Nrf2 Mediates Effect of Resveratrol in Ischemia-reperfusion Injury.

Ischemia-Reperfusion Injury (IRI) is a paradoxical phenomenon where removing the source of injury can cause additional damage. Ischemia reduces ATP production and intracellular pH, reducing oxidative reactions, increasing lactic acid release, and activating anaerobic metabolism. Reperfusion restores aerobic respiration and increases ROS production, leading to malfunction of transmembrane transport, activation of proteases, DNA dissolution, and protein denaturation, leading to apoptotic cell death. Nrf2 is a transcription factor that regulates cellular inflammation and oxidative responses. It is activated by oxidants and electrophiles and enhances detoxifying enzyme expression, maintaining redox homeostasis. It also activates ARE, which activates several ARE-regulated genes that favor cell survival by exhibiting resistance to oxidants and electrophiles. Nrf2 regulates the antioxidant defense system by producing phase II and antioxidant defense enzymes, including HO-1, NQO-1, gglutamylcysteine synthetase, and rate-limiting enzymes for glutathione synthesis. Nrf2 protects mitochondria from damage and supports mitochondrial function in stress conditions. Resveratrol is a stilbene-based compound with a wide variety of health benefits for humans, including antioxidant, anticarcinogenic, antitumor, and estrogenic/antiestrogenic. Resveratrol protects against IRI through several signaling pathways, including the Nrf2/ARE pathway. Here, we review the studies that investigated the mechanisms of resveratrol protection against IRI through modulation of the Nrf2 signaling pathway.

Pegylated nanoliposomal cisplatin ameliorates chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse effect of cisplatin. The current study aimed to determine whether PEGylated nanoliposomal cisplatin can limit CIPN in an animal model. METHODS: Cisplatin-loaded PEGylated liposome nanoparticles (Cis-PL) were produced as a combination of lecithin, cholesterol, and DSPE-mPEG2000 in a molar ratio of 50:45:5 and were characterized by polydispersity index (PDI), zeta potential, Field emission scanning electron microscopy (FESEM) analysis, as well as encapsulation efficiency (EE). Fifteen male rats were provided and randomly divided into 3 groups including Cis-PL group, cisplatin group, and control group. Behavioural tests (hot-plate test and acetone drop test) were used for evaluating CIPN. Moreover, oxidative stress markers and histopathological analysis were applied. Treatment-related toxicity was assessed by haematological analysis as well as liver and renal function tests. RESULTS: Cis-PL had an average particle size of 125.4, PDI of 0.127, and zeta potential of -40.9 mV. Moreover, the Cis-PL exhibited a high EE as well as low levels of leakage rate at 25 °C. In a hot-plate test, paw withdrawal latency was longer in Cis-PL group in comparison to rats treated with cisplatin. A lower number of withdrawal responses was detected during acetone drop test in Cis-PL group than in cisplatin-treated rats. Assessment of oxidative stress markers showed that Cis-PL could improve oxidative stress. Additionally, histopathological assessment demonstrated that the number of satellite cells was significantly reduced in the dorsal root ganglion (DRG) of Cis-PL-treated rats compared with those treated with cisplatin. The cisplatin group had elevated white blood cells counts, reduced platelet counts, and higher levels of bilirubin, ALT (alanine aminotransferase, and AST (aspartate aminotransferase), and creatinine compared with the control group, which was ameliorated in Cis-PL group. CONCLUSIONS: Data from the current study support the previous hypothesis that Cisplatin-loaded PEGylated liposome could be a promising solution for CIPN in the future by modulating oxidative stress and preventing glial cell activation in DRG, suggesting further clinical studies to investigate the efficacy of this agent and its potential application in clinical practice.

Saffron (Crocus sativus) and its constituents for pain management: A review of current evidence.

