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Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions

Authors:
Leila Hosseini at Tabriz University of Medical Sciences
Leila Hosseini
Manouchehr S Vafaee at University of Southern Denmark
Manouchehr S Vafaee
Javad Mahmoudi at Tabriz University of Medical Sciences
Javad Mahmoudi
Reza Badalzadeh at Tabriz University of Medical Sciences
Reza Badalzadeh
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Abstract and Figures

Nicotinamide adenine dinucleotide (NAD⁺) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability of death. Ischemia is the lack of nutritive blood flow that causes damage and mortality that mostly occurs in various organs during aging. During the process of aging and related ischemic conditions, NAD⁺ levels decline and lead to nuclear and mitochondrial dysfunctions, resulting in age-related pathologies. The majority of studies have shown that restoring of NAD⁺ using supplementation with intermediates such as nicotinamide mononucleotide and nicotinamide riboside can be a valuable strategy for recovery of ischemic injury and age-associated defects. This review summarizes the molecular mechanisms responsible for the reduction in NAD⁺ levels during ischemic disorders and aging, as well as a particular focus is given to the recent progress in the understanding of NAD⁺ precursor’s effects on aging and ischemia.
Schematic representation of pathways for NAD ? biosynthesis. NAD ? can be synthesized by Preiss-Handler, de novo, and salvage pathways (from left to right). Multiple enzymes such as CD38, Sirtuins and PARPS consume NAD ? and produce nicotinamide. QAquinolinic acid, QPRT Quinolinate phosphoribosyltransferase, TRP Tryptophan, NA Nicotinic acid, NAMN Nicotinic acid mononucleotide, NAAD Nicotinic acid dinucleotide, NMNATs Nicotinamide mononucleotide adenylyltransferase, NADS NAD synthase, NMN Nicotinamide mononucleotide, NR nicotinamide riboside, NAMPT Nicotinamide phosphoribosyltransferase, NRK Nicotinamide riboside kinase, Nicotinamide Phosphoribosyltransferase, NAPRT Nicotinic acid phosphoribosyltransferase, NAD ? Nicotinamide adenine dinucleotide, NAM Nicotinamide. All pathways have been explained in the text
Schematic representation of pathways for NAD ? biosynthesis. NAD ? can be synthesized by Preiss-Handler, de novo, and salvage pathways (from left to right). Multiple enzymes such as CD38, Sirtuins and PARPS consume NAD ? and produce nicotinamide. QAquinolinic acid, QPRT Quinolinate phosphoribosyltransferase, TRP Tryptophan, NA Nicotinic acid, NAMN Nicotinic acid mononucleotide, NAAD Nicotinic acid dinucleotide, NMNATs Nicotinamide mononucleotide adenylyltransferase, NADS NAD synthase, NMN Nicotinamide mononucleotide, NR nicotinamide riboside, NAMPT Nicotinamide phosphoribosyltransferase, NRK Nicotinamide riboside kinase, Nicotinamide Phosphoribosyltransferase, NAPRT Nicotinic acid phosphoribosyltransferase, NAD ? Nicotinamide adenine dinucleotide, NAM Nicotinamide. All pathways have been explained in the text
… 
Schematic diagram shows NAD ? targets which are involved in reduction of ischemic injury and aging pathology. The reduced levels of NAD ? in aging and ischemia are reversed by the use of NR, NAM, NMN or increased expression of NAMPT. Oxidative stress, inflammation, and apoptosis are induced by aging and ischemic insult. NAD ? can inhibit these processes. NAD ? also plays a protective role by increasing autophagy flux, energy metabolism and activation Sirtuin 1 and 3 (Sirt1& 3). Higher SIRT3 activity can inhibit mitochondrial fission (Mito-fission) and increase mitochondria integrity
Schematic diagram shows NAD ? targets which are involved in reduction of ischemic injury and aging pathology. The reduced levels of NAD ? in aging and ischemia are reversed by the use of NR, NAM, NMN or increased expression of NAMPT. Oxidative stress, inflammation, and apoptosis are induced by aging and ischemic insult. NAD ? can inhibit these processes. NAD ? also plays a protective role by increasing autophagy flux, energy metabolism and activation Sirtuin 1 and 3 (Sirt1& 3). Higher SIRT3 activity can inhibit mitochondrial fission (Mito-fission) and increase mitochondria integrity
