COVID-19: Are We Facing Secondary Pellagra Which Cannot Simply Be Cured by Vitamin B3?

Immune response to SARS-CoV-2 and ensuing inflammation pose a huge challenge to the host’s nicotinamide adenine dinucleotide (NAD+) metabolism. Humans depend on vitamin B3 for biosynthesis of NAD+, indispensable for many metabolic and NAD+-consuming signaling reactions. The balance between its utilization and resynthesis is vitally important. Many extra-pulmonary symptoms of COVID-19 strikingly resemble those of pellagra, vitamin B3 deficiency (e.g., diarrhoea, dermatitis, oral cavity and tongue manifestations, loss of smell and taste, mental confusion). In most developed countries, pellagra is successfully eradicated by vitamin B3 fortification programs. Thus, conceivably, it has not been suspected as a cause of COVID-19 symptoms. Here, the deregulation of the NAD+ metabolism in response to the SARS-CoV-2 infection is reviewed, with special emphasis on the differences in the NAD+ biosynthetic pathway’s efficiency in conditions predisposing for the development of serious COVID-19. SARS-CoV-2 infection-induced NAD+ depletion and the elevated levels of its metabolites contribute to the development of a systemic disease. Acute liberation of nicotinamide (NAM) in antiviral NAD+-consuming reactions potentiates “NAM drain”, cooperatively mediated by nicotinamide N-methyltransferase and aldehyde oxidase. “NAM drain” compromises the NAD+ salvage pathway’s fail-safe function. The robustness of the host’s NAD+ salvage pathway, prior to the SARS-CoV-2 infection, is an important determinant of COVID-19 severity and persistence of certain symptoms upon resolution of infection

Epigenetics and gene physiology

Za razliku od genomike, koja se temelji na proučavanju građe – anatomije gena, epigenomika se temelji na izučavanju nasljednih varijacija u aktivnosti gena, dakle njihovoj fiziologiji. Osnovni epigenetički procesi, regulatori aktivnosti gena su metilacija molekule DNA i post translacijske modifikacije histona. Ova dva procesa međusobno se nadopunjuju pri čemu stvaraju epigenetičku mrežu događaja koja u konačnici regulira aktivnost pojedinih gena. Uspostava određenog tipa epigenetičke mreže ovisi o anatomiji gena i njegovog promotora te stalnom međudjelovanju egzogenih i endogenih čimbenika koji dovode do stvaranja karakterističnog epigenetičkog biljega. Sve se više uviđa važnost reverzibilnosti uspostave i uklanjanja epigenetičkih molekularnih biljega u svim, a naročito u zloćudnim bolestima. Istraživanja u području epigenomike, primjene novih, epigenomskih pristupa u liječenju, a posebno u području razvoja “pametnih”, epigenetičkih lijekova, u uzlaznoj su putanji koja još uvijek nije dosegla svoj zenit.Epigenetics is focused on gene physiology, analyzing inherited variations in gene expression, while genomics is focused on gene anatomy, analyzing gene structure. DNA methylation and histone post-translational modifications are the basic epigentic mechanisms regulating gene activity. These two processes complement each other, creating an epigenetic network of events which regulates specifi c gene activity. Establishing a particular type of epigenetic network depends on the anatomy of both the gene and its promoter, as well as the permanent interaction of exogenic and endogenic factors, which result in a particular epigenetic mark. As a result of new data, the importance of epigenetic marks as a reversible process, is becoming increasingly relevant to disease development, especially for cancer. One looks forward to the promise, still to be fully realized, of research in epigenetics, including new approaches to therapy and the development of “smart” epigenetic drugs

Genetic coding algorithm for sense and antisense peptide interactions

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Nutritional Stress in Head and Neck Cancer Originating Cell Lines: The Sensitivity of the NRF2-NQO1 Axis

Nutritional stress disturbs the cellular redox- status, which is characterized by the increased generation of reactive oxygen species (ROS). The NRF2-NQO1 axis represents a protective mechanism against ROS. Its strength is cell type-specific. FaDu, Cal 27 and Detroit 562 cells differ with respect to basal NQO1 activity. These cells were grown for 48 hours in nutritional conditions (NC): (a) Low glucose–NC2, (b) no glucose, no glutamine– NC3, (c) no glucose with glutamine–NC4. After determining the viability, proliferation and ROS generation, NC2 and NC3 were chosen for further exploration. These conditions were also applied to IMR-90 fibroblasts. The transcripts/transcript variants of NRF2 and NQO1 were quantified and transcript variants were characterized. The proteins (NRF2, NQO1 and TP53) were analyzed by a western blot in both cellular fractions. Under NC2, the NRF2-NQO1 axis did not appear activated in the cancer cell lines. Under NC3, the NRF2- NQO1axis appeared slightly activated in Detroit 562. There are opposite trends with respect to TP53 nuclear signal when comparing Cal 27 and Detroit 562 to FaDu, under NC2 and NC3. The strong activation of the NRF2-NQO1 axis in IMR-90 resulted in an increased expression of catalytically deficient NQO1, due to NQO1*2/*2 polymorphism (rs1800566). The presented results call for a comprehensive exploration of the stress response in complex biological systems

Nicotinamide N-Methyltransferase in Acquisition of Stem CellProperties and Therapy Resistance in Cancer

The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the mainte-nance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylationof nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further me-tabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMTis important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriatelyhigh expression and activity of NNMT, commonly present in various types of cancer, has the potentialto disrupt NAD+homeostasis and cellular methylation potential. Largely overlooked, in the contextof cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effecton cellular NAD+flux by stalling liberation of NAM and reducing NAD+synthesis in the salvagepathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasionof 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 outcome