Nowadays, they are cultivated in tropical and subtropical climates all over the world. Major production hubs include Spain, Brazil, China, the US, Mexico and India 1. Interestingly, nearly a third of all citrus fruits are used to make juice 1.

You can find all kinds of citrus fruits year round. The peak season for oranges and grapefruits in the Northern Hemisphere is between mid-December and April. Citrus fruits are an excellent source of vitamin C , a nutrient that strengthens the immune system and keeps your skin smooth and elastic 2 , 3 , 4 , 5.

In fact, just one medium orange has all the vitamin C you need in a day 6. Citrus fruits also have good amounts of other vitamins and minerals that your body needs to function properly, including B vitamins, potassium, phosphorous, magnesium and copper 7.

Additionally, they are rich in plant compounds that have various health benefits, including anti-inflammatory and antioxidant effects. Citrus fruits are very nutritious, offering a host of vitamins, minerals and plant compounds that help keep you healthy.

Citrus fruits are a good source of fiber. Just one cup of orange segments contains four grams of fiber 6. Fiber has several health benefits, including improving digestive health and aiding weight loss. Oranges are particularly high in soluble fiber, the kind of fiber that helps lower cholesterol levels Compared to other fruits and vegetables, citrus fruits are unique in that they have a higher ratio of soluble to insoluble fiber Citrus fruits are good sources of soluble fiber, which helps lower cholesterol and aids digestion.

Citrus fruits are low in calories, making them a smart choice for people seeking to lose or maintain their weight. Kidney stones are painful mineral crystals. They can form when your urine is very concentrated or when you have higher-than-normal amounts of stone-forming minerals in your urine. Many fruits and vegetables, especially citrus fruits, can raise the levels of citrate in your urine, lowering the risk of kidney stones Drinking citrus juices and eating these fruits can offer a natural alternative to potassium citrate supplements.

According to data on American eating habits over the last 40 years, kidney stones are more common in people who eat fewer citrus fruits Eating citrus fruits may help lower the risk of kidney stones in some people by raising citrate levels in urine. Many studies have linked citrus fruits to a reduced risk of certain cancers 1.

In one study, people who ate one grapefruit or drank one serving of grapefruit juice daily had a lower risk of lung cancer Other studies have suggested that citrus fruits may also protect against esophageal, stomach, breast and pancreatic cancers 20 , 21 , 22 , These fruits contain a host of plant compounds, including flavonoids, that may help protect against cancer 8.

Some of these flavonoids act as antioxidants and may block the expression of certain genes that are responsible for some degenerative diseases, including cancer 8. Citrus fruits may also help fight cancer by suppressing cancers, blocking the formation of new cancers and making carcinogens inactive 8.

Citrus fruits have been widely studied for their protective effects on a variety of cancer types. In fact, a Japanese study found that people who ate higher amounts of these fruits had lower rates of heart disease and stroke Furthermore, a review suggests that grapefruits are linked to a decrease in systolic blood pressure And many of the flavonoids in citrus fruits, including one called naringin, are strong antioxidants that benefit the heart in several ways Many compounds in citrus fruits can benefit heart health by improving cholesterol levels and lowering blood pressure.

Flavonoids found in citrus fruits have anti-inflammatory capabilities that are thought to help protect against the chain of events that causes the nervous system to deteriorate 27 , Specific types of flavonoids, including hesperidin and apigenin, have been shown to protect brain cells and improve brain function in mice and test-tube studies Several studies in older adults have also shown that citrus juices may boost brain function 29 , 30 , Citrus fruits and juices may help boost brain function and protect the brain from neurodegenerative disorders.

Eating lots of citrus fruits or juices could increase the risk of cavities. Interestingly, certain compounds in citrus peels may combat the bacteria that cause dental cavities, although more research is needed to see how that information could be used First, more sugar per serving translates to more calories.

Drinking fruit juice and other high-calorie beverages can cause you to gain weight Second, when your body takes in large amounts of fructose the type of sugar in fruit juice , it is quickly absorbed into your bloodstream and delivered to your liver If your liver gets more fructose than it can handle, it turns some of the extra fructose into fat.

Over time, those fat deposits can cause fatty liver disease Plus, the fiber found in fruit buffers the fructose, causing it to be absorbed more slowly into your bloodstream. Furanocoumarin, a chemical in grapefruit, binds to this enzyme and keeps it from working properly.

