Journal articles: 'Metabolic inhibition'

1

Lee, Sung Ryul, and Jin Han. "Mitochondrial Metabolic Inhibition and Cardioprotection." Korean Circulation Journal 47, no. 2 (2017): 168. http://dx.doi.org/10.4070/kcj.2016.0401.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Delius, Ralph E., and Daniel B. Hinshaw. "Metabolic inhibition potentiates oxidant injury." Journal of Surgical Research 50, no. 4 (April 1991): 314–22. http://dx.doi.org/10.1016/0022-4804(91)90197-t.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Zhang, Yiru, Trang Nguyen, Junfei Zhao, Enyuan Shang, Consuelo Torrini, Peter D. Canoll, Georg Karpel-Massler, and Markus Siegelin. "CBMT-15. MET INHIBITION DRIVES PGC1A DEPENDENT METABOLIC REPROGRAMMING AND ELICITS UNIQUE METABOLIC VULNERABILITIES IN GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi36. http://dx.doi.org/10.1093/neuonc/noz175.137.

Full text

Abstract:

Abstract The receptor kinase, c-MET, has emerged as a target for glioblastoma therapy. However, treatment resistance evolves inevitably. By performing a global metabolite screen with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, we have identified substantial reprogramming of tumor metabolism, involving oxidative phosphorylation and fatty acid oxidation (FAO) with a substantial accumulation of acyl-carnitines accompanied by an increase of PGC1a in response to genetic (shRNA and CRISPR/Cas9) and pharmacological (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-Glucose and U-13C-Glutamine) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species (ROS). Genetic interference with PGC1a rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that CREB regulates the expression of PGC1a in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and beta-oxidation of fatty acids (etomoxir) enhanced the anti-tumor efficacy of c-MET inhibition. Moreover, based on a high-throughput drug screen, we show that gamitrinib along with c-MET inhibition results in synergistic cell death. Finally, utilizing patient-derived xenograft models, we provide evidence that the combination treatments (crizotinib+etomoxir and crizotinib+gamitrinib) were significantly more efficacious than single treatment without induction of toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibitor treatment and identified novel combination therapies that may enhance the therapeutic efficacy of c-MET inhibition.

APA, Harvard, Vancouver, ISO, and other styles

4

Riley, Robert J., and Ken Grime. "Metabolic screening in vitro: metabolic stability, CYP inhibition and induction." Drug Discovery Today: Technologies 1, no. 4 (December 2004): 365–72. http://dx.doi.org/10.1016/j.ddtec.2004.10.008.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Falezza, A., S. Cinelli, P. Ciliutti, and J. A. Vericat. "Metabolic activation in the inhibition of the metabolic cooperation assay." Mutation Research/Environmental Mutagenesis and Related Subjects 271, no. 2 (1992): 161. http://dx.doi.org/10.1016/0165-1161(92)91193-u.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Funaki, Tomoo, Hideo Fukazawa, and Isami Kuruma. "Metabolic Kinetics of Nonproductive Binding Inhibition." Journal of Pharmaceutical Sciences 83, no. 8 (August 1994): 1181–83. http://dx.doi.org/10.1002/jps.2600830820.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Loch‐Caruso, Rita, Isabel A. Corcos, and James E. Trosko. "Inhibition of metabolic coupling by metals." Journal of Toxicology and Environmental Health 32, no. 1 (January 1991): 33–48. http://dx.doi.org/10.1080/15287399109531463.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Zarrinpar, Ali. "Metabolic Pathway Inhibition in Liver Cancer." SLAS TECHNOLOGY: Translating Life Sciences Innovation 22, no. 3 (March 17, 2017): 237–44. http://dx.doi.org/10.1177/2472630317698683.

Full text

Abstract:

Liver cancer is fundamentally physiologically different from the surrounding liver tissue. Despite multiple efforts to target the altered signaling pathways created by oncogenic mutations, not many have focused on targeting the altered metabolism that allows liver cancer to develop and grow. Still to be resolved is the question of whether the altered metabolic pathways in this cancer differ enough from the surrounding noncancerous cells to allow for the development of potent and specific compounds. Clinical studies of metabolic modulators would provide some more information with regard to the feasibility of this approach. Furthermore, as it appears that oncogenic signaling is essential to this cancer’s altered metabolism, it stands to reason that targeting this altered signaling may allow the exploitation of specific metabolic vulnerabilities in combination with other drugs for enhanced efficacy. The identification of biomarkers of metabolic sensitivity will also be essential to determine whether these drugs will have the desired effect.

