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

DOI:10.1007/s10522-019-09805-6
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.
... Supported by previous studies, nicotinamide adenine dinucleotide (NAD) was confirmed to be effective at improving cognitive function after insults [4][5][6]. NAD + is essential for many mitochondrial enzymatic reactions and appropriate bioenergetic metabolism. Under normal conditions, the loss of NAD + inhibits cellular respiration, resulting in reduced mitochondrial adenosine triphosphate (ATP) production and potentially cell death [6]. ...
... NAD + is essential for many mitochondrial enzymatic reactions and appropriate bioenergetic metabolism. Under normal conditions, the loss of NAD + inhibits cellular respiration, resulting in reduced mitochondrial adenosine triphosphate (ATP) production and potentially cell death [6]. NAD + is used as a substrate by several NAD + -dependent enzymes, including poly (ADP ribose) polymerase 1 (PARP1), Sirtuin-1 (Sirt1), and ADP ribosyl cyclase (CD38). ...
Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury
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Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD⁺ precursor, emerges as a neuroprotective factor after chronic brain insults. However, researchers have not determined whether it improves cognition after acute ischemia. In the present study, mice with middle cerebral artery occlusion were treated with NR chloride (NRC, 300 mg/kg, IP., 20 min after reperfusion). The results of the Morris water maze test revealed better recovery of learning and memory function in the NRC-treated group. Acute NRC treatment decreased hippocampal infarct volume, reduced neuronal loss and apoptosis in the hippocampus. Western blot and high-performance liquid chromatography assays of hippocampal tissues revealed that the activation of Sirtin-1 and adenosine 5′ monophosphate-activated protein kinase was increased, the NAD content was elevated, and the production of adenosine triphosphate was strengthened by NRC. Collectively, acute NRC treatment increased the energy supply, reduced the neuronal loss and apoptosis, protected the hippocampus and ultimately promoted the recovery of cognitive function after brain ischemia.
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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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Purpose P53 is one of the key tumor suppressors. In normal cells, p53 is maintained at low levels by the ubiquitination of the ubiquitinated ligase MDM2. In contrast, under stress conditions such as DNA damage and ischemia, the interaction between p53 and MDM2 is blocked and activated by phosphorylation and acetylation, thereby mediating the trans-activation of p53 through its target genes to regulate a variety of cellular responses. Previous studies have shown that the expression of p53 is negligible in normal myocardium, tends to increase in myocardial ischemia and is maximally induced in ischemia-reperfused myocardium, demonstrating a possible key role of p53 in the development of MIRI. In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and describe the therapeutic agents targeting the relevant targets to provide new strategies for the prevention and treatment of MIRI. Methods We collected 161 relevant papers mainly from Pubmed and Web of Science (search terms "p53" and "myocardial ischemia-reperfusion injury"). After that, we selected pathway studies related to p53 and classified them according to their contents. We eventually analyzed and summarized them. Results and conclusion In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and validate its status as an important intermediate affecting MIRI. On the one hand, p53 is regulated and modified by multiple factors, especially non-coding RNAs; on the other hand, p53 regulates apoptosis, programmed necrosis, autophagy, iron death and oxidative stress in MIRI through multiple pathways. More importantly, several studies have reported medications targeting p53-related therapeutic targets. These medications are expected to be effective options for the alleviation of MIRI, but further safety and clinical studies are needed to convert them into clinical applications.
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... Research related to niacin supplementation are mainly focused on aging and NAD + restoration during ischemia and reperfusion injury to mention a few [75]. These have shown benefits associated with a decreased cerebral infarct volume, improved sensory and motor response [76], less death of CA 1 pyramidal neurons [77] and greater remyelination through activation of the NAD + /BDNF/TrKB pathway [78]. ...