There are several prescription and over-the-counter drugs that are affected by grapefruit, including 40 :. While citrus fruits are generally healthy, they can have some drawbacks. Their acid can erode tooth enamel and grapefruit can interact with some medications. But aim to consume whole fruits, rather than a lot of fruit juice, as its high sugar content can lead to problems.

Overall, citrus fruits are healthy, low in calories and convenient to eat. Most people could benefit from adding more citrus to their diet. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

Citrus fruits are those in the same family of oranges. The fruits in this family are orages, limes, pomeloes, kaffir limes, and lemons. Nowadays, people like to drink lime and orange juice by cutting the fruits, squeezing, then keep its juice in fridge to drink it cold.

Have you ever noticed that after leaving the juice for a while, it will have remarkable bitter flavour. It is because when you squeeze the fruit for its juice, you also squeeze some biochemicals from its skin such as Limonoate A an Limonin glucoside which are not bitter.

Nomilin has light bitter taste. These chemicals will be digested by limoninase enzyme to be limonin, a bittering biochemical. The factors of delayed enzymatic bittering are oxygen, and temperature.

With more oxygen and high temperature, the enzyme processes more effectively and causes more bittering. So, to keep delicious flavour of the juice, you should keep it in low temperature or freeze it to stop the enzyme processing.

Some beverage is more tasty with bittering.

The fruits grow on flowering plants in the Citrus genus, native to tropical and subtropical parts of Asia and Oceania. Examples of citrus fruits include:. Citrus fruits deliver tons of juicy flavor with little to no fat, sodium, or calories, making them a good choice if losing weight is a goal.

One small orange, for example, has 45 calories. These fruits are also rich sources of fiber, which can help you feel full for long periods, making them excellent snacks for weight loss.

Experts advise consuming about 28 grams g of fiber daily, and citrus fruits can help you meet that goal. One orange serves up 2. Most of that fiber is pectin, which is a soluble fiber. Soluble fiber helps lower cholesterol and regulate blood sugar. The remaining fiber is insoluble, which adds bulk to your stool and regulates your bowel movements.

Citrus fruits have relatively low glycemic index GI scores, meaning they do not spike your blood sugar as much as other foods.

One orange has a low GI, while watermelon has a high GI of 70 and higher. The sugar from citrus fruit slowly releases into your bloodstream, offering you a steady feeling of energy without a crash later on.

Citrus contains flavonoids and vitamin C, which may promote heart health. Some evidence suggests flavonoids, which are plant compounds, reduce inflammation.

Vitamin C is an antioxidant that possibly protects against atherosclerosis, or plaque build-up in the artery walls. Citrus fruits are sources of other heart-healthy nutrients, including folate and potassium. Certain metabolites, or substances your body creates when it breaks down citrus, may also reduce heart disease risk.

Adding citrus fruits to your plate may help you get more out of other foods you eat. Citrus fruits, for example, help your body absorb iron from plant-based sources. Iron is a mineral that supports your immune system and helps produce red blood cells.

Eating plenty of water-rich foods, including citrus fruits, can keep you hydrated. Staying hydrated quenches your thirst and helps your body's systems work properly. Men need about ounces oz of water daily, and women need 91oz.

Vitamin C cannot prevent colds, but some evidence suggests it might reduce their duration and severity. Try adding vitamin C, including citrus fruits, to your diet before you get sick.

The vitamin C in citrus fruits may also benefit your skin. Vitamin C plays a role in collagen production, which leads some researchers to believe it can help keep skin looking supple and smooth. A review published in found that high fruit and vegetable intake can prevent visible signs of aging.

The researchers also noted that vitamin C may protect your skin against harmful ultraviolet UV rays. Citrus fruits are rich sources of potassium. This mineral helps regulate fluids and contract your muscles. Potassium counter-regulates the amount of sodium in your diet by helping your body flush it out.

Eating plenty of potassium-rich foods can also help lower your risk of stroke and heart disease and strengthen your bones. The nutrition of citrus fruits will vary depending on the type. Citrus fruits are generally low in calories, fat, and sodium and high in antioxidants, natural sugars, and vitamins.

One small orange, for example, has the following nutrients:. Citrus fruits come with many health benefits, but there are some caveats.

Keep the following risks in mind if you want to eat more citrus fruits:. Research has shown that people who consume five servings of fruits and vegetables have a lower risk of dying from cancer, heart disease, and respiratory disease than others.