APA, Harvard, Vancouver, ISO, and other styles

9

Thibonnier, Marc, and Christine Esau. "Metabolic Benefits of MicroRNA-22 Inhibition." Nucleic Acid Therapeutics 30, no. 2 (April 1, 2020): 104–16. http://dx.doi.org/10.1089/nat.2019.0820.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Fern, Robert. "Metabolic Inhibition and Selective Axonal Injury." Neuroscientist 2, no. 6 (November 1996): 313–14. http://dx.doi.org/10.1177/107385849600200608.

Full text

Abstract:

The selective injury of CNS axons produced by exposure to Cd2+, an environmental contaminant, is a result of disruption of mitochondrial respiration (oxidative phosphorylation). An examination of the literature reveals some other poisons that have a similar effect upon oxidative phosphorylation and that also produce CNS lesions typified by damage of axons with selective sparing of neurons. These include cyanide, CO, CS2, arsenic, and azide. The neurological injuries produced by these toxins appear to constitute a distinct class of pathology in which axonal injury is dominant. Such an observation is paradoxical, considering that ischemia tends to produce selective injury of neurons with relative sparing of axons, the mirror image of the injury associated with disruption of oxidative phosphorylation by these toxins. This paradox may be resolved by considering the extent to which energy utilization is disrupted during these two classes of metabolic insult. It appears likely that low levels of cytochrome oxidase, which is required for oxidative phosphorylation, endow white matter with a relatively high sensitivity to insults that disrupt oxidative phosphorylation.

APA, Harvard, Vancouver, ISO, and other styles

11

ZIEGELSTEIN, R. "Endothelial calcium regulation during metabolic inhibition." Journal of Molecular and Cellular Cardiology 24 (June 1992): S63. http://dx.doi.org/10.1016/0022-2828(92)93043-j.

Full text

APA, Harvard, Vancouver, ISO, and other styles

12

Larion, Mioara, and Victor Ruiz-Rodado. "DDRE-01. METABOLIC PLASTICITY AND HETEROGENEITY IN IDH1MUT CELL LINES PRODUCES RESISTANCE TO GLUTAMINASE INHIBITION BY CB839." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i6. http://dx.doi.org/10.1093/noajnl/vdab024.023.

Full text

Abstract:

Abstract BACKGROUND Mutant IDH1 (IDH1mut) gliomas have characteristic genetic and metabolic profiles and exhibit phenotype that is distinct from their wild-type counterparts. The glutamine/glutamate pathway has been hypothesized as a selective therapeutic target in IDH1mut gliomas. However, little information exists on the contribution of this pathway to the formation of D-2-hydroxyglutarate (D-2HG), a hallmark of IDHmut cells, and the metabolic consequences of inhibiting this pathway. METHODS We employed an untargeted metabolic profiling approach in order to detect metabolic changes arising from glutaminase (GLS) inhibition treatment. Subsequently, 13C metabolic tracing analysis through a combined Nuclear Magnetic Resonance and Liquid Chromatography-Mass Spectrometry approach, we explored the fate of glutamine and glucose under treatment with CB839 a glutaminase-GLS-inhibitor and their respective contributions to D-2HG formation. RESULTS AND CONCLUSIONS The effects of CB839 on cellular proliferation differed among the cell lines tested, leading to designations of GLS-inhibition super-sensitive, -sensitive or -resistant. Our data indicates a decrease in the production of downstream metabolites of glutamate, including those involved in the TCA cycle, when treating the sensitive cells with CB839 (glutaminase -GLS- inhibitor). Notably, CB839-sensitive IDH1mutcells respond to GLS inhibition by upregulating glycolysis and lactate production. In contrast, CB839-resistantIDH1mut cell lines do not rely only on glutamine for the sustenance of TCA cycle. In these cells, glucose contribution to TCA is enough to compensate the downregulation of glutamine-derived TCA metabolites. This investigation reveals that the glutamine/glutamate pathway contributes differentially to D-2HG in a cell-line dependent fashion on a panel of IDHmut cell lines. Further, these results demonstrate that there is a heterogeneous landscape of IDH1mut metabolic phenotypes. This underscores the importance of detailed metabolic profiling of IDH1mut patients prior to the decision to target glutamine/glutamate pathway clinically.

APA, Harvard, Vancouver, ISO, and other styles

13

Ramasamy, Ravichandran, Nathan Trueblood, and Saul Schaefer. "Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 1 (July 1, 1998): H195—H203. http://dx.doi.org/10.1152/ajpheart.1998.275.1.h195.

