200 results on '"Guo-ping Shi"'
Search Results
2. Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis
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Cong-Lin Liu, Marcela M. Santos, Cleverson Fernandes, Mengyang Liao, Karine Iamarene, Jin-Ying Zhang, Galina K. Sukhova, and Guo-Ping Shi
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Medicine ,Science - Abstract
Abstract Toll-like receptor 7 (TLR7) mediates autoantigen and viral RNA-induced cytokine production. Increased TLR7 expression in human atherosclerotic lesions suggests its involvement in atherogenesis. Here we demonstrated TLR7 expression in macrophages, smooth muscle cells (SMCs), and endothelial cells from mouse atherosclerotic lesions. To test a direct participation of TLR7 in atherosclerosis, we crossbred TLR7-deficient (Tlr7 −/−) mice with apolipoprotein E-deficient (Apoe −/−) mice and produced Apoe −/− Tlr7 −/− and Apoe −/− Tlr7 +/+ littermates, followed by feeding them an atherogenic diet to produce atherosclerosis. Compared to Apoe −/− Tlr7 +/+ mice, Apoe −/− Tlr7 −/− mice showed reduced aortic arch and sinus lesion areas. Reduced atherosclerosis in Apoe −/− Tlr7 −/− mice did not affect lesion macrophage-positive area and CD4+ T-cell number per lesion area, but reduced lesion expression of inflammatory markers major histocompatibility complex-class II and IL6, lesion matrix-degrading proteases cathepsin S and matrix metalloproteinase-9, and systemic serum amyloid A levels. TLR7 deficiency also reduced aortic arch SMC loss and lesion intima and media cell apoptosis. However, TLR7 deficiency did not affect aortic wall elastin fragmentation and collagen contents, or plasma lipoproteins. Therefore, TLR7 contributes to atherogenesis in Apoe −/− mice by regulating lesion and systemic inflammation. A TLR7 antagonist may mitigate atherosclerosis.
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- 2017
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3. Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice.
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Marjo M P C Donners, Lili Bai, Suzanne P M Lutgens, Erwin Wijnands, Jason Johnson, Leon J Schurgers, Cong-Lin Liu, Mat J A P Daemen, Kitty B J M Cleutjens, Guo-Ping Shi, Erik A L Biessen, and Sylvia Heeneman
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Medicine ,Science - Abstract
Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response.
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- 2016
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4. Plasma cathepsin S and cystatin C levels and risk of abdominal aortic aneurysm: a randomized population-based study.
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Bing-Jie Lv, Jes S Lindholt, Xiang Cheng, Jing Wang, and Guo-Ping Shi
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Medicine ,Science - Abstract
Human abdominal aortic aneurysm (AAA) lesions contain high levels of cathepsin S (CatS), but are deficient in its inhibitor, cystatin C. Whether plasma CatS and cystatin C levels are also altered in AAA patients remains unknown.Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatS and cystatin C levels by ELISA. Student's t test demonstrated higher plasma levels of total, active, and pro-CatS in AAA patients than in controls (P
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- 2012
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5. Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus.
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Zhen Wang, Hong Zhang, Xu-Hui Shen, Kui-Li Jin, Guo-fen Ye, Li Qian, Bo Li, Yong-Hong Zhang, and Guo-Ping Shi
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Medicine ,Science - Abstract
BackgroundRecent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE) may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus.Methods and resultsA total of 340 subjects 55 to 75 years of age were grouped according to the American Diabetes Association 2003 criteria of normal glucose tolerance, pre-diabetes, and diabetes mellitus. The Kruskal-Wallis test demonstrated significant differences in plasma IgE levels (P = 0.008) among groups with different glucose tolerance status. Linear regression analysis revealed significant correlations between plasma levels of chymase (P = 0.030) or IgE (P = 0.022) and diabetes mellitus. Ordinal logistic regression analysis showed that IgE was a significant risk factor of pre-diabetes and diabetes mellitus (odds ratio [OR]: 1.674, P = 0.034). After adjustment for common diabetes risk factors, including age, sex, hypertension, body-mass index, cholesterol, homeostatic model assessment (HOMA) index, high-sensitivity C-reactive protein (hs-CRP), and mast cell chymase and tryptase, IgE remained a significant risk factor (OR: 1.866, P = 0.015). Two-variable ordinal logistic analysis indicated that interactions between hs-CRP and IgE, or between IgE and chymase, increased further the risks of developing pre-diabetes and diabetes mellitus before (OR: 2.204, P = 0.044; OR: 2.479, P = 0.033) and after (OR: 2.251, P = 0.040; OR: 2.594, P = 0.026) adjustment for common diabetes risk factors.ConclusionsBoth IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus.
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- 2011
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6. Correction: Impaired Thymic Export and Apoptosis Contribute to Regulatory T-Cell Defects in Patients with Chronic Heart Failure.
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Ting-Ting Tang, Zheng-Feng Zhu, Jun Wang, Wen-Cai Zhang, Xin Tu, Hong Xiao, Xin-Ling Du, Jia-Hong Xia, Nian-Guo Dong, Wei Su, Ni Xia, Xin-Xin Yan, Shao-Fang Nie, Juan Liu, Su-Feng Zhou, Rui Yao, Jiang-Jiao Xie, Harish Jevallee, Xiang Wang, Meng-Yang Liao, Guo-Ping Shi, Michael Fu, Yu-Hua Liao, and Xiang Cheng
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Medicine ,Science - Published
- 2011
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7. Regulation of endothelial cell adhesion molecule expression by mast cells, macrophages, and neutrophils.
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Jie Zhang, Pilar Alcaide, Li Liu, Jiusong Sun, Aina He, Francis W Luscinskas, and Guo-Ping Shi
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Medicine ,Science - Abstract
Leukocyte adhesion to the vascular endothelium and subsequent transendothelial migration play essential roles in the pathogenesis of cardiovascular diseases such as atherosclerosis. The leukocyte adhesion is mediated by localized activation of the endothelium through the action of inflammatory cytokines. The exact proinflammatory factors, however, that activate the endothelium and their cellular sources remain incompletely defined.Using bone marrow-derived mast cells from wild-type, Tnf(-/-), Ifng(-/-), Il6(-/-) mice, we demonstrated that all three of these pro-inflammatory cytokines from mast cells induced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin in murine heart endothelial cells (MHEC) at both mRNA and protein levels. Compared with TNF-α and IL6, IFN-γ appeared weaker in the induction of the mRNA levels, but at protein levels, both IL6 and IFN-γ were weaker inducers than TNF-α. Under physiological shear flow conditions, mast cell-derived TNF-α and IL6 were more potent than IFN-γ in activating MHEC and in promoting neutrophil adhesion. Similar observations were made when neutrophils or macrophages were used. Neutrophils and macrophages produced the same sets of pro-inflammatory cytokines as did mast cells to induce MHEC adhesion molecule expression, with the exception that macrophage-derived IFN-γ showed negligible effect in inducing VCAM-1 expression in MHEC.Mast cells, neutrophils, and macrophages release pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL6 that induce expression of adhesion molecules in endothelium and recruit of leukocytes, which is essential to the pathogenesis of vascular inflammatory diseases.
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- 2011
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8. Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure.
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Ting-Ting Tang, Zheng-Feng Zhu, Jun Wang, Wen-Cai Zhang, Xin Tu, Hong Xiao, Xin-Ling Du, Jia-Hong Xia, Nian-Guo Dong, Wei Su, Ni Xia, Xin-Xin Yan, Shao-Fang Nie, Juan Liu, Su-Feng Zhou, Rui Yao, Jiang-Jiao Xie, Harish Jevallee, Xiang Wang, Meng-Yang Liao, Guo-Ping Shi, Michael Fu, Yu-Hua Liao, and Xiang Cheng
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Medicine ,Science - Abstract
Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p
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- 2011
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9. Cystatin C deficiency promotes epidermal dysplasia in K14-HPV16 transgenic mice.
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Weifang Yu, Jian Liu, Michael A Shi, Jianan Wang, Meixiang Xiang, Shiro Kitamoto, Bing Wang, Galina K Sukhova, George F Murphy, Gabriela Orasanu, Anders Grubb, and Guo-Ping Shi
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Medicine ,Science - Abstract
Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors.We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived γ2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice.Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization.
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- 2010
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10. COVID-19, the Pandemic of the Century and Its Impact on Cardiovascular Diseases
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Tianxiao Liu, Guo-Ping Shi, Mingjie Wang, Peter Libby, Yuanyuan Zhang, and Xian Zhang
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Coronavirus disease 2019 (COVID-19) ,business.industry ,Environmental health ,Pandemic ,Hypertension ,Medicine ,COVID-19 ,Severe acute respiratory syndrome coronavirus 2 ,Risk factor ,Angiotensin-converting enzyme 2 ,business ,Cardiovascular disease ,State of the Art - Abstract
COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely ranks among the deadliest diseases in human history. As with other coronaviruses, SARS-CoV-2 infection damages not only the lungs but also the heart and many other organs that express angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2. COVID-19 has upended lives worldwide. Dietary behaviors have been altered such that they favor metabolic and cardiovascular complications, while patients have avoided hospital visits because of limited resources and the fear of infection, thereby increasing out-hospital mortality due to delayed diagnosis and treatment. Clinical observations show that sex, age, and race all influence the risk for SARS-CoV-2 infection, as do hypertension, obesity, and pre-existing cardiovascular conditions. Many hospitalized COVID-19 patients suffer cardiac injury, acute coronary syndromes, or cardiac arrhythmia. SARS-CoV-2 infection may lead to cardiomyocyte apoptosis and necrosis, endothelial cell damage and dysfunction, oxidative stress and reactive oxygen species production, vasoconstriction, fibrotic and thrombotic protein expression, vascular permeability and microvascular dysfunction, heart inflammatory cell accumulation and activation, and a cytokine storm. Current data indicate that COVID-19 patients with cardiovascular diseases should not discontinue many existing cardiovascular therapies such as ACE inhibitors, angiotensin receptor blockers, steroids, aspirin, statins, and PCSK9 inhibitors. This review aims to furnish a framework relating to COVID-19 and cardiovascular pathophysiology.
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- 2021
11. Regulatory T Cells Accelerate the Repair Process of Renal Fibrosis by Regulating Mononuclear Macrophages
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Jia Luo, Ying Liu, Guo-Ping Shi, Miao Zhang, Mingzhuo Zhang, Chunming Jiang, Xiang Yan, Wei Zhu, Yu-Hang Gong, and Jie Song
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Male ,Pathology ,medicine.medical_specialty ,H&E stain ,Renal function ,030204 cardiovascular system & hematology ,Kidney ,urologic and male genital diseases ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Renal fibrosis ,Animals ,Medicine ,030212 general & internal medicine ,IL-2 receptor ,Cells, Cultured ,business.industry ,Macrophages ,Interleukin ,FOXP3 ,General Medicine ,medicine.disease ,Coculture Techniques ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Inflammation Mediators ,business - Abstract
We aimed to investigate the mechanisms of renal fibrosis and explore the effect of CD4+CD25+Foxp3+ regulatory T cells (Treg) on renal fibrosis after the obstruction was removed.Fifty-five C57BL/6 mice were randomly divided into three groups: the unilateral ureteral obstruction (UUO) group, the relief for unilateral ureteral obstruction (RUUO) group, and the RUUO+Treg group. Renal fibrosis indexes of RUUO mice were evaluated using hematoxylin and eosin (HE) and, Masson staining and immunohistochemistry after CD4+CD25+Treg cells were injected into the tail vein at the moment of recanalization. We detected the levels of Treg, M1, and M2 markers by flow cytometry, and the levels of transforming growth factor (TGF)-β1, interleukin (IL)-1β, IL-6 and IL-10 using ELISA.The tubular necrosis score, AO value of α-SMA (smooth muscle actin), and collagen area on the 3rd and 14th days post RUUO were up-regulated compared with the 7th day post RUUO (P0.05). After injection of Treg via tail vein, the tubular necrosis score, AO value of α-SMA, TGF-β1 level, and collagen area in the RUUO+Treg group on the 14th day were down-regulated compared with the RUUO group (P0.05). Moreover, Treg could transform M1 macrophages into M2 macrophages, manifesting as up-regulated expression of CD206 compared with the RUUO group (P0.05). Treg could also down-regulate the secretion of IL-6 and IL-1β while up-regulating the secretion of IL-10 in vitro compared with the M1 group (P0.05).The kidney could deteriorate into a state of injury and fibrosis after the obstruction was removed, and Treg could effectively protect the kidney function.
