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Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer.
Novak Kujundžić, R, Prpić, M, Đaković, N, Dabelić, N, Tomljanović, M, Mojzeš, A, Fröbe, A, Trošelj, KG
International journal of molecular sciences. 2021;(11)
Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly-adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT's positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
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The Role of Nicotinamide in Cancer Chemoprevention and Therapy.
Nikas, IP, Paschou, SA, Ryu, HS
Biomolecules. 2020;(3)
Abstract
Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD+) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD+ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value.
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Minireview Exploring the Biological Cycle of Vitamin B3 and Its Influence on Oxidative Stress: Further Molecular and Clinical Aspects.
Doroftei, B, Ilie, OD, Cojocariu, RO, Ciobica, A, Maftei, R, Grab, D, Anton, E, McKenna, J, Dhunna, N, Simionescu, G
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Vitamin B3, or niacin, is one of the most important compounds of the B-vitamin complex. Recent reports have demonstrated the involvement of vitamin B3 in a number of pivotal functions which ensure that homeostasis is maintained. In addition, the intriguing nature of its synthesis and the underlying mechanism of action of vitamin B3 have encouraged further studies aimed at deepening our understanding of the close link between the exogenous supply of B3 and how it activates dependent enzymes. This crucial role can be attributed to the gut microflora and its ability to shape human behavior and development by mediating the bioavailability of metabolites. Recent studies have indicated a possible interconnection between the novel coronavirus and commensal bacteria. As such, we have attempted to explain how the gastrointestinal deficiencies displayed by SARS-CoV-2-infected patients arise. It seems that the stimulation of a proinflammatory cascade and the production of large amounts of reactive oxygen species culminates in the subsequent loss of host eubiosis. Studies of the relationhip between ROS, SARS-CoV-2, and gut flora are sparse in the current literature. As an integrated component, oxidative stress (OS) has been found to negatively influence host eubiosis, in vitro fertilization outcomes, and oocyte quality, but to act as a sentinel against infections. In conclusion, research suggests that in the future, a healthy diet may be considered a reliable tool for maintaining and optimizing our key internal parameters.
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Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide.
Badawy, AA
Bioscience reports. 2020;(10)
Abstract
COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is overexpressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and adenosine triphosphate (ATP), especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide (NAM), which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 (silent mating type information regulation 2 homologue 1) inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines and is effective against HIV infection. These properties qualify NAM for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.
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Biomimetic cofactors and methods for their recycling.
Zachos, I, Nowak, C, Sieber, V
Current opinion in chemical biology. 2019;:59-66
Abstract
Nicotinamide cofactor biomimetics (NCBs) belong to a class of compounds that, as the name suggests, mimic the structures and functions of natural nicotinamide cofactors, namely nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate and their corresponding reduced forms. The first set of NCBs was discovered in the 1930s; these were initially used to study the chemical properties of this class of cofactors as well as understand nicotinamide binding of oxidoreductases. Since then, various NCBs, enzymes, and recycling systems have evolved and lately, new NCBs have been developed and used to run biocatalytic reactions.
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Vitamin B Derivative (Nicotinamide)Appears to Reduce Skin Cancer Risk.
Nazarali, S, Kuzel, P
Skin therapy letter. 2017;(5):1-4
Abstract
Nicotinamide, an amide form of vitamin B3, has shown the potential to treat a variety of dermatological conditions, including acne, rosacea, and atopic dermatitis. Recent studies have demonstrated the role of nicotinamide, in both topical and oral forms, as a chemopreventive agent against skin cancer. Its anti-carcinogenic role may be due to its ability to enhance DNA repair and prevent ultraviolet (UV)-induced immunosuppression, which is known to contribute to the progression of pre-malignant lesions. Furthermore, nicotinamide is a precursor of essential coenzymes for many important reactions in the body, including the production of nicotinamide adenine dinucleotide (NAD). NAD is a key coenzyme in the synthesis of adenosine triphosphate (ATP), which transports chemical energy within cells. Therefore, nicotinamide plays a significant role in supporting energy-dependent cellular processes, including DNA repair.