Full text

Abstract:

Several studies have shown that maintenance of glycolysis limits the metabolic and functional consequences of low-flow ischemia. Because diabetic animals are known to have impaired glycolytic metabolism coupled with increased flux through the aldose reductase (AR) pathway, we hypothesized that inhibition of AR would enhance glycolysis and thereby improve metabolic and functional recovery during low-flow ischemia. Hearts ( n = 12) from nondiabetic control and diabetic rats were isolated and retrograde perfused using 11 mM glucose with or without the AR inhibitor zopolrestat (1 μM). Hearts were subjected to 30 min of low-flow ischemia (10% of baseline flow) and 30 min of reperfusion.31P NMR spectroscopy was used to monitor time-dependent changes in phosphocreatine (PCr), ATP, and intracellular pH. Changes in the cytosolic redox ratio of NADH to NAD+ were obtained by measuring the ratio of tissue lactate to pyruvate. Effluent lactate concentrations and oxygen consumption were determined from the perfusate. AR inhibition improved functional recovery in both control and diabetic hearts, coupled with a lower cytosolic redox state and greater effluent lactate concentrations during ischemia. ATP levels during ischemia were significantly higher in AR-inhibited hearts, as was recovery of PCr. In diabetic hearts, AR inhibition also limited acidosis during ischemia and normalized pH recovery on reperfusion. These data demonstrate that AR inhibition maintains higher levels of high-energy phosphates and improves functional recovery upon reperfusion in hearts subjected to low-flow ischemia, consistent with an increase in glycolysis. Accordingly, this approach of inhibiting AR offers a novel method for protecting ischemic myocardium.

APA, Harvard, Vancouver, ISO, and other styles

14

Santiappillai, Nancy T., Shatha Abuhammad, Alison Slater, Laura Kirby, Grant A. McArthur, Karen E. Sheppard, and Lorey K. Smith. "CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway." Cancers 13, no. 3 (January 29, 2021): 524. http://dx.doi.org/10.3390/cancers13030524.

Full text

Abstract:

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

15

Hermanowski-Vosatka, Anne, James M. Balkovec, Kang Cheng, Howard Y. Chen, Melba Hernandez, Gloria C. Koo, Cheryl B. Le Grand, et al. "11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice." Journal of Experimental Medicine 202, no. 4 (August 15, 2005): 517–27. http://dx.doi.org/10.1084/jem.20050119.

Full text

Abstract:

The enzyme 11β–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11β-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11β-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11β-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11β-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.

APA, Harvard, Vancouver, ISO, and other styles

16

Pinedo-Carpio, Edgar, David Davidson, Veronica L. Martinez Marignac, Justin Panasci, and Raquel Aloyz. "Adaptive metabolic rewiring to chronic SFK inhibition." Oncotarget 8, no. 40 (March 17, 2016): 66758–68. http://dx.doi.org/10.18632/oncotarget.8146.

Full text

APA, Harvard, Vancouver, ISO, and other styles

17

Stefanovic, Bojana, Jan M. Warnking, and G. Bruce Pike. "Hemodynamic and metabolic responses to neuronal inhibition." NeuroImage 22, no. 2 (June 2004): 771–78. http://dx.doi.org/10.1016/j.neuroimage.2004.01.036.

Full text

APA, Harvard, Vancouver, ISO, and other styles

18

John, Scott A., Richard Kondo, Sheng-Yong Wang, Joshua I. Goldhaber, and James N. Weiss. "Connexin-43 Hemichannels Opened by Metabolic Inhibition." Journal of Biological Chemistry 274, no. 1 (January 1, 1999): 236–40. http://dx.doi.org/10.1074/jbc.274.1.236.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

WIERZBICKI, A. S. "Rimonabant: endocannabinoid inhibition for the metabolic syndrome." International Journal of Clinical Practice 60, no. 12 (November 10, 2006): 1697–706. http://dx.doi.org/10.1111/j.1742-1241.2006.01210.x.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Vélot, Christian, and Paul A. Srere. "Reversible Transdominant Inhibition of a Metabolic Pathway." Journal of Biological Chemistry 275, no. 17 (April 21, 2000): 12926–33. http://dx.doi.org/10.1074/jbc.275.17.12926.

Full text

APA, Harvard, Vancouver, ISO, and other styles

21

Taylor, Samuel J., and Ulrich Steidl. "Metabolic strugGLS after FLT3 inhibition in AML." Blood 131, no. 15 (April 12, 2018): 1631–32. http://dx.doi.org/10.1182/blood-2018-03-836338.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Wang, Huabo, Jie Lu, James Dolezal, Sucheta Kulkarni, Weiqi Zhang, Angel Chen, Joanna Gorka, Jordan A. Mandel, and Edward V. Prochownik. "Inhibition of hepatocellular carcinoma by metabolic normalization." PLOS ONE 14, no. 6 (June 26, 2019): e0218186. http://dx.doi.org/10.1371/journal.pone.0218186.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Krauß, P. L., F. Buttgereit, T. Gaber, M. Pfeiffenberger, Y. Chen, and T. Buttgereit. "AB0029 THE METABOLIC HIERARCHY OF IMMUNE PROCESSES IN HUMAN MONOCYTES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1048.2–1048. http://dx.doi.org/10.1136/annrheumdis-2021-eular.794.