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- 2021
12. Cathepsin B deficiency ameliorates liver lipid deposition, inflammatory cell infiltration, and fibrosis after diet-induced nonalcoholic steatohepatitis
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Wenqian Fang, Chongzhe Yang, Feriel Benadjaoud, Guo-Ping Shi, and Zhiyong Deng
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Liver Cirrhosis ,Male ,0301 basic medicine ,medicine.medical_specialty ,CD36 ,Smad Proteins ,Diet, High-Fat ,Weight Gain ,Article ,Cathepsin B ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Transforming Growth Factor beta ,Fibrosis ,Physiology (medical) ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Inflammation ,biology ,Chemistry ,Macrophages ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Cell Polarity ,General Medicine ,Cadherins ,Lipid Metabolism ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Liver ,Alanine transaminase ,030220 oncology & carcinogenesis ,Lipogenesis ,biology.protein ,Liver function ,Signal Transduction ,Lipoprotein - Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by fat accumulation and inflammation in liver. Yet, the mechanistic insight and diagnostic and therapeutic options of NASH remain incompletely understood. This study tested the roles of cysteine protease cathepsin B (CatB) in mouse NASH development. Immunoblot revealed increased liver CatB expression in NASH mice. Fructose-palmitate-cholesterol diet increased body weight gain, liver to body weight ratio, blood fasting glucose, plasma total cholesterol and alanine transaminase levels, and liver triglyceride, but decreased plasma high-density lipoprotein in wild-type mice. All these changes were blunted in CatB-deficient (Ctsb(−/−)) mice. In parallel to reduced expression of genes involved in liver lipid transport and lipogenesis, liver CD36, FABP4, and PPARγ protein levels were also significantly decreased in Ctsb(−/−) mice, although CatB deficiency did not affect liver gluconeogenesis and fatty acid beta-oxidation-associated gene expression. Mechanistic studies showed that CatB deficiency decreased liver expression of adhesion molecules, inflammatory cytokine, and chemokine, along with reduced liver inflammatory cell infiltration. CatB deficiency also promoted M2 macrophage polarization and reduced liver TGF-β1 signaling and fibrosis. Together, CatB deficiency improves liver function in NASH mice by suppressing de novo lipogenesis and liver inflammation and fibrosis.
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- 2020
13. Reduced Nhe1 (Na + -H + Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysms
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Tianxiao Liu, Peter Libby, Xin Liu, Gregory R. Wojtkiewicz, Matthias Nahrendorf, Yunzhe Wang, Samuel Achilefu, Xiao-Fang Wang, Cong-Lin Liu, Jin Ying Zhang, Zhiyong Deng, Guo-Ping Shi, Galina K. Sukhova, and Rui Tang
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0301 basic medicine ,Cathepsin ,Chemistry ,Cell ,030204 cardiovascular system & hematology ,Matrix metalloproteinase ,Mast cell ,Molecular biology ,Angiotensin II ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Apoptosis ,Internal Medicine ,medicine ,Extracellular ,Fragmentation (cell biology) - Abstract
IgE-mediated activation of Nhe1 (Na + -H + exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)–induced AAA in Nhe1-insufficient Apoe −/− Nhe1 +/− mice and Apoe −/− Nhe1 +/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1 −/− mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe −/− Nhe1 +/+ mice, such acidic areas were much smaller in lesions from Apoe −/− Nhe1 +/− mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.
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- 2020
14. Frailty and incident depressive symptoms in a Chinese sample: the Rugao Longevity and Ageing Study
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Xiaofeng Wang, Jiang-Hong Guo, Zhengdong Wang, Xiaoyan Jiang, Yinsheng Zhu, Guo-Ping Shi, Na Zhang, Yong Wang, Li Jin, and Xuefeng Chu
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Gerontology ,Aging ,China ,Frail Elderly ,media_common.quotation_subject ,Longevity ,Psychological intervention ,03 medical and health sciences ,Grip strength ,0302 clinical medicine ,Humans ,Medicine ,Geriatric Assessment ,Depressive symptoms ,Depression (differential diagnoses) ,Aged ,media_common ,Aged, 80 and over ,Frailty ,030214 geriatrics ,Depression ,business.industry ,Odds ratio ,Psychiatry and Mental health ,Cross-Sectional Studies ,Ageing ,Geriatric Depression Scale ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
Background To explore the cross-sectional and longitudinal associations between frailty and incident depressive symptoms in a Chinese elderly sample. Methods We analysed data of 1264 older Chinese elders aged 70-87 years in the Rugao Longevity and Ageing Study. The frailty phenotype was assessed using the Fried criteria and depression symptoms was measured by the Geriatric Depression Scale. Results At baseline, 10.6% of participants had depressive symptoms and 9.0% had frailty. In cross-sectional analysis, both pre-frailty (odds ratio (OR) = 2.18, 95% CI 1.35-3.51) and frailty (OR = 4.64, 95% CI 2.49-8.66) were associated with depressive symptoms. In longitudinal analyses, frailty (OR = 2.12, 95% CI 1.17-3.83), instead of pre-frailty, was associated with 1.5-year incident depressive symptoms in a full-adjusted model among participants free of baseline depressive symptoms. In the components of frailty, lower grip strength was associated with increased risk of depressive symptoms onset (OR = 1.56, 95% CI 1.06-2.29). Conclusions Frailty and lower grip strength were associated with incident depressive symptoms in a Chinese elderly sample. Interventions designed to prevent depressive symptoms may be useful by utilising physical aspects of the elderly population.
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- 2020
15. Deficiency of immunoglobulin E protects mice from experimental abdominal aortic aneurysms
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Zhiyong Deng, Feng Liu, Guo-Ping Shi, Chongzhe Yang, Xian Zhang, and Jie Li
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0301 basic medicine ,CD31 ,MAPK/ERK pathway ,Chemokine ,Pathology ,medicine.medical_specialty ,Immunoglobulin E ,Biochemistry ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Medicine ,Molecular Biology ,biology ,business.industry ,FCER1 ,030104 developmental biology ,CXCL5 ,cardiovascular system ,biology.protein ,medicine.symptom ,business ,030217 neurology & neurosurgery ,CD8 ,Biotechnology - Abstract
Allergic asthma with high plasma IgE levels is a significant risk factor of human abdominal aortic aneurysm (AAA). This study tests a direct role of IgE in angiotensin-II (Ang-II) perfusion- and peri-aortic CaCl2 injury-induced AAA in mice. In both models, IgE-deficiency in Apoe-/- Ige-/- mice blunts AAA growth and reduces lesion accumulation of macrophages, CD4+ and CD8+ T cells, and lesion MHC class-II expression, CD31+ microvessel growth, and media smooth muscle cell loss, compared with those from Apoe-/- control mice. Real time-PCR reveals significant reductions in expression of neutrophil chemoattractants MIP-2α and CXCL5 in AAA lesions or macrophages from Apoe-/- Ige-/- mice, along with reduced lesion Ly6G+ neutrophil accumulation. Consistent with reduced lesion inflammatory cell accumulation, we find significant reductions of plasma and AAA lesion IL6 expression in Apoe-/- Ige-/- mice. Immunofluorescent staining and FACS analysis show that AAA lesion neutrophils express FceR1. Mechanistic study demonstrates that IgE induces neutrophil FceR1 expression, activates MAPK signaling, and promotes IL6 production. This study supports a direct role of IgE in AAA by promoting lesion chemokine expression, inflammatory cell accumulation, MAPK signaling, and cytokine expression. IgE inhibition may represent a novel therapeutic approach in AAA management.
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- 2020
16. Depressive symptoms are associated with incident frailty in a Chinese population: the Rugao Longevity and Aging Study
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Shun Yao, Jiang-Hong Guo, Jianming Shi, Yu-Chen Wang, Xiaofeng Wang, Guo-Ping Shi, Xuefeng Chu, Yinsheng Zhu, Xiaoyan Jiang, Zhengdong Wang, Na Zhang, and Yong Wang
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Gerontology ,Aging ,Frail Elderly ,media_common.quotation_subject ,Longevity ,Older population ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Humans ,Medicine ,030212 general & internal medicine ,Risk factor ,Geriatric Assessment ,Depression (differential diagnoses) ,Depressive symptoms ,Aged ,media_common ,Chinese population ,Frailty ,Depression ,business.industry ,Chinese adults ,Middle Aged ,Cross-Sectional Studies ,Geriatric Depression Scale ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
This study aimed at investigating whether depression symptoms are associated with prevalent and incident physical frailty in Chinese older population. We analyzed data of 1168 older Chinese adults aged 70 and above in the aging arm of the Rugao Longevity and Aging Study (RuLAS). Depressive symptoms (Geriatric Depression Scale ≥ 6) were assessed by the Geriatric Depression Scale. Frailty was defined using Fried phenotype criteria at baseline and 3-year survey. At baseline, 8.9% of the participants had depression symptoms. The prevalence of pre-frailty and frailty were 34.5% and 5.9%, respectively. The percentages of depressive symptoms increase from robust (5.3%) to pre-frail (11.2%), and then to frail (31.9%) groups. After adjustments of multiple covariates, depressive symptoms were associated with both prevalent pre-frailty (OR = 1.75, 95% CI 1.08–2.84) and prevalent frailty (OR = 5.64, 95% CI 2.85–11.14) at baseline. At 3-year survey, 9.3% participants reported the development of frailty. After multiple adjustments, depressive symptoms were associated with a 2.79-fold (95% CI 1.09–7.10) increased risk of 3-year incident frailty. Depressive symptoms are associated with prevalent and incident frailty in Chinese older population. Together with the observations of the European populations, depressive symptoms may be a candidate risk factor of frailty.
