Up-Regulation ,Cysteine Endopeptidases ,chemistry ,Catalase ,NADPH Oxidase 4 ,biology.protein ,Unfolded protein response ,Reactive Oxygen Species ,Microtubule-Associated Proteins - Abstract
Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux. Autophagy induction was suppressed by treating the cells with either a reactive oxygen species scavenger or an antioxidant. Administration of 7-KC concomitantly up-regulated Nox4 expression, increased intracellular hydrogen peroxide levels, and inhibited autophagy-related gene 4B activity. Catalase overexpression to remove hydrogen peroxide or Nox4 knockdown with siRNA reduced intracellular hydrogen peroxide levels, restored autophagy-related gene 4B activity, and consequently attenuated 7-KC-induced autophagy. Moreover, inhibition of autophagy aggravated both endoplasmic reticulum (ER) stress and cell death in response to 7-KC. In contrast, up-regulation of autophagic activity by rapamycin had opposite effects. Finally, activation of autophagy by chronic rapamycin treatment attenuated ER stress, apoptosis, and atherosclerosis in apolipoprotein E knockout (ApoE(-/-)) mouse aortas. In conclusion, we demonstrate that up-regulation of autophagy is a cellular protective response that attenuates 7-KC-induced cell death in human aortic smooth muscle cells.
- Published
- 2012
30. Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes
- Author
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Zhonglin Xie, Chaoyong He, Ming-Hui Zou, Mingkai Lin, Hongliang Li, and Timothy J. Lyons
- Subjects
Glycation End Products, Advanced ,medicine.medical_specialty ,Receptors, Thromboxane ,Blood–retinal barrier ,Nitric Oxide Synthase Type II ,Apoptosis ,medicine.disease_cause ,Nitric Oxide ,Antioxidants ,Retina ,Pathology and Forensic Medicine ,Nitric oxide ,Prostacyclin synthase ,Tight Junctions ,Thromboxane receptor ,Superoxide dismutase ,Cyclic N-Oxides ,chemistry.chemical_compound ,Mice ,Cytochrome P-450 Enzyme System ,Internal medicine ,Blood-Retinal Barrier ,medicine ,Animals ,Humans ,Cells, Cultured ,Diabetic Retinopathy ,biology ,Superoxide ,Superoxide Dismutase ,Regular Article ,Nitric oxide synthase ,Intramolecular Oxidoreductases ,Lipoproteins, LDL ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,NG-Nitroarginine Methyl Ester ,chemistry ,Cyclooxygenase 2 ,biology.protein ,Tyrosine ,lipids (amino acids, peptides, and proteins) ,Spin Labels ,Pericytes ,Oxidative stress - Abstract
The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N(G)-nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of diabetic retinopathy.
- Published
- 2011
31. AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells
- Author
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Shuangxi Wang, Ming-Hui Zou, Bin Liang, Benoit Viollet, Chaoyong He, Ping Song, and Shaobin Wang
- Subjects
Neointima ,Proteasome Endopeptidase Complex ,Vascular smooth muscle ,Physiology ,Myocytes, Smooth Muscle ,Biology ,AMP-Activated Protein Kinases ,Muscle, Smooth, Vascular ,Article ,Mice ,AMP-activated protein kinase ,medicine ,Myocyte ,Animals ,RNA, Small Interfering ,Protein kinase A ,S-Phase Kinase-Associated Proteins ,Cells, Cultured ,Mice, Knockout ,Hyperplasia ,Cell growth ,Ubiquitination ,AMPK ,Adenosine ,Cell biology ,Up-Regulation ,Biochemistry ,biology.protein ,RNA Interference ,Cardiology and Cardiovascular Medicine ,Carotid Artery Injuries ,Tunica Intima ,Protein Processing, Post-Translational ,Cell Division ,Cyclin-Dependent Kinase Inhibitor p27 ,Gene Deletion ,medicine.drug - Abstract
Adenosine monophosphate-activated protein kinase (AMPK), a metabolic and redox sensor, is reported to suppress cell proliferation of nonmalignant and tumor cells. Whether AMPKα alters vascular neointima formation induced by vascular injury is unknown.The aim of this study was to determine the roles of AMPKα in the development of vascular neointima hyperplasia and to elucidate the underlying mechanisms.Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia were evaluated in cultured VSMCs and wire-injured mouse carotid arteries from wild-type (WT, C57BL/6J), AMPKα2(-/-), and AMPKα1(-/-) mice. Mouse VSMCs derived from aortas of AMPKα2(-/-) mice exhibited increased proliferation compared with either WT or AMPKα1(-/-) VSMCs. Further, deletion of AMPKα2 but not AMPKα1 reduced the level of p27(Kip1), a cyclin-dependent kinase inhibitor, and increased the level of S-phase kinase-associated protein 2 (Skp2), a known E3 ubiquitin ligase for p27(Kip1), through activation of p52 nuclear factor kappa B (NF-κB)-2. Moreover, either pharmacological (ie, through compound C) or genetical (ie, through AMPKα2-specific siRNA) inhibition of AMPK decreased p27(Kip1) levels but increased the abundance of Skp2 in human VSMCs. Furthermore, gene silencing of Skp2 reversed the levels of p27(Kip1) and VSMCs proliferation. Finally, neointima formation after mechanical arterial injury was increased in AMPKα2(-/-) but not AMPKα1(-/-) mice.These findings indicate that deletion of AMPKα2 through p52-Skp2-mediated ubiquitination and degradation of p27(Kip1) accentuates neointimal hyperplasia in response to wire injury.
