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dichloroacetate

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https://www.readbyqxmd.com/read/28915065/targeting-hif-1%C3%AE-pdk1-axis-by-dichloroacetate-dca-suppresses-bleomycin-induced-pulmonary-fibrosis
#1
Justin Goodwin, Hyunsung Choi, Meng-Hsiung Hsieh, Michael L Neugent, Jung-Mo Ahn, Heather N Hayenga, Pankaj K Singh, David B Shackelford, In-Kyu Lee, Vladimir Shulaev, Shanta Dhar, Norihiko Takeda, Jung-Whan Kim
RATIONALE: Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences such as hypoxia contribute to their sustained activation and differentiation is poorly understood. OBJECTIVES: As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the pre-clinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis...
September 15, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28914978/model-informed-dose-optimization-of-dichloroacetate-for-the-treatment-of-congenital-lactic-acidosis-in-children
#2
Naveen Mangal, Margaret O James, Peter W Stacpoole, Stephan Schmidt
Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children...
September 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28881758/suppression-of-pyruvate-dehydrogenase-kinase-2-re-sensitizes-paclitaxel-resistant-human-lung-cancer-cells-to-paclitaxel
#3
Hong Sun, Anyou Zhu, Xiang Zhou, Fengchao Wang
Despite impressive initial clinical responses, the majority of lung cancer patients treated with paclitaxel eventually develop resistance to the drug. Pyruvate dehydrogenase kinase-2 (PDK2) is a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumors. In this study, the role of PDK2 in mediating paclitaxel resistance in lung cancer cells was investigated using biochemical and isotopic tracing methods. Increased expression of PDK2 was observed in paclitaxel-resistant cells ascompared totheir parental cells...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881683/inhibition-of-cox2-enhances-the-chemosensitivity-of-dichloroacetate-in-cervical-cancer-cells
#4
Bo Li, Xinzhe Li, Haojun Xiong, Peng Zhou, Zhenhong Ni, Teng Yang, Yan Zhang, Yijun Zeng, Jintao He, Fan Yang, Nan Zhang, Yuting Wang, Yingru Zheng, Fengtian He
Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881665/hpv-associated-differential-regulation-of-tumor-metabolism-in-oropharyngeal-head-and-neck-cancer
#5
Young-Suk Jung, Abdo J Najy, Wei Huang, Seema Sethi, Michael Snyder, Wael Sakr, Gregory Dyson, Maik Hüttemann, Icksoo Lee, Rouba Ali-Fehmi, Silvia Franceschi, Linda Struijk, Harold E Kim, Ikuko Kato, Hyeong-Reh Choi Kim
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878225/the-pdk1-inhibitor-dichloroacetate-controls-cholesterol-homeostasis-through-the-erk5-mef2-pathway
#6
Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Sabine Gerbal-Chaloin, Claire Gondeau, Dang-Nghiem Vo, Sana Belkahla, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Milica Bozic, Jose M Valdivielso, Fabienne Bejjani, Isabelle Jariel, Isabel C Lopez-Mejia, Lluis Fajas, Charles-Henri Lecellier, Javier Hernandez, Martine Daujat, Martin Villalba
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870456/pharmacological-synergism-of-2-2-dichloroacetophenone-and-egfr-tki-to-overcome-tki-induced-resistance-in-nsclc-cells
#7
Zheng Yang, Xiaohui Hu, Shaolin Zhang, Wen Zhang, Kin Yip Tam
Combination treatment has been used as one of the therapeutic approaches for patients suffering from lung cancer, either to cope with the issue of acquired drug resistance due to prolong the use of a particular EGFR-TKi treatment, or to decrease the doses of each compound in order to reduce potential toxicity. 2,2-dichloroacetophenone (DAP) was reported as a PDK inhibitor recently, which is much more potent than dichloroacetate (DCA) in anti-cancer therapy. In this study, we applied DAP in combined with EGFR-TKis, erlotinib or gefitinib in NSCLC cell lines and NSCLC xenograft model...