- Published
- 2019
17. Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice
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Hailong Wang, Masafumi Kuzuya, Hiroyuki Umegaki, Limei Piao, Xiangkun Meng, Xian Wu Cheng, Toyoaki Murohara, Lan Cui, Aiko Inoue, Xiang Li, Chenglin Yu, Guo-Ping Shi, and Wenhu Xu
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Male ,CD31 ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Angiogenesis ,Neovascularization, Physiologic ,030204 cardiovascular system & hematology ,Endothelial progenitor cell ,Wnt-5a Protein ,Neovascularization ,03 medical and health sciences ,0302 clinical medicine ,Ischemia ,Internal medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Medicine ,030212 general & internal medicine ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Muscle, Skeletal ,Cells, Cultured ,Endothelial Progenitor Cells ,Cathepsin S ,Mice, Knockout ,CATS ,Serine-Arginine Splicing Factors ,biology ,business.industry ,TOR Serine-Threonine Kinases ,Age Factors ,General Medicine ,Cathepsins ,Hindlimb ,Mice, Inbred C57BL ,Endothelial stem cell ,Nitric oxide synthase ,Disease Models, Animal ,Endocrinology ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Background Given that cathepsin S (CatS) gained attention due to its enzymatic and non-enzymatic functions in signaling, the role of CatS in ischemia-induced angiogenesis of aged mice was explored.Methods and Results:To study the role of CatS in the decline in aging-related vascular regeneration capacity, a hindlimb ischemia model was applied to aged wild-type (CatS+/+) and CatS-deficient (CatS-/-) mice. CatS-/-mice exhibited impaired blood flow recovery and capillary formation and increased levels of p-insulin receptor substrate-1, Wnt5a, and SC35 proteins and decreased levels of phospho-endothelial nitric oxide synthase (p-eNOS), p-mTOR, p-Akt, p-ERK1/2, p-glycogen synthase kinase-3α/β, and galatin-3 proteins, as well as decreased macrophage infiltration and matrix metalloproteinase-2/-9 activities in the ischemic muscles. In vitro, CatS knockdown altered the levels of these targeted essential molecules for angiogenesis. Together, the results suggested that CatS-/-leads to defective endothelial cell functions and that CatS-/-is associated with decreased circulating endothelial progenitor cell (EPC)-like CD31+/c-Kit+cells. This notion was reinforced by the study finding that pharmacological CatS inhibition led to a declined angiogenic capacity accompanied by increased Wnt5a and SC35 levels and decreased eNOS/Akt-ERK1/2 signaling in response to ischemia. Conclusions These findings demonstrated that the impairment of ischemia-induced neovascularization in aged CatS-/-mice is due, at least in part, to the attenuation of endothelial cell/EPC functions and/or mobilization associated with Wnt5a/SC35 activation in advanced age.
- Published
- 2019
18. MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
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Bartosz Pilecki, Paulo V. S. D. de Carvalho, Katrine L. Kirketerp-Møller, Anders Schlosser, Karin Kejling, Magdalena Dubik, Nicklas P. Madsen, Jane Stubbe, Pernille B. L. Hansen, Thomas L. Andersen, Jesper B. Moeller, Niels Marcussen, Vasco Azevedo, Svend Hvidsten, Christina Baun, Guo-Ping Shi, Jes S. Lindholt, and Grith L. Sorensen
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Apolipoprotein B ,extracellular matrix ,Integrin ,Inflammation ,macrophage ,Matrix metalloproteinase ,Cardiovascular Medicine ,Extracellular matrix ,abdominal aortic aneurysm ,Internal medicine ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Original Research ,biology ,business.industry ,Monocyte ,matrix metalloproteinases ,Angiotensin II ,medicine.anatomical_structure ,Endocrinology ,inflammation ,RC666-701 ,biology.protein ,cardiovascular system ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.
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- 2021
19. Association Study of Mitochondrial DNA Haplogroup D and C5178A Polymorphisms with Chronic Kidney Disease
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Jianming Shi, Jiang-Hong Guo, Yong Wang, Xiaofeng Wang, Shun Yao, Xuehui Sun, Yinsheng Zhu, Xuefeng Chu, Zheng-Dong Wang, Xiaoyan Jiang, and Guo-Ping Shi
- Subjects
Male ,Mitochondrial DNA ,China ,Genotype ,Longevity ,Gene Expression ,Biology ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Haplogroup ,Polymorphism (computer science) ,medicine ,Humans ,Renal Insufficiency, Chronic ,Genetics (clinical) ,Genetics ,Aged, 80 and over ,Gene Expression Profiling ,General Medicine ,Genes, erbB-1 ,medicine.disease ,Mitochondria ,Haplotypes ,Creatinine ,Female ,Transcriptome ,Kidney disease ,Glomerular Filtration Rate - Abstract
Objective: To explore the associations of common mitochondrial DNA polymorphisms with chronic kidney disease (CKD). Methods: Data from 286 longevous individuals aged 95 years or older from the long...
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- 2021
20. Innate Immune Cells in Pressure Overload-Induced Cardiac Hypertrophy and Remodeling
- Author
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Guo-Ping Shi, Junli Guo, and Xin Liu
- Subjects
0301 basic medicine ,Chemokine ,QH301-705.5 ,Cell ,cardiomyocyte ,Review ,innate immune cell ,030204 cardiovascular system & hematology ,Muscle hypertrophy ,Pathogenesis ,Cell and Developmental Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Secretion ,Biology (General) ,Pressure overload ,Innate immune system ,biology ,business.industry ,fibrosis ,cardiac fibroblast ,Cell Biology ,pressure overload ,Natural killer T cell ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,biology.protein ,hypertrophy ,business ,Developmental Biology - Abstract
Pressure overload and heart failure are among the leading causes of cardiovascular morbidity and mortality. Accumulating evidence suggests that inflammatory cell activation and release of inflammatory mediators are of vital importance during the pathogenesis of these cardiac diseases. Yet, the roles of innate immune cells and subsequent inflammatory events in these processes remain poorly understood. Here, we outline the possible underlying mechanisms of innate immune cell participation, including mast cells, macrophages, monocytes, neutrophils, dendritic cells, eosinophils, and natural killer T cells in these pathological processes. Although these cells accumulate in the atrium or ventricles at different time points after pressure overload, their cardioprotective or cardiodestructive activities differ from each other. Among them, mast cells, neutrophils, and dendritic cells exert detrimental function in experimental models, whereas eosinophils and natural killer T cells display cardioprotective activities. Depending on their subsets, macrophages and monocytes may exacerbate cardiodysfunction or negatively regulate cardiac hypertrophy and remodeling. Pressure overload stimulates the secretion of cytokines, chemokines, and growth factors from innate immune cells and even resident cardiomyocytes that together assist innate immune cell infiltration into injured heart. These infiltrates are involved in pro-hypertrophic events and cardiac fibroblast activation. Immune regulation of cardiac innate immune cells becomes a promising therapeutic approach in experimental cardiac disease treatment, highlighting the significance of their clinical evaluation in humans.
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- 2021
21. Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis
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Wenqian Fang, Joseph V. Bonventre, Yi Zhou, Xian Zhang, Galina K. Sukhova, Qin Huang, Guo-Ping Shi, Peter Libby, Jie Li, and Xueqing Yu
- Subjects
0301 basic medicine ,02 engineering and technology ,Importin ,Article ,Extracellular matrix ,03 medical and health sciences ,Fibrosis ,medicine ,Nuclear membrane ,lcsh:Science ,Cathepsin ,Functional Aspects of Cell Biology ,Multidisciplinary ,CATS ,biology ,Chemistry ,Transforming growth factor beta ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,lcsh:Q ,Molecular Mechanism of Behavior ,0210 nano-technology ,Transforming growth factor - Abstract
Summary Transforming growth factor beta (TGF-β) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-β enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-β expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the importin-β and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-β receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-β receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-β signaling and tissue fibrosis. CatB- or CatL-deficiency exacerbates fibrosis, whereas CatS- or CatK-deficiency protects kidneys from fibrosis. These cathepsins exert different effects in the TGF-β signaling cascade independent of their proteolytic properties., Graphical Abstract, Highlights • Cathepsins exert different activities in kidney TEC TGF-β signaling and fibrosis • Cathepsins regulate nuclear membrane transporter expression and form immunocomplexes • Cathepsins regulate plasma membrane TGF-β receptor expression and form immunocomplexes • Cathepsins play different roles in acute injury-induced kidney fibrosis, Fibrosis; Molecular Mechanism of Behavior; Functional Aspects of Cell Biology
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- 2019
22. Losartan accelerates the repair process of renal fibrosis in UUO mouse after the surgical recanalization by upregulating the expression of Tregs
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Wei Zhu, Chunming Jiang, Xiang Yan, Guo-Ping Shi, Yangyang Xia, Miao Zhang, Jia Luo, and Jie Song
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Male ,Nephrology ,medicine.medical_specialty ,Time Factors ,Urology ,030232 urology & nephrology ,Renal function ,Angiotensin-Converting Enzyme Inhibitors ,030204 cardiovascular system & hematology ,Kidney ,urologic and male genital diseases ,T-Lymphocytes, Regulatory ,Losartan ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,medicine ,Renal fibrosis ,Animals ,business.industry ,medicine.disease ,Obstructive Nephropathy ,Up-Regulation ,Mice, Inbred C57BL ,Treatment Outcome ,medicine.anatomical_structure ,business ,Ureteral Obstruction ,Kidney disease ,medicine.drug - Abstract
Obstructive nephropathy is a common cause for chronic kidney disease. Surgery, which is adopted to promptly relieve the obstruction, is the most important method to save damaged kidneys. However, earlier studies have shown that renal function will continue to deteriorate until the terminal stage after the obstruction' relief. The aim of this study is to explore the renal fibrosis and investigate the effect of losartan on renal fibrosis after the obstruction' relief using an improved mouse model of relief for unilateral ureteral obstruction (RUUO). Experiments carried out using C57BL/6 mice (n = 30) were randomly divided into RUUO + Losartan group, RUUO group and sham group. Using an improved mouse RUUO model, this study revealed that the mouse kidney for 3- or 7-day unilateral ureteral obstruction undergoing the RUUO surgery was still in a state of injury and fibrosis, while losartan could effectively ameliorate renal fibrosis by upregulating the expression of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) in kidney after the surgery of RUUO.
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- 2019
23. Dietary cholesterol is essential to mast cell activation and associated obesity and diabetes in mice
- Author
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Xiang Yan, Qin Huang, Jie Li, Zhiyong Deng, Peter Libby, Jari Metso, Guo-Ping Shi, Xin Wang, Matti Jauhiainen, Jian Liu, and Xian Zhang
- Subjects
Male ,0301 basic medicine ,Gene Expression ,Adipose tissue ,Immunoglobulin E ,Cell Degranulation ,Cholesterol, Dietary ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Anti-Allergic Agents ,Anti-Asthmatic Agents ,Mast Cells ,Mice, Knockout ,biology ,Degranulation ,Mast cell ,beta-N-Acetylhexosaminidases ,medicine.anatomical_structure ,Adipose Tissue ,030220 oncology & carcinogenesis ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Histamine ,Signal Transduction ,medicine.drug ,Ketotifen ,Serotonin ,medicine.medical_specialty ,Diet, High-Fat ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Internal medicine ,Cromolyn Sodium ,medicine ,Animals ,Obesity ,Molecular Biology ,Cholesterol ,Cholesterol, LDL ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Receptors, LDL ,chemistry ,biology.protein ,Lipoprotein - Abstract
Mast cell (MC) deficiency in KitW-sh/W-sh mice and inhibition with disodium chromoglycate (DSCG) or ketotifen reduced obesity and diabetes in mice on a high-cholesterol (1.25%) Western diet. Yet, Kit-independent MC-deficient mice and mice treated with DSCG disproved MC function in obesity and diabetes when mice are fed a high-fat diet (HFD) that contains no cholesterol. This study reproduced the obesity and diabetes inhibitory activities of DSCG and ketotifen from mice on a Western diet. Yet, such inhibitory effects were diminished in mice on the HFD. DSCG and ketotifen MC inhibitory activities were recovered from mice on the HFD supplemented with the same amount of cholesterol (1.25%) as that in the Western diet. DSCG and ketotifen effectively blunted the high-cholesterol diet-induced elevations of blood histamine and adipose tissue MC degranulation. Pearson's correlation test demonstrated significant and positive correlations between plasma histamine and total cholesterol or low-density lipoprotein-cholesterol (LDL). In cultured bone marrow-derived MCs, plasma from mice following a Western diet or a cholesterol-supplemented HFD, but not those from HFD-fed mice, induced MC degranulation and the release of β-hexosaminidase, histamine, and serotonin. IgE, LDL, very low-density lipoprotein, and high-density lipoprotein also induced MC activation, which can be inhibited by DSCG and ketotifen depending on the doses and types of MC inhibitors and cholesterol, and also the MC granule molecules of interest. DSCG or ketotifen lost their activities in inhibiting LDL-induced activation of MCs from LDL receptor-deficient mice. These results indicate that dietary cholesterol critically influences the function of mouse MCs.