- Published
- 2011
32. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice
- Author
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Yunzhou Dong, Shradha Rathi, Bonnie Eby, Chaoyong He, Hongliang Li, David C. Kem, Becky Pennington, Pedro Lozano, Ming-Hui Zou, Zhonglin Xie, Kai Lau, and Rong Tian
- Subjects
Cardiac function curve ,Male ,medicine.medical_specialty ,Complications ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Cardiomyopathy ,Apoptosis ,030204 cardiovascular system & hematology ,AMP-Activated Protein Kinases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,AMP-activated protein kinase ,Microscopy, Electron, Transmission ,Tuberous Sclerosis ,Internal medicine ,Diabetic cardiomyopathy ,Diabetes mellitus ,Internal Medicine ,medicine ,Autophagy ,In Situ Nick-End Labeling ,Animals ,Hypoglycemic Agents ,Myocytes, Cardiac ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Myocardium ,AMPK ,medicine.disease ,Immunohistochemistry ,Metformin ,3. Good health ,Endocrinology ,Echocardiography ,biology.protein ,Beclin-1 ,business ,Apoptosis Regulatory Proteins ,Cardiomyopathies ,medicine.drug - Abstract
OBJECTIVE Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice. RESEARCH DESIGN AND METHODS OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. RESULTS Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice. CONCLUSIONS Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.
- Published
- 2011
33. Enhanced tyrosine nitration of prostacyclin synthase is associated with increased inflammation in atherosclerotic carotid arteries from type 2 diabetic patients
- Author
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Zhonglin Xie, Hyoung Chul Choi, and Chaoyong He
- Subjects
Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,medicine.medical_treatment ,Nitric Oxide Synthase Type II ,Carotid endarterectomy ,Type 2 diabetes ,Gene Expression Regulation, Enzymologic ,Pathology and Forensic Medicine ,Prostacyclin synthase ,Nitric oxide ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Internal medicine ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,Humans ,Osteopontin ,Aged ,Peroxidase ,Inflammation ,biology ,business.industry ,Middle Aged ,medicine.disease ,Atherosclerosis ,Nitric oxide synthase ,Intramolecular Oxidoreductases ,Oxidative Stress ,Endocrinology ,Carotid Arteries ,chemistry ,Diabetes Mellitus, Type 2 ,biology.protein ,Tyrosine ,Female ,business ,Regular Articles - Abstract
Prostacyclin synthase (PGIS) is tyrosine nitrated in diseased animals. Whether PGIS nitration occurs in human diabetic atherosclerotic arteries has not been reported. The present study was designed to determine PGIS nitration and its association with the inflammatory response in atherosclerotic carotid arteries from patients with or without type 2 diabetes, and carotid plaques were obtained from patients who underwent carotid endarterectomy. PGIS nitration, nitric oxide synthases, adhesion molecules, myeloperoxidase, osteopontin, and matrix metalloproteinase (MMP) were measured by using immunohistochemistry and Western blotting. In low stenosis areas, diabetes enhanced reactive nitrogen species production, as evidenced by increases in 3-nitrotyrosine and PGIS nitration. In parallel, diabetes dramatically increased inflammatory markers including intracellular adhesion molecule-1, vascular adhesion molecule-1, and osteopontin. In both diabetic and nondiabetic patients, MMP-2 and MMP-9 protein levels were significantly increased in the arteries with high stenosis as compared with those with low stenosis. Moreover, diabetes enhanced inducible nitric oxide synthase expression in the plaques from low stenosis areas and up-regulated myeloperoxidase expression in the plaques from both high and low stenosis areas. These data demonstrate that diabetes preferentially increases PGIS nitration that is associated with excessive vascular inflammation in atherosclerotic carotid arteries from patients with type 2 diabetes, suggesting a possible role of tyrosine nitration of PGIS in the development of atherosclerosis in patients with diabetes.