Full text

Abstract:

Background:At sites of inflammation, monocytes carry out specific immunological functions while facing challenging bioenergetic restrictions.Objectives:Here, we investigated the potential of human monocytes to adapt under conditions of reduced energy supply by gradually inhibiting oxidative phosphorylation (OXPHOS) under glucose free conditions.Methods:We modelled this reduced energy supply with myxothiazol, an inhibitor of mitochondrial respiration, at 0, 2 and 4 pmol/106 cells to decrease mitochondrial ATP production for 0%, 25% and 66% under glucose free conditions. For the three energy levels, we assessed (i) phagocytosis of FITC-labelled E.coli using flow cytometry, (i) production of reactive oxygen species (ROS) through NADPH oxidase (NOX) as determined by VAS2870-sensitive OCR using a Clark-type electrode, (iii) ATP generation and steady state level using a Clark-type electrode and luminometric assessment (iv) expression of surface activation markers CD16, CD80, CD11b, HLA-DR and (v) production of the inflammatory cytokines IL-1β, IL-6 and TNF-α using flow cytometry in peripheral blood-derived human monocytes with and without LPS-stimulation.Results:As a prerequisite for our study, we demonstrate that human monocytes survived strong inhibition of mitochondrial respiration without any sign of apoptosis as determined by flow cytometry. As a result of the inhibition of OXPHOS, we demonstrate a reduction of VAS2870-sensitive OCR (ROS production through NOX), ATPase-dependent OCR and ATP steady-state levels. Focusing on immune function, we observed that phagocytosis and the production of IL-6 were the least sensitive to reduced energy supply while surface expression of CD11b, HLA-DR, production of TNF-α and IL-1β were most affected by inhibition of OXPHOS.Conclusion:Our data demonstrate an energy-dependent hierarchy of immune functions in monocytes, which may represent a potential therapeutic target in monocyte-mediated inflammatory diseases.Disclosure of Interests:None declared

APA, Harvard, Vancouver, ISO, and other styles

24

Iyer, Abishek, Kathleen Kauter, Md Ashraful Alam, Sung Hee Hwang, Christophe Morisseau, Bruce D. Hammock, and Lindsay Brown. "Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Diet-Induced Metabolic Syndrome in Rats." Experimental Diabetes Research 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/758614.

Full text

Abstract:

The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment withtrans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndromein vivoincluding glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

APA, Harvard, Vancouver, ISO, and other styles

25

Bartel, Karin, Rolf Müller, and Karin von Schwarzenberg. "Differential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells." Journal of Biological Chemistry 294, no. 46 (October 11, 2019): 17239–48. http://dx.doi.org/10.1074/jbc.ra119.010243.

Full text

Abstract:

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and nontumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In nonmalignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a prosurvival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase–independent AMPK induction in tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a prosurvival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species production. We could attribute the prosurvival effects to AMPK's ability to maintain redox homeostasis by inhibiting reactive oxygen species production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.

APA, Harvard, Vancouver, ISO, and other styles

26

Studzińska, Renata, Daria Kupczyk, Wojciech Płaziński, Szymon Baumgart, Rafał Bilski, Renata Paprocka, and Renata Kołodziejska. "Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies." International Journal of Molecular Sciences 22, no. 16 (August 10, 2021): 8609. http://dx.doi.org/10.3390/ijms22168609.

Full text

Abstract:

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

APA, Harvard, Vancouver, ISO, and other styles

27

Hull, Dominic O., Besnik Bajrami, Ingela Jansson, John B. Schenkman, and James F. Rusling. "Characterizing Metabolic Inhibition Using Electrochemical Enzyme/DNA Biosensors." Analytical Chemistry 81, no. 2 (January 15, 2009): 716–24. http://dx.doi.org/10.1021/ac802179s.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Kholdebarin, B., A. Mozafar, and E. Frossard. "Differential inhibition of nitrification by three metabolic inhibitors." Journal of Plant Nutrition 21, no. 5 (May 1998): 929–36. http://dx.doi.org/10.1080/01904169809365454.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Harwood Jr, H. James. "Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition." Expert Opinion on Therapeutic Targets 9, no. 2 (April 2005): 267–81. http://dx.doi.org/10.1517/14728222.9.2.267.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

DeFronzo, Ralph A., Luke Norton, and Muhammad Abdul-Ghani. "Renal, metabolic and cardiovascular considerations of SGLT2 inhibition." Nature Reviews Nephrology 13, no. 1 (December 12, 2016): 11–26. http://dx.doi.org/10.1038/nrneph.2016.170.

