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Zhong'e Zhou, Yong Tang, Xian Jin, Chengjun Chen, Yi Lu, Liang Liu, Chengxing Shen
Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects...
2016: Journal of Diabetes Research
Xu Zhang, Qianni Cheng, Yixiang Wang, Po Sing Leung, Kinglun Kingston Mak
Bone plays a role in energy metabolism, but the interplay between bone and other organs in this process is not completely understood. Here, we show that upregulated Hh signaling in bones results in increased whole-body energy expenditure, white adipose tissue (WAT) browning, hypoglycemia and skeletal muscle atrophy. We found that Hh signaling induces PTHrP secretion from bones and causes WAT browning. Injection of PTHrP-neutralizing antibody attenuates WAT browning and improves the circulating blood glucose level while high-fat diet treatment only rescues hypoglycemia...
October 14, 2016: Cell Death and Differentiation
Nathaniel B Bone, Zhongyu Liu, Jean-Francois Pittet, Jaroslaw W Zmijewski
Catecholamines, including β-adrenergic and dopaminergic neurotransmitters, have an essential role in regulating the "fight or flight" reflex and also affects immune cell proinflammatory action. However, little is known about whether catecholamines prevent dysfunction of metabolic pathways associated with inflammatory organ injury, including development of acute lung injury (ALI). We hypothesize that selected catecholamines may reduce metabolic alterations in LPS-stimulated macrophages and in the lungs of mice subjected to endotoxin-induced ALI, a situation characterized by diminished activity of AMP-activated protein kinase (AMPK)...
October 12, 2016: Journal of Leukocyte Biology
Leiming Li, Yan Li, Jiansong Zhao, Shuli Fan, Liguo Wang, Xu Li
Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines...
2016: OncoTargets and Therapy
Yong-Hong Wu, Quan Li, Ping Li
LPS stimulation in macrophages/monocytes induces TNFα production. We here tested the potential effect of GSK621, a novel AMP-activated protein kinase (AMPK) activator, against the process. In RAW264.7 macrophages, murine bone marrow-derived macrophages (BMDMs), and chronic obstructive pulmonary disease (COPD) patients' monocytes, GSK621 significantly inhibited LPS-induced TNFα protein secretion and mRNA synthesis. Inhibition of AMPK, through AMPKα shRNA knockdown or dominant negative mutation (T172A), almost abolished GSK621's suppression on TNFα in RAW264...
October 3, 2016: Biochemical and Biophysical Research Communications
Sílvia Rocha-Rodrigues, Amaia Rodríguez, Alexandra M Gouveia, Inês O Gonçalves, Sara Becerril, Beatriz Ramírez, Jorge Beleza, Gema Frühbeck, António Ascensão, José Magalhães
AIMS: Exercise-stimulated myokine secretion into circulation may be related with browning in white adipose tissue (WAT), representing a positive metabolic effect on whole-body fat mass. However, limited information is yet available regarding the impact of exercise on myokine-related modulation of adipocyte phenotype in WAT from obese rats. MAIN METHODS: Sprague-Dawley rats (n=60) were divided into sedentary and voluntary physical activity (VPA) groups and fed with standard (35kcal% fat) or high-fat (HFD, 71kcal% fat)-isoenergetic diets...
September 27, 2016: Life Sciences
Maria A Gubbiotti, Thomas Neill, Renato V Iozzo
Perlecan, a large basement membrane heparan sulfate proteoglycan, is expressed in a wide array of tissues where it regulates diverse cellular processes including bone formation, inflammation, cardiac development, and angiogenesis. Here we provide a contemporary review germane to the biology of perlecan encompassing its genetic regulation as well as an analysis of its modular protein structure as it pertains to function. As perlecan signaling from the extracellular matrix converges on master regulators of autophagy, including AMPK and mTOR, via a specific interaction with vascular endothelial growth factor receptor 2, we specifically focus on the mechanism of action of perlecan in autophagy and angiogenesis and contrast the role of endorepellin, the C-terminal fragment of perlecan, in these cellular and morphogenic events...