Bioactive role of vitamins as a key modulator of oxidative stress, cellular damage and comorbidities associated with spinal cord injury (SCI)
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Introduction: Spinal cord injury (SCI) cause significant disability and impact the quality of life of those affected by it. The nutritional status and diet are fundamental to diminish the progression of complications; vitamins modulate the inflammatory response and oxidative stress, promote blood-spinal cord barrier preservation and the prompt recovery of homeostasis. A deep knowledge of the benefits achieved from vitamins in patients with SCI are summarized. Information of dosage, time, and effects of vitamins in these patients are also displayed. Vitamins have been extensively investigated; however, more clinical trials are needed to clarify the scope of vitamin supplementation. Objective: The objective of this review was to offer relevant therapeutic information based on vitamins supplementation for SCI patients. Methods: Basic and clinical studies that have implemented the use of vitamins in SCI were considered. They were selected from the year 2000–2022 from three databases: PubMed, Science Direct and Google Scholar. Results: Consistent benefits in clinical trials were shown in those who were supplemented with vitamin D (prevents osteoporosis and improves physical performance variables), B3 (improves lipid profile) and B12 (neurological prophylaxis of chronic SCI damage) mainly. On the other hand, improvement related to neuroprotection, damage modulation (vitamin A) and its prophylaxis were associated to B complex vitamins supplementation; the studies who reported positive results are displayed in this review. Discussion: Physicians should become familiar with relevant information that can support conventional treatment in patients with SCI, such as the use of vitamins, a viable option that can improve outcomes in patients with this condition.
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... During the process of aging and related ischemic conditions, NAD + levels decrease and lead to nuclear and mitochondrial dysfunctions that result in age-related diseases. It has been demonstrated that restoring NAD + using intermediates, including nicotinamide mononucleotide and nicotinamide riboside, may be a good approach for recovering from ischemic injury and age-associated defects [48]. ...
The Aging Heart: A Molecular and Clinical Challenge
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Full-text available
Aging is associated with an increasing burden of morbidity, especially for cardiovascular diseases (CVDs). General cardiovascular risk factors, ischemic heart diseases, heart failure, arrhythmias, and cardiomyopathies present a significant prevalence in older people, and are characterized by peculiar clinical manifestations that have distinct features compared with the same conditions in a younger population. Remarkably, the aging heart phenotype in both healthy individuals and patients with CVD reflects modifications at the cellular level. An improvement in the knowledge of the physiological and pathological molecular mechanisms underlying cardiac aging could improve clinical management of older patients and offer new therapeutic targets.
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... Overproduction of ROS activates oxidative DNA damage signaling and PARP1, leading to decreased intracellular ATP and NAD +.218,219 NAD + is a cosubstrate for sirtuin family proteins (SIRT1-7), all of which play a critical role in regulating redox homeostasis and are associated with CVDs. 220,221 Intracellular depletion of NAD + attenuates the activity of SIRT1 222 and SIRT3, 223 further disturbing mitochondrial biogenesis and antioxidant defense, which leads to mitochondrial dysfunction, one of the hallmarks of IRI. 224 Numerous investigations have confirmed the correlation between myocardial IRI and ROS-induced oxidative DNA damage. ...
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DNA damage response (DDR) signaling ensures genomic and proteomic homeostasis to maintain a healthy genome. Dysregulation either in the form of down‐ or upregulation in the DDR pathways correlates with various pathophysiological states, including cancer and cardiovascular diseases (CVDs). Impaired DDR is studied as a signature mechanism for cancer; however, it also plays a role in ischemia‐reperfusion injury (IRI), inflammation, cardiovascular function, and aging, demonstrating a complex and intriguing relationship between cancer and pathophysiology of CVDs. Accordingly, there are increasing number of reports indicating higher incidences of CVDs in cancer patients. In the present review, we thoroughly discuss (1) different DDR pathways, (2) the functional cross talk among different DDR mechanisms, (3) the role of DDR in cancer, (4) the commonalities and differences of DDR between cancer and CVDs, (5) the role of DDR in pathophysiology of CVDs, (6) interventional strategies for targeting genomic instability in CVDs, and (7) future perspective.