September 11, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28847099/effect-of-ozonation-on-the-characteristics-of-effluent-organic-matter-fractions-and-subsequent-associations-with-disinfection-by-products-formation
#8
Weixiao Qi, Hua Zhang, Chengzhi Hu, Huijuan Liu, Jiuhui Qu
Ozonation could be used in advanced wastewater treatment plants to reduce the precursors of disinfection by-products (DBPs), or for disinfection and oxidation of trace organic compounds. Detailed analysis of effluent organic matter (EfOM) is intrinsic to the understanding of impact of ozonation on the characterization variation of EfOM, which is closely related with DBPs formation during subsequent chlorination. In this study, the raw as well as oxidized EfOM with ozone were fractionated into hydrophobic acids, neutrals and bases, and hydrophilic acids, neutrals and bases...
August 23, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28846566/activation-of-pyruvate-dehydrogenase-activity-bydichloroacetate-improves-survival-and-neurologic-outcomes-after-cardiac-arrest-in-rats
#9
Peng Wang, Mingdi Chen, Zhengfei Yang, Tao Yu, Jie Zhu, Lili Zhou, Jiali Lin, Xiangshao Fang, Zitong Huang, Longyuan Jiang, Wanchun Tang
No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which activates pyruvate dehydrogenase (PDH), and increases cell adenosine triphosphate (ATP) production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in an asphyxial cardiac arrest rat model. Asphyxial cardiac arrest was established by endotracheal tube clamping...
August 25, 2017: Shock
https://www.readbyqxmd.com/read/28783018/haloacetic-acids-degradation-by-an-efficient-ferrate-uv-process-byproduct-analysis-kinetic-study-and-application-of-response-surface-methodology-for-modeling-and-optimization
#10
Hassan Aslani, Simin Nasseri, Ramin Nabizadeh, Alireza Mesdaghinia, Mahmood Alimohammadi, Shahrokh Nazmara
Haloacetic acids (HAAs) after trihalomethanes are the second main group of chlorination byproducts. In this study, decomposition of the two most common HAAs in drinking water was studied by an advanced oxidation process using a combination of Ferrate [Fe(VI)] and UV irradiation. The decomposition rate was measured, and the byproducts formed during the process and the mass balances were also analyzed. HAAs were quantified by GC-ECD, and the final products including acetate and chloride ions were measured by ion chromatography (IC)...
August 3, 2017: Journal of Environmental Management
https://www.readbyqxmd.com/read/28774603/dbp-formation-from-degradation-of-deet-and-ibuprofen-by-uv-chlorine-process-and-subsequent-post-chlorination
#11
Ehsan Aghdam, Yingying Xiang, Jianliang Sun, Chii Shang, Xin Yang, Jingyun Fang
The formation of disinfection by-products (DBPs) from the degradation of N,N-diethyl-3-methyl benzoyl amide (DEET) and ibuprofen (IBP) by the ultraviolet irradiation (UV)/chlorine process and subsequent post-chlorination was investigated and compared with the UV/H2O2 process. The pseudo first-order rate constants of the degradation of DEET and IBP by the UV/chlorine process were 2 and 3.1 times higher than those by the UV/H2O2 process, respectively, under the tested conditions. This was due to the significant contributions of both reactive chlorine species (RCS) and hydroxyl radicals (HO) in the UV/chlorine process...
August 2017: Journal of Environmental Sciences (China)
https://www.readbyqxmd.com/read/28714513/in-vivo-evaluation-of-tumour-acidosis-for-assessing-the-early-metabolic-response-and-onset-of-resistance-to-dichloroacetate-by-using-magnetic-resonance-ph-imaging
#12
Annasofia Anemone, Lorena Consolino, Laura Conti, Francesca Reineri, Federica Cavallo, Silvio Aime, Dario Livio Longo
Dichloroacetate (DCA) can reverse the glycolytic phenotype that is responsible of increased lactate production and extracellular pH acidification in cancer cells. Magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) pH mapping is a novel non-invasive imaging approach that can measure in vivo extracellular tumour pH. We examined whether MRI-CEST pH mapping can monitor in vivo changes in tumour acidosis for assessing treatment response to DCA. Cell viability and extracellular pH were assessed in TS/A breast cancer cells treated with 1-10 mM DCA for 24 h in normoxia or hypoxia (1% O2) conditions...
