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Xubo Chen, Xueyan Zhao, Fazhang Lan, Tao Zhou, Hua Cai, Haiying Sun, Weijia Kong, Wen Kong
Studies have reported attenuation of insulin resistance (IR) by improving phosphorylation of the insulin signalling pathway. However, the upstream molecular signalling pathway is still elusive. In this study, Western blot was used to evaluate the phosphorylation level of the insulin signalling pathway and the AMPK pathway. 2-NBDG was used to evaluate glucose uptake. Ca(2+) imaging was used to assess change of intracellular Ca(2+) concentration. We found that NaHS enhanced the intracellular Ca(2+) concentration and glucose uptake and activated the insulin signalling cascade in a palmitic acid (PA)-induced IR model in C2C12 cells...
October 16, 2017: Scientific Reports
Long Jianfei, Wang Min, Ma Chunlai, Chen Bicui, Zhang Jiming, Wang Bin
Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and β-actin), oxidative stress, intracellular Ca(2+) levels, Ca(2+)-related signaling pathway (CaMKK2/AMPK), and Ca(2+)-related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs)...
October 13, 2017: Biochemical Pharmacology
Luigi Racioppi, William Lento, Wei Huang, Stephanie Arvai, Phuong L Doan, Jeffrey R Harris, Fernando Marcon, Helder I Nakaya, Yaping Liu, Nelson Chao
Hematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature...
October 5, 2017: Cell Death & Disease
Brian York, Feng Li, Fumin Lin, Kathrina L Marcelo, Jianqiang Mao, Adam Dean, Naomi Gonzales, David Gooden, Suman Maity, Cristian Coarfa, Nagireddy Putluri, Anthony R Means
Binding of calcium to its intracellular receptor calmodulin (CaM) activates a family of Ca(2+)/CaM-dependent protein kinases. CaMKK2 (Ca(2+)/CaM-dependent protein kinase kinase 2) is a central member of this kinase family as it controls the actions of a CaMK cascade involving CaMKI, CaMKIV or AMPK. CaMKK2 controls insulin signaling, metabolic homeostasis, inflammation and cancer cell growth highlighting its potential as a therapeutic target for a variety of diseases. STO-609 is a selective, small molecule inhibitor of CaMKK2...
September 18, 2017: Scientific Reports
Wei-Zhen Xue, Xiaozhen Gu, Yulan Wu, Danyang Li, Yi Xu, Hui-Li Wang
Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression...
July 27, 2017: Oncotarget
Dzana S Hukic, Urban Ösby, Eric Olsson, Agneta Hilding, Claes-Göran Östenson, Harvest F Gu, Ewa Ehrenborg, Gunnar Edman, Martin Schalling, Catharina Lavebratt, Louise Frisén
OBJECTIVE: We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference. PATIENTS AND METHODS: We analyzed the association in (i) a case-case model in which patients with schizophrenia spectrum disorder with increased waist circumference (≥80 cm for women and ≥94 cm for men) (n=534) were compared with patients with normal waist circumference (<80 cm for women; <94 cm for men) (n=124), and in (ii) a case-control model in which schizophrenia spectrum disorder patients with increased waist circumference or irrespective of waist circumference were compared with population-derived controls (n=494) adjusted for age, sex, fasting glucose, smoking, and family history of diabetes...
July 21, 2017: Psychiatric Genetics
Angela M Gocher, Gissou Azabdaftari, Lindsey M Euscher, Shuhang Dai, Loukia G Karacosta, Thomas F Franke, Arthur M Edelman
Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (β) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3)...
August 25, 2017: Journal of Biological Chemistry
Matthew T O'Brien, Jonathan S Oakhill, Naomi X Y Ling, Christopher G Langendorf, Ashfaqul Hoque, Toby A Dite, Anthony R Means, Bruce E Kemp, John W Scott
The Ca(2+)-calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity is strongly associated with prostate and hepatic cancers, whereas reduced CaMKK2 activity has been linked to schizophrenia and bipolar disease in humans. Here we report the functional effects of nine rare-variant point mutations that were detected in large-scale human genetic studies and cancer tissues, all of which occur close to two regulatory phosphorylation sites and the catalytic site on human CaMKK2...
February 23, 2017: Scientific Reports
Hua Yu, Huiqin Zhang, Mingjun Dong, Zhou Wu, Zhonglei Shen, Yangyang Xie, Zhenfang Kong, Xiaoyu Dai, Binbin Xu
Caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea is known to induce mitochondrial dysfunctions. In this study, the anticancer property of caulerpin was assessed in a panel of colorectal cancer cell lines. We demonstrated that caulerpin inhibited oxidative phosphorylation (OXPHOS) and facilitated an early intervention of the mitochondrial function, via inhibiting mitochondrial complex I, accompanied by the dissipation of mitochondrial membrane potential and a surge of reactive oxygen species (ROS) generation...
January 2017: International Journal of Oncology
Jie Yang, Jie Yu, Dongdong Li, Sanjiu Yu, Jingbin Ke, Lianyou Wang, Yanwei Wang, Youzhu Qiu, Xubin Gao, Jihang Zhang, Lan Huang
Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrow-derived EPCs from rat...
January 2, 2017: Autophagy
Cheng Ye, Duo Zhang, Lei Zhao, Yan Li, Xiaohan Yao, Hui Wang, Shengjie Zhang, Wei Liu, Hongchao Cao, Shuxian Yu, Yucheng Wang, Jingjing Jiang, Hui Wang, Xihua Li, Hao Ying
Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy...
October 24, 2016: International Journal of Molecular Sciences
Shasha Wang, Yisi Chen, Ruirui Kou, Yu Wang, Tao Zeng, Keqin Xie, Fuyong Song
Oxidative stress is associated with the pathogenesis of carbon disulfide (CS2) induced polyneuropathy. The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting cells against oxidative stress. However, whether there exists a Nrf2-mediated antioxidative machinery in CS2-induced neuropathy has not been elucidated. In the present study, male wistar rats were randomly divided into three experimental groups and one control group. The rats in experimental groups were treated with CS2 by gavage at dosages of 200, 400 and 600mg/kg/day respectively, six times per week for 6 weeks...
August 10, 2016: Toxicology
Lisa Gerner, Steffi Munack, Koen Temmerman, Ann-Marie Lawrence-Dörner, Hüseyin Besir, Matthias Wilmanns, Jan Kristian Jensen, Bernd Thiede, Ian G Mills, Jens Preben Morth
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) has been implicated in a range of conditions and pathologies from prostate to hepatic cancer. Here, we describe the expression in Escherichia coli and the purification protocol for the following constructs: full-length CaMKK2 in complex with CaM, CaMKK2 'apo', CaMKK2 (165-501) in complex with CaM, and the CaMKK2 F267G mutant. The protocols described have been optimized for maximum yield and purity with minimal purification steps required and the proteins subsequently used to develop a fluorescence-based assay for drug binding to the kinase, "Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2" [1]...
September 2016: Data in Brief
Sun Li, Xiao-Lin Liu, Xie-Lai Zhou, Su-Jun Jiang, Hong Yuan
The toxic metal lead is a widespread environmental polutant that can adversely affect human health. However, the underlying mechanisms of lead-induced toxicity are still largely unknown. The mechanism of lead toxicity was presumed to involve cross reaction between Pb(2+) and Ca(2+) with calmodulin dependent systems. The aim of the present study was thus to identify differential expression of calmodulin-related genes in the spleen of lead-exposed mice. We performed microarray analysis to identify differentially expressed genes...
December 2015: Interdisciplinary Toxicology
Kathrina L Marcelo, Anthony R Means, Brian York
Calcium (Ca(2+)) is an essential ligand that binds its primary intracellular receptor calmodulin (CaM) to trigger a variety of downstream processes and pathways. Central to the actions of Ca(2+)/CaM is the activation of a highly conserved Ca(2+)/CaM kinase (CaMK) cascade that amplifies Ca(2+) signals through a series of subsequent phosphorylation events. Proper regulation of Ca(2+) flux is necessary for whole-body metabolism and disruption of Ca(2+) homeostasis has been linked to various metabolic diseases...
October 2016: Trends in Endocrinology and Metabolism: TEM
Eduardo Cremonese Filippi-Chiela, Michelle S Viegas, Marcos Paulo Thomé, Andreia Buffon, Marcia R Wink, Guido Lenz
Autophagy is a catabolic process that is largely regulated by extracellular and intracellular signaling pathways that are central to cellular metabolism and growth. Mounting evidence has shown that ion channels and transporters are important for basal autophagy functioning and influence autophagy to handle stressful situations. Besides its role in cell proliferation and apoptosis, intracellular Ca(2+) is widely recognized as a key regulator of autophagy, acting through the modulation of pathways such as the mechanistic target of rapamycin complex 1, calcium/calmodulin-dependent protein kinase kinase 2, and protein kinase C...
September 2016: Molecular Pharmacology
Shaoheng Li, Yuhui Yan, Yanan Jiao, Zhong Gao, Yang Xia, Liang Kong, Yingjia Yao, Zhenyu Tao, Jie Song, Yaping Yan, Guangxian Zhang, Jingxian Yang
Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). It has been reported that osthole exerts its neuroprotective effect on neuronal synapses, but its exact mechanism is obscure. Recently, microRNAs have been demonstrated to play a crucial role in inducing synaptotoxicity by Aβ, implying that targeting microRNAs could be a therapeutic approach of AD. In the present study, we investigated the neuroprotective effects of osthole on a cell model of AD by transducing APP695 Swedish mutant (APP695swe, APP) into mouse cortical neurons and human SH-SY5Y cells...
September 2016: Journal of Molecular Neuroscience: MN
Jahahreeh Finley
In all mammalian species studied to date, the initiation of oocyte activation is orchestrated through alterations in intracellular calcium (Ca(2+)) signaling. Upon sperm binding to the oocyte plasma membrane, a sperm-associated phospholipase C (PLC) isoform, PLC zeta (PLCζ), is released into the oocyte cytoplasm. PLCζ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce diacylglycerol (DAG), which activates protein kinase C (PKC), and inositol 1,4,5-trisphosphate (IP3), which induces the release of Ca(2+) from endoplasmic reticulum (ER) Ca(2+) stores...
August 2016: Medical Hypotheses
Lisa Gerner, Steffi Munack, Koen Temmerman, Ann-Marie Lawrence-Dörner, Hüseyin Besir, Matthias Wilmanns, Jan Kristian Jensen, Bernd Thiede, Ian G Mills, Jens Preben Morth
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) has been implicated in the regulation of metabolic activity in cancer and immune cells, and affects whole-body metabolism by regulating ghrelin-signalling in the hypothalamus. This has led to efforts to develop specific CaMKK2 inhibitors, and STO-609 is the standardly used CaMKK2 inhibitor to date. We have developed a novel fluorescence-based assay by exploiting the intrinsic fluorescence properties of STO-609. Here, we report an in vitro binding constant of KD ∼17 nM between STO-609 and purified CaMKK2 or CaMKK2:Calmodulin complex...
July 22, 2016: Biochemical and Biophysical Research Communications
Katarina Truvé, Peter Dickinson, Anqi Xiong, Daniel York, Kartika Jayashankar, Gerli Pielberg, Michele Koltookian, Eva Murén, Hans-Henrik Fuxelius, Holger Weishaupt, Fredrik J Swartling, Göran Andersson, Åke Hedhammar, Erik Bongcam-Rudloff, Karin Forsberg-Nilsson, Danika Bannasch, Kerstin Lindblad-Toh
Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2...
May 2016: PLoS Genetics
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