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- 2019
24. Cathepsin K Knockout Exacerbates Haemorrhagic Transformation Induced by Recombinant Tissue Plasminogen Activator After Focal Cerebral Ischaemia in Mice
- Author
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Bing-Qiao Zhao, Yue Hu, Rong Zhao, Xiao-Yan Feng, Yi-Sheng Liu, Lei Zhao, Xin-Wei He, Yan-Hui Shi, Hui-Qin Liu, Mei-Ting Zhuang, Guo-Ping Shi, Jian-Ren Liu, and Feng-Di Liu
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,medicine.medical_specialty ,Cathepsin K ,Apoptosis ,Permeability ,Brain Ischemia ,Neovascularization ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Macrophage ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cerebral Hemorrhage ,Mice, Knockout ,Neurons ,Microglia ,business.industry ,Macrophages ,TOR Serine-Threonine Kinases ,Infarction, Middle Cerebral Artery ,Cell Biology ,General Medicine ,Recombinant Proteins ,Vascular endothelial growth factor ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,nervous system ,chemistry ,Blood-Brain Barrier ,Tissue Plasminogen Activator ,Knockout mouse ,medicine.symptom ,business ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk−/− mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood–brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk−/− than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk−/− than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood–brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.
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- 2019
25. IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity
- Author
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Muyang Gu, Guo-Ping Shi, Yuzhi Lu, Jingyong Li, Jiao Jiao, Ni Xia, Xiang-Ping Yang, Bingjie Lv, Shaofang Nie, Yu Hu, Dan Li, Shuang Wen, Tingting Tang, Xiang Cheng, Mengyang Liao, and Yuhua Liao
- Subjects
Calcium Phosphates ,Male ,0301 basic medicine ,Regulatory T cell ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Mice, Transgenic ,Inflammation ,Vascular Remodeling ,030204 cardiovascular system & hematology ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Macrophage ,Aorta ,Cells, Cultured ,Mice, Knockout ,Pancreatic Elastase ,business.industry ,Macrophages ,Interleukin ,FOXP3 ,Interleukin-33 ,M2 Macrophage ,Interleukin-1 Receptor-Like 1 Protein ,Recombinant Proteins ,Mice, Inbred C57BL ,Interleukin 33 ,Editorial Commentary ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Cancer research ,Cytokines ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Injections, Intraperitoneal ,Aortic Aneurysm, Abdominal - Abstract
Objective— Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results— Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO 4 injury- and aortic elastase exposure–induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4 + Foxp3 + regulatory T cells in spleens, blood, and aortas in periaorta CaPO 4 -treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33–treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO 4 -treated mice after selective depletion of regulatory T cells. Conclusions— Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.
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- 2019
26. Neutrophil-lymphocyte ratio as a predictor of slow gait speed in older adults: The Rugao Longitudinal Aging Study
- Author
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Jiang-Hong Guo, Guo-Ping Shi, Meng Hao, Xiaofeng Wang, Zhengdong Wang, Jiucun Wang, Hui Zhang, and Yi Li
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Aging ,Neutrophils ,Lymphocyte ,Logistic regression ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Physical medicine and rehabilitation ,Genetics ,medicine ,Humans ,Lymphocytes ,Neutrophil to lymphocyte ratio ,Molecular Biology ,Gait ,Aged ,Aged, 80 and over ,business.industry ,fungi ,Mean age ,Cell Biology ,Gait speed ,Walking Speed ,Preferred walking speed ,030104 developmental biology ,medicine.anatomical_structure ,Cross-Sectional Studies ,Walk test ,Female ,Inflammatory biomarker ,business ,human activities ,030217 neurology & neurosurgery - Abstract
Few studies have investigated the association of the neutrophil-to-lymphocyte ratio (NLR) with gait speed, but whether the NLR is predictive of slow gait speed in older adults remains unknown. The aim of this study is to examine the association of NLR levels with risk of slow gait speed development in older adults.Overall, 1753 participants (53.11% male, aged 60-92 years, with a mean age of 77.01 ± 4.27 years) from the second wave of the Rugao Longitudinal Aging Study were included. The second wave was recognized as the baseline in this study. Gait speed was measured using a 5-m walk test at baseline and at the 3.5-year follow-up. A slow gait speed was considered a walking speed less than 0.8 m/s. The NLR was calculated based on absolute blood neutrophil and lymphocyte counts. Logistic regression models were used to investigate the association between NLR levels and slow gait speed.In the cross-sectional analysis, 394 individuals were identified as having slow gait speed. We found that increased NLR levels were associated with a higher risk of slow gait speed in older adults with and without comorbidities (P-value0.05). During the 3.5-year follow-up period, 440 individuals had developed new-onset slowness. After confounding factors were controlled, increased NLR levels were significantly and independently associated with an increased risk of slow gait speed among older adults with (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.87-7.89) and without (OR 3.29, 95% CI: 1.54-7.10) comorbidities.The NLR is an inexpensive and easily obtainable inflammatory biomarker that robustly and independently predicts slow gait speed risk in older adults.
- Published
- 2021
27. Social frailty and longitudinal risk of depressive symptoms in a Chinese population: the Rugao Longevity and Aging Study
- Author
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Ze-Kun Chen, Zhijun Bao, Yong Wang, Xuefeng Chu, Jie Chen, Xiaoyan Jiang, Jiang-Hong Guo, Yinsheng Zhu, Xiaofeng Wang, Zhengdong Wang, and Guo-Ping Shi
- Subjects
medicine.medical_specialty ,Aging ,China ,Frail Elderly ,Longevity ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Longitudinal Studies ,Geriatric Assessment ,Depressive symptoms ,Depression (differential diagnoses) ,Aged ,Chinese population ,030214 geriatrics ,Frailty ,business.industry ,Depression ,Incidence (epidemiology) ,Odds ratio ,Confidence interval ,Psychiatry and Mental health ,Increased risk ,Cross-Sectional Studies ,Geriatric Depression Scale ,Geriatrics and Gerontology ,business ,Gerontology ,030217 neurology & neurosurgery - Abstract
Aim To explore the cross-sectional and longitudinal associations between social frailty (SF) and incident depressive symptoms in a Chinese population. Methods SF was measured with 6 questions (6 points maximum; 0-1 = non-SF, 2-3 = pre-SF, 4-6 = SF). Depressive symptoms were defined as a score of ≥6 on the Geriatric Depression Scale. Compared to baseline, participants with a ≥2-point increase in the Geriatric Depression Scale score were considered to have worsening depressive symptoms. Results At baseline, among 1764 participants, 9.9% (n = 175) had depressive symptoms, 3.6% (n = 61) were SF, and 38.2% (n = 650) were pre-SF. The percentage of depressive symptoms increased with SF status from 5.1% (non-SF) to 12.9% (pre-SF), to 41.0% (SF). In cross-sectional analysis, after adjustments for multiple covariates, depressive symptoms were significantly associated with both pre-SF (odds ratio (OR) = 2.94, 95% confidence interval (CI) 2.01-4.32) and SF (OR = 16.70, 95% CI 8.80-31.71). During the 3-year follow-up period, 10.0% (n = 117) of the participants developed depressive symptoms. In longitudinal analyses, after multiple adjustments, SF and pre-SF were associated with a 2.31-fold (95% CI 1.10-4.88) and 1.58-fold (95% CI 1.05-2.38) increased risk of incidence of depressive symptoms, respectively. Among participants without depressive symptoms at baseline, 23.2% had worsening depressive symptoms, and SF was associated with increased risk of worsening depressive symptoms (OR = 2.07, 95% CI 1.18-3.65). Conclusions Our findings suggested that SF may be a predictor of depression among Chinese community-dwelling older adults. In addition, in elders with no depressive symptoms at baseline, those with SF had greater odds of worsening depressive symptoms 3 years later.
- Published
- 2021
28. Circ_0088194 Promotes the Invasion and Migration of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the miR-766-3p/MMP2 Axis
- Author
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Qingqing Ouyang, Guo-Ping Shi, Shibai Xiao, Renge Liang, Qin Huang, Yujie Cai, Min Yang, and Dingji Zhu
- Subjects
rheumatoid arthritis ,lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,MMP2 ,Immunology ,Aggressive phenotype ,Matrix metalloproteinase ,Disease activity ,Circ_0088194 ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Immunology and Allergy ,fibroblast-like synoviocytes ,Fibroblast ,miR-766-3p ,Chemistry ,Invasion and migration ,medicine.disease ,CircRNA ,030104 developmental biology ,medicine.anatomical_structure ,matrix metalloproteinase 2 ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Cancer research ,lcsh:RC581-607 - Abstract
Dysregulation of circular RNAs (circRNAs) is involved in various human diseases. Fibroblast-like synoviocytes (FLSs), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype and contribute to joint destruction in rheumatoid arthritis (RA). In the present study, we identified a novel circRNA, Circ_0088194, which was upregulated in RA fibroblast-like synoviocytes (RA-FLSs) and correlated with the disease activity score in 28 joints. Overexpression of Circ_0088194 promoted RA-FLS migration and invasion, while inhibition of Circ_0088194 had the opposite effect. Mechanistically, Circ_0088194 acted as a miR-766-3p sponge to relieve the repressive effect of miR-766-3p on its target, MMP2 (encoding matrix metalloproteinase 2), thereby promoting migration and invasion. The expression level of Circ_0088194 was inversely correlated with that of miR-766-3p in RA-FLSs. Importantly, overexpression of miR-766-3p partially blocked the migration and invasion induced by Circ_0088194 overexpression. Collectively, this study identified a novel circRNA Circ_0088194 that promotes RA-FLS invasion and migration via the miR-766-3p/MMP2 axis. Circ_0088194 might represent a novel therapeutic target to prevent and treat RA.