August 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28672704/control-of-disinfection-byproducts-dbps-by-ozonation-and-peroxone-process-role-of-chloride-on-removal-of-dbp-precursors
#13
Popta Deeudomwongsa, Songkeart Phattarapattamawong, Kun-Yi Andrew Lin
The objective of this study was to remove regulated DBP precursors by using ozonation and peroxone process (H2O2/O3). Regarding formation potentials of trihalomethanes (THMs) and haloacetic acids (HAAs), the role of chloride in chlorination and ozonation/peroxone processes was revealed. The organic compounds in water samples from rapid sand filtration preferably yielded the THM formation potentials, rather than HAAs. Ozonation with the typical applied doses (1-5 mg L(-1)) was ineffective for removals of THM and HAA precursors...
October 2017: Chemosphere
https://www.readbyqxmd.com/read/28654916/inhibition-of-cox2-enhances-the-chemosensitivity-of-dichloroacetate-in-cervical-cancer-cells
#14
Bo Li, Xinzhe Li, Haojun Xiong, Peng Zhou, Zhenhong Ni, Teng Yang, Yan Zhang, Yijun Zeng, Jintao He, Fan Yang, Nan Zhang, Yuting Wang, Yingru Zheng, Fengtian He
Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28644886/complex-i-inhibition-augments-dichloroacetate-cytotoxicity-through-enhancing-oxidative-stress-in-vm-m3-glioblastoma-cells
#15
Nathan P Ward, Angela M Poff, Andrew P Koutnik, Dominic P D'Agostino
The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin's reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM-M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination...
2017: PloS One
https://www.readbyqxmd.com/read/28611197/treatment-of-pancreatic-cancer-patient-derived-xenograft-panel-with-metabolic-inhibitors-reveals-efficacy-of-phenformin
#16
N V Rajeshkumar, Shinichi Yabuuchi, Shweta G Pai, Elizabeth De Oliveira, Jurre J Kamphorst, Joshua D Rabinowitz, Héctor Tejero, Fátima Al-Shahrour, Manuel Hidalgo, Anirban Maitra, Chi V Dang
Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin...
June 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28591165/dichloroacetate-affects-proliferation-but-not-apoptosis-in-canine-mammary-cell-lines
#17
Tatjana P Harting, Mandy Stubbendorff, Susanne C Hammer, Patrik Schadzek, Anaclet Ngezahayo, Hugo Murua Escobar, Ingo Nolte
Targeting mitochondrial energy metabolism is a novel approach in cancer research and can be traced back to the description of the Warburg effect. Dichloroacetate, a controversially discussed subject of many studies in cancer research, is a pyruvate dehydrogenase kinase inhibitor. Dichloroacetate causes metabolic changes in cancerous glycolysis towards oxidative phosphorylation via indirect activation of pyruvate dehydrogenase in mitochondria. Canine mammary cancer is frequently diagnosed but after therapy prognosis still remains poor...
2017: PloS One
https://www.readbyqxmd.com/read/28574836/hpv-associated-differential-regulation-of-tumor-metabolism-in-oropharyngeal-head-and-neck-cancer
#18
Young-Suk Jung, Abdo J Najy, Wei Huang, Seema Sethi, Michael Snyder, Wael Sakr, Gregory Dyson, Maik Hüttemann, Icksoo Lee, Rouba Ali-Fehmi, Silvia Franceschi, Linda Struijk, Harold E Kim, Ikuko Kato, Hyeong-Reh Choi Kim
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28572638/mitochondrial-targeting-by-dichloroacetate-improves-outcome-following-hemorrhagic-shock
#19
Kumar Subramani, Sumin Lu, Marie Warren, Xiaogang Chu, Haroldo A Toque, R William Caldwell, Michael P Diamond, Raghavan Raju
Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA...
June 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28531123/evaluation-of-drinking-water-disinfectant-byproducts-compliance-data-as-an-indirect-measure-for-short-term-exposure-in-humans
#20
Shahid Parvez, Kali Frost, Madhura Sundararajan
In the absence of shorter term disinfectant byproducts (DBPs) data on regulated Trihalomethanes (THMs) and Haloacetic acids (HAAs), epidemiologists and risk assessors have used long-term annual compliance (LRAA) or quarterly (QA) data to evaluate the association between DBP exposure and adverse birth outcomes, which resulted in inconclusive findings. Therefore, we evaluated the reliability of using long-term LRAA and QA data as an indirect measure for short-term exposure. Short-term residential tap water samples were collected in peak DBP months (May-August) in a community water system with five separate treatment stations and were sourced from surface or groundwater...
May 20, 2017: International Journal of Environmental Research and Public Health
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