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Mitochondrial pharmacology

Margaret O James, Stephan C Jahn, Guo Zhong, Marci G Smeltz, Zhiwei Hu, Peter W Stacpoole
Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen...
October 19, 2016: Pharmacology & Therapeutics
Wilfried Dinh, Barbara Albrecht-Küpper, Mihai Gheorghiade, Adriaan A Voors, Michael van der Laan, Hani N Sabbah
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels...
October 22, 2016: Handbook of Experimental Pharmacology
Yanyan Zheng, Li Zhu, Lulu Fan, Wenna Zhao, Jianlong Wang, Xianxiao Hao, Yunhui Zhu, Xiufang Hu, Yaofeng Yuan, Jingwei Shao, Wenfeng Wang
Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability...
October 7, 2016: European Journal of Medicinal Chemistry
Erik Norberg, Ana Lako, Pei-Hsuan Chen, Illana A Stanley, Feng Zhou, Scott B Ficarro, Bjoern Chapuy, Linfeng Chen, Scott Rodig, Donghyuk Shin, Dong Wook Choi, Sangho Lee, Margaret A Shipp, Jarrod A Marto, Nika N Danial
Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components...
October 21, 2016: Cell Death and Differentiation
Karolina Niska, Narcyz Knap, Anna Kędzia, Maciej Jaskiewicz, Wojciech Kamysz, Iwona Inkielewicz-Stepniak
Objectives: In dentistry, silver nanoparticles (AgNPs) have drawn particular attention because of their wide antimicrobial activity spectrum. However, controversial information on AgNPs toxicity limited their use in oral infections. Therefore, the aim of the present study was to evaluate the antibacterial activities against a panel of oral pathogenic bacteria and bacterial biofilms together with potential cytotoxic effects on human gingival fibroblasts of 10 nm AgNPs: non-functionalized - uncapped (AgNPs-UC) as well as surface-functionalized with capping agent: lipoic acid (AgNPs-LA), polyethylene glycol (AgNPs-PEG) or tannic acid (AgNPs-TA) using silver nitrate (AgNO3) as control...
2016: International Journal of Medical Sciences
Ruijie Zhang, Nana Zhang, Hai Zhang, Chunxiao Liu, Xiaoqing Dong, Xiaoxue Wang, Yu Zhu, Chong Xu, Lei Liu, Sijun Yang, Shile Huang, Long Chen
BACKGROUND AND PURPOSE: Increasing evidence has suggested cadmium (Cd), as an inducer of reactive oxygen species (ROS), is a potential pathogenic factor in human neurodegenerative diseases. Thus, it is important to find effective interventions for Cd-induced oxidative stress in the central nervous system. The purpose of this study was to determine whether and how celastrol, a plant-derived triterpene, could mitigate Cd-induced ROS and cell death in neuronal cells. EXPERIMENTAL APPROACH: PC12, SH-SY5Y cells and primary murine neurons were chosen as a model to study celastrol neuroprotection against Cd-poisoning...
October 20, 2016: British Journal of Pharmacology
Marie Jazzara, Ahmed Ghannam, Chadi Soukkarieh, Hossam Murad
BACKGROUND: Sulfated Polysaccharides (SPs) possess spectrum of pharmacological and therapeutic properties that could attributed to their origins variation, chemical structures and biological activities. Various studies have shown the impact of SPs on proliferation in different cancer cell lines. OBJECTIVES: In this study, we have evaluated the biological effects of λ-carrageenan, a highly SP, extracted from the red seaweed Laurencia papillosa, on MDA-MB-231 cancer cell line...
August 2016: Iranian Journal of Cancer Prevention
Xiaopeng Zhu, Hua Bian, Xin Gao
Nonalcoholic fatty liver disease (NAFLD) is a globally observed metabolic disease with high prevalence both in adults and children. However, there is no efficient medication available yet. Increased evidence indicates that berberine (BBR), a natural plant product, has beneficial effects on NAFLD, though the mechanisms are not completely known. In this review, we briefly summarize the pathogenesis of NAFLD and factors that influence the progression of NAFLD, and focus on the potential mechanisms of BBR in the treatment of NAFLD...
October 14, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Wenwen Wang, Yanqin Yang, Zhewen Xiong, Jiamin Kong, Xinlu Fu, Feihai Shen, Zhiying Huang
Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes...
October 14, 2016: Toxicology and Applied Pharmacology
Xia Zhang, Jingyu Hu, Yan Chen
Betulinic acid (BA), a lupane-type pentacyclic triterpenoid saponin from tree bark, has the potential to induce the apoptosis of cancer cells without toxicity towards normal cells in vitro and in vivo. The antitumor pharmacological effects of BA consist of triggering apoptosis via the mitochondrial pathway, regulating the cell cycle and the angiogenic pathway via factors, including specificity protein transcription factors, cyclin D1 and epidermal growth factor receptor, inhibiting the signal transducer and activator of transcription 3 and nuclear factor‑κB signaling pathways, preventing the invasion and metastasis of tumor cells, and affecting the expression of topoisomerase I, p53 and lamin B1...