September 6, 2016: Matrix Biology: Journal of the International Society for Matrix Biology
Dipanjan Chanda, Jieyi Li, Yvonne Oligschlaeger, Mike L J Jeurissen, Tom Houben, Sofie M A Walenbergh, Ronit Shiri-Sverdlov, Dietbert Neumann
Non-alcoholic steatohepatitis (NASH), a metabolic disorder consisting of steatosis and inflammation, is considered the hepatic equivalent of metabolic syndrome and can result in irreversible liver damage. Macrophage-stimulating protein (MSP) is a hepatokine that potentially has a beneficial role in hepatic lipid and glucose metabolism via the activation of AMP-activated protein kinase (AMPK). In the current study, we investigated the regulatory role of MSP in the development of inflammation and lipid metabolism in various NASH models, both in vitro and ex vivo...
September 9, 2016: Experimental & Molecular Medicine
Min-Huan Wu, Pei-Han Huang, Mingli Hsieh, Chun-Hao Tsai, Hsien-Te Chen, Chih-Hsin Tang
Chondrosarcoma is a malignant tumor of mesenchymal origin predominantly composed of cartilage-producing cells. This type of bone cancer is extremely resistant to radiotherapy and chemotherapy. Surgical resection is the primary treatment, but is often difficult and not always practical for metastatic disease, so more effective treatments are needed. In particular, it would be helpful to identify molecular markers as targets for therapeutic intervention. Endothelin-1 (ET-1), a potent vasoconstrictor, has been shown to enhance chondrosarcoma angiogenesis and metastasis...
September 2, 2016: Oncotarget
Xiong-Ke Hu, Xin-Hua Yin, Hong-Qi Zhang, Chao-Feng Guo, Ming-Xing Tang
Liraglutide, a synthetic analogue of glucagon-like peptide‑1, is utilized in the treatment of type 2 diabetes and obesity. Liraglutide has been previously demonstrated to prevent osteoblastic differentiation of human vascular smooth muscle cells, resulting in the slowing of arterial calcification, however, its effect on bone formation remains unclear. The present study investigated the effect of liraglutide on osteoblastic differentiation using Alizarin Red S staining, and examined the molecular mechanisms underlying the regulatory effect by western blot analysis...
October 2016: Molecular Medicine Reports
Luís Martins, Patricia Seoane-Collazo, Cristina Contreras, Ismael González-García, Noelia Martínez-Sánchez, Francisco González, Juan Zalvide, Rosalía Gallego, Carlos Diéguez, Rubén Nogueiras, Manuel Tena-Sempere, Miguel López
AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice...
August 23, 2016: Cell Reports
Min Yang, Huifeng Pi, Min Li, Shangcheng Xu, Lei Zhang, Jia Xie, Li Tian, Manyu Tu, Mindi He, Yonghui Lu, Zhengping Yu, Zhou Zhou
Mesenchymal stem cells (MSCs) are a valuable in vitro model for investigating the bone toxicity of cadmium (Cd). Autophagy has been proposed to play a pivotal role in Cd-mediated toxicity. The FOXO family proteins are important transcription factors that are essential to autophagy induction. The present study investigated the role of autophagy in Cd-induced skeleton damage and its potential mechanism. We exposed MSCs to different concentrations of cadmium chloride (3.5, 7, and 14 μM) for 24 h. We demonstrated that Cd treatment increased autophagic flux, and inhibition of autophagic process using BENC1 gene silencing blocked Cd-induced cell death...
August 4, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Lin Zhao, Chongxi Fan, Yu Zhang, Yang Yang, Dongjin Wang, Chao Deng, Wei Hu, Zhiqiang Ma, Shuai Jiang, Shouyi Di, Zhigang Qin, Jianjun Lv, Yang Sun, Wei Yi
Adiponectin has been demonstrated to protect the cardiovascular system and bone marrow mesenchymal stem cells (BMSCs). However, it is unclear whether adiponectin can protect BMSCs against flow shear stress (FSS). In this study, our aim was to explore the effects of adiponectin on BMSCs and to explore the role of AMP-activated protein kinase (AMPK) signaling in this process. Shear stress significantly inhibits the survival and increases the apoptosis of BMSCs in an intensity-dependent manner. The expression levels of TGF-β, bFGF, VEGF, PDGF, and Bcl2 are simultaneously reduced, and the phosphorylation levels of AMPK and ACC, as well as the expression level of Bax, are increased...