… 
The molecular mechanisms that are involved in the reduction of NAD⁺ levels during aging and ischemia. Aging and ischemic injury lead to increased oxidative stress via reactive oxygen species overproduction, DNA damage and inflammation which decrease the levels of NAD⁺ through activation of CD38 and PARP-1. NAMPT expression reduces with advance age and in ischemic conditions that cause reduced production of NMN and NAD⁺
The molecular mechanisms that are involved in the reduction of NAD⁺ levels during aging and ischemia. Aging and ischemic injury lead to increased oxidative stress via reactive oxygen species overproduction, DNA damage and inflammation which decrease the levels of NAD⁺ through activation of CD38 and PARP-1. NAMPT expression reduces with advance age and in ischemic conditions that cause reduced production of NMN and NAD⁺
… 
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REVIEW ARTICLE
Nicotinamide adenine dinucleotide emerges as a therapeutic
target in aging and ischemic conditions
Leila Hosseini .Manouchehr S. Vafaee .Javad Mahmoudi .Reza Badalzadeh
Received: 17 December 2018 / Accepted: 27 February 2019 / Published online: 5 March 2019
ÓSpringer Nature B.V. 2019
Abstract Nicotinamide adenine dinucleotide
(NAD
?
) has been described as central coenzyme of
redox reactions and is a key regulator of stress
resistance and longevity. Aging is a multifactorial
and irreversible process that is characterized by a
gradual diminution in physiological functions in an
organism over time, leading to development of age-
associated pathologies and eventually increasing the
probability of death. Ischemia is the lack of nutritive
blood flow that causes damage and mortality that
mostly occurs in various organs during aging. During
the process of aging and related ischemic conditions,
NAD
?
levels decline and lead to nuclear and mito-
chondrial dysfunctions, resulting in age-related
pathologies. The majority of studies have shown that
restoring of NAD
?
using supplementation with inter-
mediates such as nicotinamide mononucleotide and
nicotinamide riboside can be a valuable strategy for
recovery of ischemic injury and age-associated
defects. This review summarizes the molecular mech-
anisms responsible for the reduction in NAD
?
levels
during ischemic disorders and aging, as well as a
particular focus is given to the recent progress in the
understanding of NAD
?
precursor’s effects on aging
and ischemia.
L. Hosseini
Drug Applied Research Center, Department of
Physiology, Tabriz University of Medical Sciences,
Tabriz, Iran
L. Hosseini M. S. Vafaee R. Badalzadeh (&)
Aging Research Institute, Tabriz University of Medical
Sciences, Tabriz, Iran
e-mail: badalzadehr@tbzmed.ac.ir
M. S. Vafaee
Department of Nuclear Medicine, Odense University
Hospital, Odense, Denmark
M. S. Vafaee
Department of Clinical Research, BRIDGE: Brain
Research-Inter-Disciplinary Guided Excellence,
University of Southern Denmark, Odense, Denmark
M. S. Vafaee J. Mahmoudi
Neuroscience Research Centre, Tabriz University of
Medical Sciences, Tabriz, Iran
R. Badalzadeh
Molecular Medicine Research Centre, Tabriz University
of Medical Sciences, Tabriz, Iran
123
Biogerontology (2019) 20:381–395
https://doi.org/10.1007/s10522-019-09805-6(0123456789().,-volV)(0123456789().,-volV)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... NAD+, the precursor of the major source of the reductive power for RONS detoxification, NADPH, is reduced in tachypaced HL-1 cardiomyocytes due to poly(ADP-ribose) polymerase 1 (PARP1) activation [94] . PARP1, a nuclear enzyme that carries out protein poly(ADPribosyl)ation, is upregulated by DNA damage, as is accumulated during aging, and acts as a caretaker of genome stability to promote longevity [95] . However, PARP1 activation also depletes NAD+, a major player in oxidative defense, which exacerbates oxidative damage [ Figure 3]. ...
