Re: 식이 질산염, 아질산염의 기능!!

[문형철]

Aging Dis

. 2018 Oct 1;9(5):938–945. doi: 10.14336/AD.2017.1207

Nitrate and Nitrite in Health and Disease

Linsha Ma 1, Liang Hu 2, Xiaoyu Feng 3, Songlin Wang 4,*

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PMCID: PMC6147587  PMID: 30271668

Abstract

The source of dietary nitrate (NO3) is mainly green, leafy vegetables, partially absorbed into blood through intestinal mucosa. The recycled nitrate is reabsorbed and concentrated by the salivary glands and then secreted into saliva. In 2012, sialin was first discovered as the mammalian membrane nitrate transporter in salivary glands and plays a key role in circulation of inorganic nitrate, providing a scientific basis for further investigation into the circulation and functions of nitrate. Dietary nitrate can be converted to nitrite (NO2) by oral commensal bacteria under the tongue or in the stomach, following which nitrite is converted to nitric oxide (NO) through non-enzymatic synthesis. Previously, nitrate and nitrite were thought to be carcinogenic due to the potential formation of nitrogen compounds, whereas the beneficial functions of NO3--NO2--NO pathway were ignored. Under conditions of hypoxia and ischemia, the production of endogenous NO from L-arginine is inhibited, while the activity of exogenous NO3--NO2--NO is enhanced. Recently, a greater amount of evidence has shown that nitrate and nitrite serve as a reservoir and perform positive biological NO-like functions. Therefore, exogenous dietary nitrate plays an important role in various physiological activities as an effective supplement of nitrite and NO in human body. Here we generally review the source, circulation and bio-functions of dietary nitrate.

요약

식이성 질산염(NO3)의 공급원은 

주로 녹색 잎채소(비트, 마늘, 시금치)이며, 

장 점막을 통해 혈액으로 부분적으로 흡수됩니다. 

재활용된 질산염은 

침샘에 의해 재흡수되고 

농축된 다음 타액으로 분비됩니다. 

2012년, 

침샘의 포유류 막 질산염 수송체로서 시알린이 최초로 발견되었으며, 

무기질 질산염의 순환에 중요한 역할을 담당하고 있어 

질산염의 순환과 기능에 대한 추가적인 연구에 대한 과학적 근거를 제공합니다. 

식이성 질산염은 

혀 밑이나 위장에 있는 구강 공생 박테리아에 의해 

아질산염(NO2)으로 전환될 수 있으며, 

이후 아질산염은 비효소 합성을 통해 산화질소(NO)로 전환됩니다. 

이전에는 

질산염과 아질산염이 

질소 화합물의 잠재적 형성으로 인해 발암 물질로 여겨졌지만, 

NO3--NO2--NO 경로의 유익한 기능은 무시되었습니다. 

저산소증과 허혈의 조건 하에서, 

L-아르기닌으로부터의 내인성 NO의 생성은 억제되는 반면, 

외인성 NO3--NO2--NO의 활동은 강화됩니다. 

최근에, 

질산염과 아질산염이 저장소 역할을 하고 

긍정적인 생물학적 NO와 유사한 기능을 수행한다는 더 많은 증거가 나타났습니다. 

따라서, 

외인성 식이 질산염은 인체에서 아질산염과 NO의 효과적인 보충제로서 

다양한 생리 활동에 중요한 역할을 합니다. 

여기에서는 

일반적으로 

식이 질산염의 출처, 순환, 생체 기능을 살펴봅니다.