Try adding more citrus fruits to your diet to help meet that goal. Here are some ways you can eat more citrus fruits:. Citrus fruit contains vitamins, minerals, and antioxidants that help protect against heart disease and support your immune system.

These fruits are also mostly water, which can help keep you hydrated. Enjoy citrus fruits, especially in their whole forms. Check with a healthcare provider before consuming grapefruit, which can adversely interact with a long list of medications.

Office of Dietary Supplements. Vitamin C - health professional fact sheet. Borghi SM, Pavanelli WR. Antioxidant compounds and health benefits of citrus fruits. Antioxidants Basel.

Food and Agriculture Organization of the United Nations. Department of Agriculture. FoodData Central: Oranges, raw, all commercial varieties. Dietary fiber.

Food and Drug Administration. Daily value on the new nutrition and supplements facts labels. FoodData Central: Tangerines, mandarin oranges , raw. Blanco-Pérez F, Steigerwald H, Schülke S, et al. The dietary fiber pectin: Health benefits and potential for the treatment of allergies by modulation of gut microbiota.

Curr Allergy Asthma Rep. The role of the immune system is to protect the individual against pathogenic organisms including bacteria, viruses, fungi, and parasites. There is a wide array of potentially threatening organisms in the environment.

Thus, in order to provide effective protection, the human immune system has evolved to include many different cell types and communicating molecules, and multiple functional responses. The immune system has four general actions. Firstly, it acts as a barrier keeping microbes from entering the body.

Examples of barriers include the skin; the mucosal lining of the gastrointestinal, respiratory, and genitourinary tracts; the acid pH of the stomach which kills many bacteria; and anti-microbial proteins in secretions such as tears and saliva. Secondly, the immune system acts to recognise microbes and to identify whether they are harmful or not.

Recognition can be of general structural features of microbes called molecular patterns or of specific and unique microbial antigens.

The mechanism of recognition involves ligand-receptor pairs, but these are different for recognition of molecular patterns compared with recognition of specific antigens and the type of response that is initiated is also different; this is elaborated further in this section. Thirdly, the immune system acts to eliminate those microbes identified as being harmful; this involves the destructive actions of various types of immune cell.

Fourthly and finally, the immune response generates immunological memory. This involves long-term maintenance of memory T lymphocytes T cells and B lymphocytes B cells so that, if there is re-exposure to the harmful microbe, the immune response becomes faster and stronger than it was for the original response.

The generation of immunological memory is the basis of vaccination. These complex and sophisticated actions can be achieved because the human immune system is comprised of many cell types Figure 1 1 , each with their own individual functional capabilities.

These different cell types interact with one another as part of the immune response to assure effective protection of the host from pathogens.

The immune system may be classified in different ways, most commonly into innate or natural and acquired or adaptive immunity Figure 1. Figure 1 The components of the immune system and their division into innate and acquired immunity. IFN, interferon; IL, interleukin; ILCs, innate lymphoid cells; MAIT, mucosal associated invariant T; TGF, transforming growth factor; TNF, tumour necrosis factor.

Taken from 1. Innate sometimes called natural immunity includes the barrier functions and the cells involved in recognition of molecular patterns on microbes these are called microbe-associated molecular patterns or MAMPs and the subsequent destruction of those microbes.

Examples of MAMPs include the cell wall lipopolysaccharides of Gram-negative bacteria and the peptidoglycans of Gram-positive bacteria. These general structural features are recognised by pattern recognition receptors; toll-like receptors are examples of pattern recognition receptors but there are many others.

The typical response following recognition would be to engulf the microbe carrying the MAMP by the process of phagocytosis, with subsequent destruction of the microbe within lysosomes by the so-called respiratory burst which generates destructive reactive oxygen species.

Neutrophils, monocytes, macrophages, and dendritic cells are all phagocytic cells. The inflammatory response is also triggered by this process, with the aim of creating an environment that is hostile to the invading microbes; in fact, an inflammatory response can be triggered by isolated MAMPs, not only by microbes bearing MAMPs.

Note too that the inflammatory response can be damaging to the host if it is not properly controlled and many pathologies involve adverse inflammation 2. Acquired sometimes called adaptive immunity includes antigen recognition and antigen-specific effector functions such as the proliferation of T cells, the killing of virally-infected cells by cytotoxic T cells, and the production of antibodies by B cells.