Full text

APA, Harvard, Vancouver, ISO, and other styles

31

El-Bassossy, Hany M., Rania El-Fawal, Ahmed Fahmy, and Malcolm L. Watson. "Arginase inhibition alleviates hypertension in the metabolic syndrome." British Journal of Pharmacology 169, no. 3 (May 16, 2013): 693–703. http://dx.doi.org/10.1111/bph.12144.

Full text

APA, Harvard, Vancouver, ISO, and other styles

32

Otter, D., C. Austin, and A. Heagerty. "Hypoxia, Metabolic Inhibition and Rat Mesenteric Vascular Tone." Clinical Science 92, s36 (February 1, 1997): 11P. http://dx.doi.org/10.1042/cs092011p.

Full text

APA, Harvard, Vancouver, ISO, and other styles

33

Hayashi, H., H. Miyata, N. Noda, A. Kobayashi, M. Hirano, T. Kawai, and N. Yamazaki. "Intracellular Ca2+ concentration and pHi during metabolic inhibition." American Journal of Physiology-Cell Physiology 262, no. 3 (March 1, 1992): C628—C634. http://dx.doi.org/10.1152/ajpcell.1992.262.3.c628.

Full text

Abstract:

To study the changes in intracellular Ca2+ concentration ([Ca2+]i) and pH (pHi) during metabolic inhibition, rat ventricular myocytes were dual loaded with the acetoxymethyl esters of fura-2 (fura-2/AM) and 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF/AM) and perfused with 2 mM sodium cyanide (NaCN). The percent of rod-shaped cells was 30% of the control after 30 min NaCN in the absence of glucose. [Ca2+]i increased from 82 +/- 8 to 151 +/- 25 (SE) nM (P less than 0.05) when cells were shortened, and to 421 +/- 106 nM (P less than 0.05) when cells were rounded. There was a positive relationship between pCai and pHi (r = 0.425, P less than 0.01). When 50 mM glucose was added during NaCN, there were no significant changes in [Ca2+]i and the percent of rod-shaped cells after 30 min. The pHi of rod-shaped cells, however, decreased to 6.95 +/- 0.03 (P less than 0.01). Although the acidic solution (70% O2-30% CO2) decreased pHi to 6.90 +/- 0.05 (P less than 0.01), there were no changes in the cell shape or [Ca2+]i. The addition of NaCN for 30 min decreased the rod-shaped cells to 18% of the control. Mild acidosis did not cause the changes in cell shape or [Ca2+]i. There was also no protection of the NaCN-induced changes in cell shape by intracellular acidosis. It is likely that the changes in cell shape during metabolic inhibition were related to the depletion of metabolic energy and the increase in [Ca2+]i.

APA, Harvard, Vancouver, ISO, and other styles

34

Waldvogel, Daniel, Peter van Gelderen, Wolf Muellbacher, Ulf Ziemann, Ilka Immisch, and Mark Hallett. "The relative metabolic demand of inhibition and excitation." Nature 406, no. 6799 (August 2000): 995–98. http://dx.doi.org/10.1038/35023171.

Full text

APA, Harvard, Vancouver, ISO, and other styles

35

Thibonnier, Marc, Christine Esau, Sujoy Ghosh, Edward Wargent, and Claire Stocker. "Metabolic and energetic benefits of microRNA-22 inhibition." BMJ Open Diabetes Research & Care 8, no. 1 (October 2020): e001478. http://dx.doi.org/10.1136/bmjdrc-2020-001478.

Full text

Abstract:

IntroductionWe previously demonstrated in primary cultures of human subcutaneous adipocytes and in a mouse model of diet-induced obesity that specific microRNA-22-3p antagomirs produce a significant reduction of fat mass and an improvement of several metabolic parameters. These effects are related to the activation of target genes such as KDM3A, KDM6B, PPARA, PPARGC1B and SIRT1 involved in lipid catabolism, thermogenesis, insulin sensitivity and glucose homeostasis.Research design and methodsWe now report a dedicated study exploring over the course of 3 months the metabolic and energetic effects of subcutaneous administration of our first miR-22-3p antagomir drug candidate (APT-110) in adult C57BL/6 male mice. Body composition, various blood parameters and energy expenditure were measured at several timepoints between week 12 and week 27 of age.ResultsWeekly subcutaneous injections of APT-110 for 12 weeks produced a sustained increase of energy expenditure as early as day 11 of treatment, a significant fat mass reduction, but no change of appetite nor physical activity. Insulin sensitivity as well as circulating glucose, cholesterol and leptin were improved. There was a dramatic reduction of liver steatosis after 3 months of active treatment. RNA sequencing revealed an activation of lipid metabolism pathways in a tissue-specific manner.ConclusionsThese original findings suggest that microRNA-22-3p inhibition could lead to a potent treatment of fat accumulation, insulin resistance, and related complex metabolic disorders such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease.