- Published
- 2021
29. Abstract 15122: Il18 Uses Both Il18 Receptor and Na-cl Co-transporter to Support Islet β Cell Proliferation and Insulin Secretion
- Author
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Guo-Ping Shi, Songyuan Luo, Wang Min-jie, and Xian Zhang
- Subjects
medicine.medical_specialty ,geography ,geography.geographical_feature_category ,Cell growth ,business.industry ,Insulin ,medicine.medical_treatment ,Regeneration (biology) ,Transporter ,Islet ,medicine.disease ,Endocrinology ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,medicine ,Interleukin 18 ,Cardiology and Cardiovascular Medicine ,Receptor ,business - Abstract
Introduction: The regeneration of pancreatic β cells to restore insulin production is a promising therapeutic strategy for insulin-dependent type-1 (T1D) and type-2 diabetes (T2D). Plasma IL18 levels are increased in these patients. Prior studies suggest a role for IL18 in inducing islet insulin production. IL18 administration suppressed autoimmune diabetes in non-obese diabetic mice. We recently discovered that IL18 uses two receptors IL18r and NCC (Na-Cl co-transporter) with equal binding kinetics. Hypothesis: IL18r and NCC use different mechanisms to mediate IL18 activity in islet β cell insulin production. Methods and Results: Immunoblot and immunofluorescent staining localized IL18 on islet α cells, NCC on islet β cells, and IL18r on pancreas acinar cells. Development of T1D or T2D increased the α cell IL18 expression. From high fat diet (HFD)-induced T2D, deficiency of IL18r ( Il18r -/- ) or NCC ( Ncc -/- ), or combined deficiency of both receptors ( Il18r -/- Ncc -/- ) reduced insulin secretion, exacerbated β cell failure, decreased α cell content, reduced islet size, reduced β cell proliferation, and decreased the expression of islet proliferation markers. Deficiency of IL18r in Il18r -/- and Il18r -/- Ncc -/- mice aggravated β cell content and size reductions and glucose metabolism and increased β cell apoptosis after streptozotocin (STZ)-induced T1D. Il18r -/- Ncc -/- mice also showed increased macrophage accumulation in the islets from both T1D and T2D mice. Using α cell-selective IL18-deficient Gcg CreERT2 IL18 fl/fl mice, acinar cell-selective IL18r-deficient Mist1 CreERT2 Il18r fl/fl mice, and β cell NCC-deficient Ins1 Cre Ncc fl/fl mice, we demonstrated that these mice showed impaired insulin secretion and glucose metabolism, exacerbated β cell failure, and aggravated HFD-induced T2D. Mechanistic studies suggested that IL18 uses NCC on β cells to promote insulin secretion and uses IL18r on acinar cells to assist β cell development. Conclusions: Islet α cell IL18 uses NCC on β cells to promote β cell proliferation and uses IL18r on acinar cells to produce inflammatory molecules to assist β cell generation and insulin secretion. Both the IL18r and NCC signaling pathways are essential to β cell function in diabetic patients.
- Published
- 2020
30. Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm
- Author
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Marie Dahl, Lars Melholt Rasmussen, Tianxiao Liu, Xin Liu, Jing Liu, Yunzhe Wang, Guo-Ping Shi, Gilbert R. Upchurch, Chongzhe Yang, Guanyi Lu, Axel Cosmus Pyndt Diederichsen, Jes S. Lindholt, Cong-Lin Liu, Junli Guo, Yuanyuan Zhang, Peter Libby, Galina K. Sukhova, Songyuan Luo, and Jinying Zhang
- Subjects
0301 basic medicine ,Male ,Physiology ,Mice, Knockout, ApoE ,030204 cardiovascular system & hematology ,Monocytes ,0302 clinical medicine ,cardiovascular disease ,Aorta, Abdominal ,Cells, Cultured ,Eosinophil cationic protein ,interleukin ,Angiotensin II ,NF-kappa B ,Interleukin ,Adoptive Transfer ,Abdominal aortic aneurysm ,Interleukin-10 ,medicine.anatomical_structure ,Phenotype ,monocyte ,Female ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Dilatation, Pathologic ,Inflammation ,Vascular Remodeling ,Article ,03 medical and health sciences ,Ribonucleases ,medicine ,Animals ,Humans ,eosinophil ,Interleukin 4 ,Aged ,business.industry ,Monocyte ,Macrophages ,Eosinophil ,medicine.disease ,Eosinophils ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,inflammation ,Immunology ,Interleukin-4 ,business ,Aortic Aneurysm, Abdominal - Abstract
Rationale: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. Objective: To test whether and how eosinophils affect AAA growth. Methods and Results: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 10 9 /L, P P P =0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion–induced AAA in Apoe −/− and eosinophil-deficient Apoe −/− ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b + Ly6C hi monocytes, and increased CD11b + Ly6C lo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13 −/− mice, but not eosinophil from Il4 −/− mice, blocked AAA growth in Apoe −/− ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. Conclusions: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.
- Published
- 2020
31. The Modified Healthy Ageing Index Is Associated with Mortality and Disability: The Rugao Longevity and Ageing Study
- Author
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Yinsheng Zhu, Xiaoyan Jiang, Guo-Ping Shi, Zhijun Bao, Xiaofeng Wang, Zhengdong Wang, Jiucun Wang, Xuefeng Chu, Meng Hao, and Hui Zhang
- Subjects
Male ,medicine.medical_specialty ,Aging ,China ,business.industry ,Proportional hazards model ,Hazard ratio ,Longevity ,Odds ratio ,Disease ,Logistic regression ,Confidence interval ,Healthy Aging ,Ageing ,Risk Factors ,Epidemiology ,medicine ,Humans ,Disabled Persons ,Geriatrics and Gerontology ,business ,Demography ,Aged - Abstract
Introduction: The Healthy Ageing Index (HAI) has been shown not only to have wider applicability and predictive ability but also to adequately predict mortality in Western populations. There is still a lack of studies validating the applicability of the HAI in China. Objective: To evaluate the applicability of the HAI and validate whether the HAI is suitable for monitoring ageing in the elderly population in China. Methods: Data were obtained from the Rugao Longevity and Ageing Study. The modified HAI was constructed based on systolic blood pressure, chronic pulmonary diseases, cognitive function, fasting glucose, and kidney function. It was calculated in 1719 individuals aged 70–84 years at baseline. The adverse outcomes were mortality and disability. Demographic, physiologic, and clinical data were collected. Cox proportional hazards and logistic regression models were used to analyze the relationship between the modified HAI and adverse outcomes. Results: A total of 1,719 older adults were analyzed in our study. A total of 793 (46.13%) males were recruited. The mean age was 75.69 ± 3.93 years. At the 5-year follow-up, there were 266 deaths and 275 individuals with disabilities. In the multivariable models, the modified HAI was associated with mortality (hazard ratio = 1.11, 95% confidence interval [CI]: 1.03–1.20) and disability (odds ratio = 1.11, 95% CI: 1.05–1.18). In the sensitivity analyses, similar associations remained after imputing missing data using multiple imputation and excluding participants with major cardiovascular disease at baseline. Conclusion: The modified HAI was a robust and independent predictor of adverse outcomes. It is a valid and feasible tool for monitoring ageing in older adults.
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- 2020
32. Eosinophils improve cardiac function after myocardial infarction
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Dafeng Yang, Xian Zhang, Dazhu Li, Axel Cosmus Pyndt Diederichsen, Yunzhe Wang, Tianxiao Liu, Zhiyong Deng, Chongzhe Yang, Cong-Lin Liu, Lars Melholt Rasmussen, Jing Liu, Jing Wang, Peter Libby, Francis W. Luscinskas, Gail Newton, Wenqian Fang, Lijun Liu, Qin Huang, Guo-Ping Shi, Galina K. Sukhova, Junli Guo, Jes S. Lindholt, and Jie Li
- Subjects
0301 basic medicine ,Myocardium/pathology ,Male ,Myocardial Infarction ,General Physics and Astronomy ,030204 cardiovascular system & hematology ,Electrocardiography ,0302 clinical medicine ,Fibrosis ,Medicine ,Myocyte ,Diphtheria Toxin ,Myocytes, Cardiac ,Myocardial infarction ,Mice, Inbred BALB C ,Multidisciplinary ,Cell Death ,Interleukin-4/genetics ,respiratory system ,Endothelial stem cell ,medicine.anatomical_structure ,cardiovascular system ,Diphtheria Toxin/toxicity ,Female ,Cardiac function curve ,Programmed cell death ,Science ,Heart failure ,Mice, Transgenic ,Ribonucleases/genetics ,General Biochemistry, Genetics and Molecular Biology ,Article ,Myocytes, Cardiac/pathology ,03 medical and health sciences ,Ribonucleases ,Animals ,Humans ,Interleukin 4 ,Aged ,Eosinophils/drug effects ,business.industry ,Myocardial Infarction/physiopathology ,Myocardium ,General Chemistry ,Eosinophil ,Fibroblasts ,medicine.disease ,Fibroblasts/pathology ,Eosinophils ,Mice, Inbred C57BL ,030104 developmental biology ,Immunology ,Interleukin-4 ,business - Abstract
Clinical studies reveal changes in blood eosinophil counts and eosinophil cationic proteins that may serve as risk factors for human coronary heart diseases. Here we report an increase of blood or heart eosinophil counts in humans and mice after myocardial infarction (MI), mostly in the infarct region. Genetic or inducible depletion of eosinophils exacerbates cardiac dysfunction, cell death, and fibrosis post-MI, with concurrent acute increase of heart and chronic increase of splenic neutrophils and monocytes. Mechanistic studies reveal roles of eosinophil IL4 and cationic protein mEar1 in blocking H2O2- and hypoxia-induced mouse and human cardiomyocyte death, TGF-β-induced cardiac fibroblast Smad2/3 activation, and TNF-α-induced neutrophil adhesion on the heart endothelial cell monolayer. In vitro-cultured eosinophils from WT mice or recombinant mEar1 protein, but not eosinophils from IL4-deficient mice, effectively correct exacerbated cardiac dysfunctions in eosinophil-deficient ∆dblGATA mice. This study establishes a cardioprotective role of eosinophils in post-MI hearts., Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.
- Published
- 2020
33. Deficiency of cysteinyl cathepsin K suppresses the development of experimental intimal hyperplasia in response to chronic stress
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Toyoaki Murohara, Haiying Jiang, Kae Nakamura, Masafumi Kuzuya, Xian Wu Cheng, Xiang Li, Chenglin Yu, Guo-Ping Shi, Wenhu Xu, Hongxian Wu, Takeshi Sasaki, Aiko Inoue, Zhe Huang, Lina Hu, Limei Piao, Xiangkun Meng, and Hailong Wang
- Subjects
Neointima ,medicine.medical_specialty ,Intimal hyperplasia ,Physiology ,Cathepsin K ,030204 cardiovascular system & hematology ,medicine.disease_cause ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,Medicine ,Animals ,Chronic stress ,030212 general & internal medicine ,Neointimal hyperplasia ,Hyperplasia ,biology ,business.industry ,medicine.disease ,Disease Models, Animal ,Endocrinology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Tunica Intima ,Elastin ,Oxidative stress ,Stress, Psychological - Abstract
Background Chronic psychological stress (CPS) is linked to cardiovascular disease initiation and progression. Given that cysteinyl cathepsin K (CatK) participates in vascular remodeling and atherosclerotic plaque growth in several animal models, we investigated the role of CatK in the development of experimental neointimal hyperplasia in response to chronic stress. Methods and results At first, male wild-type (CatK) mice that underwent carotid ligation injury were subjected to chronic immobilization stress. On postoperative and stressed day 14, the results demonstrated that stress accelerated injury-induced neointima hyperplasia. On day 4, stressed mice showed following: increased levels of monocyte chemoattractant protein-1, gp91phox, toll-like receptor-2 (TLR2), TLR4, and CatK mRNAs or/and proteins, oxidative stress production, aorta-derived smooth muscle cell (SMC) migration, and macrophage infiltration as well as targeted intracellular proliferating-related molecules. Stressed mice showed increased matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA expressions and activities and elastin disruption in the injured carotid arteries. Second, CatK and CatK deficiency (CatK) mice received ligation injury and stress to explore the role of CatK. The stress-induced harmful changes were prevented by CatK. Finally, CatK mice that had undergone ligation surgery were randomly assigned to one of two groups and administered vehicle or CatK inhibitor for 14 days. Pharmacological CatK intervention produced a vascular benefit. Conclusion These data indicate that CatK deletion protects against the development of experimental neointimal hyperplasia via the attenuation of inflammatory overaction, oxidative stress production, and VSMC proliferation, suggesting that CatK is a novel therapeutic target for the management of CPS-related restenosis after intravascular intervention therapies.
