Energy metabolism: a new target for gastric cancer treatment

Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer (AU)

A tripartite tricarboxylate transporter (MIM_c39170-MIM_c39210) of Advenella mimigardefordensis DPN7T is involved in citrate uptake

To date, tripartite tricarboxylate transport (TTT) systems are not well characterized in most organisms. To investigate which carbon sources are transported by the TTT system of A. mimigardefordensis DPN7T, single deletion mutants were generated lacking either completely both sets of genes encoding for these transport systems tctABCDE1 and tctABDE2 in the organism or the two genes encoding for the regulatory components of the third chosen TTT system, tctDE3. Deletion of tctABCDE1 (MIM_c39170-MIM_c39210) in Advenella mimigardefordensis strain DPN7T led to inhibition of growth of the cells with citrate indicating that TctABCDE1 is the transport system for the uptake of citrate. Because of the negative phenotype, it was concluded that this deletion cannot be substituted by other transporters encoded in the genome of strain DPN7T. A triple deletion mutant of A. mimigardefordensis lacking both complete TTT transport systems and the regulatory components of the third chosen system (ΔTctABCDE1 ΔTctABDE2 ΔTctDE3) showed a leaky growth with alpha-ketoglutarate in comparison with the wild type. The other investigated TTT (TctABDE3, MIM_c17190-MIM_c17220) is most probably involved in the transport of alpha-ketoglutarate. Additionally, thermoshift assays with TctC1 (MIM_c39190) showed a significant shift in the melting temperature of the protein in the presence of citrate whereas no shift occurred with alpha-ketoglutarate. A dissociation constant Kd for citrate of 41.7 μM was determined. Furthermore, alternative alpha-ketoglutarate transport was investigated via in silico analysis

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Effects of branched-chain amino acids on muscles under hyperammonemic conditions

The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-14C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and alfa-ketoglutarate (alfa -KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in alfa-KG found in the NH3 group. We conclude that (I) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and alfa-KG levels and (II) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in alfa-KG

Sodium butyrate protects against oxidative stress in HepG2 cells through modulating Nrf2 pathway and mitochondrial function

Sodium butyrate (NaBu) is a by-product of microbial fermentation of dietary fiber in the gastrointestinal tract and has been shown to increase the activity of antioxidant enzymes, such as catalase or heme oxidase-1, in vivo. However, the mechanism of this effect is still unclear. This study investigated the antioxidant effect of NaBu on HepG2 cells under H2O2-induced oxidative stress. NaBu (0.3 mM) attenuated cell death and accumulation of reactive oxygen species and improved multiple antioxidant parameters in H2O2-injured HepG2 cells. NaBu inhibited glycogen synthase kinase-3 beta (GSK-3Beta) by increasing the p-GSK-3 Beta (Ser9) level and promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increased the expression of downstream antioxidant enzymes. Together with promotion of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial DNA copy number, NaBu modulated energy metabolism and mitochondrial function, decreasing glycolysis, increasing Beta -oxidation, and enhancing the tricarboxylic acid cycle and oxidative phosphorylation. NaBu increased mitochondrial manganese-superoxide dismutase and glutathione peroxidase activity. In conclusion, NaBu protected HepG2 cells against oxidative stress by modulating Nrf2 pathway activity and mitochondrial function

A phylogenetic approach to the early evolution of autotrophy: the case of the reverse TCA and the reductive acetyl-CoA pathways

In recent decades, a number of hypotheses on the autotrophic origin of life have been presented. These proposals invoke the emergence of reaction networks leading from CO or CO2 to the organic molecules required for life. It has also been suggested that the last (universal) common ancestor (LCA or LUCA) of all extant cell lineages was a chemolitho-autotrophic thermophilic anaerobe. The antiquity of some carbon fixation pathways, the phylogenetic basal distribution of some autotrophic organisms, and the catalytic properties of iron-sulfur minerals have been advanced in support of these ideas. Here we critically examine the phylogenetic distribution and evolution of enzymes that are essential for two of the most ancient autotrophic means of metabolism: the reductive tricarboxylic acid (rTCA) cycle and the reductive acetyl-CoA pathway. Phylogenetic analysis of citryl-CoA synthetase and of citryl-CoA lyase, key enzymatic components of the rTCA cycle, and of CO dehydrogenase/acetyl-CoA synthase, a key enzyme in the reductive acetyl-CoA pathway, revealed that all three enzymes have undergone major lateral transfer events and therefore cannot be used as proof of the LCA’s metabolic abilities nor as evidence of an autotrophic origin of life (AU)

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Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

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There are major variations in the susceptibility to weight gain among individuals under similar external influences (decreased physical activity and excessive calorie intake), depending on the genetic background. In the present study, we performed a microarray analysis and real-time PCR validations in order to find out differential gene expression in subcutaneous abdominal adipose tissue from two groups of subjects that despite living in similar environmental conditions such as a habitual high-fat dietary intake (energy as fat >40%) and similar moderate physical activity, some of them were successfully “resistant” (lean) to weight gain, while others were “susceptible” to fat deposition (obese). The classification of up- and downregulated genes into different categories, together with the analysis of the altered biochemical pathways, revealed a coordinated downregulation of catabolic pathways operating in the mitochondria: fatty acid (..) (AU)

La miopatía isquémica en la enfermedad arterial periférica / Ischaemic myopathy of peripheral arterial occlusive disease

Introducción. La mitocondria afectada por la isquemia provoca una miopatía y un aumento deradicales libres de oxígeno (RLO), que conduce a daño oxidativo y activación del proceso infl amatorio,ambos asociados al fenómeno isquemia-reperfusión.Objetivo. Estudiar la alteración mitocondrial del músculo estriado, provocada por la isquemia,y sus repercusiones en la enfermedad arterial periférica (EAP).Métodos. Estrategia de búsqueda avanzada en Pub-Med (http://www.ncbi.nlm.nih.gov/Pub-Med) y búsqueda manual de bibliografía.Desarrollo. Los principales trabajos consultados indican la existencia de una disfunción mitocondrialcaracterística con alteración de los complejos de la cadena respiratoria. Esto conducea un incremento de RLO que dañan el ADN mitocondrial, perpetuándose el círculo vicioso deempeoramiento de cadena respiratoria-daño oxidativo-alteración del ADN mitocondrial, al estarlos complejos CI, CIII y CIV codifi cados por el ADN mitocondrial lesionado.Conclusión. Se necesitan más trabajos para comprender la miopatía isquémica provocada porladisminución del fl ujo en la EAP(AU)

Introduction. Ischemic injury involves a mitochondrial dysfunction causing a typical miopathyand an increase of free radicals. It may lead to oxidative tissue injury and activation ofinfl ammatory response, both of them in relation to reperfusion ischemia injury.Aim. To study mitochondrial impairment in skeletal muscle as a consequence of ischemia andeffects of mitochondrial dysfunction in peripheral arterial disease (PAD).Methods. Advanced search strategy: PubMed (http://www.ncbi.nlm.nih.gov/PubMed) andmanual literature search. Results. The main studies reviewed indicate that there is a mitochondrial dysfunction havingspecial characteristics. Dysfunctions in the electron transport chain lead to increased productionof reactive oxygen species which cause damage to mitochondrial DNA, launching a vicious cycleof worsening electron transport chain disruption-oxidant production-further mitochondrialdeterioration since impaired complex are encoded by damaged mitochondrial DNA.Conclusion. Further work is required to understand ischemic miopathy as a consequence of adecreased blood fl ow in PAD(AU)