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Mitochondria-targeted combination treatment strategy counteracts myocardial reperfusion injury of aged rats by modulating autophagy and inflammatory response
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Background Aging, as a recognized risk factor for ischemic heart disease, interferes with protective mechanisms and abolishes the optimal effectiveness of cardioprotective interventions, leading to the loss of cardioprotection following myocardial ischemia/reperfusion (I/R) injury. This study was designed to explore the possible interaction of aging with cardioprotection induced by combination therapy with coenzyme Q10 (CoQ10) and mitochondrial transplantation in myocardial I/R injury of aged rats. Methods Male Wistar rats (n = 72, 400–450 g, 22–24 months old) were randomized into groups with/without I/R and/or CoQ10 and mitochondrial transplantation, alone or in a combinational mode. An in vivo model of myocardial I/R injury was established by left anterior descending coronary artery occlusion and re-opening. Mitochondria were isolated from donor rats and injected intramyocardially (150 µl of the mitochondrial suspension containing 2 × 10⁵±0.3 × 10⁵ mitochondria) at the onset of reperfusion in recipient groups. CoQ10 (20 mg/kg/day) was injected intramuscularly for 7 days before I/R operation. Lastly, myocardial function, cTn-I level, expression of autophagy-associated proteins (Beclin1, p62, and LC3-II/LC3-I), and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were assessed. Results Co-application of CoQ10 and mitotherapy concomitantly improved myocardial function and decreased cTn-I level in aged reperfused hearts (P < .001). This combination therapy also modulated autophagic activity and decreased pro-inflammatory cytokines (P < .01 to P < .001). This combinational approach induced noticeable cardioprotection in comparison with monotherapies-received groups. Conclusion We found that combination of CoQ10 and mitochondrial transplantation attenuated myocardial I/R injury in aged rats, in part by modulating autophagy and inflammatory response, hence, appears to restore aging-related loss of cardioprotection in aged patients.
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Nicotinamide adenine dinucleotide attenuates acetaminophen-induced acute liver injury via activation of PARP1, Sirt1, and Nrf2 in mice
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The aim of this study was to investigate the protective effect of nicotinamide adenine dinucleotide (NAD+) against acute liver injury (ALI) induced by acetaminophen (APAP) overdose in mice. First, serum transaminases were used to assess the protective effect of NAD+, and the data revealed that NAD+ mitigated the APAP-induced ALI in a dose-dependent manner. Then, we performed hematoxylin–eosin staining of liver tissues and found that NAD+ alleviated the abnormalities of histopathology. Meanwhile, increase in the malondialdehyde content and decrease in glutathione, superoxide dismutase (SOD), and glutathione peroxidase were identified in the APAP group, which were partially prevented by the NAD+ pretreatment. Moreover, compared with the mice treated with APAP only, the expression of poly ADP-ribose polymerase 1 (PARP1), Sirtuin1 (Sirt1), SOD2, nuclear factor erythroid 2-related factor 2 (Nrf2), and hemoxygenase-1 was upregulated, while Kelch-like ECH-associated protein 1 and histone H2AX phosphorylated on Ser-139 were downregulated by NAD+ in NAD+ + APAP group. Conversely, NAD+ could not correct the elevated expression of phospho-Jun N-terminal kinase and phospho-extracellular signal-regulated kinase induced by APAP. Taken together, these findings suggest that NAD+ confers an anti-ALI effect to enhance the expression of PARP1 and Sirt1, and to simultaneously stimulate the Nrf2 anti-oxidant signaling pathway.
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Distribution of Nicotinamide Mononucleotide After Intravenous Injection in Normal and Ischemic Stroke Mice
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Photobiomodulation and Coenzyme Q10 Treatments Attenuate Cognitive Impairment Associated With Model of Transient Global Brain Ischemia in Artificially Aged Mice
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Disturbances in mitochondrial biogenesis and bioenergetics, combined with neuroinflammation, play cardinal roles in the cognitive impairment during aging that is further exacerbated by transient cerebral ischemia. Both near-infrared (NIR) photobiomodulation (PBM) and Coenzyme Q10 (CoQ10), administration are known to stimulate mitochondrial electron transport that potentially may reverse the effects of cerebral ischemia in aged animals. We tested the hypothesis that the effects of PBM and CoQ10, separately or in combination improve cognition in a mouse model of transient cerebral ischemia superimposed on a model of aging. We modeled aging by 6-week administration of D-galactose (500 mg/kg/subcutaneous) to mice. We subsequently, induced transient cerebral ischemia by bilateral occlusion of the common carotid artery (BCCAO). We treated the mice with PBM (810 nm transcranial laser) or CoQ10 (500 mg/kg; by gavage), or both, for two weeks after surgery. We assessed cognitive function by the Barnes and Lashley III mazes and the What-Where-Which (WWWhich) task. PBM or CoQ10, or both, improved spatial and episodic memory in the mice. Separately and together, the treatments lowered reactive oxygen species, and raised ATP and general mitochondrial activity, as well as biomarkers of mitochondrial biogenesis, including SIRT1, PGC-1α, NRF1, and TFAM. Neuroinflammatory responsiveness declined, as indicated by decreased iNOS, TNF-α, and IL-1β levels with the PBM and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice.