- Published
- 2020
34. Associations of TNF-α -308 GA and TNF-β 252 AG with Physical Function and BNP-Rugao Longevity and Ageing Study
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Yinsheng Zhu, Xiaofeng Wang, Zhengdong Wang, Xiaoyan Jiang, Li Jin, Guo-Ping Shi, Xuefeng Chu, Jiang-Hong Guo, and Shun Yao
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Male ,medicine.medical_specialty ,Aging ,030309 nutrition & dietetics ,medicine.drug_class ,media_common.quotation_subject ,Longevity ,Medicine (miscellaneous) ,Physical function ,03 medical and health sciences ,0302 clinical medicine ,Polymorphism (computer science) ,Internal medicine ,Genotype ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Medicine ,Humans ,030212 general & internal medicine ,media_common ,Aged ,Aged, 80 and over ,0303 health sciences ,Nutrition and Dietetics ,business.industry ,Walking test ,Tumor Necrosis Factor-alpha ,Endocrinology ,Ageing ,Population study ,Female ,Geriatrics and Gerontology ,business ,human activities - Abstract
To explore the associations of TNF-α -308 GA (rs1800629) and TNF-β 252 AG (rs909253) with physical function and plasma B-type natriuretic peptide (BNP).Data of 1747 community-dwelling elders from the ageing arm of the Rugao Longevity and Ageing Study was used. Physical function was measured by handgrip strength, Timed Up and Go (TUG) test and 5-meter walking test (5MWT).AA genotype of the TNF-α -308 GA was associated with higher mean time of TUG test and 5MWT (multivariable adjusted β=5.75 and 5.70, respectively, p0.05), compared with GG genotype. For the TNF-β 252 AG polymorphism, GG genotype was associated with higher mean time of TUG test and 5MWT (multivariable adjusted β=1.55 and 0.83, respectively, p0.05) and lower handgrip strength (multivariable adjusted β=-0.69, p0.05), compared with AA genotype. Further, GG was associated with greater odds of low handgrip strength (OR=1.47, 95% CI=1.06-2.04), low speed of TUG test (OR=1.87, 95% CI=1.20-2.01) and elevated BNP (OR=1.30, 95% CI=1.08-1.84). GG also interacted with elevated BNP to be associated with greater odds of low handgrip strength and 5MWT.TNF-β 252 AG was associated with physical function measurements, plasma BNP level, and odds of elevated BNP in an elderly population. TNF-β 252 AG also interacted with elevated BNP to be associated with greater odds of physical function measurements.
- Published
- 2020
35. IgE contributes to atherosclerosis and obesity by affecting macrophage polarization, macrophage protein network, and foam cell formation
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Songyuan Luo, Guo-Ping Shi, Zhiyong Deng, Jari Metso, Pei Xiong Liew, Caroline de Febbo, Junli Guo, Matti Jauhiainen, Qin Huang, Aida Daoui, Galina K. Sukhova, Jie Li, Xian Zhang, and Minjie Wang
- Subjects
Blood Glucose ,Male ,Mice, Knockout, ApoE ,Macrophage polarization ,Immunoglobulin E ,Article ,Insulin resistance ,medicine ,Macrophage ,Animals ,Gene Regulatory Networks ,Obesity ,Receptor ,Aorta ,Cells, Cultured ,Foam cell ,Inflammation ,biology ,Chemistry ,Receptors, IgE ,FCER1 ,Macrophage Activation ,medicine.disease ,Atherosclerosis ,Plaque, Atherosclerotic ,Mice, Inbred C57BL ,Disease Models, Animal ,Sterols ,Phenotype ,Immunology ,biology.protein ,Macrophages, Peritoneal ,Cytokines ,Inflammation Mediators ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,Protein network ,Foam Cells ,Signal Transduction - Abstract
Objective: By binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe −/− mice and IgE-deficient Ige −/− mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe −/− Ige −/− mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency. Conclusions: IgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.
- Published
- 2020
36. Association of BNP with Frailty in Elderly Population: Rugao Longevity and Ageing Study
- Author
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Xuefeng Chu, Jiang-Hong Guo, Li Jin, Yong Wang, Zhengdong Wang, Xiaoyan Jiang, Shun Yao, Xiaofeng Wang, Yinsheng Zhu, and Guo-Ping Shi
- Subjects
Male ,Aging ,Weakness ,medicine.medical_specialty ,030309 nutrition & dietetics ,medicine.drug_class ,Frail Elderly ,media_common.quotation_subject ,Longevity ,Medicine (miscellaneous) ,Cohort Studies ,03 medical and health sciences ,Grip strength ,0302 clinical medicine ,Weight loss ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Humans ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,Aged ,media_common ,Aged, 80 and over ,0303 health sciences ,Nutrition and Dietetics ,business.industry ,Physical activity level ,Cross-Sectional Studies ,Ageing ,Female ,Geriatrics and Gerontology ,medicine.symptom ,business ,human activities - Abstract
To explore the associations of B-type natriuretic peptide (BNP) with physical frailty status as well as each domain of frailty in a general elderly population. Cross-sectional analysis of prospective cohort study. All of 31 communities in Jiang’an township. Overall 1338 participants (aged 70–89 years, mean 77.42±4.08 years) without a history of cardiovascular diseases in the third-wave of the aging arm of the Rugao Longevity and Aging Study (RuLAS). Frailty was defined as the presence of ≥3 domains among five modified Fried’s criteria (unintentional weight loss, low physical activity level, weakness (low grip strength), exhaustion, and slowness (slow gait speed)) and pre-frailty as the presence of 1–2 domains. The prevalence of frailty and pre-frailty was 10.4% and 53.3%, respectively, in this elderly population. Elevated BNP (≥100 pg/mL) was significantly associated with pre-frailty (OR: 1.61, 95% CI: 1.13-2.29) and frailty (OR: 2.63, 95% CI: 1.61-4.32) after adjustment for covariates. In addition, elevated BNP was associated with low grip strength (OR: 2.00, 95% CI: 1.41-2.82) and low gait speed (OR: 1.62, 95% CI: 1.15-2.28) after adjustment for multiple covariates. Log BNP was inversely associated with grip strength (r= -0.265, p
- Published
- 2018
37. PLF‐1 (Proliferin‐1) Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia
- Author
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Masafumi Kuzuya, Hideki Ishii, Xiang Li, Zhe Huang, Weon Kim, Lina Hu, Susumu Suzuki, Yanna Lei, Guangxian Zhao, Guo-Ping Shi, Limei Piao, Enbo Zhu, Xian Wu Cheng, Haiying Jiang, Hongxian Wu, Aiko Inoue, Toyoaki Murohara, and Kenji Okumura
- Subjects
Male ,Neointima ,Vascular smooth muscle ,Intimal hyperplasia ,proliferation ,vascular remodeling ,p38 mitogen-activated protein kinases ,Myocytes, Smooth Muscle ,Apoptosis ,030204 cardiovascular system & hematology ,Vascular Medicine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Original Research ,030304 developmental biology ,Neointimal hyperplasia ,0303 health sciences ,Hyperplasia ,business.industry ,Cell growth ,medicine.disease ,Prolactin ,Rats ,Cell biology ,Animal Models of Human Disease ,vascular smooth muscle ,Tunica Intima ,Cardiology and Cardiovascular Medicine ,business ,Basic Science Research - Abstract
Background Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results Cathepsin K–mediated caspase‐8 maturation is a key initial step for oxidative stress–induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth‐stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF‐1 (proliferin‐1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3‐kinase/protein kinase B/p38 mitogen‐activated protein kinase)‐dependent and ‐independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll‐like receptor‐2/caspase‐8–mediated PLF ‐1 expression. Interestingly, PLF ‐1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild‐type mice. Contrarily, administration of recombinant mouse PLF ‐1 accelerated injury‐induced vascular actions. Conclusions This is the first study detailing PLF ‐1 as a communicator between apoptosis and proliferation during injury‐related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis‐driven expression of PLF ‐1 is thus a novel target for treatment of apoptosis‐based hyperproliferative disorders.
