Niacinamide
Pentose Phosphate Pathway
Abnormalities, Drug-Induced
Effect of 6-aminonicotinamide and other protein synthesis inhibitors on formation of platinum-DNA adducts and cisplatin sensitivity. (1/52)
The present study was undertaken to examine the mechanistic basis for the recent observation that the pyridine nucleotide derivative 6-aminonicotinamide (6AN, NSC 21206) enhances the accumulation and resulting cytotoxicity of cisplatin in a variety of tumor cell lines. When A549 lung cancer cells or K562 leukemia cells were treated with 62.5 microM 6AN for 21 h and then pulse-labeled with [(35)S]methionine for 1 h, increased labeling of five polypeptides, one of which corresponded to a M(r) approximately 78,000 glucose-regulated protein (GRP78), was observed. Two subsequent observations, however, suggested that up-regulation of these polypeptides was unlikely to explain the interaction between 6AN and cisplatin: 1) the concentration of 6AN required to induce GRP78 was 4-fold higher than the dose required to sensitize cells to cisplatin; and 2) simultaneous treatment of cells with 6AN and cycloheximide prevented the increase in GRP78 but not the sensitizing effect of 6AN. On the contrary, treatment with the protein synthesis inhibitors cycloheximide, anisomycin, or puromycin as well as prolonged exposure to the RNA synthesis inhibitor actinomycin D mimicked the biochemical modulating effects of 6AN on cisplatin action. Conversely, 6AN inhibited protein synthesis, whereas 18 6AN analogs that failed to enhance Pt-DNA adducts and cisplatin cytotoxicity failed to inhibit protein synthesis. These observations are consistent with a model in which 6AN and other inhibitors of protein synthesis act as modulating agents by increasing cisplatin accumulation, thereby enhancing the formation of Pt-DNA adducts and subsequent cisplatin-induced cell death. (+info)Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum. (2/52)
The low density lipoprotein (LDL) receptor is responsible for removing the majority of the LDL cholesterol from the plasma. Mutations in the LDL receptor gene cause the disease familial hypercholesterolemia (FH). Approximately 50% of the mutations in the LDL receptor gene in patients with FH lead to receptor proteins that are retained in the endoplasmic reticulum (ER). Misfolding of mutant LDL receptors is a probable cause of this ER retention, resulting in no functional LDL receptors at the cell surface. However, the specific factors and mechanisms responsible for retention of mutant LDL receptors are unknown. In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors. A pulse-chase study shows that the interaction between the wild type LDL receptor and Grp78 is no longer detectable after 2(1/2) h, whereas it persists for more than 4 h with the mutant receptors. Furthermore, about five times more Grp78 is co-immunoprecipitated with the mutant receptors than with the wild type receptor suggesting that Grp78 is involved in retention of mutant LDL receptors in the ER. Overexpression of Grp78 causes no major alterations on the steady state level of active LDL receptors at the cell surface. However, overexpression of Grp78 decreases the processing rate of newly synthesized wild type LDL receptors. This indicates that the Grp78 interaction is a rate-limiting step in the maturation of the wild type LDL receptor and that Grp78 may be an important factor in the quality control of newly synthesized LDL receptors. (+info)Inhibitors of pentose phosphate pathway cause vasodilation: involvement of voltage-gated potassium channels. (3/52)
Cytosolic reducing cofactors, such as NADPH and NADH, are thought to regulate vascular smooth muscle ion channel activity and vascular tone. In this study, the effects of pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN), epiandrosterone (EPI), and dehydroepiandrosterone (DHEA), on vascular tone were studied in isolated perfused lungs and pulmonary artery (PA) and aortic rings from rats. In addition, effects of 6-AN on voltage-gated K(+) (K(v)) current in PA smooth muscle cells (SMCs) were also examined. Pretreatment of lungs with 6-AN and EPI reduced the pressor response to acute hypoxia and decreased tissue NADPH levels. 6-AN, EPI, and DHEA relaxed isolated PA and aortic rings precontracted with 30 mM KCl in a dose-dependent manner. The PPP inhibitor-induced PA relaxations were reduced in PA rings precontracted with 80 mM KCl but not by pretreatment with nitro-L-arginine or endothelial removal. Pretreatment of PA rings with tetraethylammonium chloride or 4-aminopyridine caused rightward shifts of concentration-relaxation curves for 6-AN, EPI, and DHEA. In contrast, glybenclamide, charybdotoxin, or apamin did not inhibit the relaxant effects of 6-AN, EPI, and DHEA. 6-AN caused an increase in K(v) current in PASMC. These results indicate that reduction of NADPH by the PPP inhibitors causes vasodilation at least partly through opening of K(v) channels. (+info)Up-regulation of glucose metabolism during male pronucleus formation determines the early onset of the s phase in bovine zygotes. (4/52)
