Association between dietary intakes of Nitrate and Nitrite with Angina and atherogenic index in adults: A cross-sectional study from Tehran University of Medical Sciences employees` cohort (TEC) study.

BACKGROUND: Previous studies have shown that the intake of nitrate and nitrite may be associated with cardiovascular disease. Therefore, this study sought to investigate the association between dietary intakes of nitrate and nitrite with the odds of angina and atherogenic index in adults. METHODS: The study analyzed 1182 adults aged 20+ in the Tehran University of Medical Sciences (TUMS) Employee's Cohort study (TEC), focusing on dietary intakes, angina, and atherogenic indexes, using a validated food frequency questionnaire (FFQ) and the Rose Angina Questionnaire (RAQ). RESULT: The study found a significant inverse relationship between nitrate intake and odds of grade 2 angina. The highest dietary nitrate was associated with 29 % lower odds of grade 1 angina and also, 46 % lower odds of angina possible (P<0.05). Adults with the highest nitrate intake had 29 % lower odds of grade 1 angina and 46 % lower odds of angina possible. Adherence to nitrate reduced CRI, Atherogenic index of plasma, and TyG in participants, but no significant association was found with other factors. CONCLUSION: The study suggests that high nitrate and nitrite intake can alter angina risk, and a reverse association was found between dietary nitrate intake and various atherogenic indices.

Prenatal exposure to nitrosatable drugs and timing of puberty in sons and daughters: A nationwide cohort study.

BACKGROUND: N-nitroso compounds (NOCs) can be formed by endogenous reactions between nitrosatable drugs and nitrite. Animal studies have found that several NOCs are teratogenic, and epidemiological studies report associations between prenatal exposure to nitrosatable drugs and adverse birth outcomes. It is unknown whether prenatal exposure to nitrosatable drugs is harmful to the child's reproductive health, including pubertal development. OBJECTIVES: We investigated whether prenatal exposure to nitrosatable drugs was associated with timing of puberty and whether nitrate, nitrite and antioxidant intake modified any association. METHODS: The population-based Danish National Birth Cohort (DNBC) Puberty Cohort, which includes 15,819 children, was used to investigate the association between prenatal exposure to nitrosatable drugs and timing of puberty. Around gestational week 11 and gestational week 18, mothers provided information about drug use during pregnancy. The children's self-reported information on onset of pubertal milestones was collected every six months from 11 years of age and throughout puberty. To investigate potential effect modification by nitrite, nitrate and antioxidant intake, information on these factors was obtained from a food frequency questionnaire completed by the mothers in gestational week 25, and information on nitrate concentration in maternal drinking water at her residential address was obtained from monitoring data from public waterworks. Data were analysed using a multivariable regression model for interval-censored data estimating difference in months in timing of puberty between exposure groups. RESULTS: A total of 2,715 children were prenatally exposed to nitrosatable drugs. We did not find an association between prenatal exposure to nitrosatable drugs and timing of puberty. This finding was supported by null-findings in the following sub-analyses investigating: 1. subtypes of nitrosatable drugs (secondary and tertiary amines and amides), 2. dose-dependency (duration of drug intake), 3. effect modification by maternal intake of nitrate, nitrite, and antioxidants. 4. confounding by indication. CONCLUSIONS: Prenatal exposure to nitrosatable drugs was not associated with timing of puberty. Nitrosatable drugs are commonly used drugs in pregnancy, and further research is needed to allow firm conclusions on the potential effect of prenatal exposure to nitrosatable drugs on the child's reproductive health.

Nitrite and nitrate intake from processed meat is associated with elevated diastolic blood pressure (DBP).