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Combination of Vildagliptin and Ischemic Postconditioning in Diabetic Hearts as a Working Strategy to Reduce Myocardial Reperfusion Injury by Restoring Mitochondrial Function and Autophagic Activity
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Purpose: Diabetic hearts are resistant to cardioprotection by ischemic-postconditioning (IPostC). Protection of diabetic hearts and finding related interfering mechanisms would have clinical benefits. This study investigated the combination effects of vildagliptin (Vilda) and IPostC on cardioprotection and the levels of autophagy and mitochondrial function following myocardial ischemia/reperfusion (I/R) injury in type-II diabetic rats. Methods: Diabetes was established by high fat diet/low dose of streptozotocin and lasted for 12 weeks. The diabetic rats received Vilda (6 mg/kg/day, orally) for one month before I/R. Myocardial regional ischemia was induced through the ligation of left coronary artery, and IPostC was applied immediately at the onset of reperfusion. The infarct size was assessed by a computerised planimetry and left ventricles samples were harvested for cardiac mitochondrial function studies (ROS production, membrane potential and staining) and western blotting was used for determination of autophagy markers. Results: None of Vilda or IPostC but combination of them could significantly reduce the infarct size of diabetic hearts, comparing to control (P<0.001). IPostC could not significantly affect p62 expression level in diabetic hearts, but pre-treatment with Vilda alone (p<0.05) and in combination with IPostC (p<0.01) more significantly decreased p62 expression in comparison with corresponding control group. The expression of LC3B-II and LC3BII/LC3BI as well as mitochondrial ROS production were decreased significantly in treatment groups (p<0.001). Mitochondrial membrane depolarization was significantly higher and mitochondrial density was lower in untreated diabetic I/R hearts than treated groups (p<0.001). IPostC in combination with vildagliptin prevented the mitochondrial membrane depolarization and increased the mitochondrial content more potent than IPostC alone in diabetic hearts. Conclusion: Combination of vildagliptin and IPostC in diabetic hearts was a well-working strategy to reduce myocardial I/R damages by restoring mitochondrial membrane potential and ROS production and modulating the autophagic activity in I/R hearts.
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Protective Effect of Nicotinamide Adenine Dinucleotide Phosphate on Renal Ischemia-Reperfusion Injury
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Background/aims: Renal ischemia-reperfusion injury (IRI) is a common consequence of acute kidney injury. Nicotinamide adenine dinucleotide phosphate (NADPH), which is derived from the pentose phosphate pathway, is essential for the proper functioning of essential redox and antioxidant defense systems. Previous studies have indicated that NADPH is responsible for protecting the brain from ischemic injury. The goal of this study was to analyze the protective function of NADPH in renal IRI. Methods: The IRI animal model was generated through a midline laparotomy surgery that clamped both sides of the renal pedicles for 40 min to induce renal ischemia. The in vitro model was generated by removing oxygen and glucose from human kidney epithelial cells (HK-2 cells), followed by reoxygenation to imitate IRI. Renal function and histopathological changes were observed and evaluated. Additionally, malondialdehyde and glutathione levels were determined in renal tissue homogenate as indicators of oxidative stress. ROS production in cells was determined by DHE staining. Protein biomarker expression was evaluated by western blot, apoptosis was analyzed by TUNEL staining, and p65 nuclear translocation was visualized by immunofluorescence. Results: Our data indicated that NADPH safeguarded the kidneys from histological and functional damage, and significantly reduce cell injury along with preventing potential increases in blood urea nitrogen and creatinine levels. Furthermore, we observed that NADPH increased glutathione levels, while reducing levels of malondialdehyde and reactive oxygen species. Additionally, our results suggested that NADPH treatment may alleviate IRI-induced apoptosis and inflammation. Conclusion: NADPH treatment may protect against renal IRI and should be further developed as a new treatment for acute kidney injury.