After in vitro fertilization with spermatozoa from bulls with high in vitro fertility, a beneficial paternal effect is manifested during the G1 phase of the first cell cycle. This benefit determines an earlier onset of the first S phase, and then a successful morula-blastocyst transition 7 days later. We hypothesized that the origin of the paternal effect could be a shift of the metabolism of the fertilized oocyte, because in mice, sperm decondensation is responsible for a dramatic increase in glucose metabolism. In this study we investigated the interaction between both pronuclei and compared glycolysis and pentose phosphate pathway (PPP) activities in bovine oocytes fertilized with spermatozoa from bulls of high or low fertility. Here we demonstrate that male pronucleus formation is necessary for the onset of the S phase in the female pronucleus, and that the component promoting an early S phase in both pronuclei is metabolic and linked to an up-regulation of the PPP during the male pronucleus formation. This long-lasting paternal effect is more evidence of the important role of epigenetic control during early embryo development. (+info)Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries. (5/52)
Pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (Epi), were employed to examine whether changes in NADP(H) redox regulates contractile force in endothelium-removed bovine coronary arteries (BCAs). 6-AN (0.01-5 mM) or Epi (1-500 microM) elicited dose-dependent relaxation in BCAs contracted with 30 mM KCl, 0.1 microM U-44619, and endothelin-1 but not with phorbol 12,13-dibutyrate, a protein kinase C activator that causes Ca2+-independent contraction. Relaxation to PPP inhibition was associated with oxidation of NADPH and glutathione (GSH). Relaxation to 6-AN was not mediated by H2O2, because it was not altered by hypoxia or the peroxide scavenger ebselen (100 microM). The thiol reductant DTT (3 mM) attenuated the relaxation to 6-AN and Epi by 30-40%. Inhibition of glycolysis or mitochondrial electron transport did not elicit relaxation in BCAs contracted with 30 mM KCl, suggesting these pathways may not be involved in relaxation elicited by PPP inhibition. High doses of K+ channel blockers [e.g., TEA (10 mM) and 4-aminopyridine (10 mM)] only partially inhibited the relaxation to 6-AN. On the basis of changes in the fura-2 fluorescence ratio, 6-AN and Epi appeared to markedly reduce intracellular Ca2+. Thus PPP inhibition oxidizes NADPH and GSH and appears to activate a novel coordination of redox-controlled relaxing mechanisms in BCAs mediated primarily through decreasing intracellular Ca2+. (+info)Biochemical modulation of tumor cell energy: regression of advanced spontaneous murine breast tumors with a 5-fluorouracil-containing drug combination. (6/52)
This report describes a highly active chemotherapeutic drug combination, consisting of N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide plus 5-fluorouracil, in CD8F1 mice bearing spontaneous, autochthonous, breast tumors or first-passage advanced transplants of these spontaneous tumors. The combination and sequence of administration of these drugs were selected on the basis of known potentiating biochemical interactions. High performance liquid chromatography and nuclear magnetic resonance spectroscopy measurements of biochemical changes resulting from treatment with N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide indicated a severe depletion of cellular energy levels in the treated tumors. 6-Aminonicotinamide produced a severe block of the pentose shunt, and 5-fluorouracil severely inhibited both thymidylate synthase and thymidine kinase in the treated tumors. This quadruple drug combination, administered on a 10-11-day schedule, produced an impressive partial tumor regression rate of 67% of large, spontaneous, autochthonous, murine breast tumors and a tumor regression rate of 74% of first-passage transplants of the spontaneous breast tumors. (+info)Insulin stimulates glucose metabolism via the pentose phosphate pathway in Drosophila Kc cells. (7/52)
Drosophila melanogaster has become a prominent and convenient model for analysis of insulin action. However, to date very little is known regarding the effect of insulin on glucose uptake and metabolism in Drosophila. Here we show that, in contrast to effects seen in mammals, insulin did not alter [(3)H]2-deoxyglucose uptake and in fact decreased glycogen synthesis ( approximately 30%) in embryonic Drosophila Kc cells. Insulin significantly increased ( approximately 1.5-fold) the production of (14)CO(2) from D-[1-(14)C]glucose while the production of (14)CO(2) from D-[6-(14)C]glucose was not altered. Thus, insulin-stimulated glucose oxidation did not occur via increasing Krebs cycle activity but rather by stimulating the pentose phosphate pathway. Indeed, inhibition of the oxidative pentose phosphate pathway by 6-aminonicotinamide abolished the effect of insulin on (14)CO(2) from D-[U-(14)C]glucose. A corresponding increase in lactate production but no change in incorporation of D-[U-(14)C]glucose into total lipids was observed in response to insulin. Glucose metabolism via the pentose phosphate pathway may provide an important source of 5'-phosphate for DNA synthesis and cell replication. This novel observation correlates well with the fact that control of growth and development is the major role of insulin-like peptides in Drosophila. Thus, although intracellular signaling is well conserved, the metabolic effects of insulin are dramatically different between Drosophila and mammals. (+info)Effects of small molecules on chaperone-mediated autophagy. (8/52)