Pain can become a chronic and deliberating experience with a significant burden. In preclinical and clinical studies, Saffron (Crocus sativus L.) has shown analgesic activities. Considering the unsatisfactory results of current therapeutic management for chronic pain conditions, we aimed to review saffron's analgesic activity and underlying mechanisms. Saffron showed antinociceptive activities in formalin-, carrageenan-, and capsaicin-induced experimental pain models. Saffron analgesic activities affected several targets, including ion channels of nociceptors; the adrenergic system and central histaminic system; inhibition of inflammatory pathways, apoptotic pathways, and oxidative stress; regulation of NO pathway, and the endocannabinoid system. Clinical studies showed analgesia of Saffron in rheumatoid arthritis, after-pain following childbirth, dysmenorrhea, and fibromyalgia. Our literature review showed that saffron can be beneficial as an adjunct therapy to commonly used analgesics in practice, particularly in chronic pain conditions.

Anti-arthritic and Antioxidant Effects of Trehalose in an Experimental Model of Arthritis.

BACKGROUND: The purpose of the present study was to study the potential anti-arthritic and antioxidant effects of trehalose in an experimental model of complete Freund's adjuvant (CFA)-induced arthritis. METHODS: Arthritis was induced via subcutaneous injection of CFA (0.1) into the right footpad of each rat. Trehalose (10 mg/kg per day) and indomethacin (5 mg/kg) as a reference drug were intraperitoneally injected into CFA-induced arthritic rats from days 0 to 21. Changes in paw volume, pain responses, arthritic score, and oxidative/antioxidative parameters were determined. RESULTS: Trehalose administration could significantly decrease arthritis scores (p <0.01) and paw edema (p <0.001), and significantly increase the nociceptive threshold (p <0.05) in CFA-induced arthritic rats. Trehalose also significantly reduced the pro-oxidant-antioxidant balance values when compared to CFA treatment alone. In addition, no significant difference was found between the trehalose group and indomethacin as a positive control group. CONCLUSION: The current study suggests that trehalose has a protective effect against arthritis, which may be mediated by antioxidative effects of this disaccharide.

The Role of Resveratrol in Aging and Senescence: A Focus on Molecular Mechanisms.

Resveratrol (Res), a polyphenol found in red wine, has been shown to decelerate aging, the progressive loss of physiological integrity and cellular senescence, characterized by the inability to progress through the cell cycle. No successful clinical trials have yet to be completed in humans on dose limitations. Yet, the potent anti-aging and anti-senescence efficacy of Res has been documented in several in vivo animal models. In this review, we highlight the molecular mechanisms of Res efficacy in anti-aging disorders, such as diabetes, neurodegenerative disorders, eye diseases, and cardiovascular diseases.

Phytochemicals as substances that affect astrogliosis and their implications for the management of neurodegenerative diseases.

Astrocytes are a multifunctional subset of glial cells that are important in maintaining the health and function of the central nervous system (CNS). Reactive astrocytes may release inflammatory mediators, chemokines, and cytokines, as well as neurotrophic factors. There may be neuroprotective (e.g., cytokines, like IL-6 and TGF-b) and neurotoxic effects (e.g., IL-1ß and TNF-a) associated with these molecules. In response to CNS pathologies, astrocytes go to a state called astrogliosis which produces diverse and heterogenic functions specific to the pathology. Astrogliosis has been linked to the progression of many neurodegenerative disorders. Phytochemicals are a large group of compounds derived from natural herbs with health benefits. This review will summarize how several phytochemicals affect neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease) in basic medical and clinical studies and how they might affect astrogliosis in the process.

Evaluation of the hepatotoxicity of buprenorphine in rat pups born to an exposed mother during lactation.

