scholarly journals Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Giorgia Colombo ◽  
Edoardo Luigi Maria Gelardi ◽  
Federica Carolina Balestrero ◽  
Marianna Moro ◽  
Cristina Travelli ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metabolic Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cellular Metabolism ◽  
Redox Status ◽  
Tumour Cells ◽  
Present Review ◽  
Nicotinamide Adenine ◽  
Key Enzymes ◽  
Insight Into

Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).

CSIG-02. NRF2-GUIDED GLUTATHIONE SYNTHESIS IS AN ESSENTIAL METABOLIC PATHWAY IN IN IDH1-MUTATED GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi33-vi33
Author(s):  
Yang Liu ◽  
Di Yu ◽  
Chunzhang Yang
Keyword(s):  
Metabolic Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Redox Homeostasis ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Who Grade ◽  
Glutathione Synthesis ◽  
Synergistic Cytotoxicity ◽  
Idh Mutations

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in WHO Grade II/III glioma, which result in the reprogramming of cellular metabolism and redox homeostasis. Many lines of evidence showed that IDH mutations are critical for glioma formation, whereas the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we used the patient-derived glioma cell lines to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) governed glutathione de novo synthesis. Further, we evaluated the therapeutic value of NRF2 inhibitors in IDH1-mutated cells and preclinical orthotopic models. RESULTS The neomorphic activity of mutant IDH reprogrammed the metabolic pathways involving enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The depletion of NAD(P) in IDH1-mutated cells resulted in elevated oxidative stress and constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1 (Keap1). Activation of NRF2 enhanced glutathione synthesis by enhancing the gene transcription of GCLC, GCLM, and SLC7A11, which are the critical for glutathione de novo synthesis. Further, evidence from both in vitro assays and patient cohort indicated that NRF2 governed glutathione synthesis is important for maintaining the redox homeostasis and cell survival, especially in IDH1-mutated glioma. Finally, Blockade of the NRF2/glutathione metabolic pathway exhibited synergistic cytotoxicity with the metabolic stress in IDH1-mutated cells, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION In this study, we highlighted that NRF2 plays critical roles in the disease progression of IDH1-mutated glioma by prompting glutathione synthesis. Targeting NRF2 governed glutathione metabolism could serve as a valuable synthetic lethality approach for IDH1-mutated malignancies.

scholarly journals Effects of Early Resveratrol Intervention on Skeletal Muscle Mitochondrial Function and Redox Status in Neonatal Piglets with or without Intrauterine Growth Retardation

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Kang Cheng ◽  
Ting Wang ◽  
Simian Li ◽  
Zhihua Song ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Growth Retardation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Intrauterine Growth Retardation ◽  
Redox Status ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Mitochondrial Morphology ◽  
Intrauterine Growth

Skeletal muscle mitochondrial malfunction of offspring induced by intrauterine growth retardation (IUGR) may be a contributor to growth restriction and metabolic disorder at various periods of life. This study explored the effects of IUGR and resveratrol (RSV) on mitochondrial function and redox status in the longissimus dorsi muscle (LM) of piglets during the sucking period. A total of 36 pairs of IUGR and normal birth weight male piglets were orally fed with either 80 mg RSV/kg body weight/d or 0.5% carboxymethylcellulose sodium during days 7-21 after birth. The results showed that RSV treatment improved anomalous mitochondrial morphology, increased adenosine triphosphate and glycogen contents, and enhanced nicotinamide adenine dinucleotide/reduced form of nicotinamide-adenine dinucleotide ratio in the LM of IUGR piglets. Moreover, the IUGR-induced increased malondialdehyde and protein carbonyl concentrations, abnormal mtDNA number, and suppressed genes expression of mitochondrial biogenesis such as nuclear respiratory factor 1, estrogen-related receptor alpha, and polymerase gamma in the LM were restored to some extent by RSV treatment. Additionally, RSV increased mitochondrial complex V activity in the LM of piglets. Collectively, RSV administration alleviated the LM mitochondrial dysfunction and oxidative damage of IUGR piglets.