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... NAD + plays an important role in basic life activities and functions, including cellular energy metabolism and cell survival (Hou et al., 2021). NAD + directly and indirectly affects many functions, including inflammatory response, metabolic pathways, DNA repair, chromatin remodeling, gene expression regulation, cell aging, cell apoptosis, and immune cell function (Hosseini et al., 2019). NMN is the most effective and direct substance used to supplement NAD + and participates in the entire process of NAD + metabolism. ...
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... EGCG, curcumin, ginsenoside Rb2, and RES as plant extracts need further studies to prove their safety and to solve their bioavailability, metabolism rate, and other issues. In addition, basic and clinical studies based on exogenous NAD supplementation have been robustly conducted in several systems [192][193][194][195]. Although there is still some distance to clinical application, exogenous NAD supplementation has been proven to have a promising future in MIRI treatment. ...
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Background Emerging evidence reveals that nicotinamide phosphoribosyltransferase (NAMPT) has a significant role in the pathophysiology of the inflammatory process. NAMPT inhibition has a beneficial effect in the treatment of a variety of inflammatory diseases. However, it remains unclear whether NAMPT inhibition has an impact on ischemia-reperfusion (I/R)-induced acute lung injury. In this study, we examined whether NAMPT inhibition provided protection against I/R lung injury in rats. Methods Isolated perfused rat lungs were subjected to 40 min of ischemia followed by 60 min of reperfusion. The rats were randomly allotted to the control, control + FK866 (NAMPT inhibitor, 10 mg/kg), I/R, or I/R + FK866 groups (n = 6 per group). The effects of FK866 on human alveolar epithelial cells exposed to hypoxia-reoxygenation (H/R) were also investigated. Results Treatment with FK866 significantly attenuated the increases in lung edema, pulmonary arterial pressure, lung injury scores, and TNF-α, CINC-1, and IL-6 concentrations in bronchoalveolar lavage fluid in the I/R group. Malondialdehyde levels, carbonyl contents and MPO-positive cells in lung tissue were also significantly reduced by FK866. Additionally, FK866 mitigated I/R-stimulated degradation of IκB-α, nuclear translocation of NF-κB, Akt phosphorylation, activation of mitogen-activated protein kinase, and downregulated MKP-1 activity in the injured lung tissue. Furthermore, FK866 increased Bcl-2 and decreased caspase-3 activity in the I/R rat lungs. Comparably, the in vitro experiments showed that FK866 also inhibited IL-8 production and NF-κB activation in human alveolar epithelial cells exposed to H/R. Conclusions Our findings suggest that NAMPT inhibition may be a novel therapeutic approach for I/R-induced lung injury. The protective effects involve the suppression of multiple signal pathways.
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The role of autophagy, neuroprotective mechanisms of nicotinamide adenine dinucleotide (NAD ⁺ ), and their relationship in spinal cord ischemic reperfusion injury (SCIR) was assessed. Forty-eight Sprague-Dawley rats were divided into four groups: sham, ischemia reperfusion (I/R), 10 mg/kg NAD ⁺ , and 75 mg/kg NAD ⁺ . Western blotting, immunofluorescence, and immunohistochemistry were used to assess autophagy and apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were used to assess neurological function. Expression levels of Beclin-1, Atg12-Atg5, LC3B-II, cleaved caspase 3, and Bax were upregulated in the I/R group and downregulated in the 75 mg/kg NAD ⁺ group; p-mTOR, p-AKT, p62, and Bcl-2 were downregulated in the I/R group and upregulated in the 75 mg/kg NAD ⁺ group. Numbers of LC3B-positive, caspase 3-positive, Bax-positive, and TUNEL-positive cells were significantly increased in the I/R group and decreased in the 75 mg/kg NAD ⁺ group. The mean integrated option density of Bax increased and that of Nissl decreased in the I/R group, and it decreased and increased, respectively, in the 75 mg/kg NAD ⁺ group. BBB scores significantly increased in the 75 mg/kg NAD ⁺ group relative to the I/R group. No difference was observed between I/R and 10 mg/kg NAD ⁺ groups for these indicators. Therefore, excessive and sustained autophagy aggravates SCIR; administration of NAD ⁺ alleviates injury.
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Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury
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  • Jul 2017
Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.
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