Aim/ Background: This study aimed to evaluate the hepatotoxicity of buprenorphine in lactating rat pups of buprenorphine-injected mothers. Buprenorphine (BUP), a semisynthetic opioid, is increasingly administrated as a first-line standard maintenance treatment for opioid dependence due to its high safety and efficacy compared to other opioids. Numerous studies have confirmed the safety of BUP maintenance treatment in addicted patients Objective: This study was designed to assess the effects of BUP on the activities of liver enzymes, oxidative parameters, and liver histopathological changes in pups born to a mother exposed to this drug during lactation. METHODS: BUP at a dose of 0.5 or 0.1 mg/kg was subcutaneously administrated to lactating rats for 28 days. At the end of the experiment, the pups were anesthetized, and blood samples were obtained from their hearts for measuring liver enzymes. Then the livers of the animals were dissected to measure oxidative stress parameters. In addition, the liver samples were fixed for histopathological evaluation. RESULTS: The findings indicated a decrease in the activities of serum liver enzymes (ALT and AST) of the pups born to mothers exposed to 0.5 and 1 mg/kg of BUP during lactation. BUP could not change malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels, nor superoxide dismutase (SOD) activity in the liver tissue of animals. Some vacuolated hepatocytes with dark, eccentric nuclei, necrosis with karyolytic nuclei, mitotic figures, and multiple binucleated cells were seen in the pups which received 1 mg/kg of BUP. CONCLUSION: In conclusion, BUP may induce liver dysfunction in pups born to mothers exposed to this drug during lactation.

Susceptibility of domestic and companion animals to SARS-CoV-2: a comprehensive review.

The ongoing coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a large global outbreak. The reports of domestic animals' infection with SARS-CoV-2 raise concerns about the virus's longer-lasting spread, the establishment of a new host reservoir, or even the evolution of a new virus, as seen with COVID-19. In this review, we focus on the susceptibility of domestic animals, especially companion animals, towards SARS-CoV-2 in light of existing studies of natural infection, experimental infection, and serological surveys. Susceptibility of domestic and companion animals to SARS-CoV-2 infection.

Synergistic effect of ellagic acid and gabapentin in a rat model of neuropathic pain.

BACKGROUND: Neuropathic pain is a subtype of chronic pain characterized by a primary lesion or dysfunction of the peripheral or central nervous system. The current pain management of neuropathic pain is inadequate and needs new medications. AIM: We studied the effects of 14 days of intraperitoneal ellagic acid (EA) and gabapentin administration in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the right sciatic nerve. METHODS: Rats were divided into six groups: (1) control, (2) CCI, (3) CCI + EA (50 mg/kg), 4) CCI + EA (100 mg/kg), 5) CCI + gabapentin (100 mg/kg), and 6) CCI + EA (100 mg/kg) + gabapentin (100 mg/kg). Behavioral tests, including mechanical allodynia, cold allodynia, and thermal hyperalgesia, were conducted on days - 1(pre-operation), 7, and 14 post-CCI. In addition, at day 14 post-CCI, spinal cord segments were collected to measure the expression of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and oxidative stress markers, including malondialdehyde (MDA) and thiol. RESULTS: CCI increased mechanical allodynia, cold allodynia, and thermal hyperalgesia in rats which were reduced by treatment with EA (50 or 100 mg/kg), gabapentin, or their combination. CCI increased TNF-α, NO, and MDA levels and decreased thiol content in the spinal cord, which all were reverted by administration of EA (50 or 100 mg/kg), gabapentin, or their combination. CONCLUSION: This is the first report on ellagic acid's ameliorative effect in rats' CCI-induced neuropathic pain. This effect can be attributed to its anti-oxidative and anti-inflammatory, thus making it potentially useful as an adjuvant to conventional treatment.

Cerium Oxide Nanoparticles Ameliorate Oxidative Stress, Inflammation, and Pain Behavior in Neuropathic Rats.

BACKGROUND: Neuropathic pain originating from a dysfunction in the nervous system is often intractable and chronic. Recently, several studies using nanoparticles suggested a new way to control neuropathic pain. This study intended to explore the potential neuroprotective effect of Cerium Oxide Nanoparticles (CNPs) synthesized by pullulan in neuropathic pain in rats. METHODS: On the right common sciatic nerve of male Wistar rats, the chronic constriction injury (CCI) procedure was used to establish a neuropathic pain model. CNPs were injected into the caudal vein of the rat. Behavioral methods were used to detect mechanical allodynia, cold allodynia, and thermal hyperalgesia in rats. Besides, inflammation factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, nitric oxide (NO), and markers of oxidative stress, including Malondialdehyde (MDA) and total thiol, were measured in the spinal cord segment of rats. RESULTS: In rats with CCI, mechanical allodynia, cold allodynia, and thermal hyperalgesia developed, which improved when the rats were administered CNPs. Spinal cord specimens of CCI rats had elevated inflammation and oxidative stress status (↑IL-1ß, ↑TNF-α, ↑NO, ↑MDA) and decreased antioxidative levels (↓total thiol). As a result of CNPs treatment, these changes were reversed in the spinal cord specimens. CONCLUSION: CNPs alleviate neuropathic pain by exhibiting antioxidative and anti-inflammatory activities.