October 4, 2016: Molecular Medicine Reports
Liying Guo, Kai Tan, Hao Wang, Xuan Zhang
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second cause of cancer-related deaths around the world. Pterostilbene (PTE), is a natural analog of resveratrol, possessing diverse pharmacological activities. In the present study, we aimed to examine the effect of PTE on tumor growth in mouse models of HCC and to elucidate the possible molecular mechanism in vivo and in vitro. We showed that PTE dose-dependently suppressed tumor growth in mice induced by diethylnitrosamine plus carbon tetrachloride, as evidenced by a decrease in the number of tumors and in the maximum size of the tumors...
October 5, 2016: Oncology Reports
Adrienne Wang, Jacob Mouser, Jason Pitt, Daniel Promislow, Matt Kaeberlein
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS...
October 11, 2016: Oncotarget
Sonia Goineau, Vincent Castagné
Gastric mucosa is frequently exposed to various gastric irritants and there is a continuing requirement to develop new gastro-protective agents. The present study compares the effects of three such agents, sucralfate, rebamipide and cimetidine in both in vivo and in vitro indomethacin-induced gastric damage models. For the in vivo approach, rats were orally administered sucralfate, rebamipide and cimetidine at 300 mg/kg before an acute dose of indomethacin (30 mg/kg). Gastric lesions were then macroscopically examined...
October 14, 2016: Fundamental & Clinical Pharmacology
Marina Villanueva-Paz, Mario D Cordero, Ana Delgado Pavón, Beatriz Castejón Vega, David Cotán, Mario De la Mata, Manuel Oropesa-Ávila, Elizabet Alcocer-Gomez, Isabel de Lavera, Juan Garrido-Maraver, José Carrascosa, Ana Paula Zaderenko, Jordi Muntané, Manuel de Miguel, José Antonio Sánchez-Alcázar
Systemic treatments for hepatocellular carcinoma (HCC) have been largely unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved early mitophagy activation that subsequently switched to apoptosis. Amitriptyline induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibited mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (∆Ψm) and increased reactive oxygen species (ROS) production...
July 2016: Genes & Cancer
Upendarrao Golla, Deepthi Joseph, Raghuvir Singh Tomar
Valproic acid (VA) is a pharmacologically important histone deacetylase inhibitor that recently garnered attention as an anticancer agent. Since the molecular mechanisms behind the multiple effects of VA are unclear, this study was aimed to unravel the comprehensive cellular processes affected by VA and its molecular targets in vivo using budding yeast as a model organism. Interestingly, genome-wide transcriptome analysis of cells treated with VA showed differential regulation of 30% of the genome. Functional enrichment analysis of VA transcriptome evidenced alteration of various cellular processes including cell cycle, cell wall biogenesis, DNA repair, ion homeostasis, metabolism, stress response, transport and ribosomal biogenesis, etc...
October 13, 2016: Scientific Reports
Suriyan Ponnusamy, Quynh T Tran, Innocence Harvey, Heather S Smallwood, Thirumagal Thiyagarajan, Souvik Banerjee, Daniel L Johnson, James T Dalton, Ryan D Sullivan, Duane D Miller, Dave Bridges, Ramesh Narayanan
Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands...
October 12, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Zachary S Bailey, Eric Nilson, John Bates, Adewole Oyalowo, Kevin S Hockey, Sujith Sajja, Chevon Thorpe, Heidi Rogers, Bryce Dunn, Aaron S Frey, Marc J Billings, Christopher A Sholar, Amy Hermundstad, Challa Kumar, Pamela J VandeVord, Beverly A Rzigalinski
Mild traumatic brain injury results in aberrant free radical generation, which is associated with oxidative stress, secondary injury signaling cascades, mitochondrial dysfunction, and poor functional outcome. Pharmacological targeting of free radicals with antioxidants has been examined as an approach for treatment, but has met with limited success. Conventional antioxidants currently available scavenge a single free radical, before they are destroyed in the process. Here, we report for the first time, that a novel regenerative cerium oxide nanoparticle antioxidant reduces neuronal death and calcium dysregulation after in vitro trauma...
October 12, 2016: Journal of Neurotrauma
Kaname Akamata, Jun Wei, Mitra Bhattacharyya, Paul Cheresh, Michael Y Bonner, Jack L Arbiser, Kirtee Raparia, Mahesh P Gupta, David W Kamp, John Varga
Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts...
October 6, 2016: Oncotarget
Izaskun Buendia, Giammarco Tenti, Patrycja Michalska, Iago Méndez-López, Enrique Luengo, Michele Satriani, Juan Fernando Padin Nogueira, Manuela G López, María Teresa Ramos, Antonio G García, J Carlos Menéndez, Rafael León
During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets...
October 12, 2016: ACS Chemical Neuroscience
H Abdul Jaffarali, Soban Akram, Kaleem Ml Arshan
DNA barcoding involving the sequencing of a short mitochondrial DNA segment, cytochrome c oxidase subunit 1 (COI) gene, is a specialized technique for the identification of species even at the early embryonic and larval stages, which is quite difficult in morphology-based taxonomy. Ascidians are sessile invertebrate chordates possessing numerous biochemical as well as pharmacological activities. In this study, a total of 36 ascidian samples belonging to the family Didemnidae were sequenced for a 650 bp region of the mitochondrial COI gene...
October 11, 2016: Mitochondrial DNA. Part A. DNA Mapping, Sequencing, and Analysis
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