APA, Harvard, Vancouver, ISO, and other styles

36

Kim, Grace E., and Lawrence H. Young. "AMPK and the Atrial Response to Metabolic Inhibition∗." Journal of the American College of Cardiology 66, no. 1 (July 2015): 59–61. http://dx.doi.org/10.1016/j.jacc.2015.04.054.

Full text

APA, Harvard, Vancouver, ISO, and other styles

37

KAY, H. "Placental response to metabolic inhibition and oxygen content." Journal of the Society for Gynecologic Investigation 3, no. 2 (March 1996): 230A. http://dx.doi.org/10.1016/1071-5576(96)82791-2.

Full text

APA, Harvard, Vancouver, ISO, and other styles

38

Kim, Jae Won, Myeong Uk Kuk, Hyon E. Choy, Sang Chul Park, and Joon Tae Park. "Mitochondrial metabolic reprograming via BRAF inhibition ameliorates senescence." Experimental Gerontology 126 (October 2019): 110691. http://dx.doi.org/10.1016/j.exger.2019.110691.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Lu, Zhongju, Junyuan Gao, Joan Zuckerman, Richard T. Mathias, Glenn Gaudette, Irvin Krukenkamp, and Ira S. Cohen. "Two-pore K+ channels, NO and metabolic inhibition." Biochemical and Biophysical Research Communications 363, no. 1 (November 2007): 194–96. http://dx.doi.org/10.1016/j.bbrc.2007.08.131.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Kim, Eui-Jin, and Jeong K. Lee. "Competitive Inhibitions of the Chlorophyll Synthase of Synechocystis sp. Strain PCC 6803 by Bacteriochlorophyllide a and the Bacteriochlorophyll Synthase of Rhodobacter sphaeroides by Chlorophyllide a." Journal of Bacteriology 192, no. 1 (October 30, 2009): 198–207. http://dx.doi.org/10.1128/jb.01271-09.

Full text

Abstract:

ABSTRACT The photosynthetic growth of Synechocystis sp. strain PCC 6803 is hampered by exogenously added bacteriochlorophyllide a (Bchlide a) in a dose-dependent manner. The growth inhibition caused by Bchlide a, however, is relieved by an increased level of exogenously added chlorophyllide a (Chlide a). The results are explained by the competitive inhibition of chlorophyll synthase by Bchlide a, with inhibition constants (K Is) of 0.3 mM and 1.14 mM in the presence of sufficient geranylgeranyl pyrophosphate (GGPP) and phytyl pyrophosphate (PPP), respectively. Surprisingly, the bacteriochlorophyll synthase of Rhodobacter sphaeroides is inhibited competitively by Chlide a, with K Is of 0.54 mM and 0.77 mM in the presence of sufficient GGPP and PPP, respectively. Consistently, exogenously added Chlide a inhibits the metabolic conversion of exogenously added Bchlide a to bacteriochlorophyll a by an R. sphaeroides bchFNB-bchZ mutant that neither synthesizes nor metabolizes Chlide a. The metabolic inhibition by Chlide a, however, is relieved by the elevated level of Bchlide a. Thus, the chlorophyll synthase of Synechocystis sp. PCC 6803 and the bacteriochlorophyll synthase of R. sphaeroides, both of which perform ping-pong-type reactions, are inhibited by Bchlide a and Chlide a, respectively. Although neither inhibitor is catalyzed by the target enzyme, inhibitions in the competitive mode suggest a structural similarity between their active sites.

APA, Harvard, Vancouver, ISO, and other styles

41

Marín-Aguilar, Fabiola, Beatriz Castejón-Vega, Elísabet Alcocer-Gómez, Debora Lendines-Cordero, Matthew A. Cooper, Patricia de la Cruz, Eloísa Andújar-Pulido, et al. "NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity." Journals of Gerontology: Series A 75, no. 8 (October 11, 2019): 1457–64. http://dx.doi.org/10.1093/gerona/glz239.

Full text

Abstract:

Abstract The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.

APA, Harvard, Vancouver, ISO, and other styles

42

Atsma, D. E., E. M. Bastiaanse, L. Van der Valk, and A. Van der Laarse. "Low external pH limits cell death of energy-depleted cardiomyocytes by attenuation of Ca2+ overload." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 6 (June 1, 1996): H2149—H2156. http://dx.doi.org/10.1152/ajpheart.1996.270.6.h2149.