Effects of Capparis Spinosa extract on the neuropathic pain induced by chronic constriction injury in rats.

Neuropathic pain, a chronic pain condition, puts a considerable burden on its patients. However, different pathophysiological characteristics of neuropathic pain make the current treatment medications insufficient in controlling pain. Identifying treatment effects with Capparis Spinosa hydro-alcoholic extract in an animal model of neuropathic pain. Liquid chromatography-mass spectrometry (LC-MS) was used to identify the components of C. Spinosa hydro-alcoholic extract. To establish a neuropathic pain model, adult male Wistar rats underwent chronic constriction injury (CCI) surgery in their left sciatic nerve. Male wistar rats were divided into four groups: CCI, Sham, CCI with C. Spinosa (100 mg/kg), and CCI with C. Spinosa (200 mg/kg). Rats were treated with a hydro-alcoholic extract from aerial parts of the C. Spinosa (orally, daily) starting from CCI induction until 14 days after. Behavioral tests (mechanical allodynia, cold allodynia, and thermal hyperalgesia) and biochemical tests (IL-1ß, TNF-α, MDA, and total thiol) were taken from animals. The LC-MS analysis identified 22 compounds in C. Spinosa extract with the predominance of flavonoids. CCI produced a significant (P < 0.001) increase allodynia (mechanical and cold) and thermal hyperalgesia in comparison with sham group. Oral administration of C. Spinosa significantly (P < 0.05) ameliorated CCI-induced nociceptive pain compared with CCI group. Spinal cord specimens of CCI rats had significant (P < 0.05) elevated inflammation status (↑IL-1ß, ↑TNF-α), and significant (P < 0.05) decreased antioxidative status (↑MDA, ↓total thiol) in comparison with the sham group. These changes were reversed following C. Spinosa treatment. C. Spinosa alleviates neuropathic pain by exhibiting antioxidative and anti-inflammatory effects. The responsible components for these effects are possibly the flavonoid compounds in C. Spinosa extract.

Evaluation of Antiarthritic and Antinociceptive Effects of Cedrol in a Rat Model of Arthritis.

Pharmacological studies revealed that cedrol, a natural sesquiterpene, has antioxidant, anti-inflammatory, and analgesic properties. This study is aimed at evaluating the potential antiarthritic activity of cedrol in a rat experimental model of arthritis induced by using complete Freund's adjuvant (CFA). Arthritis was induced in Wistar rats by CFA (0.1 ml) injection. Cedrol (10 and 20 mg/kg) and indomethacin (5 mg/kg) were orally administered from day one and continued for 21 days. The antiarthritic activity was assessed through mechanical allodynia and thermal hyperalgesia responses, paw edema assessment, and arthritis scores. Serum TNF-α and IL-1ß levels were measured for the evaluation of inflammation. Furthermore, serum oxidative stress markers, including malondialdehyde (MDA) and thiol levels, as well as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, were also assessed. Oral administration of cedrol and indomethacin significantly decreased paw edema and arthritis score. Besides, cedrol and indomethacin significantly decreased pain responses. In the serum of the CFA group, TNF-α, IL-1ß, and MDA were higher, while thiol and SOD and GPx were lower than the control group. Treatment by cedrol and indomethacin corrected the biochemical parameters in the serum. In this study, cedrol offers potential antiarthritic properties through its anti-inflammatory and antioxidant effects.

The interplay between oxidative stress and autophagy: focus on the development of neurological diseases.

