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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/27923872/dopamine-directly-increases-mitochondrial-mass-and-thermogenesis-in-brown-adipocytes
#1
Rose Kohlie, Nina Perwitz, Julia Resch, Sebastian Michael Schmid, Hendrik Lehnert, Johannes Klein, Karl Alexander Iwen
Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential it may dissipate excessive energy, regulate body weight, and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT-thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT-thermogenesis but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells...
December 6, 2016: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/27923837/the-nci-60-methylome-and-its-integration-into-cellminer
#2
William C Reinhold, Sudhir Varma, Margot Sunshine, Vinodh Rajapakse, Augustin Luna, Kurt W Kohn, Holly Stevenson, Yonghong Wang, Holger Heyn, Vanesa Nogales, Sebastian Moran, David J Goldstein, James H Doroshow, Paul S Meltzer, Manel Esteller, Yves Pommier
A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (~21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and microRNA transcripts, DNA copy number, and protein levels. Here we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2...
December 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27923790/dynamin-related-protein-1-mediates-low-glucose-induced-endothelial-dysfunction-in-human-arterioles
#3
Michael John Tanner, Jingli Wang, Rong Ying, Tisha B Suboc, Mobin Malik, Allison Couillard, Amberly Branum, Venkata Puppala, Michael Eric Widlansky
Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process...
December 6, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27908258/neurotoxicity-induced-by-mephedrone-an-up-to-date-review
#4
Flaminia Pantano, Roberta Tittarelli, Giulio Mannocchi, Roberta Pacifici, Alessandro di Luca, Francesco Paolo Busardò, Enrico Marinelli
Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc...
November 30, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27904677/an-engineered-fgf21-variant-ly2405319-can-prevent-non-alcoholic-steatohepatitis-by-enhancing-hepatic-mitochondrial-function
#5
Ju Hee Lee, Yea Eun Kang, Joon Young Chang, Ki Cheol Park, Hyeon-Woo Kim, Jung Tae Kim, Hyun Jin Kim, Hyon-Seung Yi, Minho Shong, Hyo Kyun Chung, Koon Soon Kim
Non-alcoholic fatty liver disease (NAFLD) is a prevalent obesity-related disease that affects large populations throughout the world due to excessive calorie intake and an increasingly sedentary lifestyle. Fibroblast growth factor 21 (FGF21) has recently emerged as a promising therapeutic candidate for the treatment of obesity and diabetes. FGF21 is a starvation-induced pleiotropic hormone with various beneficial metabolic effects, and pharmacological treatment in rodents has been shown to improve insulin sensitivity and decrease simple fatty liver disease...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27904474/poly-adp-ribose-polymerase-inhibition-reveals-a-potential-mechanism-to-promote-neuroprotection-and-treat-neuropathic-pain
#6
REVIEW
Prashanth Komirishetty, Aparna Areti, Ranadeep Gogoi, Ramakrishna Sistla, Ashutosh Kumar
Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death...
October 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27902689/using-intrinsic-flavoprotein-and-nad-p-h-imaging-to-map-functional-circuitry-in-the-main-olfactory-bulb
#7
Cedric R Uytingco, Adam C Puche, Steven D Munger
Neurons exhibit strong coupling of electrochemical and metabolic activity. Increases in intrinsic fluorescence from either oxidized flavoproteins or reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] in the mitochondria have been used as an indicator of neuronal activity for the functional mapping of neural circuits. However, this technique has not been used to investigate the flow of olfactory information within the circuitry of the main olfactory bulb (MOB). We found that intrinsic flavoprotein fluorescence signals induced by electrical stimulation of single glomeruli displayed biphasic responses within both the glomerular (GL) and external plexiform layers (EPL) of the MOB...