scholarly journals Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinhui Liu ◽  
Denggui Luo ◽  
Shiying Huang ◽  
Siqi Liu ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Periodic Acid ◽  
Public Health Problem ◽  
Nicotinamide Adenine ◽  
High Morbidity ◽  
Rat Models ◽  
Key Enzymes

Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD+) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD+ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD+ levels and tested the expression of key enzymes in three NAD+ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD+ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD+ and NADH content were both declined in two CKD rat models, and NAD+ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD+ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD+-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD+ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.

scholarly journals Significance and Transformation of 3-Alkyl-2-Methoxypyrazines Through Grapes to Wine: Olfactory Properties, Metabolism, Biochemical Regulation, and the HP–MP Cycle

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4598 ◽  
Author(s):  
Xianfang Zhao ◽  
Yanlun Ju ◽  
Xiaofeng Wei ◽  
Shuo Dong ◽  
Xiangyu Sun ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Poor Quality ◽  
Present Review ◽  
Factors Affecting ◽  
Future Studies ◽  
Environmental Stimuli ◽  
History Of ◽  
Biochemical Regulation ◽  
Insight Into ◽  
Gaining Insight

3-Alkyl-2-methoxypyrazines (MPs) contribute to the herbaceous flavor characteristics of wine and are generally considered associated with poor-quality wine. To control the MPs in grapes and wine, an accurate understanding of MP metabolism is needed. This review covers factors affecting people in the perception of MPs. Also, the history of O-methyltransferases is revisited, and the present review discusses the MP biosynthesis, degradation, and biochemical regulation. We propose the existence of a cycle between MPs and 3-alkyl-2-hydropyrazines (HPs), which proceeds via O-(de)methylation steps. This cycle governs the MP contents of wines, which make the cycle the key participant in MP regulation by genes, environmental stimuli, and microbes. In conclusion, a comprehensive metabolic pathway on which the HP–MP cycle is centered is proposed after gaining insight into their metabolism and regulation. Some directions for future studies on MPs are also proposed in this paper.

Coenzyme A, more than ‘just’ a metabolic cofactor

2014 ◽  
Vol 42 (4) ◽  
pp. 1075-1079 ◽  
Author(s):  
Balaji Srinivasan ◽  
Ody C.M. Sibon
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Coenzyme A ◽  
Cellular Metabolism ◽  
Vital Role ◽  
Nicotinamide Adenine ◽  
Direct Role ◽  
Age Related ◽  
Moonlighting Proteins ◽  
Metabolic Reactions

In all organisms biomolecules play a vital role to enable proper cellular metabolism. Alteration of metabolite homoeostasis disrupts the physiology of cells, leading to various diseases [DeBerardinis and Thompson (2012) Cell, 148, 1132–1144]. Recent studies advances our understanding that some metabolites are not only involved in cellular metabolism, but also have other molecular functions. It has become evident that similar to multifunctional ‘moonlighting proteins’, ‘moonlighting metabolites’ also exists. One clear example is nicotinamide adenine dinucleotide (NAD). NAD is a ubiquitous molecule with a well-known function in many metabolic reactions, but it also has become clear that NAD is involved in the regulation of sirtuins. Sirtuins play a role in cancer, diabetes, and cardiovascular, neurodegenerative and other diseases [Donmez and Outeiro (2013) EMBO Mol. Med. 5, 344–352] and the deacetylation capacity of sirtuin proteins is NAD-dependent. This direct role of NAD in age-related diseases could not be anticipated when NAD was initially discovered as a metabolic cofactor [Donmez and Outeiro (2013) EMBO Mol. Med. 5, 344–352; Mouchiroud et al. (2013) Crit. Rev. Biochem. Mol. Biol. 48, 397–408]. Recent findings now also indicate that CoA (coenzyme A), another metabolic cofactor, can be considered as being more than ‘just’ a metabolic cofactor, and altered CoA levels lead to severe and complex effects.

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