Regarding the epidemiological studies, neurological dysfunctions caused by cerebral ischemia or neurodegenerative diseases (NDDs) have been considered a pointed matter. Mount-up shreds of evidence support that both autophagy and reactive oxygen species (ROS) are involved in the commencement and progression of neurological diseases. Remarkably, oxidative stress prompted by an increase of ROS threatens cerebral integrity and improves the severity of other pathogenic agents such as mitochondrial damage in neuronal disturbances. Autophagy is anticipated as a cellular defending mode to combat cytotoxic substances and damage. The recent document proposes that the interrelation of autophagy and ROS creates a crucial function in controlling neuronal homeostasis. This review aims to overview the cross-talk among autophagy and oxidative stress and its molecular mechanisms in various neurological diseases to prepare new perceptions into a new treatment for neurological disorders. Furthermore, natural/synthetic agents entailed in modulation/regulation of this ambitious cross-talk are described.

Anti-inflammatory action of astaxanthin and its use in the treatment of various diseases.

Astaxanthin (AST) is a red pigmented carotenoid with significant antioxidant, anti-inflammatory, anti-proliferative, and anti-apoptotic properties. In this study, we summarize the available literature on the anti-inflammatory efficacy of AST in various chronic and acute disorders, such as neurodegenerative, renal-, hepato-, skin- and eye-related diseases, as well as gastrointestinal disorders. In addition, we elaborated on therapeutic efficacy of AST and the role of several pathways, including PI3K/AKT, Nrf2, NF-κB, ERK1/2, JNK, p38 MAPK, and JAK-2/STAT-3 in mediating its effects. However, additional experimental and clinical studies should be performed to corroborate the anti-inflammatory effects and protective effects of AST against inflammatory diseases in humans. Nevertheless, this review suggests that AST with its demonstrated anti-inflammatory property may be a suitable candidate for drug design with novel technology.

Promising Protective Effects of Chrysin in Cardiometabolic Diseases.

Cardiometabolic diseases (CMD) have caused a great burden in terms of morbidity and mortality worldwide. The vicious cycle of CMD consists of type II diabetes, hypertension, dyslipidemia, obesity, and atherosclerosis. They have interlinked pathways, interacting and interconnecting with each other. The natural flavonoid chrysin has been shown to possess a broad spectrum of therapeutic activities for human health. Herein, we did an in-depth investigation of the novel mechanisms of chrysin's cardioprotection against cardiometabolic disorders. Studies have shown that chrysin protects the cardiovascular system by enhancing the intrinsic antioxidative defense system. This antioxidant property enhanced by chrysin protects against several risk factors of cardiometabolic disorders, including atherosclerosis, vascular inflammation and dysfunction, platelet aggregation, hypertension, dyslipidemia, cardiotoxicity, myocardial infarction, injury, and remodeling, diabetes-induced injuries, and obesity. Chrysin also exhibited anti-inflammatory mechanisms through inhibiting pro-inflammatory pathways, including NF-κB, MAPK, and PI3k/Akt. Furthermore, chrysin modulated NO, RAS, AGE/RAGE, and PPARs pathways which contributed to the risk factors of cardiometabolic disorders. Taken together, the mechanisms in which chrysin protects against cardiometabolic disorder are more than merely antioxidation and anti-inflammation in the cardiovascular system.

Key miRNAs in Modulating Aging and Longevity: A Focus on Signaling Pathways and Cellular Targets.

Aging is a multifactorial process accompanied by gradual deterioration of most biological procedures of cells. MicroRNAs (miRNAs) are a class of short non-coding RNAs that post-transcriptionally regulate the expression of mRNAs through sequence-specific binding, contributing to many crucial aspects of cell biology. Several miRNAs are expressed differently in various organisms through aging. The function of miRNAs in modulating aging procedures has been disclosed recently with the detection of miRNAs that modulate longevity in the invertebrate model organisms through the IIS pathway. In these model organisms, several miRNAs have been detected to both negatively and positively regulate lifespan via commonly aging pathways. miRNAs modulate age-related procedures and disorders in different mammalian tissues by measuring their tissue- specific expression in older and younger counterparts, including heart, skin, bone, brain, and muscle tissues. Moreover, several miRNAs have contributed to modulating senescence in different human cells, and the roles of these miRNAs in modulating cellular senescence have allowed illustrating some mechanisms of aging. The review discusses the available data on the role of miRNAs in the aging process, and the roles of miRNAs as aging biomarkers and regulators of longevity in cellular senescence, tissue aging, and organism lifespan have been highlighted.

Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review.

INTRODUCTION: Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity. METHODS: A scoping review was performed using standardized search terms from inception through July 2021. RESULTS: Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects. CONCLUSION: Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.

The Roles of Mitochondrial Dysfunction and Reactive Oxygen Species in Aging and Senescence.

The aging process deteriorates organs' function at different levels, causing its progressive decline to resist stress, damage, and disease. In addition to alterations in metabolic control and gene expression, the rate of aging has been connected with the generation of high amounts of Reactive Oxygen Species (ROS). The essential perspective in free radical biology is that reactive oxygen species (ROS) and free radicals are toxic, mostly cause direct biological damage to targets, and are thus a major cause of oxidative stress. Different enzymatic and non-enzymatic compounds in the cells have roles in neutralizing this toxicity. Oxidative damage in aging is mostly high in particular molecular targets, such as mitochondrial DNA and aconitase, and oxidative stress in mitochondria can cause tissue aging across intrinsic apoptosis. Mitochondria's function and morphology are impaired through aging, following a decrease in the membrane potential by an increase in peroxide generation and size of the organelles. Telomeres may be the significant trigger of replicative senescence. Oxidative stress accelerates telomere loss, whereas antioxidants slow it down. Oxidative stress is a crucial modulator of telomere shortening, and that telomere-driven replicative senescence is mainly a stress response. The age-linked mitochondrial DNA mutation and protein dysfunction aggregate in some organs like the brain and skeletal muscle, thus contributing considerably to these post-mitotic tissues' aging. The aging process is mostly due to accumulated damage done by harmful species in some macromolecules such proteins, DNA, and lipids. The degradation of non-functional, oxidized proteins is a crucial part of the antioxidant defenses of cells, in which the clearance of these proteins occurs through autophagy in the cells, which is known as mitophagy for mitochondria.

STAT3 pathway as a molecular target for resveratrol in breast cancer treatment.

Signal transducer and activator of transcription 3 (STAT3) induces breast cancer malignancy. Recent clinical and preclinical studies have demonstrated an association between overexpressed and activated STAT3 and breast cancer progression, proliferation, metastasis, and chemoresistance. Resveratrol (RES), a naturally occurring phytoalexin, has demonstrated anti-cancer activity in several disease models. Furthermore, RES has also been shown to regulate the STAT3 signaling cascade via its anti-oxidant and anti-inflammatory effects. In the present review, we describe the STAT3 cascade signaling pathway and address the therapeutic targeting of STAT3 by RES as a tool to mitigate breast cancer.

An Overview of NO Signaling Pathways in Aging.

Nitric Oxide (NO) is a potent signaling molecule involved in the regulation of various cellular mechanisms and pathways under normal and pathological conditions. NO production, its effects, and its efficacy, are extremely sensitive to aging-related changes in the cells. Herein, we review the mechanisms of NO signaling in the cardiovascular system, central nervous system (CNS), reproduction system, as well as its effects on skin, kidneys, thyroid, muscles, and on the immune system during aging. The aging-related decline in NO levels and bioavailability is also discussed in this review. The decreased NO production by endothelial nitric oxide synthase (eNOS) was revealed in the aged cardiovascular system. In the CNS, the decline of the neuronal (n)NOS production of NO was related to the impairment of memory, sleep, and cognition. NO played an important role in the aging of oocytes and aged-induced erectile dysfunction. Aging downregulated NO signaling pathways in endothelial cells resulting in skin, kidney, thyroid, and muscle disorders. Putative therapeutic agents (natural/synthetic) affecting NO signaling mechanisms in the aging process are discussed in the present study. In summary, all of the studies reviewed demonstrate that NO plays a crucial role in the cellular aging processes.