Autophagy, including macroautophagy (MA), chaperone-mediated autophagy (CMA), crinophagy, pexophagy and microautophagy, are processes by which cells select internal components such as proteins, secretory vesicles, organelles, or foreign bodies, and deliver them to lysosomes for degradation. MA and CMA are activated during conditions of serum withdrawal in cell culture and during short-term and prolonged starvation in organisms, respectively. Although MA and CMA are activated under similar conditions, they are regulated by different mechanisms. We used pulse/chase analysis under conditions in which most intracellular proteolysis is due to CMA to test a variety of compounds for effects on this process. We show that inhibitors of MA such as 3-methyladenine, wortmannin, and LY294002 have no effect on CMA. Protein degradation by MA is sensitive to microtubule inhibitors such as colcemide and vinblastine, but protein degradation by CMA is not. Activators of MA such as rapamycin also have no effect on CMA. We demonstrate that CMA, like MA, is inhibited by protein synthesis inhibitors anisomycin and cycloheximide. CMA is also partially inhibited when the p38 mitogen activated protein kinase is blocked. Finally we demonstrate that the glucose-6-phophate dehydrogenase inhibitor, 6-aminonicotinamide, and heat shock protein of 90 kilodaltons inhibitor, geldanamycin, have the ability to activate CMA. (+info)6-Aminonicotinamide (6-AN) is a chemical compound that is structurally similar to nicotinamide, a form of vitamin B3. It has been studied for its potential therapeutic effects in various medical conditions, including cancer, diabetes, and neurodegenerative diseases. In cancer research, 6-AN has been shown to inhibit the growth and proliferation of cancer cells by blocking the activity of certain enzymes involved in DNA replication and repair. It has also been found to induce apoptosis (cell death) in some cancer cell lines. In diabetes research, 6-AN has been shown to improve insulin sensitivity and glucose metabolism in animal models of diabetes. It has also been found to reduce inflammation and oxidative stress, which are key factors in the development and progression of diabetes. In neurodegenerative disease research, 6-AN has been shown to protect against neurotoxicity and improve cognitive function in animal models of Alzheimer's disease and Parkinson's disease. It has been suggested that 6-AN may work by inhibiting the activity of certain enzymes involved in the production of reactive oxygen species, which are toxic to brain cells. Overall, 6-AN is a promising compound with potential therapeutic applications in various medical conditions. However, more research is needed to fully understand its mechanisms of action and to determine its safety and efficacy in humans.
Niacinamide, also known as vitamin B3, is a water-soluble vitamin that plays a crucial role in various bodily functions. In the medical field, niacinamide is used as a dietary supplement and medication to treat a variety of conditions, including: 1. Hyperpigmentation: Niacinamide is used to treat hyperpigmentation, which is the darkening of the skin caused by exposure to the sun or other factors. It works by inhibiting the production of melanin, the pigment that gives skin its color. 2. Rosacea: Niacinamide is used to treat rosacea, a chronic skin condition characterized by redness, flushing, and bumps on the face. It helps to reduce inflammation and improve the skin's barrier function. 3. Acne: Niacinamide is used to treat acne by regulating oil production, reducing inflammation, and improving the skin's barrier function. 4. Dermatitis: Niacinamide is used to treat dermatitis, a skin condition characterized by redness, itching, and inflammation. It helps to reduce inflammation and improve the skin's barrier function. 5. Aging skin: Niacinamide is used to treat aging skin by improving skin elasticity, reducing fine lines and wrinkles, and improving skin texture. Niacinamide is generally considered safe when taken in recommended doses. However, it can cause side effects such as flushing, itching, and stinging when applied topically. It is important to consult a healthcare professional before taking niacinamide as a supplement or medication.