BACKGROUND AND AIMS: Processed meat consumption has been linked to high blood pressure (BP), a key risk factor for cardiovascular disease (CVD), but gaps remain with regards to the ingredients which contribute to this association. This study, therefore, aimed to examine the association between nitrite and nitrate intake from processed meat with diastolic (DBP) and systolic (SBP) blood pressure, while accounting for sodium intake. METHODS: Dietary nitrite and nitrate intake from processed meat, assessed as total nitrite equivalent, was estimated for 1774 adult, processed meat consumers (≥18 years, 55.1% females) who had enrolled in the Hellenic National Nutrition and Health Survey (HNNHS). To avoid selection and reverse causality bias, associations with measured DBP and SBP were considered instead of self-reported data of hypertension presence. Participants were divided by tertile of dietary nitrite intake and by level of dietary guideline adherence for sodium (<1500; 1500-2300; ≥2300). Multiple regression models were used to examine associations with SBP and DBP, including an interaction term of nitrite with dietary sodium intake, for potential synergy. RESULTS: Overall, DBP increased by 3.05 mmHg (95% CI: 0, 6.06), per tertile increase in nitrite intake and 4.41 mmHg (95% CI: 0.17, 8.64) per level increase in sodium intake, when the interaction effect between nitrite and total sodium intakes was accounted for. By considering the significant synergistic effect of the two factors, DBP finally increased by 0.94 mgHg overall and 2.24 mgHg for subjects in the third tertile compared to those in the first. Also, a rise in total sodium intake of approximately 800 mg, above 1500 mg, caused a 2.30 mgHg increase in DBP. No significant correlations were found with SBP. CONCLUSIONS: Higher nitrite and nitrate intake from processed meats contributed to the increase of DBP, but the interaction effect with total sodium intake levels should be accounted for to properly interpret the findings.

Dietary exposure to nitrites and nitrates in association with type 2 diabetes risk: Results from the NutriNet-Santé population-based cohort study.

BACKGROUND: Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives. METHODS AND FINDINGS: Overall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HRtertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), Ptrend = 0.009 and 1.26 (95% CI 1.03 to 1.54), Ptrend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (i.e., above the sex-specific median) and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), Ptrend < 0.001 and 1.54 (95% CI 1.26 to 1.90), Ptrend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all Ptrend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort's participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment. CONCLUSIONS: The findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644 (https://clinicaltrials.gov/ct2/show/NCT03335644).

Nitrites, Nitrates, and Cardiovascular Outcomes: Are We Living "La Vie en Rose" With Pink Processed Meats?

Background Nitrates and nitrites are used as food additives in processed meats. They are also commonly ingested from water and several foods. Several short-term clinical studies suggested beneficial effects of dietary nitrates on blood pressure, while deleterious effects on oxidative damage have been suggested in some experimental studies. However, there is a lack of evidence from longitudinal epidemiological studies linking foods and water-originated and additives-originated nitrites and nitrates, separately, to hypertension and cardiovascular diseases risk. We aimed to study these associations in a large population-based cohort. Methods and Results Overall, 106 288 adults from the French NutriNet-Santé cohort (2009-2022) were included. Associations between nitrites and nitrates intakes and hypertension and cardiovascular disease risks were assessed using multi-adjusted Cox proportional hazard models. During follow-up, 3810 incident cases of hypertension and 2075 cases of cardiovascular diseases were ascertained. Participants with higher intakes of additives-originated nitrites (sodium nitrite in particular [European code e250]) had a higher hypertension risk compared with nonconsumers (hazard ratio, 1.19 [95% CI, 1.08-1.32], P=0.001, and 1.19 [95% CI, 1.08-1.32], P=0.002), respectively. No association was detected between foods and water-originated nitrites, or nitrates with hypertension risk (all P values >0.3). We found no association between nitrites or nitrates and risks of cardiovascular diseases (all P values >0.2). Conclusions These results do not support a protective role of nitrites or nitrates in cardiovascular health. Instead, they suggest a positive association between nitrites from food additives and hypertension risk, which needs confirmation in other large-scale studies. These findings provide new evidence in the context of current discussions about updating regulations on the use of nitrites as food additives.

Risk Assessment of Nitrite and Nitrate Intake from Processed Meat Products: Results from the Hellenic National Nutrition and Health Survey (HNNHS).

