sodium-nitrite and Inflammation

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one-electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability, which is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO-based therapeutic agent through the unique action of sodium nitrite as an NO prodrug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities for nitrite-based therapies.

Topics: Animals; Autoimmune Diseases; Bacteria; Humans; Inflammation; Inorganic Chemicals; Ischemia; Mouth; Neoplasms; Nitric Oxide; Oxidation-Reduction; Sodium Nitrite

Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD.. This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted.. Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-. This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD.. Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.

Topics: Aged; Amine Oxidase (Copper-Containing); Antioxidants; Arginine; Biomarkers; Cell Adhesion Molecules; Drug Therapy, Combination; E-Selectin; Endostatins; Endothelium; Female; Glomerular Filtration Rate; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Medication Adherence; Middle Aged; Oxidative Stress; Pilot Projects; Quercetin; Renal Insufficiency, Chronic; Sodium Nitrite; Vasodilation; von Willebrand Factor

Food safety and nutrition during pregnancy are important concerns related to fetal brain development. In the present study, we aimed to explore the effects of omega-3 polyunsaturated fatty acids (PUFA ω-3) on exogenous sodium nitrite intervention-induced fetal brain injury in pregnant rats.. During pregnancy, rats were exposed to water containing sodium nitrite (0.05%, 0.15%, and 0.25%) to establish a fetal rat brain injury model. Inflammatory factors and oxidative stress levels were detected using enzyme-linked immunosorbent assay (ELISA) or flow cytometry. Subsequently, animals were divided into three groups: control, model, and 4% PUFA ω-3. Pregnancy outcomes were measured and recorded. Hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC) were utilized to observe brain injury. ELISA, quantitative real-time PCR (qRT-PCR), western blot, flow cytometry, and transmission electron microscopy (TEM) were adopted to measure the levels of inflammatory factors, the NRF1/HMOX1 signaling pathway, and mitochondrial and oxidative stress damage.. With the increase of sodium nitrite concentration, the inflammatory factors and oxidative stress levels increased. Therefore, the high dose group was set as the model group for the following experiments. After PUFA ω-3 treatment, the fetal survival ratio, average body weight, and brain weight were elevated. The cells in the PUFA ω-3 group were more closely arranged and more round than the model. PUFA ω-3 treatment relieved inflammatory factors, oxidative stress levels, and mitochondria damage while increasing the indicators related to brain injury and NRF1/HMOX1 levels.. Sodium nitrite exposure during pregnancy could cause brain damage in fetal rats. PUFA ω-3 might help alleviate brain inflammation, oxidative stress, and mitochondrial damage, possibly through the NRF1/HMOX1 signaling pathway. In conclusion, appropriately reducing sodium nitrite exposure and increasing PUFA omega-3 intake during pregnancy may benefit fetal brain development. These findings could further our understanding of nutrition and health during pregnancy.

Topics: Animals; Brain Injuries; Dietary Supplements; Encephalitis; Fatty Acids, Omega-3; Female; Inflammation; Pregnancy; Rats; Sodium Nitrite

Despite wide application of sodium nitrite (SN) as food additive, it exhibits considerable side effects on various body organs at high dose or chronic exposure. The aim of this study was to test whether Glycyrrhizic acid (GA) could ameliorate SN-induced toxicity in lung and submandibular salivary gland (SMG). A sample size of 30 adult male albino rats was randomly allocated into 3 groups. Group 1 served as control group. Rats were treated orally with 80 mg/kg of SN in group 2 or SN preceded by (15 mg/kg) GA in group 3. Lung & SMG tissues were used for oxidative stress assessment, examination of histopathological changes, fibrosis (MTC, TGF-β and α-SMA) and inflammation (TNF-α, IL-1β and CD-68). Concurrent administration of GA ameliorated pulmonary and salivary SN-induced toxicity via restoring the antioxidant defense mechanisms with reduction of MDA levels. GA reduced the key regulators of fibrosis TGF-β and α-SMA and collagen deposition. In addition to reduction of inflammatory cytokine (TNF-α, IL-1β) and macrophages recruitments, GA amended both pulmonary and salivary morphological changes. The present study proposed GA as a promising natural herb with antioxidant, anti-inflammatory and antifibrotic effects against pulmonary and salivary SN-induced toxicity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Fibrosis; Glutathione; Glycyrrhizic Acid; Inflammation; Lung; Male; Malondialdehyde; Oxidative Stress; Rats, Sprague-Dawley; Salivary Glands; Sodium Nitrite