- Published
- 2010
34. Effect of polysaccharides from Ganoderma lucidum on streptozotocin-induced diabetic nephropathy in mice
- Author
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Wei Li, S.-Q. Lin, Chaoyong He, Shu-Ying Guo, and Z.-B. Lin
- Subjects
Blood Glucose ,medicine.medical_specialty ,Reishi ,Kidney Glomerulus ,Pharmaceutical Science ,Streptozocin ,Analytical Chemistry ,Nephropathy ,Blood Urea Nitrogen ,Diabetic nephropathy ,chemistry.chemical_compound ,Mice ,Polysaccharides ,Transforming Growth Factor beta ,Internal medicine ,Diabetes mellitus ,Malondialdehyde ,Drug Discovery ,medicine ,Albuminuria ,Animals ,Diabetic Nephropathies ,Blood urea nitrogen ,Triglycerides ,Pharmacology ,Creatinine ,Analysis of Variance ,Triglyceride ,business.industry ,Superoxide Dismutase ,Organic Chemistry ,General Medicine ,medicine.disease ,Streptozotocin ,Immunohistochemistry ,Mice, Inbred C57BL ,Endocrinology ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,business ,medicine.drug - Abstract
The effects of Ganoderma lucidum polysaccharides (GL-PS) on renal complication in streptozotocin-induced diabetic mice have been investigated in the present study. C57BL/6J mice were made diabetic by injection of streptozotocin and GL-PS (125 and 250 mg kg-1) was administered for 8 weeks. Body weight was monitored every week. Serum glucose, creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG) and urinary albumin excretion (UAE) were measured after 8 weeks of treatment. Glomerular size and mesangial matrix index were assayed by morphometric analysis. Renal expression of transforming growth factor-beta1 (TGF-beta1) were determined by immunochemistry. Renal malondialdehyde (MDA) level and superoxide dismutase (SOD) activities were also evaluated. GL-PS was able to reduce the serum Cr and BUN levels and UAE compared with diabetic model mice in a dose-dependent manner. Increasing serum glucose and triglyceride levels in diabetic mice could also be lowered by GL-PS. Moreover, GL-PS had the capacity to improve the renal morphometric changes and oxidative stress state of diabetic mice. In summary, GL-PS can improve the metabolic abnormalities of diabetic mice and prevent or delay the progression of diabetic renal complications.
- Published
- 2006
35. AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy
- Author
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Ming-Hui Zou, Zhonglin Xie, and Chaoyong He
- Subjects
Cardiac function curve ,Diabetic Cardiomyopathies ,Cardiomyopathy ,Apoptosis ,AMP-Activated Protein Kinases ,Pharmacology ,Models, Biological ,Diabetes Mellitus, Experimental ,Mice ,AMP-activated protein kinase ,Diabetes mellitus ,Diabetic cardiomyopathy ,Autophagy ,medicine ,Animals ,Protein kinase A ,Molecular Biology ,biology ,Myocardium ,AMPK ,Cell Biology ,medicine.disease ,Autophagic Punctum ,Oxidative Stress ,cardiovascular system ,biology.protein - Abstract
We have recently shown that in diabetic OVE26 mice (type I diabetes), the AMP-activated protein kinase (AMPK) is reduced along with cardiac dysfunction and decreased cardiac autophagy. Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. More importantly, we have found chronic AMPK activation with metformin, one of the most used antidiabetes drugs and a well-characterized AMPK activator, significantly enhances autophagic activity, preserves cardiac function and prevents most of the primary characteristics of diabetic cardiomyopathy in OVE26 mice, but not in dominant negative-AMPK diabetic mice. We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.