- Published
- 2019
38. Late-Breaking Science Abstracts and Featured Science Abstracts From the American Heart Association’s Scientific Sessions 2019 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2019
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Jing Liu, Guo-Ping Shi, Peter Libby, Junli Guo, and Jes S. Lindholt
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medicine.medical_specialty ,business.industry ,Physiology (medical) ,Internal medicine ,Cardiology ,Medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease - Published
- 2019
39. Association between a frailty index based on common laboratory tests and QTc prolongation in older adults: the Rugao Longevity and Ageing Study
- Author
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Shun Yao, Yinsheng Zhu, Yong Wang, Guo-Ping Shi, Zhengdong Wang, Xuefeng Chu, Jian Cai, Xiaofeng Wang, Xiaoyan Jiang, and Teng Ma
- Subjects
Male ,Aging ,China ,medicine.medical_specialty ,Longitudinal study ,media_common.quotation_subject ,Longevity ,Diastole ,QT interval ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Risk Factors ,Internal medicine ,Odds Ratio ,Prevalence ,Humans ,Medicine ,cardiovascular diseases ,030212 general & internal medicine ,Geriatric Assessment ,Original Research ,Aged ,media_common ,Aged, 80 and over ,frailty index ,Chinese elderly ,Frailty ,business.industry ,Arrhythmias, Cardiac ,General Medicine ,Odds ratio ,Quartile ,Ageing ,Clinical Interventions in Aging ,Cardiology ,Female ,Geriatrics and Gerontology ,QTc prolongation ,business ,Body mass index ,030217 neurology & neurosurgery - Abstract
Teng Ma,1–3,* Jian Cai,4,* Yin-Sheng Zhu,5 Xue-Feng Chu,5 Yong Wang,5 Guo-Ping Shi,5 Zheng-Dong Wang,5 Shun Yao,1–3 Xiao-Feng Wang,1–3 Xiao-Yan Jiang6–8 1Unit of Epidemiology, Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, People’s Republic of China; 2State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China; 3National Clinical Research Center for Aging and Medicine (Huashan), Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Rugao People’s Hospital, Rugao, Jiangsu, People’s Republic of China; 6Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, People’s Republic of China; 7Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, People’s Republic of China; 8Institute of Medical Genetics, Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Risk factors for heart rate-corrected QT interval (QTc) proglongation should be explored to stratify high-risk individuals to aid the prevention of incident cardiovascular events and mortality. The diversity of risk factors for QTc prolongation suggests that use of the frailty index (FI), indicating general health deficits, may be an effective approach, especially in the elderly, to identify the risk of QTc prolongation. Methods: We used the data of 1,780 individuals aged 70–87years from the Rugao Longevity and Ageing Study (RuLAS), a community-based longitudinal study. The FI was constructed using 20 routine laboratory tests, plus the body mass index and measures of systolic and diastolic blood pressures (FI-Lab). Results: The mean FI-Lab value was 0.24±0.09. The mean heart rate-corrected QT interval (QTc) was 407±38ms. The prevalence of QTc prolongation was 5.2% in elderly community populations aged 70–87years. A higher FI-Lab value was associated with a higher risk for QTc prolongation. Each 10% increase in the FI-Lab value increased the odds ratio (OR) by 33% (OR: 1.33; 95% CI: 1.07–1.64). Compared with the lowest quartile, the top quartile FI-Lab score was associated with a 2.50-fold QTc prolongation risk in elderly individuals (95% CI: 1.21–5.19). Conclusion: An FI based on routine laboratory data can identify older adults at increased risk for QTc prolongation. The FI approach may therefore be useful for the risk stratification of QTc prolongation. Keywords: QTc prolongation, frailty, frailty index, Chinese elderly
- Published
- 2018
40. Sleep disturbances and risk of falls in an old Chinese population-Rugao Longevity and Ageing Study
- Author
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Teng Ma, Wang Zhendong, Hongfei Wang, Xiaofeng Wang, Jian Cai, Guo-Ping Shi, Yinsheng Zhu, Xuefeng Chu, Li Jin, Zuyun Liu, Yong Wang, and Xiaoyan Jiang
- Subjects
Male ,Risk ,Sleep Wake Disorders ,Gerontology ,Aging ,Health (social science) ,Longevity ,Population ,Poison control ,Risk Assessment ,Pittsburgh Sleep Quality Index ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Sleep debt ,Sleep Initiation and Maintenance Disorders ,Injury prevention ,medicine ,Humans ,030212 general & internal medicine ,education ,Aged ,education.field_of_study ,Sleep disorder ,business.industry ,Middle Aged ,medicine.disease ,Sleep in non-human animals ,Quality of Life ,Accidental Falls ,Female ,Geriatrics and Gerontology ,Sleep ,business ,030217 neurology & neurosurgery ,Fall prevention ,Demography - Abstract
Background To explore the relationship between sleep disturbances and falls in an elderly Chinese population. Methods Data from 1726 individuals aged 70–87 years from the Rugao Longevity and Ageing Study were used. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep variables. Outcomes were falls ≥1 time per year and falls ≥2 times per year. Results A total of 22.7% of the participants experienced ≥1 fall, and 9.8% experienced ≥2 falls per year. Poor sleep quality was associated with ≥1 fall (OR 1.08, 95% CI 1.05–1.12; OR 1.27, 95% CI 1.14–1.41) and ≥2 falls (OR 1.08, 95% CI 1.03–1.14; OR 1.28, 95% CI 1.10–1.48), with an increase per PSQI score and SD PSQI score, respectively. In addition, sleep quality, sleep latency, sleep efficiency, and sleep disturbance subcomponents were associated with an increased risk of ≥1 fall with ORs of 1.44 (95% CI, 1.21–1.72), 1.23 (95%CI,1.09–1.40), 1.12 (95%CI, 1.01–1.23) and 1.70 (95% CI,1.35–2.14), respectively, and were associated with an increased risk of ≥2 falls with ORs 1.54 (95%CI, 1.22–1.96), 1.21(95%CI, 1.02–1.44), 1.17 (95% CI 1.02–1.33), and 1.78 (95%CI, 1.31–2.44), respectively. Further, participants slept ≤5 h per night had an increased risk of ≥1 fall (OR 2.34; 95%CI, 1.59–3.46) and ≥2 falls (OR 2.19; 95%CI, 1.30–3.69). Conclusions Poor sleep quality and several subcomponent sleep symptoms were consistently associated with increased risk of falls ≥1 time and ≥2 times in Chinese elderly. The identification of sleep disturbances may help identify high-risk Chinese elders who may benefit from fall prevention education.
- Published
- 2017
41. Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice
- Author
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Guang Yang, Hiroyuki Umegaki, Masafumi Kuzuya, Xian Wu Cheng, Hiroki Goto, Aiko Inoue, Limei Piao, Guo-Ping Shi, Wenhu Xu, Yanna Lei, Shinyu Ogasawara, Lina Hu, Guangxian Zhao, Kaoru Kimura, and Chenglin Yu
- Subjects
0301 basic medicine ,Cathepsin ,medicine.medical_specialty ,Pathology ,Skeletal muscle ,Inflammation ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Cardiotoxin ,Physiology (medical) ,Internal medicine ,medicine ,Cathepsin K ,Myocyte ,Orthopedics and Sports Medicine ,Desmin ,medicine.symptom ,C2C12 - Abstract
Background Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non-enzymatic functions in signalling. Here, we examined whether CatK-deficiency (CatK−/−) would mitigate injury-related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis. Methods Cardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild-type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies. Results On post-injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2 and toll-like receptor-4, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. CatK deletion also restored the protein levels of caspase-3 and cleaved caspase-8 and the ratio of the BAX to the Bcl-2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK-specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase-3 proteins induced by CTX. Conclusions These results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.
- Published
- 2017
42. Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease
- Author
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Xue-Xi Xuan, Zhaozhong Zhu, Deliang Shen, Xiao-Fang Wang, Tian-Xia Zhang, Jinying Zhang, Yunzhe Wang, Xiao-Dan Zhu, Dong-Yi Jin, Guo-Ping Shi, Junnan Tang, and Cong-Lin Liu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Inflammation ,030204 cardiovascular system & hematology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Risk factor ,Prospective cohort study ,General Veterinary ,business.industry ,Confounding ,General Medicine ,Odds ratio ,030104 developmental biology ,Endocrinology ,Cytokine ,Mann–Whitney U test ,Cardiology ,Interleukin 18 ,medicine.symptom ,business - Abstract
Background: Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression. Methods and results: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P=0.007), MMP-22 (OR=1.213, P=0.040), and MMP-29 (OR=1.198, P=0.033) were independent risk factors of CHD. Pearson’s correlation test showed that IL18 (coefficient (r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22 (r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson’s correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) (r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride (r=−0.169, P=0.018). Spearman’s correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 (r=0.845, P
- Published
- 2017
43. CD74 Deficiency Mitigates Systemic Lupus Erythematosus–like Autoimmunity and Pathological Findings in Mice
- Author
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Joseph V. Bonventre, Galina K. Sukhova, Isaac E. Stillman, Takaharu Ichimura, Min Yang, Peter Libby, Guo-Ping Shi, Lijun Zhang, Yi Zhou, Huimei Chen, Li Liu, Vasileios C. Kyttaris, Xueqing Yu, and George C. Tsokos
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,Blotting, Western ,Immunology ,Lupus nephritis ,Antigen-Presenting Cells ,Graft vs Host Disease ,Autoimmunity ,Enzyme-Linked Immunosorbent Assay ,Spleen ,Biology ,Lymphocyte Activation ,Real-Time Polymerase Chain Reaction ,medicine.disease_cause ,Article ,Autoimmune Diseases ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Mice, Knockout ,Antigen Presentation ,Kidney ,Histocompatibility Antigens Class II ,Epithelial Cells ,medicine.disease ,Immunohistochemistry ,Lupus Nephritis ,Antigens, Differentiation, B-Lymphocyte ,Mice, Inbred C57BL ,Disease Models, Animal ,Kidney Tubules ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Lymphocyte Culture Test, Mixed ,030215 immunology - Abstract
CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6 Faslpr mice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN-γ or IL-6 induced CD74 expression in kidney TECs in vitro. The presence of kidney TECs from Faslpr mice, rather than from wild-type mice, produced significantly stronger histones, dsDNA, and ribonucleoprotein-Smith Ag complex–induced CD4+ T cell activation. Splenocytes from CD74-deficient FaslprCd74−/− mice had muted responses in a MLR and to the autoantigen histones. Compared with FaslprCd74+/+ mice, FaslprCd74−/− mice had reduced kidney and spleen sizes, splenic activated T cells and B cells, serum IgG and autoantibodies, urine albumin/creatinine ratio, kidney Periodic acid–Schiff score, IgG and C3 deposition, and serum IL-6 and IL-17A levels, but serum IL-2 and TGF-β levels were increased. Study of chronic graft-versus-host C57BL/6 mice that received donor splenocytes from B6.C-H2bm12/KhEg mice and those that received syngeneic donor splenocytes yielded similar observations. CD74 deficiency reduced lupus-like autoimmunity and kidney pathology in chronic graft-versus-host mice. This investigation establishes the direct participation of CD74 in autoimmunity and highlights a potential role for CD74 in kidney TECs, together with professional APCs in systemic lupus erythematosus.
- Published
- 2017
44. Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis
- Author
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Marcela M. Santos, Mengyang Liao, Cong-Lin Liu, Guo-Ping Shi, Karine Iamarene, Cleverson Rodrigues Fernandes, Galina K. Sukhova, and Jinying Zhang
- Subjects
CD4-Positive T-Lymphocytes ,Apolipoprotein E ,medicine.medical_specialty ,Pathology ,Apolipoprotein B ,medicine.medical_treatment ,Science ,030204 cardiovascular system & hematology ,Diet, High-Fat ,Article ,Lesion ,Mice ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Serum amyloid A ,Receptor ,Aorta ,Cells, Cultured ,Cathepsin S ,Membrane Glycoproteins ,Multidisciplinary ,biology ,Interleukin-6 ,virus diseases ,Atherosclerosis ,Cathepsins ,Elastin ,Mice, Inbred C57BL ,Endocrinology ,Cytokine ,Matrix Metalloproteinase 9 ,Toll-Like Receptor 7 ,biology.protein ,Medicine ,Collagen ,medicine.symptom ,030215 immunology - Abstract
Toll-like receptor 7 (TLR7) mediates autoantigen and viral RNA-induced cytokine production. Increased TLR7 expression in human atherosclerotic lesions suggests its involvement in atherogenesis. Here we demonstrated TLR7 expression in macrophages, smooth muscle cells (SMCs), and endothelial cells from mouse atherosclerotic lesions. To test a direct participation of TLR7 in atherosclerosis, we crossbred TLR7-deficient (Tlr7−/−) mice with apolipoprotein E-deficient (Apoe−/−) mice and produced Apoe−/−Tlr7−/− and Apoe−/−Tlr7+/+ littermates, followed by feeding them an atherogenic diet to produce atherosclerosis. Compared to Apoe−/−Tlr7+/+ mice, Apoe−/−Tlr7−/− mice showed reduced aortic arch and sinus lesion areas. Reduced atherosclerosis in Apoe−/−Tlr7−/− mice did not affect lesion macrophage-positive area and CD4+ T-cell number per lesion area, but reduced lesion expression of inflammatory markers major histocompatibility complex-class II and IL6, lesion matrix-degrading proteases cathepsin S and matrix metalloproteinase-9, and systemic serum amyloid A levels. TLR7 deficiency also reduced aortic arch SMC loss and lesion intima and media cell apoptosis. However, TLR7 deficiency did not affect aortic wall elastin fragmentation and collagen contents, or plasma lipoproteins. Therefore, TLR7 contributes to atherogenesis in Apoe−/− mice by regulating lesion and systemic inflammation. A TLR7 antagonist may mitigate atherosclerosis.
- Published
- 2017
45. Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice
- Author
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Min Yang, Vasileios C. Kyttaris, Bruce D. Gelb, Li Liu, Isaac E. Stillman, Huimei Chen, Peter Libby, Guo-Ping Shi, Xueqing Yu, Yi Zhou, Galina K. Sukhova, and George C. Tsokos
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Chemokine ,Kidney ,Systemic lupus erythematosus ,biology ,Immunology ,Spleen ,TLR7 ,medicine.disease ,medicine.disease_cause ,Bone resorption ,Autoimmunity ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Cathepsin K ,medicine ,biology.protein ,Immunology and Allergy ,030215 immunology - Abstract
Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Faslpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Faslpr mice also showed elevated serum CatK levels. CatK deficiency in Faslpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Faslpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.