Full text

Abstract:

We studied the effect of external pH (pHe) on cell injury, ATP content, and intracellular concentration of Ca2+ ([Ca2+]i), Na+ ([Na+]i), and H+ (pHi) during metabolic inhibition (NaCN + 2-deoxyglucose) in neonatal rat cardiomyocytes. Cell death during metabolic inhibition decreased at pHe < 7.4, with almost no cell death at pHe 6.0. Lowering pHe resulted in only temporary ATP conservation. During metabolic inhibition at pHe 7.4, [Ca2+]i rose from 86 +/- 44 nM to 2.5 +/- 0.4 microM, but at pHe 6.0, [Ca2+]i rose to only 510 +/- 215 nM. During metabolic inhibition at pHe 7.4, pHi decreased from 7.25 +/- 0.06 to 6.82 +/- 0.16, but at pHe 6.0, pHi decreased to 6.34 +/- 0.17. During metabolic inhibition at pHe 7.4, [Na+]i increased from 9.1 +/- 0.86 to 26.1 +/- 4.1 mM. At pHe 6.0, [Na+]i rose more rapidly, to 27.3 +/- 3.5 mM. At pHe < 7.4, sarcolemmal Na+/Ca2+ exchanger activity, involved in the development of Ca2+ overload, was decreased, as assessed during Na(+)-free incubation. We conclude that low pHe protects cardiomyocytes during metabolic inhibition by limiting Ca2+ overload via Na+/Ca2+ exchanger inhibition.

APA, Harvard, Vancouver, ISO, and other styles

43

Zhang, Liang, Yixin Yao, Shaojun Zhang, Yang Liu, Hui Guo, Makhdum Ahmed, Taylor Bell, et al. "Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma." Science Translational Medicine 11, no. 491 (May 8, 2019): eaau1167. http://dx.doi.org/10.1126/scitranslmed.aau1167.

Full text

Abstract:

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

APA, Harvard, Vancouver, ISO, and other styles

44

Gebru, Yoseph, Teng-Yue Diao, Hai Pan, Emmanuel Mukwaya, and Yan Zhang. "Potential of RAS Inhibition to Improve Metabolic Bone Disorders." BioMed Research International 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/932691.

Full text

Abstract:

Metabolic bone disorder is usually caused by abnormalities of minerals and hormones metabolism. Recently, it has been proved by several studies that the renin-angiotensin system (RAS) in local bone tissue is directly involved in bone metabolism. Activation of skeletal RAS plays an important role in bone metabolic disorders. Based onin vitro,in vivo, and clinical studies, this review explains the roles of RAS in bone metabolism and also covers the potential approaches and beneficial effects of RAS inhibition on bone health. Differential strategies for inhibiting RAS can be employed to maintain bone health, which are attributed primarily to the reduced level of angiotensin II (AngII) and suppressed stimulation of the AngII signaling pathway. The use of renin inhibitors, angiotensin-converting enzyme inhibitors, and AngII receptor blockers either individually or in combination with each other could have promising results in fighting bone metabolic disorders associated with other cardiovascular diseases as well as independent bone injuries.

APA, Harvard, Vancouver, ISO, and other styles

45

Mukherjee, Sandip, Jake Haubner, and Anutosh Chakraborty. "Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases." Molecules 25, no. 6 (March 19, 2020): 1403. http://dx.doi.org/10.3390/molecules25061403.

Full text

Abstract:

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

APA, Harvard, Vancouver, ISO, and other styles

46

Plishker, G. A. "Iodoacetic acid inhibition of calcium-dependent potassium efflux in red blood cells." American Journal of Physiology-Cell Physiology 248, no. 5 (May 1, 1985): C419—C424. http://dx.doi.org/10.1152/ajpcell.1985.248.5.c419.

Full text

Abstract:

The metabolic inhibitor, iodoacetic acid (IAA), has commonly been used to increase Ca-dependent K efflux in red blood cells. It is thought that this effect of IAA involves the irreversible inhibition of glyceraldehyde-phosphate dehydrogenase (EC 1.2.1.12), resulting in the energy depletion of the cell. Without energy, active transport stops, and the K loss is enhanced both by increasing cellular Ca and by preventing K reuptake. The present study shows that in addition to this metabolic effect, which increases Ca-dependent K efflux, IAA also inhibits this efflux. This inhibition is irreversible and is not related to the ATP or Ca concentrations of the cells. The carboxymethylation of a specific protein band correlates with IAA inhibition of K efflux.

APA, Harvard, Vancouver, ISO, and other styles

47

Imig, J. D., and L. G. Navar. "Afferent arteriolar response to arachidonic acid: involvement of metabolic pathways." American Journal of Physiology-Renal Physiology 271, no. 1 (July 1, 1996): F87—F93. http://dx.doi.org/10.1152/ajprenal.1996.271.1.f87.

