NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Окт. 7, 2020

Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions redox balance. NADPH homeostasis regulated by varied signaling pathways several metabolic enzymes that undergo adaptive alteration cancer cells. The reprogramming of renders cells both highly dependent on this network antioxidant capacity more susceptible to oxidative stress. Modulating unique might be effective strategy eliminate these In review, we summarize current existing literatures homeostasis, including its biological functions, regulatory mechanisms corresponding therapeutic interventions human cancers, providing insights into implications targeting metabolism associated mechanism therapy.

Язык: Английский

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NAD+ metabolism, stemness, the immune response, and cancer

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Янв. 1, 2021

NAD+ was discovered during yeast fermentation, and since its discovery, important roles in redox metabolism, aging, longevity, the immune system DNA repair have been highlighted. A deregulation of levels has associated with metabolic diseases aging-related diseases, including neurodegeneration, defective responses, cancer. acts as a cofactor through interplay NADH, playing an essential role many enzymatic reactions energy such glycolysis, oxidative phosphorylation, fatty acid oxidation, TCA cycle. also plays deacetylation by sirtuins ADP ribosylation damage/repair PARP proteins. Finally, different NAD hydrolase proteins consume while converting it into ADP-ribose or cyclic counterpart. Some these proteins, CD38, seem to be extensively involved response. Since cannot taken directly from food, metabolism is essential, NAMPT key enzyme recovering nicotinamide generating most cellular pools. Because complex network pathways which enzyme, NAMPT, cancer understandable. In present work, we review ways that they may influence system, stemness, some ongoing research on therapeutic approaches.

Язык: Английский

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Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review

The Protein Journal, Год журнала: 2020, Номер 39(6), С. 644 - 656

Опубликована: Окт. 26, 2020

Novel coronavirus disease 2019 (COVID-19) has resulted in a global pandemic and is caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Several studies have suggested that precise disulfide-thiol balance crucial for viral entry fusion into the host cell oxidative stress generated from free radicals can affect this balance. Here, we reviewed current knowledge about role of on SARS-CoV SARS-CoV-2 infections. We focused impact antioxidants, like NADPH glutathione, redox proteins, such as thioredoxin protein disulfide isomerase, maintain cell. The possible influence these biomolecules binding with angiotensin-converting enzyme II receptor well severity COVID-19 infection was discussed.

Язык: Английский

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Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

Molecules, Год журнала: 2019, Номер 24(5), С. 968 - 968

Опубликована: Март 9, 2019

Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of glutathione peroxiredoxin, produce α-ketoglutarate, co-factor numerous enzymes. IDH1/2 is mutated in ~70–80% lower-grade gliomas the majority secondary glioblastomas. The mutant IDH1 (R132H), addition losing its normal catalytic activity, gains function producing d-(R)-2-hydroxyglutarate (2-HG). Overproduction 2-HG cancer cells interferes with cellular metabolism inhibits histone DNA demethylases, which results hypermethylation blockade differentiation. We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated IDH1/2, their impact on tumor microenvironment antitumor immunity. Isoform-selective IDH inhibitors suppress production induce responses IDH2 mutations were developed validated preclinical settings. Inhibitors entered clinical trials represent novel drug class for targeted therapy gliomas. describe development small-molecule compounds peptide vaccines targeting IDH-mutant testing studies. All those support translational potential strategies carrying mutations.

Язык: Английский

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Review of various NAMPT inhibitors for the treatment of cancer

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Сен. 7, 2022

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the NAD salvage pathway of mammalian cells and overexpressed numerous types cancers. These include breast cancer, ovarian prostate gastric colorectal glioma, b-cell lymphoma. NAMPT also known to impact NADPH pool. Research has demonstrated that can be inhibited. inhibitors are diverse anticancer medicines with significant anti-tumor efficacy ex vivo tumor models. A few notable specific which have been produced FK866, CHS828, OT-82. Despite encouraging preclinical evidence potential utility cancer models, early clinical trials yielded only modest results, necessitating adaptation additional tactics boost efficacy. This paper examines number treatment methods target NAMPT, including usage individual inhibitors, pharmacological combinations, dual ADCs, all promising experimental or results. We intend contribute further ideas regarding development therapy advance field research on this intriguing target.