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Use of nicotinamide in dermatology.
Forbat, E, Al-Niaimi, F, Ali, FR
Clinical and experimental dermatology. 2017;(2):137-144
Abstract
Nicotinamide (niacinamide) is the water-soluble, amide form of vitamin B3. We review the evidence underlying the use of nicotinamide for various dermatological indications, including nonmelanoma cancer prophylaxis, blistering disorders, acne vulgaris and cosmetic indications, and speculate upon its future role in dermatological practice.
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Definition of a tolerable upper intake level of niacin: a systematic review and meta-analysis of the dose-dependent effects of nicotinamide and nicotinic acid supplementation.
Minto, C, Vecchio, MG, Lamprecht, M, Gregori, D
Nutrition reviews. 2017;(6):471-490
Abstract
CONTEXT Nicotinic acid and nicotinamide are soluble compounds of the vitamin B group, widely used to regulate the lipid profile in hyperlipidemic individuals. Higher doses of nicotinic acid are associated with adverse effects, especially flushing. A unique tolerable upper intake level (UL) of nicotinic acid has not been defined. OBJECTIVE This meta-analysis aims to evaluate adverse effects and their incidence after supplementation with different doses of nicotinic acid and nicotinamide, comparing results with current ULs in Europe and the United States. DATA SOURCES PubMed was searched for articles providing detailed information about nicotinic acid or nicotinamide supplementation and related outcomes. STUDY SELECTION A total of 2670 citations were selected for screening. Two primary outcomes were considered: occurrence of adverse effects following nicotinic acid or nicotinamide supplementation, and dose at which adverse effects occurred. DATA EXTRACTION Details on study population, type and duration of treatment, dosage of vitamins, association with lipid-influencing drugs, length of follow-up, and incidence and type of adverse events were extracted. RESULTS After screening, 47 articles involving 11 741 individuals were included. Meta-analysis was based on estimation of benchmark doses for the probability of adverse effects after supplementation. In individuals with dyslipidemia or cardiovascular disease, nicotinic acid monotherapy seems to be protective against any adverse effects considered, as adverse events occurred at doses above those used with other treatments. In healthy individuals treated with nicotinic acid alone, major adverse effects occurred at doses below 1000 mg/d. CONCLUSIONS Results may indicate a high degree of conservativeness in the UL of nicotinic acid, fixed at 35 mg/d in United States and 10 mg/d in Europe. Reconsideration of the UL of nicotinic acid for nutritional supplements, possibly differentiating between ULs in healthy and unhealthy individuals, may be warranted.
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[New approaches for the prevention of actinic keratosis].
Stege, H, Krutmann, J
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2017;(5):354-358
Abstract
Actinic keratosis is one of the most common skin diseases. Because of the ongoing demographic changes, it is anticipated that the incidence will further increase. Prevention of actinic keratoses is thus of great importance. By far the most important cause of actinic keratoses is the chronic cumulative irradiation of human skin with ultraviolet B and A radiation from natural sunlight. There is no doubt that use of sunscreens is effective in preventing actinic keratoses. Recent studies indicate that in high-risk groups the regular use of medical devices which are characterized by a very high SPF and which contain liposomally encapsulated DNA repair enzymes are effective in preventing the development of new actinic keratoses even when field cancerization is already present in human skin. There is also evidence that oral photoprotective strategies based on the regular intake of vitamin B3 may be used to prevent actinic keratoses.
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A survey of synthetic nicotinamide cofactors in enzymatic processes.
Paul, CE, Hollmann, F
Applied microbiology and biotechnology. 2016;(11):4773-8
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Abstract
Synthetic nicotinamide cofactors are analogues of the natural cofactors used by oxidoreductases as redox intermediates. Their ability to be fine-tuned makes these biomimetics an attractive alternative to the natural cofactors in terms of stability, reactivity, and cost. The following mini-review focuses on the current state of the art of those biomimetics in enzymatic processes.