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1.
J Proteome Res ; 15(2): 563-71, 2016 Feb 05.
Article in English | MEDLINE | ID: mdl-26696396

ABSTRACT

Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. for 5 days) decreased cecal bacterial fermentation and increased fecal energy excretion in a dose-dependent manner. Liver (1)H NMR-based metabolomics identified a dose-dependent decrease in glycogen and glucose, enhanced glucogenic and ketogenic activity (tyrosine and phenylalanine), and increased activation of the glycolysis pathway. Serum (1)H NMR-based metabolomics indicated that tempol promotes enhanced glucose catabolism. Hepatic gene expression was significantly altered as demonstrated by an increase in Pepck and G6pase and a decrease in Hnf4a, ChREBP, Fabp1, and Cd36 mRNAs. No significant change in the liver and serum metabolomic profiles was observed in germ-free mice, thus establishing a significant role for the gut microbiota in mediating the beneficial metabolic effects of tempol. These results demonstrate that tempol modulates the gut microbial community and its function, resulting in reduced host energy availability and a significant shift in liver metabolism toward a more catabolic state.


Subject(s)
Cyclic N-Oxides/pharmacology , Gastrointestinal Microbiome/drug effects , Metabolome/drug effects , Metabolomics/methods , Animals , Antioxidants/pharmacology , Dose-Response Relationship, Drug , Energy Metabolism/drug effects , Energy Metabolism/genetics , Gas Chromatography-Mass Spectrometry , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Gene Expression/drug effects , Host-Pathogen Interactions , Liver/drug effects , Liver/metabolism , Male , Metabolome/genetics , Mice, Inbred BALB C , Reverse Transcriptase Polymerase Chain Reaction , Spin Labels
2.
J Bacteriol ; 195(10): 2262-9, 2013 May.
Article in English | MEDLINE | ID: mdl-23475974

ABSTRACT

The carbonic anhydrase (Cpb) from Clostridium perfringens strain 13, the only carbonic anhydrase encoded in the genome, was characterized both biochemically and physiologically. Heterologously produced and purified Cpb was shown to belong to the type I subclass of the ß class, the first ß class enzyme investigated from a strictly anaerobic species of the domain Bacteria. Kinetic analyses revealed a two-step, ping-pong, zinc-hydroxide mechanism of catalysis with Km and kcat/Km values of 3.1 mM CO2 and 4.8 × 106 s⁻¹ M⁻¹, respectively. Analyses of a cpb deletion mutant of C. perfringens strain HN13 showed that Cpb is strictly required for growth when cultured in semidefined medium and an atmosphere without CO2. The growth of the mutant was the same as that of the parent wild-type strain when cultured in nutrient-rich media with or without CO2 in the atmosphere, although elimination of glucose resulted in decreased production of acetate, propionate, and butyrate. The results suggest a role for Cpb in anaplerotic CO2 fixation reactions by supplying bicarbonate to carboxylases. Potential roles in competitive fitness are discussed.


Subject(s)
Bacterial Proteins/metabolism , Carbonic Anhydrases/metabolism , Clostridium perfringens/enzymology , Carbon Dioxide , Carbonic Anhydrases/classification , Carbonic Anhydrases/genetics , Models, Theoretical , Phylogeny
3.
Toxicol Pathol ; 41(2): 410-8, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23197196

ABSTRACT

The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone transcription factors (PPARα, PPARß/δ, and PPARγ) is regulated by a wide array of ligands including natural and synthetic chemicals. PPARs have important roles in control of energy metabolism and are known to influence inflammation, differentiation, carcinogenesis, and chemical toxicity. As such, PPARs have been targeted as therapy for common disorders such as cancer, metabolic syndrome, obesity, and diabetes. The recent application of metabolomics, or the global, unbiased measurement of small molecules found in biofluids, or extracts from cells, tissues, or organisms, has advanced our understanding of the varied and important roles that the PPARs have in normal physiology as well as in pathophysiological processes. Continued development and refinement of analytical platforms, and the application of new bioinformatics strategies, have accelerated the widespread use of metabolomics and have allowed further integration of small molecules into systems biology. Recent studies using metabolomics to understand PPARα function, as well as to identify PPARα biomarkers associated with drug efficacy/toxicity and drug-induced liver injury, will be discussed.


Subject(s)
Metabolomics/methods , PPAR alpha/metabolism , Toxicology/methods , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Chromatography , Humans , Mass Spectrometry
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