2016: Scientific Reports
Gantsetseg Tumurkhuu, Kenichi Shimada, Jargalsaikhan Dagvadorj, Timothy R Crother, Wenxuan Zhang, Daniel Luthringer, Roberta A Gottlieb, Shuang Chen, Moshe Arditi
RATIONALE: Activation of NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediating interleukin (IL)-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis, and mitochondria are central regulators of the nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage...
September 2, 2016: Circulation Research
Jia-Wen Yu, Ya-Ping Deng, Xue Han, Guo-Fei Ren, Jian Cai, Guo-Jun Jiang
BACKGROUND: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. METHODS: Streptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice...
2016: Cardiovascular Diabetology
Yu-Gang Wang, Xin-Hua Qu, Ying Yang, Xiu-Guo Han, Lei Wang, Han Qiao, Qi-Ming Fan, Ting-Ting Tang, Ke-Rong Dai
Several metabolic, genetic and oncogenic bone diseases share the common pathological phenotype of defective bone marrow stromal cell (BMSC) differentiation. Many reports in bone science in the past several years have suggested that the skeleton also has an endocrine role. The role of AMP-activated protein kinase (AMPK) as an energy metabolism sensor and how it regulates BMSC differentiation is largely unknown. In the current study, we used AMPK agonists to activate AMPK in MC3T3-E1 cells to investigate the functional roles of AMPK in osteogenesis...
September 2016: Cellular Signalling
Ajay Kumar, Shailendra Giri, Ashok Kumar
The retina is considered to be the most metabolically active tissue in the body. However, the link between energy metabolism and retinal inflammation, as incited by microbial infection such as endophthalmitis remains unexplored. In this study, using a mouse model of Staphylococcus aureus (SA) endophthalmitis, we demonstrate that the activity (phosphorylation) of AMP-activated protein kinase alpha (AMPKα), a cellular energy sensor, and its endogenous substrate; acetyl-CoA carboxylase (ACC) is downregulated in the SA-infected retina...
June 5, 2016: Cellular Microbiology
Chun-Yin Huang, An-Chen Chang, Hsien-Te Chen, Shih-Wei Wang, Yuan-Shun Lo, Chih-Hsin Tang
Chondrosarcoma is the second most frequently occurring type of bone malignancy characterized by distant metastatic propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumour lymphangiogenesis and lymphatic metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. In recent years, adiponectin has also been indicated as facilitating tumorigenesis, angiogenesis and metastasis. However, the effect of adiponectin on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has remained largely a mystery...
September 1, 2016: Clinical Science (1979-)
Wei Ming, Gan Lu, Sha Xin, Lu Huanyu, Jiang Yinghao, Lei Xiaoying, Xu Chengming, Ruan Banjun, Wang Li, Lu Zifan
Therapeutic targeting bone loss has been the focus of the study in osteoporosis. The present study is intended to evaluate whether MOTS-c, a novel mitochondria related 16 aa peptide, can protect mice from ovariectomy-induced osteoporosis. After ovary removal, the mice were injected with MOTS-c at a dose of 5 mg/kg once a day for 12 weeks. Our results showed that MOTS-c treatment significantly alleviated bone loss, as determined by micro-CT examination. Mechanistically, we found that the receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclast differentiation was remarkably inhibited by MOTS-c...
August 5, 2016: Biochemical and Biophysical Research Communications
Se Jeong Oh, Dong Ryun Gu, Su Hyun Jin, Keun Ha Park, Seoung Hoon Lee
Cytosolic malate dehydrogenase (malate dehydrogenase 1, MDH1) plays pivotal roles in the malate/aspartate shuttle that might modulate metabolism between the cytosol and mitochondria. In this study, we investigated the role of MDH1 in osteoclast differentiation and formation. MDH1 expression was induced by receptor activator of nuclear factor kappa-B ligand (RANKL) treatment. Knockdown of MDH1 by infection with retrovirus containing MDH1-specific shRNA (shMDH1) reduced mature osteoclast formation and bone resorption activity...
June 17, 2016: Biochemical and Biophysical Research Communications
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