Long-term exposure to a high nitrite and nitrate intake through processed meat is of concern, as it has been related to adverse health effects. Individual consumption data from 2152 participants (46.7% males) in the Hellenic National Nutrition and Health Survey (HNNHS) were linked with current Maximum Permitted Levels (MPLs) to calculate exposure to nitrite and nitrate from processed meat products (assessed as nitrite equivalent), evaluate potential risk and identify the major contributors. Processed meat intakes were determined by combining data from 24 h recalls and frequency of consumption reported in Food Propensity Questionnaires (FPQs). Median exposure was estimated to be within safe levels for all population groups. However, 6.6% (n = 143) of the consumers exceeded the Acceptable Daily Intake (ADI) of nitrite (0.07 mg/kg bw/day), of which 20.3% were children aged 0-9 years (N = 29) (15.3% of all children participants in the study, N = 190). In total, pork meat was the major contributor (41.5%), followed by turkey meat (32.7%) and sausages (23.8%), although contribution variations were found among age groups. The outcomes are of public health concern, especially exposure among children, and future research is warranted to evaluate possible associations with health effects, by using more refined occurrence data if available.

Neuroprotective Potential of Hydroalcoholic Extract of Centella asiatica Against 3-Nitropropionic Acid-Induced Huntington's Like Symptoms in Adult Zebrafish.

Huntington's disease (HD) is an inherited neurodegenerative disease. 3-Nitropropionic acid (3-NP) causes increased reactive oxygen species production and neuroinflammation. Centella asiatica (CA) is a strong antioxidant. The aim of this study is to investigate the effect of hydroalcoholic extract of C. asiatica (HA-CA) on 3-NP-induced HD in adult zebrafish. Adult zebrafish (∼5-6 months old) weighing 470 to 530 mg was used and treated with 3-NP (5 mg/kg intraperitoneal [i.p.]). The animals received HA-CA (80 and 100 mg/L) daily for up to 28 days in water. Tetrabenazine (3 mg/kg i.p.) was used as a standard drug. We have done an open field test (for locomotor activity), a novel tank diving test (for anxiety), and a light and dark tank test (for memory), followed by biochemical analysis (acetyl-cholinesterase [AchEs], nitrite, lipid peroxidation [LPO], and glutathione [GSH]) and histopathology to further confirm memory dysfunctions. 3-NP-treated zebrafish exhibit reductions in body weight, progressive neuronal damage, cognition, and locomotor activity. The HA-CA group significantly reduced the 3-NP-induced increase in LPO, AchEs, and nitrite levels while decreasing GSH levels. Oral administration of HA-CA (80 or 100 mg/L) significantly reduces 3-NP-induced changes in body weight and behaviors, in addition to neuroinflammation in the brain by lowering tumor necrosis factor-α and interleukin-1ß levels. Moreover, HA-CA significantly decreases the 3-NP-induced neuronal damage in the brain. HA-CA ameliorates neurotoxicity and neurobehavioral deficits in 3-NP-induced HD-like symptoms in adult zebrafish.

Nitrites and nitrates from food additives and natural sources and cancer risk: results from the NutriNet-Santé cohort.

BACKGROUND: Nitrates and nitrites occur naturally in water and soil. They are also used as food additives (preservatives) in processed meats. They could play a role in the carcinogenicity of processed meat. The objective was to investigate the relationship between nitrate and nitrite intakes (natural food, water and food additive sources) and cancer risk in a large prospective cohort with detailed dietary assessment. METHODS: Overall, 101    056 adults from the French NutriNet-Santé cohort (2009-ongoing, median follow-up 6.7 years) were included. Nitrites/nitrates exposure was evaluated using repeated 24-h dietary records, linked to a comprehensive composition database and accounting for commercial names/brands of industrial products. Associations with cancer risk were assessed using multi-adjusted Cox hazard models. RESULTS: In total, 3311 incident cancer cases were diagnosed. Compared with non-consumers, high consumers of food additive nitrates had higher breast cancer risk [hazard ratio (HR) = 1.24 (95% CI 1.03-1.48), P = 0.02], more specifically for potassium nitrate. High consumers of food additive nitrites had higher prostate cancer risk [HR = 1.58 (1.14-2.18), P = 0.008], specifically for sodium nitrite. Although similar HRs were observed for colorectal cancer for additive nitrites [HR = 1.22 (0.85-1.75)] and nitrates [HR = 1.26 (0.90-1.76)], no association was detected, maybe due to limited statistical power for this cancer location. No association was observed for natural sources. CONCLUSION: Food additive nitrates and nitrites were positively associated with breast and prostate cancer risks, respectively. Although these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of these additives from the food industry.

Association between Dietary Nitrate, Nitrite Intake, and Site-Specific Cancer Risk: A Systematic Review and Meta-Analysis.

BACKGROUND: People consume nitrates, nitrites, nitrosamines, and NOCs compounds primarily through processed food. Many studies have yielded inconclusive results regarding the association between cancer and dietary intakes of nitrates and nitrites. This study aimed to quantify these associations across the reported literature thus far. METHODS: We performed a systematic review following PRISMA and MOOSE guidelines. A literature search was performed using Web of Science, Embase, PubMed, the Cochrane library, and google scholar up to January 2020. STATA version 12.0 was used to conduct meta-regression and a two-stage meta-analysis. RESULTS: A total of 41 articles with 13 different cancer sites were used for analysis. Of these 13 cancer types/sites, meta-regression analysis showed that bladder and stomach cancer risk was greater, and that pancreatic cancer risk was lower with increasing nitrite intakes. Kidney and bladder cancer risk were both lower with increasing nitrate intakes. When comparing highest to lowest (reference) categories of intake, meta-analysis of studies showed that high nitrate intake was associated with an increased risk of thyroid cancer (OR = 1.40, 95% CI: 1.02, 1.77). When pooling all intake categories and comparing against the lowest (reference) category, higher nitrite intake was associated with an increased risk of glioma (OR = 1.12, 95% CI: 1.03, 1.22). No other associations between cancer risk and dietary intakes of nitrates or nitrites were observed. CONCLUSION: This study showed varied associations between site-specific cancer risks and dietary intakes of nitrate and nitrite. Glioma, bladder, and stomach cancer risks were higher and pancreatic cancer risk was lower with higher nitrite intakes, and thyroid cancer risk was higher and kidney cancer risk lower with higher nitrate intakes. These data suggest type- and site-specific effects of cancer risk, including protective effects, from dietary intakes of nitrate and nitrite.

A Case Report of Hypotension and Methemoglobinemia Associated With Gunshot Residue Poisoning: Nitrite-Induced Methemoglobinemia.

A patient with gunshots within inches of the skin developed intraoperative vasodilatory hypotension and methemoglobinemia, both recognized consequences of nitrite poisoning. A 1- mg/kg dose of methylene blue transiently and partially reversed methemoglobinemia, but the color of the methylene blue faded rapidly, consistent with bleaching of methylene blue by nitrite in vivo. Methylene blue did not raise blood pressure, consistent with inhibition of nitric oxide (NO) synthase. Because NO production from nitrite uses an NO synthase (NOS)-independent pathway, methylene blue is expected to have little effect on reversing hypotension from nitrite poisoning. Consider nitrite toxicity in gunshot patients with refractory vasodilatory hypotension and elevated methemoglobin.

Dietary nitrate and nitrite and human health: a narrative review by intake source.

Nitrate and nitrite are plant nutrients that, although ubiquitous in plant foods, are highly controversial substances in human nutrition because they are also used as additives in processed foods and may be found as contaminants in drinking water. The aim for this narrative review is to provide a thorough insight into the current literature on the relationship between dietary nitrate and nitrite and the health risks and benefits by source of intake. The results highlight beneficial effects of nitrate and nitrite consumption from plant origin on cardiovascular disease and, to date, no positive correlation has been reported with cancer. On the contrary, high intake of these compounds from processed animal-based foods is related to an increased risk of gastro-intestinal cancer. Nitrate in drinking water also raises some concern, because it appears to be related to adverse health effects. The up-to-date debate on the role of nitrate and nitrite in human nutrition seems to be justified and more research is required to verify safe consumption.

Supplemental nitrite increases choroidal neovascularization in mice.

Low doses of nitrite, close to physiological levels, increase blood flow in normal and ischemic tissues through a nitric oxide (NO) dependent mechanism. Given that nitrite therapy and dietary supplementation with vegetables high in nitrate (e.g. beets) are gaining popularity we decided to determine if low doses of nitrite impact the development of choroidal neovascularization (CNV), a key feature of wet age related macular degeneration (AMD). Sodium nitrite (at 50 mg/L, 150 mg/L, and 300 mg/L), nitrate (1 g/L) or water alone were provided in the drinking water of C57BL/6 J mice aged 2 or 12 months. Mice were allowed to drink ad libitum for 1 week at which time laser-induced choroidal neovascularization (L-CNV) was induced. The mice continued to drink the supplemented water ad libitum for a further 14 days at which point optical coherence tomography (OCT) was performed to determine the volume of the CNV lesion. Blood was drawn to determine nitrite and nitrate levels and eyes taken for histology. CNV volume was 2.86 × 107 µm3 (±0.4 × 107) in young mice on water alone but CNV volume more than doubled to >6.9 × 107 µm3 (±0.8 × 107) in mice receiving 300 mg/L nitrite or 7.34 × 107 µm3 (±1.4 × 107) in 1 g/L nitrate (p < 0.01). A similar trend was observed in older mice. CNV volume was 5.3 × 107 µm3 (±0.5 × 107) in older mice on water alone but CNV volume almost doubled to approximately 9.3 × 107 µm3 (±1.1 × 107) in mice receiving 300 mg/L nitrite or 8.7 × 107 µm3 (±0.9 × 107) 1 g/L nitrate (p < 0.01). Plasma nitrite levels were highest in young mice receiving 150 mg/L in the drinking water with no changes in plasma nitrate observed. In older mice, drinking water nitrite did not significantly change plasma nitrite, but plasma nitrate was increased. Plasma nitrate was elevated in both young and old mice provided with nitrate supplemented drinking water. Our data demonstrate that the CNV lesion is larger in older mice compared to young and that therapeutic levels of oral nitrite increase the volume of CNV lesions in both young and older mice. Therapeutic nitrite or nitrate supplementation should be used with caution in the elderly population prone to CNV.

Replacement of Nitrite in Meat Products by Natural Bioactive Compounds Results in Reduced Exposure to N-Nitroso Compounds: The PHYTOME Project.

SCOPE: It has been proposed that endogenously form N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, the impact of replacing the additive sodium nitrite (E250) by botanical extracts in the PHYTOME project is evaluated. METHOD AND RESULTS: A human dietary intervention study is conducted in which healthy subjects consume 300 g of meat for 2 weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affects molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E250 by natural plant extracts. CONCLUSION: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically support by gene expression analyses.

Methemoglobinemia caused by volatile nitrites derivates ('poppers') / Illékony nitritszármazékok ("popperek") által okozott methaemoglobinaemia.

Összefoglaló. A methaemoglobinaemia az oxigén szállítására képtelen methemoglobin szintjének kóros emelkedését jelenti a vérben, ami jelentos szöveti oxigénhiányt okozhat, súlyos, akár életveszélyes tünetekhez vezethet. Methaemoglobinaemiát számos, oxidáló hatású exogén anyag idézhet elo, ezek közé tartoznak a partidrogként használt alkil-nitritek, az ún. "popperek" is. A "poppereket" korábban "alacsony rizikójú" drogként tartották számon, azonban számos esetet közöltek, amikor súlyos, idonként fatális kimenetelu methaemoglobinaemiát okoztak. A folyadékok gozének belélegzése euforizáló, szexuálisvágy-fokozó és simaizom-lazító hatású, ezért a "popperek" igen népszeruek a homo- és biszexuális férfiak körében, de fiatal felnottek és tinédzserek is használják. A folyadékok szájon át való fogyasztása különösen veszélyes. A szerzok két esetet ismertetnek, amelyekben a "popperek" használatát követoen methaemoglobinaemia alakult ki. Mindkét betegnél, a jó általános állapot mellett, centrális és perifériás cyanosis tüneteit észlelték. Az alkalmazás módja (inhaláció/lenyelés), a methaemoglobinaemia súlyossága (16,4% és 57%) és a terápia eltéro volt a két betegnél. Az elso beteg oxigén adása és tüneti kezelés mellett gyógyult, a másodiknál antidotum (metilénkék) adására is szükség volt. Mindketten panaszmentesen távoztak a kórházból. A szerzok célja az volt, hogy felhívják a figyelmet az illékony alkil-nitrit-származékok által okozott methaemoglobinaemiára, annak felismerésére, kezelésére, és bemutassák azok kevésbé ismert szövodményeit is. Orv Hetil. 2021; 162(8): 306-313. Summary. Methemoglobinemia means the abnormally elevated level of methemoglobin in the blood, which is incapable of oxygen transport, accordingly it can cause significant tissue hypoxia, leading to severe or even life-threatening clinical symptoms. Several exogen oxidative agents can induce methemoglobinemia, including alkyl-nitrites which are also used as party drugs, the so-called 'poppers'. The 'poppers' were previously considered 'low-risk' drugs, however, several cases have been published when they caused severe, sometimes fatal methemoglobinemia. Inhaling vapours from liquids has euphoric, smooth-muscle relaxing and aphrodisiac effects, therefore 'poppers' are extremely popular among gay and bisexual men but also used by young adults and teenagers. Oral consumption of the fluids is particularly dangerous. The authors present two cases when methemoglobinemia developed after 'poppers' usage. Both patients were in good general condition and symptoms of central and peripheral cyanosis were detected. The method of application (inhalation/ ingestion), the severity of methemoglobinemia (16,4% and 57%) and the treatment were different in the two patients. The first patient recovered with inhalation of oxygen and symptomatic treatment; the second patient required administration of antidote (methylene blue). Both patients left the hospital without complaints. The authors' aim was to attract attention to methemoglobinemia caused by volatile alkyl-nitrites, its recognition, treatment and to present their lesser-known complications. Orv Hetil. 2021; 12(8): 306-313.

Nitrate-nitrite exposure through drinking water and diet and risk of colorectal cancer: A systematic review and meta-analysis of observational studies.

BACKGROUND: Considerable controversy exists regarding the association between nitrate intake and risk of colorectal cancer. Therefore, we performed a dose-response meta-analysis of observational studies. METHODS: We identified relevant studies by searching PubMed, Scopus and ISI Web of Knowledge until April 2020 and references of retrieved relevant articles. The random-effects model was used to calculate pooled effect size (ESs) and 95% confidence intervals (CIs). RESULTS: Fifteen prospective cohort and case-control papers were included in this systematic review and meta-analysis. In total, 2,573,524 participants with an age range between 20 and 85 years were included. The total number of colorectal cancer cases was 38,848. Intake of nitrate from diet was associated with a risk of colorectal cancer (Pooled HR: 1.13; 95% CI: 1.04-1.23, I2 = 38%; P = 0.08). Nitrite in diet was not significantly associated with risk of colorectal cancer (pooled HR: 1.07; 95% CI: 0.95-1.21, I2 = 61.6%; P = 0.005). Nitrate in water did not show an association with risk of colorectal cancer (pooled HR: 1.04; 95% CI: 0.92-1.19, I2 = 64.7%; P = 0.002). Non-linear dose-response analysis revealed no significant association of dietary nitrite and also nitrate of drinking water with risk of colorectal cancer. However, dietary nitrate was marginally associated with a greater risk of colorectal cancer. Linear dose-response analysis of nitrate from diet was not associated with colorectal cancer risk by an additional 50 mg per day. Such a non-significant association was also seen for colorectal cancer risk by an additional 1 mg per day and 1 mg/l from dietary nitrite and water nitrate respectively. CONCLUSIONS: Dietary nitrate was related to a higher risk of colorectal cancer risk. However, intake of nitrite from diet and nitrate from the drinking water was not associated with colorectal cancer risk.

Nitrate and nitrite-based therapy to attenuate cardiovascular remodelling in arterial hypertension.

Hypertension is a highly prevalent disease marked by vascular and cardiac maladaptive remodelling induced mainly by renin-angiotensin system activation followed by oxidative stress. Here, we briefly describe these damages and review the current evidence supporting a potential role for nitrate and nitrite as antihypertensive molecules that act via nitric oxide (NO) formation-dependent and NO formation-independent mechanisms and how nitrate/nitrite inhibits cardiovascular remodelling in hypertension. The renin-angiotensin system activation and oxidative stress converge to activate proteases involved in cardiovascular remodelling in hypertension. Besides these proteases, several investigations have demonstrated that reduced endogenous NO bioavailability is a central pathological event in hypertension. In this regard, nitrate/nitrite, long considered inert products of NO, is now known as physiological molecules able to reduce blood pressure in hypertensive patients and in different experimental models of hypertension. These effects are associated with the formation of NO and other NO-related molecules, which could induce S-nitrosylation of target proteins. However, it remains unclear whether S-nitrosylation is an essential mechanism for the anti-remodelling effects of nitrate/nitrite in hypertension. Moreover, nitrate/nitrite produces antioxidant effects associated with the inhibition of signalling pathways involved in cardiovascular remodelling. Together, these findings may help to establish nitrate and nitrite as effective therapies in hypertension-induced cardiovascular remodelling.

Nitrite inhalants use, sexual behaviors and HIV/syphilis infection among men who have sex with men in Chongqing, China.

BACKGROUND: Emerging evidence indicates nitrite inhalants have become increasingly prevalent among men who have sex with men (MSM). The present study aimed to describe the prevalence and correlates of nitrite inhalants use and its association with risky sexual behaviors and human immunodeficiency virus (HIV)/syphilis infection among MSM in Chongqing, a city in China where MSM were burdened with the highest pooled HIV prevalence in the country. METHODS: This cross-sectional study was conducted in Chongqing between March 2019 and February 2020. Information of demographics, drug use, sexual behaviors and HIV testing was collected through an anonymous survey. Blood samples were drawn from each participant for the diagnoses of HIV and syphilis. Logistic regression analysis was performed to evaluate factors correlated with nitrite inhalants use and its relationship with risky sexual behaviors and HIV/syphilis infection. RESULTS: Of the 1151 eligible participants, 18.9% (218) reported use of at least one type of recreational drugs in the past 6 months, and nitrite inhalants were the most commonly used substance (17.7, 95% confidence interval [CI]: 15.6-20.2%). The proportions of participants reported engaging in group sex and practicing condomless internal ejaculation during anal sex in the past six months were 5.8% (95% CI: 4.4-7.2%) and 41.7% (95% CI: 38.7-44.7%), respectively. The general prevalence of HIV and syphilis infection among the enrolled MSM were 16.8% (95% CI: 14.7-19.0%) and 12.6% (95% CI: 10.7-14.4%), respectively. Factors positively associated with nitrite inhalants use included: age ≤ 25 (adjusted odds ratio [aOR] = 2.08, 95% CI: 1.10-3.94), monthly individual income ≥ CNY 3000 (Chinese Yuan) (aOR = 1.95, 95% CI: 1.18-3.22), preferring receptive anal intercourse (aOR = 2.27, 95% CI: 1.34-3.84) and versatile anal intercourse (aOR = 2.60, 95% CI: 1.64-4.13), age at first anal intercourse < 18 (aOR = 1.79, 95% CI: 1.21-2.67), engaging in group sex in the past six months (aOR = 9.34, 95% CI: 4.95-17.63), having multiple male sex partners in the past 6 months (aOR = 2.32, 95% CI: 1.50-3.58), practicing CIE during anal sex in the past six months (aOR = 1.71, 95% CI: 1.19-2.46), HIV infection (aOR = 1.72, 95% CI: 1.11-2.66) and syphilis infection (aOR = 1.98, 95% CI: 1.23-3.17). CONCLUSIONS: This study found that nitrite inhalants were the most commonly used recreational substance among MSM and nitrite inhalants use were associated with higher probability of HIV and syphilis infection. Therefore, increased attention and counselling should be given to nitrite inhalants-using MSM.