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Signaling mediators modulated by cardioprotective interventions in healthy and diabetic myocardium with ischaemia–reperfusion injury
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Ischaemic heart diseases are one of the major causes of death in the world. In most patients, ischaemic heart disease is coincident with other risk factors such as diabetes. Patients with diabetes are more prone to cardiac ischaemic dysfunctions including ischaemia–reperfusion injury. Ischaemic preconditioning, postconditioning and remote conditionings are reliable interventions to protect the myocardium against ischaemia–reperfusion injuries through activating various signaling pathways and intracellular mediators. Diabetes can disrupt the intracellular signaling cascades involved in these myocardial protections, and studies have revealed that cardioprotective effects of the conditioning interventions are diminished in the diabetic condition. The complex pathophysiology and poor prognosis of ischaemic heart disease among people with diabetes necessitate the investigation of the interaction of diabetes with ischaemia–reperfusion injury and cardioprotective mechanisms. Reducing the outcomes of ischaemia–reperfusion injury using targeted strategies would be particularly helpful in this population. In this study, we review the protective interventional signaling pathways and mediators which are activated by ischaemic conditioning strategies in healthy and diabetic myocardium with ischaemia–reperfusion injury.
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Mitochondria: A Common Target for Genetic Mutations and Environmental Toxicants in Parkinson’s Disease
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Parkinson’s disease (PD) is a devastating neurological movement disorder. Since its first discovery 200 years ago, genetic and environmental factors have been identified to play a role in PD development and progression. Although genetic studies have been the predominant driving force in PD research over the last few decades, currently only a small fraction of PD cases can be directly linked to monogenic mutations. The remaining cases have been attributed to other risk associated genes, environmental exposures and gene–environment interactions, making PD a multifactorial disorder with a complex etiology. However, enormous efforts from global research have yielded significant insights into pathogenic mechanisms and potential therapeutic targets for PD. This review will highlight mitochondrial dysfunction as a common pathway involved in both genetic mutations and environmental toxicants linked to PD.
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Aims Stroke is a leading cause of morbidity and mortality. This study aimed to determine whether nicotinamide administration could improve remyelination after stroke and reveal the underlying mechanism. Methods Adult male C57BL/6J mice were intraperitoneally (i.p.) administered with nicotinamide (200 mg/kg, daily) or saline after stroke induced by photothrombotic occlusion of the middle cerebral artery. FK866 (3 mg/kg, daily, bis in die), an inhibitor of NAMPT, and ANA-12 (0.5 mg/kg, daily), an antagonist of tropomyosin-related kinase B (TrkB), were administered intraperitoneally 1 h before nicotinamide administration. Functional recovery, MRI, and histological assessment were performed after stroke at different time points. Results The nicotinamide-treated mice showed significantly lower infarct area 7 d after stroke induction and significantly higher fractional anisotropy (FA) in the ipsilesional internal capsule (IC) 14 d after stroke induction than the other groups. Higher levels of NAD⁺, BDNF, and remyelination markers were observed in the nicotinamide-treated group. FK866 administration reduced NAD⁺ and BDNF levels in the nicotinamide-treated group. ANA-12 administration impaired the recovery from stroke with no effect on NAD⁺ and BDNF levels. Furthermore, lesser functional deficits were observed in the nicotinamide-treated group than in the control group. Conclusions Nicotinamide administration improves remyelination after stroke via the NAD⁺/BDNF/TrkB pathway.
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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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NAD replenishment with nicotinamide mononucleotide protects blood‐brain barrier integrity and attenuates delayed tPA‐induced haemorrhagic transformation after cerebral ischemia
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Background and purpose: Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischemia; however, a major limitation of tPA is the haemorrhagic transformation followed by tPA treatment. Here, we determine whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, would affect tPA-induced haemorrhagic transformation. Experimental approach: Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 hours. When the filament was removed for reperfusion, tPA was infused from tail vein. NMN was injected intraperitoneally with a single dose (300 mg/kg). Mice were euthanized at 24 hours post ischemia and their brains were evaluated for brain infarction, edema, hemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, tight junction proteins (TJPs) expression and matrix metalloproteinases (MMPs) activities/expression. Key results: In the mice infused with tPA at 5 hours post ischemia, there were significant increases in mortality, brain infarction, brain edema, brain hemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and MPO staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment induced BBB permeability by downregulating tight junction proteins, including claudin-1, occludin and ZO-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. Conclusions and implications: Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischemia by maintaining BBB integrity.
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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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