Keywords: dietary nitrate, NO3--NO2--NO pathway, circulation, sialin

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Nitrate (NO3) and nitrite (NO2) widely exist in water, soil, air, and plants [1]. The main source of absorbed nitrate in the body is food, with green vegetables contributing the major portion. Although nitrates are stable, dietary nitrate is converted to nitrite through a non-enzymatic process and nitric oxide (NO) by symbiotic bacteria in the oral cavity and stomach, therefore performing physiological NO functions. NO, the metabolic product of dietary nitrate, plays an important role in protecting the cardiovascular system and gastric mucosa, and in metabolic diseases [2, 3]. Endogenous NO is derived from the arginine pathway and is regulated by nitric oxide synthase (NOS) and its redox state. However, under conditions of hypoxia and ischemia, the activity of NOS is down-regulated resulting in a decreased production of endogenous NO. The skeletal muscle cells of rats were found to be capable of nitrate intake from peripheral blood, following which nitrate was deoxidized to NO by xanthine oxidation-reductase pathway, thereby increasing blood flow rate and enhancing metabolism [4]. Dietary nitrate served as an effective donor of NO, and the possible functions of NO from dietary nitrate are being widely studied.

Nitrate was thought to be harmful due to the potential production of carcinogenic nitrosamines under certain conditions such as an acidic stomach. Nitrosamines were reported to be related to esophageal cancer, gastric cancer, colon cancer, and other tumors [5, 6]. Thus, the World Health Organization (WHO) recommended the upper limit of concentration of daily nitrate and nitrite uptake to be 3.7 mg/kg and 0.06-0.07 mg/kg, respectively [4]. However, recent epidemiological investigations of nitrates and tumors have shown that no clear evidence has verified that dietary nitrate could increase the occurrence of tumors [7]. In 2012, sialin was first reported as a nitrate cell membrane transporter which played an important role in the circulation of dietary nitrate. Nitrate is actively transported by sialin in salivary glands, concentrated in saliva, and then secreted into the oral cavity, after which it reenters body circulation through the stomach and intestine [8]. As dietary nitrate is converted to NO by oral and stomach bacteria through non-enzymatic synthesis, nitrate could be considered indispensable in physiological activities.

질산염(NO3)과 아질산염(NO2)은

물, 토양, 공기, 식물 등에 널리 존재합니다 [1].

인체에 흡수되는 질산염의 주요 공급원은 음식이며,

녹색 채소가 주요 부분을 차지합니다.

질산염은 안정적이지만,

식이성 질산염은 비효소적 과정을 통해 아질산염으로 전환되고,

구강과 위장의 공생 박테리아에 의해 산화질소(NO)로 전환되어

생리학적 NO 기능을 수행합니다.

NO는

식이성 질산염의 대사 산물로,

심혈관계와 위 점막을 보호하고

대사성 질환을 예방하는 데 중요한 역할을 합니다 [2, 3].

내인성 NO는

아르기닌 경로에서 생성되며,

산화질소 합성효소(NOS)와 산화 환원 상태에 의해 조절됩니다.

그러나

저산소증과 허혈 상태에서는

NOS의 활동이 하향 조절되어

내인성 NO의 생성이 감소합니다.

쥐의 골격근 세포는 말초혈액으로부터 질산염을 섭취할 수 있는 것으로 밝혀졌으며,

그 후 질산염은 크산틴 산화-환원 효소 경로를 통해

NO로 산화되어 혈류량을 증가시키고 신진대사를 촉진합니다 [4].

식이성 질산염은

효과적인 NO 공급원 역할을 하며,

식이성 질산염으로부터 생성된 NO의 가능한 기능에 대한 연구가 활발히 진행되고 있습니다.

질산염은

위산과 같은 특정 조건에서 발암성 니트로사민이 생성될 수 있기 때문에

유해한 것으로 여겨졌습니다.

니트로사민은

식도암, 위암, 대장암 및 기타 종양과 관련이 있는 것으로 보고되었습니다 [5, 6].

따라서

세계보건기구(WHO)는

일일 질산염과 아질산염 섭취의 상한선을 각각 3.7mg/kg과 0.06-0.07mg/kg으로 권장하고 있습니다 [4].

그러나

최근의 질산염과 종양에 대한 역학 조사에 따르면,

식이성 질산염이 종양의 발생을 증가시킬 수 있다는 명확한 증거는 없습니다 [7].

2012년,

시알린이

식이성 질산염의 순환에 중요한 역할을 하는

질산염 세포막 수송체로서 최초로 보고되었습니다.