The herb thyme (Thymus vulgaris) has multiple therapeutic uses. In this study, we explored how T. vulgaris leaf extract protects liver cells against sodium nitrite-(NaNO

Topics: Animals; Antioxidants; Biomarkers; Cytokines; Flavonoids; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation; Inflammation; Liver; Mice; Models, Biological; Oxidative Stress; Phenols; Plant Extracts; Protective Agents; RNA, Messenger; Sodium Nitrite; Thymus Plant

Sodium nitrite is a widely used color fixative and preservative. However, it has been reported to exert deleterious toxic effects on various body organs. Moreover, thymoquinone (TQ), the active constituent of Nigella sativa oil is known to possess beneficial antioxidant and anti-inflammatory effects. The present study was conducted to evaluate the potential protective effects of TQ against sodium nitrite-induced renal toxicity.. Male Sprague-Dawley rats were treated with sodium nitrite (80mg/kg, po, daily) in presence or absence of TQ (25 and 50mg/kg, po, daily). Morphological changes in renal sections were assessed by staining with Hematoxylin/Eosin and Periodic acid-Schiff. Renal homogenate was used for measurement of oxidative stress markers (MDA and GSH), inflammatory markers (CRP, TNF-α, IL-6, IL-1β), anti-inflammatory cytokines (IL-10 and IL-4) and apoptotic markers (caspase-3/caspase-8/caspase-9).. Treatment with sodium nitrite significantly increased markers of renal dysfunction, oxidative stress, inflammation and apoptosis. These effects were markedly attenuated by TQ in dose dependent manner.. TQ has a potential protective effect against sodium nitrite-induced renal toxicity. This can be attributed to its ability to dampen oxidative stress, restore the normal balance between pro- and anti-inflammatory cytokines and protect renal tissue form extrinsic and intrinsic apoptosis.

Topics: Animals; Apoptosis; Benzoquinones; Cytokines; Dose-Response Relationship, Drug; Food Preservatives; Inflammation; Inflammation Mediators; Kidney Diseases; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Nitrite

The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Male; Organ Specificity; Proto-Oncogene Proteins c-akt; Quercetin; Rats; Rats, Wistar; Smad2 Protein; Sodium Nitrite; Transforming Growth Factor beta

Scientific evidence illustrated the health hazards of exposure to nitrites for prolonged time. Nitrites affected several body organs due to oxidative, inflammatory and apoptosis properties. Furthermore, thymoquinone (TQ) had curative effects against many diseases. We tried to discover the impact of both sodium nitrite and TQ on inflammatory cytokines contents in testicular tissues and hormonal balance both in vivo and in vitro. Fifty adult male SD rats received 80mg/kg sodium nitrite and treated with either 25 or 50mg/kg TQ daily by oral-gavage for twelve weeks. Testis were removed for sperms' count. Testicular tissue homogenates were used for assessment of protein and gene expression of IL-1β, IL-6, TNF-α, Nrf2 and caspase-3. Serum samples were used for measurement of testosterone, LH, FSH and prolactin. Moreover, all the parameters were measured in human normal testis cell-lines, CRL-7002. Sodium nitrite produced significant decrease in serum testosterone associated with raised FSH, LH and prolactin. Moreover, sodium nitrite significantly elevated TNF-α, IL-1β, IL-6, caspase-3 and reduced Nrf2. TQ significantly reversed all these effects both in vivo and in vitro. In conclusion, TQ ameliorated testicular tissue inflammation and restored the normal balance of sex hormones induced by sodium nitrite both in vivo and in vitro.