2016: PloS One
https://www.readbyqxmd.com/read/27900015/celastrol-negatively-regulates-cell-invasion-and-migration-ability-of-human-osteosarcoma-via-downregulation-of-the-pi3k-akt-nf-%C3%AE%C2%BAb-signaling-pathway-in-vitro
#8
Xiaolong Yu, Qiang Wang, Xin Zhou, Changlin Fu, Ming Cheng, Runsheng Guo, Hucheng Liu, Bin Zhang, Min Dai
Osteosarcoma (OS) is a primary malignant tumor of the bone, with a tendency to metastasize early. Despite the advances in treatment options, more than 30% of patients develop distant metastases, and the prognosis of these patients with metastases is extremely poor. Celastrol has been demonstrated to manifest multiple pharmacological activities, including induction of apoptosis in numerous types of cancer cell lines. Our previous studies have also suggested that Celastrol is capable of inducing apoptosis of human osteosarcoma cells via the mitochondrial-dependent pathway...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27898069/clozapine-modifies-the-differentiation-program-of-human-adipocytes-inducing-browning
#9
E Kristóf, Q-M Doan-Xuan, A K Sárvári, Á Klusóczki, P Fischer-Posovszky, M Wabitsch, Z Bacso, P Bai, Z Balajthy, L Fésüs
Administration of second-generation antipsychotic drugs (SGAs) often leads to weight gain and consequent cardio-metabolic side effects. We observed that clozapine but not six other antipsychotic drugs reprogrammed the gene expression pattern of differentiating human adipocytes ex vivo, leading to an elevated expression of the browning marker gene UCP1, more and smaller lipid droplets and more mitochondrial DNA than in the untreated white adipocytes. Laser scanning cytometry showed that up to 40% of the differentiating single primary and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes had the characteristic morphological features of browning cells...
November 29, 2016: Translational Psychiatry
https://www.readbyqxmd.com/read/27897416/curcumin-an-effective-adjunct-in-patients-with-statin-associated-muscle-symptoms
#10
REVIEW
Amirhossein Sahebkar, Nikou Saboni, Matteo Pirro, Maciej Banach
In spite of the unequivocal efficacy of statins in reducing primary and secondary cardiovascular events, the use of these drugs in a considerable number of patients is limited because of statin intolerance, mainly statin-associated muscle symptoms (SAMS). SAMS encompass a broad spectrum of clinical presentations, including mild muscular aching and other types of myalgias, myopathy with the significant elevation of creatine kinase, and the rare but life-threatening rhabdomyolysis. Among several pathophysiologic mechanisms of SAMS, mitochondrial dysfunction is thought to be one of the main one...
September 22, 2016: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/27896594/global-cerebral-ischemia-due-to-circulatory-arrest-insights-into-cellular-pathophysiology-and-diagnostic-modalities
#11
REVIEW
Santosh K Sanganalmath, Purva Gopal, John R Parker, Richard K Downs, Joseph C Parker, Buddhadeb Dawn
Circulatory arrest (CA) remains a major unresolved public health problem in the United States; the annual incidence of which is ~0.50 to 0.55 per 1000 population. Despite seminal advances in therapeutic approaches over the past several decades, brain injury continues to be the leading cause of morbidity and mortality after CA. In brief, CA typically results in global cerebral ischemia leading to delayed neuronal death in the hippocampal pyramidal cells as well as in the cortical layers. The dynamic changes occurring in neurons after CA are still unclear, and predicting these neurological changes in the brain still remains a difficult issue...
November 28, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27895577/fus1-ko-mouse-as-a-model-of-oxidative-stress-mediated-sporadic-alzheimer-s-disease-circadian-disruption-and-long-term-spatial-and-olfactory-memory-impairments
#12
Guillermo Coronas-Samano, Keeley L Baker, Winston J T Tan, Alla V Ivanova, Justus V Verhagen
Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology...
2016: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/27894066/obesity-associated-extracellular-mtdna-activates-central-tgf%C3%AE-pathway-to-cause-blood-pressure-increase
#13
Alberto Ale, Yalin Zhang, Cheng Han, Dongsheng Cai
Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid, and that central delivery of mtDNA mimics TGFβ excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ are both sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in pro-opiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout...