시알린은

타액선에서 질산염을 활발하게 수송하고,

이를 타액에 농축시킨 다음 구강으로 분비합니다.

이후,

위와 장을 통해 다시 체내 순환계로 들어갑니다 [8].

식이성 질산염은

비효소적 합성을 통해 구강과 위 내 세균에 의해 NO로 전환되기 때문에,

질산염은 생리 활동에 필수적인 것으로 간주될 수 있습니다.

Source of nitrate and nitrite

Systemic circulating nitrate is mainly obtained from two sources, diet and oxidation of endogenous NO, which correspond to exogenous and endogenous nitrates, respectively [9]. Exogenous sources of nitrate for human intake are primarily foods which account for approximately 60%-80% of the total nitrate intake [10]. In keeping with recent reports, vegetables, especially green leafy vegetables, such as spinach and beetroot contain an abundance of nitrate [11], which contributes nearly 80%-90% of the total dietary nitrate [12]. Other sources of nitrate are drinking water (15%-20%) and other foods, including animal-based products (10%-15%) [13].

With respect to nitrite, approximately 80%-85% [9, 14] of total systemic nitrite is obtained through endogenous conversion from nitrate [15]. Nearly 93% nitrite is converted from nitrate [16]. An individual consumes about 1.2-3.0 mg nitrite every day [17]. The other sources of nitrite are oxidation of endogenous NO and exogenous nutritional sources (cured meats comprise 4.8% and vegetables account for 2.2%) [10]. Exogenous nitrite is almost completely absorbed in the duodenum and jejunum [18]. Most systemic circulating nitrite is converted to NO and serves as a relatively stable reservoir of NO.

질산염과 아질산염의 공급원

전신 순환 질산염은 주로 두 가지 공급원,

즉 식이요법과 내인성 NO의 산화 작용을 통해 얻어지며,

각각 외인성 질산염과 내인성 질산염에 해당합니다 [9].

인체 섭취를 위한 외인성 질산염 공급원은

주로 전체 질산염 섭취량의

약 60%-80%를 차지하는 식품입니다 [10].

최근 보고서에 따르면,

채소, 특히 시금치와 비트 같은 녹색 잎채소에는

질산염이 풍부하게 함유되어 있으며,

이는 전체 식이성 질산염의 약 80%-90%를 차지합니다 [12].

그 밖의 질산염 공급원은

식수(15%-20%)와 동물성 식품을 포함한 기타 식품(10%-15%)입니다 [13].

아질산염과 관련하여,

전신 아질산염의 약 80%-85% [9, 14]는

질산염으로부터의 내인성 전환을 통해 얻어집니다 [15].

거의 93%의 아질산염은

질산염으로부터 전환됩니다 [16].

개인은 매일 약 1.2-3.0 mg의 아질산염을 섭취합니다 [17].

아질산염의 다른 공급원은 내인성 NO의 산화와 외인성 영양 공급원(경화육은 4.8%, 채소는 2.2%)입니다 [10].

외인성 아질산염은

십이지장과 공장(空腸)에서

거의 완전히 흡수됩니다 [18].

대부분의 전신 순환 아질산염은

NO로 전환되어

비교적 안정적인 NO 저장소 역할을 합니다

Distribution and conversion of nitrate and nitrite

Nitrate and nitrite exist widely in the human body, while the distribution is quite different. Volunteers receiving water labeled nitrogen 13 (13N03-) were found that nitrate did not rapidly absorbed into blood from the stomach but rather stably existed in the intestine. While after intravenous administration of 13NO3-, the distribution of nitrate was active in heart, reaching peak concentration of about 3% percent of total nitrate at 2 minutes, then fell rapidly in the next 2 minutes [19, 20].

Systemic nitrate and nitrite was circulating among blood, saliva and tissues, after a rich nitrate diet, the nitrate was absorbed and the plasma level peak up in 15-30 minutes with a half-life of about 5-8 hours [3, 21, 22]. As the concentration of nitrate was about 10 times of that in plasma, saliva contained large amount of total nitrate [23]. The active ingestion ability of nitrate in different organs differs greatly, possibly depending on the expression‎ of nitrate transporter protein-sialin [8, 24].