- Published
- 2011
36. AMPK Suppresses Vascular Inflammation In Vivo by Inhibiting Signal Transducer and Activator of Transcription-1.
- Author
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Chaoyong He, Hongliang Li, Viollet, Benoit, Ming-Hui Zou, Zhonglin Xie, He, Chaoyong, Li, Hongliang, Zou, Ming-Hui, and Xie, Zhonglin
- Subjects
- *
VASCULITIS , *CELLULAR signal transduction , *TRANSCRIPTION factors , *SMOOTH muscle , *FLUDARABINE , *SMALL interfering RNA , *ANGIOTENSIN II , *PROTEASOMES , *ANIMAL experimentation , *BIOCHEMISTRY , *CARRIER proteins , *CELL culture , *GENES , *INTERFERONS , *PHENOMENOLOGY , *MICE , *NONSTEROIDAL anti-inflammatory agents , *PHOSPHATASES , *PHOSPHORYLATION , *PHOSPHOTRANSFERASES , *PROTEINS , *RECOMBINANT proteins , *RESEARCH funding , *STATISTICAL sampling , *THORACIC aorta , *CHEMICAL inhibitors , *PHARMACODYNAMICS - Abstract
Activation of AMPK suppresses inflammation, but the underlying mechanisms remain poorly understood. This study was designed to characterize the molecular mechanisms by which AMPK suppresses vascular inflammation. In cultured human aortic smooth muscle cells, pharmacologic or genetic activation of AMPK inhibited the signal transducer and activator of transcription-1 (STAT1), while inhibition of AMPK had opposite effects. Deletion of AMPKα1 or AMPKα2 resulted in activation of STAT1 and in increases in proinflammatory mediators, both of which were attenuated by administration of STAT1 small interfering RNA or fludarabine, a selective STAT1 inhibitor. Moreover, AMPK activation attenuated the proinflammatory actions induced by STAT1 activators such as interferon-γ and angiotensin II (AngII). Mechanistically, we found that AMPK activation increased, whereas AMPK inhibition decreased, the levels of mitogen-activated protein kinase phosphatase-1 (MKP-1), an inducible nuclear phosphatase, by regulating proteasome-dependent degradation of MKP-1. Gene silencing of MKP-1 increased STAT1 phosphorylation and prevented 5-aminoimidazole-4-carboxyamide ribonucleoside-reduced STAT1 phosphorylation. Finally, we found that infusion of AngII caused a more severe inflammatory response in AMPKα2 knockout mouse aortas, all of which were suppressed by chronic administration of fludarabine. We conclude that AMPK activation suppresses STAT1 signaling and inhibits vascular inflammation through the upregulation of MKP-1. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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37. Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids.
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Hongliang Li, Jiyeon Lee, Chaoyong He, Ming-Hui Zou, and Zhonglin Xie
- Subjects
IMMUNOSUPPRESSION ,RAPAMYCIN ,MITOGEN-activated protein kinases ,INSULIN resistance ,AMINO acids ,OBESITY ,TYPE 2 diabetes ,GENE expression - Abstract
Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser
473 and insulin receptor substrate-1 (IRS-1) Tyr612 . Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/ STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway. [ABSTRACT FROM AUTHOR]- Published
- 2014
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- View/download PDF
38. Dissociation of Bcl-2--Beclin1 Complex by Activated AMPK Enhances Cardiac Autophagy and Protects Against Cardiomyocyte Apoptosis in Diabetes.
