Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.ne of the prominent characteristics of rapidly growing tumor cells is their capacity to sustain high rates of glycolysis for ATP generation irrespective of oxygen availability, termed the Warburg effect (1). Recent studies have shown that cancer cells shift metabolic pathways to facilitate the uptake and incorporation of abundant nutrients, such as glucose and glutamine (2, 3), into cell building blocks, such as nucleotides, amino acids, and lipids, that are essential for highly proliferating cells (4). This seems to be a universal characteristic of highly malignant tumors (5), independent of their carcinogenetic origin (6). Understanding how cancer cells reprogram metabolism can stimulate the development of new approaches in cancer therapy.Although there is now substantial information about how these pathways are regulated, most existing studies on cancer metabolism have used in vitro cell lines. In addition to genetic and epigenetic alterations, altered tumor microenvironment (e.g., blood flow, oxygen and nutrient supply, pH distribution, redox state, and inflammation) plays a profound role in modulating tumor cell metabolism (7-9). Therefore, a systematic characterization of in vivo metabolic pathways was deemed necessary to understand how metabolic phenotypes are regulated in intact human tumors.Here we applied multiomics-based approaches [i.e., metabolomics, target sequencing of cancer-related genes, transcriptomics, and methylated DNA immunoprecipitation sequencing (MeDIPseq)] to paired normal and tumor tissues obtained from 275 patients with colorectal cancer (CRC) and uncovered the details of which factors contributed, and when they contributed, to metabolic reprogramming in colorectal cancer. The results were confirmed by analysis of colorectal tissue from Apc mutant mice and cancer cell lines.
Seventy-five cirrhotic patients with hyperammonemia in ing number of patients with compensated or noncompenthe past or at the time of the study were randomly divided sated cirrhosis are managed in outpatient clinics over a long into two groups (treated with lactulose or nontreated) in 14 period. In these patients, prevention of the above complicahospitals in Japan. Thirty-six cirrhotic patients were diag-tions is necessary in long-term home care to improve the nosed as having subclinical hepatic encephalopathy (SHE), quality of life (QOL). and 39 were diagnosed as non-SHE. SHE was diagnosedIn hepatic encephalopathy, psychoneurological symptoms when the results of all three of the quantitative psychometric are clinically absent before the onset and during the interval tests used (number connection test, and symbol digit and period of encephalopathic episodes. However, subclinical heblock design tests of the Wechsler adult intelligence scale patic encephalopathy (SHE), in which behavior abnormali-[revised]) were abnormal as compared with age-matched ties and impairment in cognitive functions can be shown by normal values. The mean number of abnormal psychometric quantitative psychometric (neuropsychologic) tests, has been test results and the prevalence of SHE were used for a quanti-reported recently in cirrhotic patients who have no history tative evaluation of the efficacy of the lactulose treatment. of encephalopathy, and clinically appear to be free of encephTwenty-two of the SHE patients were treated with lactulose alopathy.1,2 Moreover, recent imaging analysis of the brain (45 mL/d) for 8 weeks, and the other 14 SHE patients did in cirrhotic patients with and without encephalopathy has not receive lactulose. In the SHE patients administered lactu-shown brain atrophy on computed tomography, 3 abnormal lose, the results of the quantitative psychometric evaluation regional cerebral blood flow on single photon emission comwere significantly improved at 4 and 8 weeks after the begin-puted tomography, 4 and high signals in the basal ganglia on ning of the lactulose administration. The SHE had disap-T1-weighted magnetic resonance imaging. Therefore, it is important for the long-term management it persisted in 11 (85%) of the untreated 13 patients. We of cirrhotic patients to understand the presence of these morconcluded that lactulose treatment in cirrhotic patients with phological changes and functional impairments of the brain, SHE is effective with respect to psychometric tests. (HEPA-and to pay attention to changes in daily behavior and sleep. TOLOGY 1997;26:1410-1414.)This approach would be useful for maintaining the compensated stage of cirrhosis over a long period and for reversing Because the treatment for complications of cirrhosis such as hepatic encephalopathy, jaundice, ascites, and gastrointes-the noncompensated cirrhosis to compensated cirrhosis. tinal bleeding has improved, the survival period of cirrhotic Lactulose has been used worldwide for the treatment of patients has been markedly prolonged. Th...
Ganglioside GM3 (Siaα2-3Galβ1-4Glcβ1-1Cer) has been known to participate in insulin signaling by regulating the association of the insulin receptor in caveolae microdomains (lipid rafts), which is essential for the execution of the complete insulin metabolic signaling in adipocytes. Macrophage-secreted factors including proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β, in adipose tissues have been known to limit the local adipogenesis and induce insulin resistance; however, the interplay between adipocytes and macrophages upon regulation of GM3 expression is not clear. GM3 was virtually absent in primary adipocytes differentiated from macrophage-depleted mesenteric stromal vesicular cells, which accompanies enhancement of insulin signaling and adipogenesis. We found that the expression of GM3 is governed by soluble factors including steady-state levels of proinflammatory cytokines secreted from resident macrophages. The direct involvement of GM3 in insulin signaling is demonstrated by the fact that embryonic fibroblasts obtained from GM3 synthase (GM3S)-deficient mice have increased insulin signaling, when compared with wild-type embryonic fibroblasts, which in turn leads to enhanced adipogeneis. In addition, GM3 expression in primary adipocytes is increased under proinflammatory conditions as well as in adipose tissue of diet-induced obese mice. Moreover, GM3S-deficient mice fed high-fat diets become obese but are resistant to the development of insulin resistance and chronic low-grade inflammatory states. Thus, GM3 functions as a physiological regulatory factor of the balance between homeostatic and pathological states in adipocytes by modulating insulin signaling in lipid rafts.
A novel disulfide-containing aniline, 1,4-dihydrobenzo [d][1,2]dithiin-5-ylamin (1), was synthesized by the alkylbromination of 1,2-dimethyl-3-nitrobenzene, followed by the formation of a disulfide bond via thioesterification and then the reduction of the nitro group. The monomer showed a reductive and oxidative potential of the disulfide bond at -0.63 and 1.25 V (vs Ag/Ag + ), respectively. Although the monomer showed the oxidative potential of aniline at 0.85 V (vs SCE), the electro-or chemical-oxidative polymerization of the monomer resulted in the formation of only the oligomer, suggesting that the disulfidecontaining condensed ring would prevent further propagation of the polymerization due to steric hindrance. However, the nearly ideal copolymerization of 1 with aniline (An) was carried out by chemical oxidative polymerization. The resulting copolymers (1/An ) 1/1 and 2/1, by mole) had weight-averaged molecular weights (M h w) of 10 000 and 6600, respectively, and good redox activities coupled with those of the polyaniline and disulfide group. The copolymer showed conductivities of 5.1 × 10 -2 S/cm for 1/1 and 1.3 × 10 -2 S/cm for 2/1 after being redoped with camphorsulfonic acid. It is suggested that these copolymers might be good candidates for the cathode materials of secondary polymer batteries.
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