Topics: Animals; Caspase 3; Cytokines; Gonadal Steroid Hormones; Inflammation; Male; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Testis

Exposure to sodium nitrites, a food additive, at high levels has been reported to produce reactive nitrogen and oxygen species that cause dysregulation of inflammatory responses and tissue injury. In this work, we examined the impact of dietary cod liver oil on sodium nitrite-induced inflammation in rats.. Thirty-two adult male Sprague-Dawely rats were treated with 80 mg/kg sodium nitrite in presence/absence of 5 ml/kg cod liver oil. Liver sections were stained with hematoxylin/eosin. We measured hepatic tumor necrosis factor (TNF)-α, interleukin-1 beta (IL)-1β, C-reactive protein (CRP), transforming growth factor (TGF)-β1, and caspase-3.. Cod liver oil reduced sodium nitrite-induced hepatocyte damage. In addition, cod liver oil results in reduction of hepatic TNF-α, IL-1β, CRP, TGF-β1, and caspase-3 when compared with the sodium nitrite group.. Cod liver oil ameliorates sodium nitrite-induced hepatic injury via multiple mechanisms including blocking sodium nitrite-induced elevation of inflammatory cytokines, fibrosis mediators, and apoptosis markers.

Topics: Animals; Apoptosis; C-Reactive Protein; Caspase 3; Chemical and Drug Induced Liver Injury; Cod Liver Oil; Fibrosis; Inflammation; Interleukin-1beta; Liver; Liver Function Tests; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; Reactive Oxygen Species; Sodium Nitrite; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Aging is associated with motor declines that lead to functional limitations and disability, necessitating the development of therapies to slow or reverse these events. We tested the hypothesis that sodium nitrite supplementation attenuates declines in motor function in older C57BL/6 mice. Motor function was assessed using a battery of tests (grip strength, open-field distance, rota-rod endurance) in old animals (age 20-24 mo) at baseline and after 8 wk of sodium nitrite (old nitrite, n = 22, 50 mg/liter) or no treatment (old control, n = 40), and in young reference animals (3 mo, n = 87). Eight weeks of sodium nitrite supplementation improved grip strength (old nitrite, +12.0 ± 14.9% vs. old control, +1.5 ± 15.2%, P < 0.05) and open field distance (old nitrite, +9.5 ± 7.7%, P < 0.01 vs. old control, -28.1 ± 2.0%) and completely restored rota-rod endurance-run time (old nitrite, +3.2 ± 7.1%, P < 0.01 vs. old control, -21.5 ± 7.2%; old nitrite after treatment P > 0.05 vs. young reference). Inflammatory cytokines were markedly increased in quadriceps of old compared with young reference animals (by ELISA, interleukin-1β [IL-1β] 3.86 ± 2.34 vs. 1.11 ± 0.74, P < 0.05; interferon-gamma [INF-γ] 8.31 ± 1.59 vs. 3.99 ± 2.59, P < 0.01; tumor necrosis factor-alpha [TNF-α] 1.69 ± 0.44 vs. 0.76 ± 0.30 pg/ml, P < 0.01), but were reduced to young reference levels after treatment (old nitrite, IL-1β 0.67 ± 0.95; INF-γ 5.22 ± 2.01, TNF-α 1.21 ± 0.39 pg/ml, P < 0.05 vs. old control, P > 0.05 vs. young reference). Cytokine expression and treatment (old nitrite vs. old control) predicted strength (R(2) = 0.822, P < 0.001, IL-1β, INF-γ, group), open field distance (R(2) = 0.574, P < 0.01, IL-1β, group) and endurance run time (R(2) = 0.477, P < 0.05, INF-γ). Our results suggest that sodium nitrite improves motor function in old mice, in part by reducing low-grade inflammation in muscle.