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Chaoyong He, Huaiping Zhu, Hongliang Li, Ming-Hui Zou, and Zhonglin Xie
- Subjects
- *
AUTOPHAGY , *CYCLIC-AMP-dependent protein kinase , *CARDIOMYOPATHIES , *ANIMAL models of diabetes , *APOPTOSIS , *CELLULAR signal transduction , *METFORMIN - Abstract
Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose--treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)--B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1- Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose--induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice.
- Author
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Hongliang Li, Mingjiang Xu, Jiyeon Lee, Chaoyong He, and Zhonglin Xie
- Abstract
Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD+ levels, which decreased acetylation of peroxisome proliferator-activated receptor-7 coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1a and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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40. Improvement of Cardiac Functions by Chronic Metformin Treatment Is Associated With Enhanced Cardiac Autophagy in Diabetic OVE26 Mice.
- Author
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Zhonglin Xie, Kai Lau, Eby, Bonnie, Lozano, Pedro, Chaoyong He, Pennington, Becky, Hongliang Li, Rathi, Shradha, Yunzhou Dong, Rong Tian, Kem, David, and Ming-Hui Zou
- Subjects
HEART failure ,HEART diseases ,CARDIOVASCULAR diseases ,APOPTOSIS ,CARDIOMYOPATHIES - Abstract
OBJECTIVE--Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice. RESEARCH DESIGN AND METHODS--OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. RESULTS--Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice. CONCLUSIONS--Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
41. AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response
- Author
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Chaoyong He, Ming-Hui Zou, Hongliang Li, Qing Min, Jiyeon Lee, Changhan Ouyang, and Zhonglin Xie
- Subjects
Male ,AMPK ,Lipid accumulation ,mTORC1 ,AMP-Activated Protein Kinases ,Endoplasmic Reticulum ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,AMP-activated protein kinase ,2. Zero hunger ,0303 health sciences ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,TOR Serine-Threonine Kinases ,Hep G2 Cells ,Endoplasmic Reticulum Stress ,Lipids ,Cholesterol ,Liver ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Sterol Regulatory Element Binding Protein 1 ,ER stress ,medicine.medical_specialty ,Blotting, Western ,Mechanistic Target of Rapamycin Complex 1 ,Diet, High-Fat ,Real-Time Polymerase Chain Reaction ,SREBP ,Article ,03 medical and health sciences ,Internal medicine ,Hyperinsulinism ,medicine ,Animals ,Humans ,RNA, Messenger ,Protein kinase A ,Molecular Biology ,Triglycerides ,030304 developmental biology ,Endoplasmic reticulum ,Sterol regulatory element-binding protein ,Mice, Inbred C57BL ,Endocrinology ,Glucose ,chemistry ,Multiprotein Complexes ,Sweetening Agents ,Unfolded protein response ,biology.protein ,Glucose Clamp Technique ,030217 neurology & neurosurgery - Abstract
Lipid accumulation is a central event in the development of chronic metabolic diseases, including obesity and type 2 diabetes, but the mechanisms responsible for lipid accumulation are incompletely understood. This study was designed to investigate the mechanisms for excess nutrient-induced lipid accumulation and whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic lipid accumulation in excess nutrient-treated HepG2 cells and high fat diet (HFD)-fed mice. Exposure of HepG2 cells to high levels of glucose or palmitate induced the endoplasmic reticulum (ER) stress response, activated sterol regulatory element-binding protein-1 (SREBP-1), and enhanced lipid accumulation, all of which were sensitive to ER stress inhibitor and gene silencing of eukaryotic initiation factor 2α. The increases in ER stress response and lipid accumulation were associated with activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Inhibition of mTORC1 signaling attenuated the ER stress response and lipid accumulation induced by high glucose or by deletion of tuberous sclerosis 2. In addition, AMPK activation prevented the mTORC1 activation, ER stress response, and lipid accumulation. This effect was mimicked or abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Finally, treatment of HFD-fed mice with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside inhibited the mTORC1 pathway, suppressed the ER stress response, and prevented insulin resistance and hepatic lipid accumulation. We conclude that activation of AMPK prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 and ER stress response.
- Full Text
- View/download PDF
42. AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy.
- Author
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Zhonglin Xie, Chaoyong He, and Ming-Hui Zou
- Published
- 2011
- Full Text
- View/download PDF
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