Abnormalities, Drug-Induced refer to changes in the body's normal functioning or structure that are caused by the use of drugs. These abnormalities can occur as a direct result of the drug's chemical action on the body, or as an indirect effect of the drug's metabolism and elimination from the body. Drug-induced abnormalities can affect any organ or system in the body, and can range from mild and temporary to severe and life-threatening. Some common examples of drug-induced abnormalities include liver damage, kidney damage, heart arrhythmias, blood disorders, and neurological problems. The severity and duration of drug-induced abnormalities can vary depending on the type of drug, the dose, the duration of use, and the individual's age, sex, health status, and genetic makeup. In some cases, drug-induced abnormalities may resolve on their own once the drug is discontinued, while in other cases, medical intervention may be necessary to manage the symptoms or prevent complications. It is important for healthcare providers to be aware of the potential for drug-induced abnormalities when prescribing medications, and to monitor patients closely for any signs of adverse effects. In some cases, alternative treatments or medications may be necessary to minimize the risk of drug-induced abnormalities.
Tumor metabolome
Glucose-6-phosphate dehydrogenase
List of MeSH codes (D03)
Effect of 6-Aminonicotinamide and Other Protein Synthesis Inhibitors on Formation of Platinum-DNA Adducts and Cisplatin...
Effects of neonatal treatment with 6-aminonicotinamide on basal and isoproterenol-stimulated ornithine decarboxylase activity...
Wnt9b MGI Mouse Gene Detail - MGI:1197020 - wingless-type MMTV integration site family, member 9B
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Pesquisa | Prevenção e Controle de Câncer
The suitability of glioblastoma cell lines as models for primary glioblastoma cell metabolism | Research Square
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Variation in pentose phosphate pathway-associated metabolism dictates cytotoxicity outcomes determined by tetrazolium reduction...
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In vitro and in vivo studies on the degradation of metallothionein. | Environmental Health Perspectives | Vol. 102, No. suppl 3
DeCS
Inhibitor2
- Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN), abolished the effects of HK replacement. (bvsalud.org)
- B[a]P caused enhanced metabolism of each dye assessed despite reductions in mitochondrial membrane potential and was reversed by 6-aminonicotinamide (6AN)-a glucose-6-phosphate dehydrogenase inhibitor. (cdc.gov)
Enzyme3
- To explore the biochemical mechanisms which underlie these actions, we evaluated effects of 6-aminonicotinamide on ornithine decarboxylase, an enzyme involved in cellular replication and differentiation. (duke.edu)
- When given to neonatal rats, 6-aminonicotinamide (10 mg/kg, i.p., on days 1, 3, 5 and 7) caused a prompt and persistent inhibition of the enzyme well in advance of adverse effects on tissue weight or on general growth. (duke.edu)
- Dichloroacetate, which targets a key glycolytic pathway enzyme pyruvate dehydrogenase kinase (5, 6), has been demonstrated to inhibit tumour progression in vivo in lung and breast cancer (5, 7). (researchsquare.com)
Effects2
- Scholars@Duke publication: Effects of neonatal treatment with 6-aminonicotinamide on basal and isoproterenol-stimulated ornithine decarboxylase activity in cerebellum of the development rat. (duke.edu)
- These data support the view that reduced ornithine decarboxylase activity and impairment of its reactivity to growth stimuli participate in the toxic effects of 6-aminonicotinamide on brain development. (duke.edu)
Brain2
- 6-Aminonicotinamide (6-AN) is a nicotinic acid (vitamin B3) antagonist which, when administered to immature animals, has a profound influence on brain development. (duke.edu)
- Assessment of cerebellar morphology indicated an early adverse effect of 6-AN on granule' cell division, resulting in eventual disruption of the characteristic laminar structure of this brain region. (duke.edu)
Glucose-6-phosphate d2
- B[a]P caused enhanced metabolism of each dye assessed despite reductions in mitochondrial membrane potential and was reversed by 6-aminonicotinamide (6AN)-a glucose-6-phosphate dehydrogenase inhibitor. (cdc.gov)
- The requirement of the hexose monophosphate pathway for 10 s oscillations was verified using 6-aminonicotinamide and dexamethasone, which are inhibitors of glucose-6-phosphate dehydrogenase. (nih.gov)
Nicotinamide1
- In the validation studies, flies were fed 6-amino- nicotinamide (1320861) (ANA) at 3 to 5mg/g, cyclophosphamide (50180) at 0.10mg/g, and hydroxyurea (127071) at 0.2microl/g. (cdc.gov)
Differential1
- 6. Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity. (nih.gov)
Cancer3
- 2. Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells. (nih.gov)
- 4. Radiosensitization by 2-deoxy-D-glucose and 6-aminonicotinamide involves activation of redox sensitive ASK1-JNK/p38MAPK signaling in head and neck cancer cells. (nih.gov)
- 5. Contribution of oxidative stress to radiosensitization by a combination of 2-DG and 6-AN in human cancer cell line. (nih.gov)