Topics: Aging; Animals; Cytokines; Dietary Supplements; Drug Evaluation, Preclinical; Inflammation; Male; Mice, Inbred C57BL; Motor Activity; Muscle, Skeletal; Nitrates; Nitrites; Sodium Nitrite

Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

Topics: Allopurinol; Animals; Benzoates; Brain Death; Gene Expression; Hemodynamics; Imidazoles; Inflammation; Kidney; Kidney Transplantation; Lipid Peroxidation; Male; Nitrites; Rats; Rats, Inbred Lew; Reperfusion Injury; Signal Transduction; Sodium Nitrite

The nitrite anion is an endogenous product of mammalian nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants, and a constituent of many foods. Research over the past 6 years has revealed surprising biological and cytoprotective activity of this anion. Hypercholesterolemia causes a proinflammatory phenotype in the microcirculation. This phenotype appears to result from a decline in NO bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide, or both. Since nitrite has been shown to be potently cytoprotective and restore NO biochemical homeostasis, we investigated if supplemental nitrite could attenuate microvascular inflammation caused by a high cholesterol diet. C57Bl/6J mice were fed either a normal diet or a high cholesterol diet for 3 wk to induce microvascular inflammation. Mice on the high cholesterol diet received either nitrite-free drinking water or supplemental nitrite at 33 or 99 mg/l ad libitum in their drinking water. The results from this investigation reveal that mice fed a cholesterol-enriched diet exhibited significantly elevated leukocyte adhesion to and emigration through the venular endothelium as well as impaired endothelium-dependent relaxation in arterioles. Administration of nitrite in the drinking water inhibited the leukocyte adhesion and emigration and prevented the arteriolar dysfunction. This was associated with sparing of reduced tetrahydrobiopterin and decreased levels of C-reactive protein. These data reveal novel anti-inflammatory properties of nitrite and implicate the use of nitrite as a new natural therapy for microvascular inflammation and endothelial dysfunction associated with hypercholesterolemia.

Topics: Animals; Anti-Inflammatory Agents; Biopterins; Blood Pressure; C-Reactive Protein; Cholesterol, Dietary; Diet; Disease Models, Animal; Endothelium, Vascular; Hypercholesterolemia; Inflammation; Leukocyte Rolling; Liver; Male; Mice; Mice, Inbred C57BL; Microvessels; Myocardium; Nitric Oxide; Sodium Nitrite; Triglycerides; Vasodilation; Vasodilator Agents

Peroxynitrite anion is a powerful oxidant which can initiate nitration and hydroxylation of aromatic rings. Peroxynitrite can be formed in several ways, e.g. from the reaction of nitric oxide with superoxide or from hydrogen peroxide and nitrite at acidic pH. We investigated pH dependent nitration and hydroxylation resulting from the reaction of hydrogen peroxide and nitrite to determine if this reaction proceeds at pH values which are known to occur in vivo. Nitration and hydroxylation products of tyrosine and salicyclic acid were separated with an HPLC column and measured using ultraviolet and electrochemical detectors. These studies revealed that this reaction favored hydroxylation between pH 2 and pH 4, while nitration was predominant between pH 5 and pH 6. Peroxynitrite is presumed to be an intermediate in this reaction as the hydroxylation and nitration profiles of authentic peroxynitrite showed similar pH dependence. These findings indicate that hydrogen peroxide and nitrite interact at hydrogen ion concentrations present under some physiologic conditions. This interaction can initiate nitration and hydroxylation of aromatic molecules such as tyrosine residues and may thereby contribute to the biochemical and toxic effects of the molecules.

Topics: Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxylation; Inflammation; Iron; Nitrates; Oxidative Stress; Salicylates; Salicylic Acid; Sodium Nitrite; Tyrosine