Nitrite in blood soon converts to nitrate with half-life about 110s, while nitrite in plasma is relatively stable with half-life about 20-30 mins [4, 25-28]. Normal plasma levels of nitrite are 50-100 nM and increase 4-5 times after a nitrate-rich meal, in which process numerous proteins and enzymes in blood and tissues catalyze the reduction of nitrate to nitrite [2, 29]. The conversion of nitrate to nitrite was an enzymatic process, while the conversion of nitrite to NO was a non-enzymatic process.

질산염과 아질산염의 분포와 전환

질산염과 아질산염은

인체에서 광범위하게 존재하지만,

그 분포는 상당히 다릅니다.

질소 13(13N03-)으로 표지된 물을 섭취한 자원 봉사자들은

질산염이 위장에서 혈액으로 빠르게 흡수되지 않고

오히려 장에 안정적으로 존재한다는 사실이 밝혀졌습니다.

13NO3-의 정맥 투여 후,

질산염의 분포는

심장에서 활발하게 이루어졌으며,

2분 만에 총 질산염의 약 3%에 해당하는 최고 농도에 도달한 후,

그 후 2분 동안 급격히 감소했습니다 [19, 20].

혈액, 타액, 조직에 순환하는 질산염과 아질산염은

질산염이 풍부한 식사를 한 후 흡수되어

혈장 농도가 15-30분 내에 최고치에 도달하고

반감기는 약 5-8시간입니다 [3, 21, 22].

Systemic nitrate and nitrite was circulating among blood, saliva and tissues,

after a rich nitrate diet,

the nitrate was absorbed and the plasma level peak up in 15-30 minutes with a half-life of about 5-8 hours

질산염의 농도가 혈장 농도의 약 10배에 달하기 때문에

타액에는 총 질산염이 다량 함유되어 있습니다 [23].

다른 기관에서 질산염의 활성 섭취 능력은 크게 다르며,

이는 아마도 질산염 수송 단백질인 시알린의 발현에 따라 달라질 수 있습니다 [8, 24].

혈액 속의 아질산염은 반감기가 약 110초인 질산염으로 빠르게 전환되는 반면,

혈장 속의 아질산염은 반감기가 약 20-30분으로 비교적 안정적입니다 [4, 25-28].

Nitrite in blood soon converts to nitrate with half-life about 110s,

while nitrite in plasma is relatively stable with half-life about 20-30 mins

아질산염의 정상 혈중 농도는 50-100 nM이며,

질산염이 풍부한 식사를 한 후에는 4-5배 증가합니다.

이 과정에서

혈액과 조직의 수많은 단백질과 효소가

질산염을 아질산염으로 환원하는 과정을 촉매합니다 [2, 29].

질산염이 아질산염으로 전환되는 것은 효소 과정이고,

아질산염이 NO로 전환되는 것은 비효소 과정입니다.

Circulation of nitrate and nitrite

The salivary glands and oral bacteria play an essential role in the circulation and conversion process of exogenous NO3--NO2--NO pathway. Dietary nitrate is absorbed almost entirely owing to its bioavailability in the stomach and the small intestine, and about 75% is excreted in urine, while the remaining amount is reabsorbed in the kidney, by biliary and in salivary glands [3, 30, 31]. Under normal conditions, up to 25% of recycled nitrate can be found in salivary glands, where the nitrate concentration reached 10 times that of the plasma [32]. In 2012, based on the organ model of salivary glands, sialin was discovered as the nitrate transporter in mammalian cell membranes, which provided the scientific foundation for the study of the biological effect and metabolism of nitrates in the body [8, 24, 33] Approximately 5%-7% of dietary nitrate is converted to nitrite in the oral cavity by commensal facultative anaerobic bacteria located in the deep crypts of the posterior part of the tongue [34, 35]. Thereafter, most nitrite is converted to nitric oxide in the stomach and absorbed systematically (Fig. 1).

질산염과 아질산염의 순환

타액선과 구강 내 세균은

외인성 NO3--NO2--NO 경로의 순환과 전환 과정에서 중요한 역할을 합니다.

식이성 질산염은

위와 소장에서 생체이용률이 높아 거의 대부분 흡수되며,

그 중 약 75%는 소변으로 배출되고,

나머지 양은 신장, 담도, 타액선에서 재흡수됩니다 [3, 30, 31].

정상적인 조건에서,

타액선에서는 재활용된 질산염의 25%까지 발견될 수 있으며,

이 때의 질산염 농도는 혈장 농도의 10배에 달합니다 [32].

2012년, 침샘의 기관 모델을 기반으로,

포유류 세포막의 질산염 수송체로서 시알린이 발견되었고,

이 발견은 체내 질산염의 생물학적 영향과 대사에 대한 연구의 과학적 토대를 제공했습니다 [8, 24, 33]

식이성 질산염의 약 5%-7%는

구강 내 후방 깊숙한 곳에 위치한

공생성 통성 혐기성 세균에 의해 아질산염으로 전환됩니다.

혀의 [34, 35]. 그 후, 대부분의 아질산염은

위장에서 산화질소로 전환되어 체계적으로 흡수됩니다(그림 1).

Figure 1. Circulation of nitrate in the body.

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The recycling of dietary nitrate is mainly in salivary glands, where sialin plays a key role in active transport and concentration of nitrate. Part of the nitrate is converted to nitrite by oral bacteria and subsequently absorbed in the stomach and intestine. Nearly 25% of circulating nitrate is reabsorbed by the salivary glands, whereas the majority is excreted by the kidneys. Nitrate performs physiological functions through the exogenous NO3--NO2--NO pathway.

NO, nitric oxide; NO2-, nitrite; NO3-, nitrate.

Function of nitrate and nitrite

Under conditions of hypoxia and ischemia, the production of endogenous NO from L-arginine is inhibited. On the contrary, the activity of exogenous NO3--NO2--NO is enhanced. Thus, dietary nitrate and nitrite serve as effective donors of NO under conditions of hypoxia and ischemia [34]. Nitrate and nitrite are used as food additives in processed food where they act as preservatives by inhibiting the growth of microorganisms, notably Clostridium botulinum. Besides the direct anti-microbial effect of nitrite, the physiological effects of nitrogen species including inorganic nitrate and nitrite have been reported recently.

When dietary nitrate is not available, the excretion of total nitrate calculated in health volunteers was much larger than the amount of intake, indicating that nitrate and nitrite could be formed by endogenous synthesis. The endogenous production of nitrate was mainly in intestine mucosa tissues [36]. Nitrate performs physiological functions in various systemic activities, including blood pressure reduction, platelet aggregation inhibition, and vessel protective effect - functions similar to those of NO [3, 37]. Nitrate prevents ischemic heart disease by increasing epicardial blood flow through vasodilation, decreasing vascular resistance, blunting coronary steal, and reducing preload [38]. Dietary nitrate (10 mmol/L soldium nitrate in drinking water) can partly improve age-related hypertension and metabolic activities in mice through a decrease of endogenous NO generation via inhibition of NADPH oxidase and modulation of angiotensin (ANG) II receptor expression‎ [39]. Furthermore, inorganic nitrates suppress (15 mmol/L KNO3) acute and chronic inflammation by raising the neutrophil count, which may reduce the occurrence of atheromatous plaque [40]. Moreover, a long-term dietary nitrate and nitrite deficiency experiment showed that mice would suffer from metabolic syndrome, endothelial dysfunction, and cardiovascular death after 22 months of a low-nitrite/nitrate diet [41]. Inorganic nitrate performs functions of decreasing blood pressure and improving myocardial ischemia by enhancing epithelial cell activity and diastole blood vessels, and reducing platelet aggregation [42].