Full text

Abstract:

Arachidonic acid (AA) metabolites have been implicated in the control of renal hemodynamics, but the nature of the metabolites produced by renal cells when AA is released has remained uncertain. Experiments were performed using the in vitro perfused juxtamedullary nephron preparation to examine the effects of perfusion and superfusion of AA on the renal microvasculature. Extraluminal exposure of the vessels by superfusion with solutions containing 0.1, 1.0, and 10 microM AA decreased afferent arteriolar diameter by 8 +/- 2, 16 +/- 3, and 20 +/- 3%, respectively. The same doses of AA added to the perfusate produced a similar afferent arteriolar vasoconstriction. Inhibition of the major enzymatic pathways unmasked differential responses of AA that were dependent on the direction from which the vasculature was exposed to AA. 17-Octadecynoic acid (1 microM), an inhibitor of the cytochrome P-450 pathway, eliminated the vasoconstrictor response to superfused AA but had little effect on the response to perfused AA. Lipoxygenase inhibition with baicalein (0.5 microM) did not alter the afferent arteriolar vasoconstriction during superfusion with AA but did attenuate the vasoconstrictor response to perfused AA by 34%. Cyclooxygenase inhibition with 10 microM indomethacin reduced the afferent arteriolar response to superfusion with 10 microM AA by 46%, but the responses to perfusion with AA were reversed, leading to the unmasking of a 17% afferent arteriolar dilation. The AA-induced vasorelaxation observed during cyclooxygenase inhibition was prevented by the subsequent addition of a P-450 inhibitor. Additionally, after endothelial removal with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), the vasodilatory response reverted to a vasoconstriction. The results of this study demonstrate that in the rat, AA metabolites exert predominant actions on afferent arterioles, but differential responses are mediated via different enzymatic pathways depending on the origin of AA. Increased AA availability of intraluminal origin leads to production of cyclooxygenase-derived vasoconstrictor metabolites and also to endothelial-derived cytochrome P-450 vasodilatory metabolites. In contrast, increased AA availability of interstitial origin leads to production of vasoconstrictor cytochrome P-450 metabolites.

APA, Harvard, Vancouver, ISO, and other styles

48

Elgogary, Amira, Qingguo Xu, Brad Poore, Jesse Alt, Sarah C. Zimmermann, Liang Zhao, Jie Fu, et al. "Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer." Proceedings of the National Academy of Sciences 113, no. 36 (August 24, 2016): E5328—E5336. http://dx.doi.org/10.1073/pnas.1611406113.

Full text

Abstract:

Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.

APA, Harvard, Vancouver, ISO, and other styles

49

Khachatourians, George G. "Metabolic effects of trichothecene T-2 toxin." Canadian Journal of Physiology and Pharmacology 68, no. 7 (July 1, 1990): 1004–8. http://dx.doi.org/10.1139/y90-153.

Full text

Abstract:

Cereals and other agricultural products contaminated with trichothecene mycotoxins are unfit for consumption. Until recently, the metabolic effects of T-2 toxin (T-2) were thought to reside in its ability to inhibit protein synthesis. It is now clear that trichothecenes have multiple effects, including inhibition of DNA, RNA, and protein synthesis in several cellular systems, inhibition of in vitro protein synthesis, inhibition of mitochondrial functions, effects on cell division, normal cell shape, and hemolysis of erythrocytes. It is argued that these effects are pleiotropic responses of the cell's biosynthetic network to protein synthesis inhibition. However, in studies with erythrocytes, which lack nuclei and protein synthesis, changes in cell shape and lytic response towards T-2 are observed. Susceptibility to lysis is species dependent and correlates with the presence of phosphatidylcholine. Owing to their amphipathic nature, T-2 and other trichothecenes could exert their cytotoxicity by acting on cell membranes. As for cell energetics, T-2 inhibits the mitochondrial electron transport system, with succinic dehydrogenase as one site of action. Although initial investigations of the metabolic effects of T-2 mediated cytotoxicity suggested the inhibition of protein synthesis as the principal site of action, current thought suggests that the effects of trichothecenes are much more diverse.Key words: T-2 toxin, erythrocyte deformability, membrane lipids, yeast, anaesthetics.

APA, Harvard, Vancouver, ISO, and other styles

50

Samokhvalov, Victor, John R. Ussher, Natasha Fillmore, Ian K. G. Armstrong, Wendy Keung, Daniel Moroz, David G. Lopaschuk, John Seubert, and Gary D. Lopaschuk. "Inhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 303, no. 12 (December 15, 2012): E1459—E1468. http://dx.doi.org/10.1152/ajpendo.00018.2012.

Full text

Abstract:

We previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM-301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Metabolic inhibition'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles