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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-Dærner, Hìseyin 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...
May 11, 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
Sarah Fogarty, Fiona A Ross, Diana Vara Ciruelos, Alexander Gray, Graeme J Gowans, D Grahame Hardie
UNLABELLED: The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca(2+)/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1-AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 reexpression in these cells causes cell-cycle arrest...
August 2016: Molecular Cancer Research: MCR
Da-Ming Liu, Hong-Jun Wang, Bo Han, Xiang-Qi Meng, Ming-Hui Chen, Dong-Bo Yang, Ying Sun, Yong-Li Li, Chuan-Lu Jiang
AIMS: To explore the expression, methylation pattern, the prognostic value, and the biological consequences of CAMKK2 in gliomas. METHODS: The expression and methylation pattern of CAMKK2 was inferred and validated from mRNA expression profile (N = 866) and methylation profile (N = 426) of glioma tissue samples, and independent samples were used for further validation by IHC and pyrosequencing. To explore the function of CAMKK2 in gliomas, in vitro studies, colony formation assays and migration and invasion assays were performed...
June 2016: CNS Neuroscience & Therapeutics
Ping Yu, Xiongying Chen, Wan Zhao, Zhifang Zhang, Qiumei Zhang, Bingqian Han, Jinguo Zhai, Min Chen, Boqi Du, Xiaoxiang Deng, Feng Ji, Chuanyue Wang, Yu-Tao Xiang, Dawei Li, Hongjie Wu, Jun Li, Qi Dong, Chuansheng Chen
Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N-back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed...
July 2016: Human Brain Mapping
Kathrina L Marcelo, Thomas Ribar, Christopher R Means, Anna Tsimelzon, Robert D Stevens, Olga Ilkayeva, James R Bain, Susan G Hilsenbeck, Christopher B Newgard, Anthony R Means, Brian York
A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to increased release of intracellular Ca(2+) stores from the endoplasmic reticulum. These findings suggest that insulin resistance associated with the obese state is linked to activation of canonical Ca(2+) signaling pathways. Mechanistically, increased intracellular Ca(2+) binds calmodulin (CaM) to activate a set of Ca(2+)/CaM-dependent protein kinases...
May 2016: Molecular Endocrinology
Uma Sankar, Zachary J Pritchard, Michael J Voor
Shorter generation time and the power of genetic manipulation make mice an ideal model system to study bone biology as well as bone diseases. However their small size presents a challenge to perform strength measurements, particularly of the weight-bearing cancellous bone in the murine long bones. We recently developed an improved method to measure the axial compressive strength of the cancellous bone in the distal femur metaphysis in mice. Transverse micro-computed tomography image slices that are 7µm thick were used to locate the position where the epiphysis-metaphysis transition occurs...
May 3, 2016: Journal of Biomechanics
Bin Wang, Zhenlong Wu, Yun Ji, Kaiji Sun, Zhaolai Dai, Guoyao Wu
BACKGROUND: The tight junctions (TJs) are essential for maintenance of the intestinal mucosal barrier integrity. Results of our recent work show that dietary l-glutamine (Gln) supplementation enhances the protein abundance of TJ proteins in the small intestine of piglets. However, the underlying mechanisms remain largely unknown. OBJECTIVE: This study was conducted to test the hypothesis that Gln regulates TJ integrity through calcium/calmodulin-dependent kinase 2 (CaMKK2)-AMP-activated protein kinase (AMPK) signaling which, in turn, contributes to improved intestinal mucosal barrier function...
March 2016: Journal of Nutrition
Hayley Goullee, Antonia L Wadley, Catherine L Cherry, Richard J N Allcock, Michael Black, Peter R Kamerman, Patricia Price
HIV-associated sensory neuropathy (HIV-SN) is the most common neurological condition associated with HIV. HIV-SN has characteristics of an inflammatory pathology caused by the virus itself and/or by antiretroviral treatment (ART). Here, we assess the impact of single-nucleotide polymorphisms (SNPs) in a cluster of three genes that affect inflammation and neuronal repair: P2X7R, P2X4R and CAMKK2. HIV-SN status was assessed using the Brief Peripheral Neuropathy Screening tool, with SN defined by bilateral symptoms and signs...
August 2016: Journal of Neurovirology
Loukia G Karacosta, Laura A Kuroski, Wilma A Hofmann, Gissou Azabdaftari, Michalis Mastri, Angela M Gocher, Shuhang Dai, Allen J Hoste, Arthur M Edelman
BACKGROUND: Re-activation of the transcriptional activity of the androgen receptor (AR) is an important factor mediating progression from androgen-responsive to castrate-resistant prostate cancer (CRPC). However, the mechanisms regulating AR activity in CRPC remain incompletely understood. Ca(2+) /calmodulin-dependent kinase kinase (CaMKK) 2 was previously shown to regulate AR activity in androgen-responsive prostate cancer cells. Our objective was to further explore the basis of this regulation in CRPC cells...
February 15, 2016: Prostate
Jing Li, Jun Song, Heidi L Weiss, Todd Weiss, Courtney M Townsend, B Mark Evers
AMP-activated protein kinase (AMPK), a critical fuel-sensing enzyme, regulates the metabolic effects of various hormones. Neurotensin (NT) is a 13-amino acid peptide predominantly localized in enteroendocrine cells of the small bowel and released by fat ingestion. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with an increased risk of diabetes, cardiovascular disease, and mortality; however, the mechanisms regulating NT release are not fully defined...
January 2016: Molecular Endocrinology
Minoo Atakhorrami, Simin Rahimi-Aliabadi, Javad Jamshidi, Elham Moslemi, Abolfazl Movafagh, Mina Ohadi, Arash Mirabzadeh, Babak Emamalizadeh, Hamid Ghaedi, Fatemeh Gholipour, Atena Fazeli, Marzieh Motallebi, Shaghayegh Taghavi, Azadeh Ahmadifard, Saeed Mohammadihosseinabad, Amir Ehtesham Shafiei Zarneh, Neda Shahmohammadibeni, Faranak Madadi, Monavvar Andarva, Hossein Darvish
A recent large-scale study have reported that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene is highly associated with schizophrenia in European and Han Chinese populations. Increasing evidences show that schizophrenia and bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant with schizophrenia and bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500 schizophrenic patients, 500 bipolar patients and 500 normal controls and all were genotyped for the rs1063843 using a PCR-RFLP method...
March 2016: Journal of Neural Transmission
Rohit A Sinha, Brijesh K Singh, Jin Zhou, Yajun Wu, Benjamin L Farah, Kenji Ohba, Ronny Lesmana, Jessica Gooding, Boon-Huat Bay, Paul M Yen
Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T3) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T3 is coupled to oxidative phosphorylation and ROS production...
2015: Autophagy
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