Nitrates secreted from saliva protect against gastric ulcers by promoting gastric NO expression‎ and stimulating concomitant mucus formation [43]. Stress-induced gastric damage was reported with a water immersion-restraint stress (WIRS) assay in a rat model. Results showed that stress promotes salivary nitrate secretion and nitrite formation in health volunteers, and that exogenous nitrate administration (5 mmol/L NaNO3) recovered gastric mucosal blood flow and introgastric NO level, thereby rescuing the WIRS-induced gastric damage [44]. The concentration of bioactive NO in the stomach increased 50-fold after ingestion of dietary nitrate [45]. Meanwhile, the non-enzymatic production of NO from dietary nitrate (0.1 or 1 mmol/kg NaNO3) could effectively alleviate diclofenac-induced stomach mucosa injury and improve the thickness of slime layer in the stomach [43].

NO could regulate metabolic disorder-induced cardiovascular diseases and other metabolic disease. Moreover, the synthesis of NO was reduced in obese mice [46]. Metabolic disorder-induced high blood pressure, insulin resistance, and carbohydrate tolerance were found in ENOS (endothelial nitric oxide synthase)-knockout mice [47]. Dietary nitrate effectively supplements NO by the activated exogenous NO3--NO2--NO pathway under conditions of hypoxia. With a continuous 3-day supplement of 0.1 mmol/kg sodium nitrate pre-exercise, the oxygen consumed was reduced to an average of 5% [48]. Besides, nitrate enhanced the exercise tolerance of health volunteers by NO-cGMP-PPAR pathway and increased the metabolism of fatty acid in skeletal muscle cells [49]. Exogenous nitrate (0.7 mmol/L NaNO3) could active the cGMP pathway in mice and promote the conversion of white adipose to brown adipose, therefore enhancing fat metabolism and decreasing body weight [50]. As metabolic diseases were mostly accompanied with NO synthetic disorder, the supplement of exogenous NO from dietary nitrate could partially alleviate metabolic diseases. Therefore, exogenous dietary nitrate is an essential element in the human body and plays an important role in various physiological activities as an effective supplement of nitrite and NO.

Safety of nitrate and nitrite

Previously nitrate and nitrite were considered as precursors of N-nitroso compounds that were classified as human carcinogens. Nitrate was converted to nitrite and then gets into the stomach, where the condition of low pH promotes the conversion of nitrite to reactive nitrous acid [51]. Besides under conditions of inflammation and bacteria (Helicobacter Pylori), the formation of nitrate related nitrosamine was enhanced. Patients with achlorhydria and bacterial overgrowth were at high risk of developing gastric cancer possibly because of the formation of nitrosamine [52, 53]. However, this process would be weakened by polyphenols and other antioxidants such as vitamin C. With enough amounts of antioxidants as vitamin C, the nitrosylation of secondary amine through nitrite was inhibited [54, 55].

The International Agency for Research on Cancer (IARC) has concluded that there was no substantial evidence implicating nitrates as animal carcinogens in 2010 [56]. Moreover, in recent epidemiological investigations, dietary nitrate showed no association with gastric cancer or esophageal cancer in humans [7, 57]. Some research even showed that nitrate could decrease the occurrence of gastric cancer [11, 58], possibly because the main source of dietary nitrate are vegetables, which contain a large amount of fiber, vitamin C, and other reductants. An investigation in Korea, where the intake of dietary nitrates (390-742 mg/day) is considerably higher than that of European countries (52-156 mg/day) and China (422.8 mg/day), showed that no correlation was found between high intake of nitrate and cancer [59]. Besides, the safety of high dietary nitrate (91 g/L potassium nitrate) supply was identified in a miniature pig model. Liver and kidney tissues were checked after high-dose nitrate feeding for 2 years, and no observed systemic toxicity or damage was found in miniature pigs [60]. With 17 continuous weeks of 85 mg/L sodium nitrate-water supplement, increased insulin sensitivity, decreased plasma IL-10 level, and tendency of pro-long lifetime were found without body injury in these mice [61].

The association of nitrite with cancer seems conflicted [11]. The correlation between nitrite and gastric cancer is contradictory in different epidemiological surveys [57]. In 2011, carrying out a large cohort study including approximately 50000 individuals, followed up on for almost 10 years, Cross and his teammates concluded that nitrate and nitrite were not associated with esophageal or gastric cancer, whereas positive associations were found between red meat intake and esophageal squamous cell carcinoma [62]. Some epidemiological studies use processed or smoked meat as a source of exogenous nitrite ignoring complex compounds such as nitrosamines in such foods, resulting in lack of uniformity and scientific accuracy in conclusions. Therefore, association of exogenous nitrite with cancer seems less likely because large amounts of nitrite are formed endogenously. The nitrite concentration in saliva may rise as high as 72 mg/L after consumption of nitrate equivalent to 200 g of spinach [63]. Besides, people are in contact with nitrosamine in many circumstances, such as through smoke, beer, water, working environment, especially cigarettes which contain about 100-1000 times the level of nitrosamine in the daily diet.

Methemoglobinemia was found to be caused on ingestion of excessive nitrite [64], whereas ingestion of excessive nitrate did not lead to the disorder. A study in America showed that even though the mother ingested a large amount of nitrate, the baby would not get methemoglobinemia through breast feeding [65]. On the other hand, dietary nitrate, the source of which is mostly vegetables, which contain a large amount of antioxidants, effectively decreases the occurrence of methemoglobinemia [3].

Clinical application of nitrate and nitrite

Under conditions of illness or senescence, the activity of eNOS was reduced and the production of NO was decreased, as reported [46, 66, 67], thus indicating exogenous source of NO supplement might have a potential therapeutic treatment for patients undergoing illness or senescence. Nitrate was reported could lower blood pressure in health volunteers [68] and established in several experiments in human trials [69]. The aortic pulse wave velocity was improved, and the platelet-monocyte aggregates reduced in nitrate supplemental patients which resulting in decreased blood pressure [70]. Whilst with positive clinical trials, negative results were reported showing no significant effect was found in lowing blood pressure with nitrate supplement [71, 72]. The reason of these complex results was uncertain and more clinical trials were needed for further research.

Although many positive effects were found in animal models, the clinical usage of nitrate was quite limited. In recent years, nitrate-rich fruit and vegetable drinks especially beetroot drinks, Biotta veggie drink (Biotta®, Switzerland) [73], and BEET-IT (James White Drinks, Ipswich, UK) [74-76] have become popular. With increasing awareness on nitrates, nitrates and nitrate-related products are being accepted.

Conclusion

As part of their daily diet, people ingest inorganic nitrate mostly through green, leafy vegetables. Apart from their negatives, dietary nitrate and nitrite have been reported as exogenous donors of biological NO, playing an important role in physiological activity. Furthermore, dietary nitrate supplements seem to have potential protective effect for body balance, improvement of disorders (stroke, myocardial infarction, systemic and pulmonary hypertension, etc.), and in alleviation of gastric ulcers. Normal dietary nitrate and nitrite showed no harm to human health and no confirmed evidence stated the explicit association of dietary nitrate and cancer. Most existing research on nitrite and tumors ignored the complicated compounds in target foods, resulting in contradictory conclusions among researchers. Considering the various protective effects, other than the formal harmful suspects, dietary nitrate and nitrite play an important role in physiological functions through the provision of non-enzymatic NO. With a new understanding of nitrates and nitrites, their biological functions and applications need further investigation in the future.

Acknowledgments

This study was supported by grant from the National Natural Science Foundation of China (91649124) and grants from Beijing Municipality Government grants (Beijing Scholar Program- PXM2016_014226_000034, PXM2016_014226_000006, PXM2015_014226_000116, PXM2015_014226_000055, PXM2015_014226_000052, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, PXM2013_014226_000055, Z121100005212004, PXM2013_014226_07_000080, PXM2013_014226_000021, and TJSHG201310025005).

Contributor Information

Linsha Ma, Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University, Beijing 100069, China.

Liang Hu, Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University, Beijing 100069, China.

Xiaoyu Feng, Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University, Beijing 100069, China.

Songlin Wang, Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University, Beijing 100069, China.

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