November 15, 2016: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27890875/induction-of-apoptosis-by-ethanol-extract-of-evodia-rutaecarpa-in-hela-human-cervical-cancer-cells-via-activation-of-amp-activated-protein-kinase
#14
Seon Young Park, Cheol Park, Shin-Hyung Park, Su-Hyun Hong, Gi-Young Kim, Sang Hoon Hong, Yung-Hyun Choi
The fruit of Evodia rutaecarpa (Juss.) Benth has been used widely in traditional medicine therapy. Although it has been shown to possess many pharmacological activities, the molecular mechanisms of its anti-cancer activity have not been clearly elucidated. In the present study, we investigated the pro-apoptotic effects of an ethanol extract isolated from immature fruits of E. rutaecarpa (EEER) in HeLa human cervical cancer cells. EEER treatment decreased the cell viability of HeLa cells in a concentration-dependent manner, which was related to apoptotic cell death resulting from apoptotic body formation, DNA fragmentation, and an increased population of annexin V(+)-positive cells...
November 27, 2016: Bioscience Trends
https://www.readbyqxmd.com/read/27890727/synthetic-tambjamine-analogues-induce-mitochondrial-swelling-and-lysosomal-dysfunction-leading-to-autophagy-blockade-and-necrotic-cell-death-in-lung-cancer
#15
Ananda M Rodilla, Luís Korrodi-Gregório, Elsa Hernando, Pilar Manuel-Manresa, Roberto Quesada, Ricardo Pérez-Tomás, Vanessa Soto-Cerrato
Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with innovative mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favours cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as novel antitumour drugs...
November 24, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27889640/inhibition-of-autophagy-with-bafilomycin-and-chloroquine-decreases-mitochondrial-quality-and-bioenergetic-function-in-primary-neurons
#16
Matthew Redmann, Gloria A Benavides, Taylor F Berryhill, Willayat Y Wani, Xiaosen Ouyang, Michelle S Johnson, Saranya Ravi, Stephen Barnes, Victor M Darley-Usmar, Jianhua Zhang
Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms. Since it is now clear that mitochondrial quality control, particularly in neurons, is dependent on autophagy, it is important to determine whether these compounds modify cellular bioenergetics...
November 18, 2016: Redox Biology
https://www.readbyqxmd.com/read/27885630/vesicular-glutamate-uptake
#17
Tetsufumi Ueda
Glutamate is an excitatory neurotransmitter widely used in the vertebrate central nervous systems. The synaptic transmission process is characterized by three steps: (1) presynaptic vesicular transmitter uptake, (2) presynaptic release, and (3) postsynaptic receptor activation. Presynaptic vesicular glutamate uptake plays an initial pivotal role in glutamate transmission by concentrating glutamate in the vesicular lumen prior to its release. This active glutamate transport harnesses energy derived from ATP hydrolysis, and intra- or extravesicular chloride, and is highly specific to glutamate...
2016: Advances in Neurobiology
https://www.readbyqxmd.com/read/27879319/amp-activated-kinase-ampk-promotes-innate-immunity-and-antiviral-defense-through-modulation-of-stimulator-of-interferon-genes-sting-signaling
#18
Daniel Prantner, Darren J Perkins, Stefanie N Vogel
The host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-beta induction independently of ATP synthesis. Since mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined...
November 22, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27878299/antioxidant-and-antitumor-activities-of-capparis-spinosa-l-and-the-related-mechanisms
#19
Lei Yu, Jinghhui Yang, Xin Wang, Bo Jiang, Yongxue Sun, Yubin Ji
The 'ethnodrug' Capparis spinosa L. has several pharmacological activities. First, it was found in previous experiments that an ethyl acetate extract of Capparis spinosa L. (CSE) exhibited antioxidant activity. In order to further research this finding, the present study investigate the blood biochemical indices, injury, energy metabolism, oxidative damage and mitochondrial membrane potential (Δψm) level of cardiac cells to study the effect of CSE on doxorubicin-induced cardiac toxicity. CSE had protective effects on the cardiac toxic effect of doxorubicin, and decreased the activity of lactic dehydrogenase (LDH) and creatine kinase (CK)...
November 16, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27876411/disruption-of-mitochondrial-quality-control-in-peripheral-artery-disease-new-therapeutic-opportunities
#20
REVIEW
Cintia B Ueta, Katia S Gomes, Márcio A Ribeiro, Daria Mochly-Rosen, Julio C B Ferreira
Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increases blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase...
November 19, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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