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Zhang C.,Capital Medical University | Li Y.,Capital Medical University | Wu Y.,Capital Medical University | Wang L.,Capital Medical University | And 3 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Interleukin-6 (IL-6), as a multifunctional cytokine, was involved in the inflammation microenvironment of muscle regeneration. Results: In mice lacking IL-6, less macrophage recruitment and decreased myoblast proliferation impairs muscle regeneration. Conclusion: In monocytes/macrophages, activation of the IL-6/STAT3 pathway is critical to macrophage migration and myoblast proliferation during muscle regeneration. Significance: IL-6/STAT3 pathway is essential for muscle regeneration. Inflammation and microenvironment play a crucial role in muscle regeneration. IL (interleukin)-6, as a multifunctional cytokine is involved in the processes. However, the causative effect of IL-6 in muscle regeneration remains unclear. In a mouse model of cardiotoxin-induced muscle injury/regeneration, infiltrated monocytes/ macrophages produce a high level of IL-6 started on 1 day (24 h) after injury. In IL-6 knock-out (/) mice, the muscle regeneration procedure was impaired along with decreased myogenic determination factor (MyoD) and myogenin mRNA level and increased interstitial fibrosis. The IL-6/ mice exhibited less macrophage infiltration, lower inflammatory cytokine (IL-1, inducible NO synthase, Transforming growth factor (TGF)-1, and IL-10) and chemokine (CCL2, CCL3, and CCL5) expression, and inhibited myoblast proliferation. In vitro, IL-6 deficiency or Signal Transducer and Activator of Transcription 3 (STAT3) knockdown in activated macrophage attenuated the expression of CCL2, CCL3, but not CCL5, which resulted in less macrophage migration. Moreover, inflammatory macrophages promoted myoblast proliferation in an IL-6-dependent manner. Finally, adoptive transfer IL-6/ BM cells into IL-6/ mice rescued the impaired regeneration with improved MyoD and myogenin expression. Taken together, IL-6 expression and the activated STAT3 signaling pathway in monocytes/ macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Qiu S.,Capital Medical University | Qiu S.,Key Laboratory of Remodeling related Cardiovascular Diseases | Qiu S.,Beijing Institute of Heart | Xiao Z.,Capital Medical University | And 19 more authors.
Journal of Pathology | Year: 2015

TGFβ1/Smad, Wnt/β-catenin and snail1 are preferentially activated in renal tubular epithelia after injury, leading to epithelial-mesenchymal transition (EMT). The stress response is coupled to EMT and kidney injury; however, the underlying mechanism of the stress response in EMT remains elusive. AMP-activated protein kinase (AMPK) signalling is responsive to stress and regulates cell energy balance and differentiation. We found that knockdown of AMPKα, especially AMPKα2, enhanced EMT by up-regulating β-catenin and Smad3 in vitro. AMPKα2 deficiency enhanced EMT and fibrosis in a murine unilateral ureteral obstruction (UUO) model. AMPKα2 deficiency also increased the expression of chemokines KC and MCP-1, along with enhanced infiltration of inflammatory cells into the kidney after UUO. CK2β interacted physically with AMPKα and enhanced AMPKα Thr172 phosphorylation and its catalytic activity. Thus, activated AMPKα signalling suppresses EMT and secretion of chemokines in renal tubular epithelia through interaction with CK2β to attenuate renal injury. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Xie P.,Peking Union Medical College | Kadegowda A.K.G.,University of Maryland University College | Ma Y.,University of Maryland University College | Guo F.,Nantong University | And 6 more authors.
Endocrinology | Year: 2015

Intramyocellular accumulation of lipids is often associated with insulin resistance. Deficiency of comparative gene identification-58 (CGI-58) causes cytosolic deposition of triglyceride (TG)-rich lipid droplets in most cell types, including muscle due to defective TG hydrolysis. It was unclear, however, whether CGI-58 deficiency-induced lipid accumulation in muscle influences insulin sensitivity. Here we show that muscle-specific CGI-58 knockout mice relative to their controls have increased glucose tolerance and insulin sensitivity on a Western-type high-fat diet, despite TG accumulation in both heart and oxidative skeletal muscle and cholesterol deposition in heart. Although the intracardiomyocellular lipid deposition results in cardiac ventricular fibrosis and systolic dysfunction, muscle-specific CGI-58 knockout mice show increased glucose uptake in heart and soleus muscle, improved insulin signaling in insulin-sensitive tissues, and reduced plasma concentrations of glucose, insulin, and cholesterol. Hepatic contents of TG and cholesterol are also decreased in these animals. Cardiac steatosis is attributable, at least in part, to decreases in cardiac TG hydrolase activity and peroxisome proliferator-activated receptor-α;/peroxisome proliferatoractivated receptor-γ coactivator-1-dependent mitochondrial fatty acid oxidation. In conclusion, muscle CGI-58 deficiency causes cardiac dysfunction and fat deposition in oxidative muscles but induces a series of favorable metabolic changes in mice fed a high-fat diet. Copyright © 2015 by the Endocrine Society.


Lan A.,Key Laboratory of Remodeling related Cardiovascular Diseases | Du J.,Key Laboratory of Remodeling related Cardiovascular Diseases
Nephrology Dialysis Transplantation | Year: 2015

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all chronic kidney diseases. However, the mechanisms involved in the development of renal fibrosis are poorly understood. The Akt (also known as protein kinase B, PKB) family is serine/threonine protein kinases that play critical roles in regulating growth, proliferation, survival, metabolism and other cellular activities. Cytokines, high-glucose medium, transforming growth factor-' 21 or advanced glycation end-products activate Akt in different renal cells. Increased Akt activation has been found in experimental tubulointerstitial fibrosis. In addition, Akt activation is also an important node in diverse signaling cascades involved in kidney damage. These data give evidence for a role for Akt in renal fibrosis, but no reviews are available on the role of Akt in the process. Thus, our aim is to review the role of Akt activation and signaling in renal fibrosis. © The Author 2014.


Zhen P.,Capital Medical University | Zhao Q.,Capital Medical University | Zhao Q.,Key Laboratory of Remodeling related Cardiovascular Diseases | Hou D.,Capital Medical University | And 10 more authors.
Journal of Biomedicine and Biotechnology | Year: 2012

Hyperhomocysteinemia (HHcy) is a well-known independent risk factor for vascular diseases in the general population. This study was to explore the effect of genistein (GST), a natural bioactive compound derived from legumes, on HHcy-induced vascular endothelial impairment in ovariectomized rats in vivo. Thirty-two adult female Wistar rats were assigned randomly into four groups (n=8): (a) Con: control; (b) Met: 2.5 methionine diet; (c) OVX + Met: ovariectomy + 2.5 methionine diet; (d) OVX + Met + GST: ovariectomy + 2.5 methionine diet + supplementation with genistein. After 12 wk of different treatment, the rats' blood, toracic aortas and liver samples were collected for analysis. Results showed that high-methionine diet induced both elevation of plasma Hcy and endothelial dysfunction, and ovariectomy deteriorated these injuries. Significant improvement of both functional and morphological changes of vascular endothelium was observed in OVX + Met + GST group; meanwhile the plasma Hcy levels decreased remarkably. There were significant elevations of plasma ET-1 and liver MDA levels in ovariectomized HHcy rats, and supplementation with genistein could attenuate these changes. These results implied that genistein could lower the elevated Hcy levels, and prevent the development of endothelial impairment in ovariectomized HHcy rats. This finding may shed a novel light on the anti-atherogenic activities of genistein in HHcy patients. © 2012 Panpan Zhen et al.

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