- Published
- 2017
46. Cathepsin S inhibition changes regulatory T-cell activity in regulating bladder cancer and immune cell proliferation and apoptosis
- Author
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Hongqiang Guo, Xiang Yan, Lijun Zhang, Sha Liao, Chun Wu, Tao Chen, Jingyuan Ren, Chongzhe Yang, Cong-Lin Liu, Galina K. Sukhova, Guo-Ping Shi, and Marcela M. Santos
- Subjects
0301 basic medicine ,Regulatory T cell ,Immunology ,Apoptosis ,Mice, Transgenic ,chemical and pharmacologic phenomena ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cysteine Proteases ,PD-L1 ,Immune Tolerance ,Splenocyte ,medicine ,Animals ,Molecular Biology ,Cell Proliferation ,Carcinoma, Transitional Cell ,biology ,Cell growth ,hemic and immune systems ,Flow Cytometry ,Adoptive Transfer ,Cathepsins ,Immunohistochemistry ,Coculture Techniques ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,CD8 - Abstract
Regulatory T cells (Tregs) are immune suppressive cells, but their roles in tumor growth have been elusive, depending on tumor type or site. Our prior study demonstrated a role of cathepsin S (CatS) in reducing Treg immunosuppressive activity. Therefore, CatS inhibition in Tregs may exacerbate tumor growth. Using mouse bladder carcinoma MB49 cell subcutaneous implant tumor model, we detected no difference in tumor growth, whether mice were given saline- or CatS inhibitor-treated Tregs. However, mice that received inhibitor-treated Tregs had fewer splenic and tumor Tregs, and lower levels of tumor and splenic cell proliferation than mice that received saline-treated Tregs. In vitro, inhibitor-treated Tregs showed lower proliferation and higher apoptosis than saline-treated Tregs when cells were exposed to MB49. In contrast, both types of Tregs showed no difference in proliferation when they were co-cultured with normal splenocytes. Inhibitor-treated Tregs had less apoptosis in splenocytes, but more apoptosis in splenocytes with MB49 conditioned media than saline-treated Tregs. In turn, we detected less proliferation and more apoptosis of MB94 cells after co-culture with inhibitor-treated Tregs, compared with saline-treated Tregs. B220+ B-cell, CD4+ T-cell, and CD8+ T-cell proliferation and apoptosis were also lower in splenocytes co-cultured with inhibitor-treated Tregs than with saline-treated Tregs. Under the same conditions, the addition of cancer cell-conditioned media greatly increased CD8+ T-cell proliferation and reduced CD8+ T-cell apoptosis. These observations suggest that CatS inhibition of Tregs may reduce overall T-cell immunity under normal conditions, but enhance CD8+ T-cell immunity in the presence of cancer cells.
- Published
- 2017
47. Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia
- Author
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Naoya Matsumoto, Robin Bosse, George C. Tsokos, Mayya Geha, Maria Tsokos, Peter H. Lapchak, Guo-Ping Shi, Jurandir J. Dalle Lucca, Lakshmi Kannan, and Abhigyan Satyam
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Blotting, Western ,Immunology ,Ischemia ,Enzyme-Linked Immunosorbent Assay ,Pharmacology ,Polymerase Chain Reaction ,Mice ,03 medical and health sciences ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cathepsin ,business.industry ,Complement C3 ,medicine.disease ,Cathepsins ,Immunohistochemistry ,In vitro ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Caco-2 ,Mesenteric ischemia ,Mesenteric Ischemia ,Reperfusion Injury ,Caco-2 Cells ,business ,Reperfusion injury ,Intracellular - Abstract
Intestinal ischemia followed by reperfusion leads to local and remote organ injury attributed to inflammatory response during the reperfusion phase. The extent to which ischemia contributes to ischemia/reperfusion injury has not been thoroughly studied. After careful evaluation of intestinal tissue following 30 min of ischemia, we noticed significant local mucosal injury in wild-type mice. This injury was drastically reduced in C3-deficient mice, suggesting C3 involvement. Depletion of circulating complement with cobra venom factor eliminated, as expected, injury recorded at the end of the reperfusion phase but failed to eliminate injury that occurred during the ischemic phase. Immunohistochemical studies showed that tissue damage during ischemia was associated with increased expression of C3/C3 fragments primarily in the intestinal epithelial cells, suggesting local involvement of complement. In vitro studies using Caco2 intestinal epithelial cells showed that in the presence of LPS or exposure to hypoxic conditions the cells produce higher C3 mRNA as well as C3a fragment. Caco2 cells were also noted to produce cathepsins B and L, and inhibition of cathepsins suppressed the release of C3a. Finally, we found that mice treated with a cathepsin inhibitor and cathepsin B–deficient mice suffer limited intestinal injury during the ischemic phase. To our knowledge, our findings demonstrate for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. Modulation of cathepsin activity may prevent injury of organs exposed to ischemia.
- Published
- 2017
48. Microarray Expression Profile of Circular RNAs in Peripheral Blood Mononuclear Cells from Rheumatoid Arthritis Patients
- Author
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Jinjun Zhao, Guo-Ping Shi, Min Yang, Aiju Lou, Ran Wang, Dingji Zhu, Zhenlan Jiang, Jing Wu, and Qingqing Ouyang
- Subjects
Adult ,Male ,0301 basic medicine ,Large class ,Microarray ,Physiology ,Arthritis ,Biology ,Peripheral blood mononuclear cell ,lcsh:Physiology ,lcsh:Biochemistry ,Arthritis, Rheumatoid ,03 medical and health sciences ,medicine ,Humans ,lcsh:QD415-436 ,Rheumatoid arthritis ,Aged ,lcsh:QP1-981 ,RNA ,RNA, Circular ,Middle Aged ,medicine.disease ,Microarray assay ,C-Reactive Protein ,030104 developmental biology ,Gene Expression Regulation ,Immunology ,Leukocytes, Mononuclear ,Female ,Circular RNAs ,Biomarkers - Abstract
Background/Aims: Circular RNAs (circRNAs) compose a large class of RNAs that can be used as biomarkers in clinical blood samples. This study aimed to determine the expression of circRNAs in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients to identify novel biomarkers for RA screening. Methods: We started with a microarray screening of circRNA changes in PBMCs from 5 RA patients and 5 healthy controls. We then confirmed the selected circRNA changes in PBMCs from 30 RA patients and 25 age- and sex-matched controls using the real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spearman correlation test was performed to assess the correlation of circRNAs and clinical variables. Receiver operating characteristic (ROC) curve was calculated to evaluate the diagnostic value. Results: We identified and verified five circRNAs (092516, 003524, 103047, 104871, 101873) that were significantly elevated in PBMCs from RA patients. Among these RA patients, we detected no significant correlation between the five circRNAs and the disease severity, including disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and health assessment questionnaire (HAQ). Yet, ROC curve analysis suggested that circRNA_104871 has significant value of RA diagnosis (AUC=0.833, P
- Published
- 2017
49. Regulatory T cells promote adipocyte beiging in subcutaneous adipose tissue
- Author
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Feriel Benadjaoud, Wenqian Fang, Chongzhe Yang, Dafeng Yang, Zhiyong Deng, and Guo-Ping Shi
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Regulatory T cell ,Adipose Tissue, White ,Macrophage polarization ,Subcutaneous Fat ,Mice, Obese ,chemical and pharmacologic phenomena ,White adipose tissue ,Biology ,Biochemistry ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Adipose Tissue, Brown ,Internal medicine ,Adipocyte ,Genetics ,medicine ,Animals ,Obesity ,Molecular Biology ,hemic and immune systems ,Thermogenesis ,M2 Macrophage ,Thermogenin ,Mice, Inbred C57BL ,Interleukin 10 ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Female ,Insulin Resistance ,Energy Metabolism ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Regulatory T cells (Tregs) play essential roles in obesity and diabetes. Here, we report a role of Tregs in enhancing β3-adrenergic receptor agonist CL316243 (CL)-stimulated thermogenic program in subcutaneous adipose tissue (SAT), but not in visceral fat. CL treatment for 7 days increased SAT adipocyte beiging and thermogenic gene expression in male or female mice. Adoptive transfer of Tregs enhanced this CL activity. Such Treg activity lost in male epididymal white adipose tissue (eWAT) and female gonadal gWAT. Adipocyte culture yielded the same conclusion. Tregs enhanced the expression of CL-induced thermogenic genes in SAT from male and female mice. This activity of Tregs reduced or disappeared in adipocytes from eWAT or gWAT. Both CL and Tregs induced much higher UCP-1 (uncoupling protein-1) expression in SAT from females than that from males. A mechanistic study demonstrated a role of Tregs in suppressing the expression of M1 macrophage markers (Tnfa, Il6, iNos, Ip10) and promoting the expression of M2 macrophage markers (Mrc1, Arg1, Il10) in bone-marrow-derived macrophages or in SAT from male or female mice. In female mice with pre-established obesity, Treg adoptive transfer reduced the gWAT weight in 2 weeks. Together with CL treatment, Treg adoptive transfer reduced the SAT weight and further improved CL-induced glucose metabolism and insulin sensitivity in female obese mice, but did not affect CL-induced body weight loss in male or female obese mice. This study revealed a predominant role of Tregs in female mice in promoting adipocyte beiging and thermogenesis in SAT, in part by slanting M2 macrophage polarization.
- Published
- 2019
50. Cysteinyl cathepsins in cardiovascular diseases
- Author
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Guo-Ping Shi, Xian Zhang, Songyuan Luo, and Minjie Wang
- Subjects
0301 basic medicine ,Proteases ,Cell signaling ,Biophysics ,030204 cardiovascular system & hematology ,Protein degradation ,Pharmacology ,Biochemistry ,Article ,Analytical Chemistry ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Risk Factors ,Extracellular ,Medicine ,Animals ,Humans ,Molecular Biology ,Cathepsin ,business.industry ,Atherosclerosis ,Cathepsins ,Cytosol ,030104 developmental biology ,Cardiovascular Diseases ,business ,Intracellular ,Biomarkers ,Aortic Aneurysm, Abdominal - Abstract
Cysteinyl cathepsins are lysosomal/endosomal proteases that mediate bulk protein degradation in these intracellular acidic compartments. Yet, studies indicate that these proteases also appear in the nucleus, nuclear membrane, cytosol, plasma membrane, and extracellular space. Patients with cardiovascular diseases (CVD) show increased levels of cathepsins in the heart, aorta, and plasma. Plasma cathepsins often serve as biomarkers or risk factors of CVD. In aortic diseases, such as atherosclerosis and abdominal aneurysms, cathepsins play pathogenic roles, but many of the same cathepsins are cardioprotective in hypertensive, hypertrophic, and infarcted hearts. During the development of CVD, cathepsins are regulated by inflammatory cytokines, growth factors, hypertensive stimuli, oxidative stress, and many others. Cathepsin activities in inflammatory molecule activation, immunity, cell migration, cholesterol metabolism, neovascularization, cell death, cell signaling, and tissue fibrosis all contribute to CVD and are reviewed in this article in memory of Dr. Nobuhiko Katunuma for his contribution to the field.
- Published
- 2019
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