Язык: Английский

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In cancer, all roads lead to NADPH

Pharmacology & Therapeutics, Год журнала: 2021, Номер 226, С. 107864 - 107864

Опубликована: Апрель 22, 2021

Язык: Английский

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Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

Cancers, Год журнала: 2021, Номер 13(23), С. 6062 - 6062

Опубликована: Дек. 1, 2021

Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation progression. The growing level of inflammatory damage was shown increase severity contribute tumor spread. overproduction reactive oxygen species (ROS), is associated with reduced capacity endogenous cell defense mechanisms and/or metabolic imbalance, main contributor stress. An abnormal ROS defined as a predisposing factor for transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, facilitate accumulation mutations, DNA damage, genomic instability. Additionally, activation transcription factors caused by prolonged stress, including NF-κB, p53, HIF1α, etc., leads expression several genes responsible inflammation. resulting hyperactivation mediators, TNFα, TGF-β, interleukins, prostaglandins can development neoplasia. Pro-inflammatory cytokines were adaptive reactions acquisition resistance cells apoptosis, while promoting proliferation, invasion, angiogenesis. Moreover, chronic response excessive production free radicals, further aggravate initiated reactions. This review summarizes recent data progress discovery associate onset metastasis. In addition, provides insights therapeutic approaches natural substances will be able simultaneously inhibit key oncological inflammation-related targets.

Язык: Английский

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The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

AJP Cell Physiology, Год журнала: 2022, Номер 322(3), С. C521 - C545

Опубликована: Фев. 9, 2022

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is substrate for number of nonredox enzymes. NAD fundamental to variety cellular processes including energy metabolism, cell signaling, epigenetics. homeostasis appears be paramount importance health span longevity, its dysregulation associated with multiple diseases. metabolism dynamic maintained by synthesis degradation. The enzyme CD38, one the main NAD-consuming enzymes, key component homeostasis. majority CD38 localized plasma membrane catalytic domain facing extracellular environment, likely purpose controlling systemic levels NAD. Several types express but expression predominates on endothelial cells immune capable infiltrating organs tissues. Here we review potential roles disease postulate ways which causes changes contributes pathophysiology conditions. Indeed, animal models development infectious diseases, autoimmune disorders, fibrosis, metabolic age-associated diseases cancer, heart disease, neurodegeneration are altered enzymatic activity. Many these conditions modified CD38-deficient mice or blocking NADase In play role, CD38-dependent decline often common denominator pathophysiology. Thus, understanding may open new avenues treatment human

Язык: Английский

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An Activatable NIR Fluorescent Probe for NAD(P)H and Its Application to the Real‐Time Monitoring of p53 Abnormalities In Vivo

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(19)

Опубликована: Март 3, 2023

NAD(P)H is crucial for biosynthetic reactions and antioxidant functions. However, the current probes developed detecting in vivo require intratumoral injection, which limited their application animal imaging. To address this issue, we have a liposoluble cationic probe, KC8, exhibits excellent tumor-targeting ability near-infrared (NIR) fluorescence after reaction with NAD(P)H. By using it was demonstrated first time that level of mitochondria living colorectal cancer (CRC) cells highly related to abnormality p53. Furthermore, KC8 successfully used differentiate not only between tumor normal tissue but also tumors p53 when administered intravenously. Finally, evaluated heterogeneity through two fluorescent channels treating 5-Fu. This study provides new tool real-time monitoring CRC cells.

Язык: Английский

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WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts

Journal of the American Society of Nephrology, Год журнала: 2024, Номер 35(6), С. 696 - 718

Опубликована: Март 19, 2024

Key Points WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis progression. uncouples profibrotic activation cell proliferation renal myofibroblasts. controls mitochondrial respiration myofibroblasts through metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Background Renal fibrosis a common pathologic end point that challenging reverse, are responsible for accumulation fibrillar collagen–rich extracellular matrix. Recent studies have unveiled myofibroblasts' diversity proliferative characteristics, which linked different states. We previously demonstrated regulation matrix genes tissue by WWP2, multifunctional E3 ubiquitin–protein ligase. Here, we investigate reprograming CKD. Methods used kidney samples from patients with -null disease mice models leveraged single-cell RNA sequencing analysis detail cell-specific kidneys. Experiments primary cultured bulk-RNA sequencing, chromatin immunoprecipitation metabolomics, cellular metabolism assays were study its downstream signaling. Results The tubulointerstitial was associated progression murine models. deficiency promoted myofibroblast halted activation, reducing severity vivo . In myofibroblasts, increased fatty acid oxidation activated pentose phosphate pathway, boosting at expense glycolysis. suppressed transcription 1-alpha (PGC-1α), mediator response, pharmacologic inhibition PGC-1 α partially abrogated protective effects on Conclusions regulates reprogramming WWP2-PGC-1 axis, protects against

Язык: Английский

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