Acquired immunity can be further sub-classified into cell-mediated immunity involving T cells and humoral immunity involving B cells and antibody production. There are multiple types of T cells, each with different roles in the immune response Figure 1.

Innate and acquired immunity are linked. As mentioned already, phagocytic cells such as macrophages and dendritic cells, which are part of innate immunity, act as antigen-presenting cells, whereby they process and then present antigens derived from engulfed microbes to antigen-specific T cells so eliciting acquired immunity.

Conversely, cytokines produced by activated T cells regulate the activity of innate immune cells. Furthermore, antibodies produced by B cells coat microbes, making the process of phagocytosis more efficient. Thus, there is bidirectional communication between innate and acquired immunity and this can involve both cell-to-cell contact and production of, and responses to, chemical mediators.

It is obvious that effective defense against pathogenic organisms requires a well-functioning immune system. Consequently, individuals with weakened immune systems are at increased risk of becoming infected and of infections being more serious, even fatal.

Seriously immunocompromised individuals must live their lives in protected environments, where they are guarded against exposure to harmful microbes. The immune system also plays a role in assuring immunologic tolerance towards non-threating exposures including harmless microbes e.

commensal bacteria in the gastrointestinal tract and food components. If this tolerance is lost, adverse immune reactions are triggered. Inflammation is an essential and normal component of the innate immune response. In general, inflammation acts to create an environment that is hostile to pathogens, it initiates pathogen killing, and it causes changes in the metabolism of the host.

Many immune cell types play roles in the inflammatory response, which involves the production of, and responses to, a vast number of chemical mediators.

The cardinal signs of inflammation are redness, swelling, heat, pain and loss of function. These are caused by the cellular activation and chemical mediator release that occur during the initiation and perpetuation of the inflammatory response.

The chemical mediators released from cells during inflammation include lipids e. prostaglandins, leukotrienes, endocannabinoids, platelet activating factor , proteins e.

cytokines, chemokines , reactive oxygen species e. superoxide anion, hydrogen peroxide , amino acid derivatives e. histamine, nitric oxide and enzymes e. matrix proteases depending upon the cell types present, the nature of the inflammatory stimulus, the anatomical site involved, and the stage during the inflammatory response.

Although the inflammatory response is designed to be damaging to pathogens, the cellular activities involved and the chemical mediators produced can cause damage to host tissues.

Fortunately, therefore, inflammation is normally self-limiting and typically resolves rapidly. This is because various inhibitory mechanisms are activated as inflammation runs its course.

Loss of the regulatory processes involved in resolution of inflammation can result in excessive, inappropriate or on-going inflammation that can cause irreparable damage to host tissues leading to pathology and disease 3.

Inflammation is an important component of a wide array of human conditions including classic chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel diseases, allergy and asthma which are all controlled or treated with varying degrees of success with anti-inflammatory medications 2 , 3.

Inflammation is also involved in cardiovascular diseases, metabolic diseases, neurodegenerative disorders and cognitive decline; in many cancers; and in ageing 4 — 6. The relationship between inflammation and oxidative stress is bidirectional: oxidative stress induces inflammation and inflammation induces oxidative stress Figure 2.

Hence, agents that act to reduce oxidative stress can also be anti-inflammatory. Figure 2 The bidirectional links between inflammation and oxidative stress.

Reactive oxygen species ROS can act as inflammatory trigger initiating inflammation. On the other hand inflammation induces oxidative stress.

IκB, inhibitory subunit of NFκB; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, phosphate; ROS, reactive oxygen species.

The aim of this article is to review the literature that relates to the modulation of components of the immune response, including inflammation, by citrus fruit juices and their bioactive components and to describe the mechanisms involved.

The bioactive components considered are vitamin C, folate, hesperidin, narirutin and naringin. Narirutin and naringin are glycosides of naringenin Figure 3. Naringin is the major flavonoid in grapefruits with far lower amounts seen in sweet oranges, lemons, limes and tangelos.

Narirutin is found in grapefruits and in sweet oranges, tangerines and tangelos. Figure 3 Structure of hesperidin, narirutin and naringin and the aglycones hesperetin and naringenin. Clearly the immune system is highly complex involving many different cell types and subtypes and functional responses, and the production of, and responses to, many chemical mediators Figure 1.

Each of these components can be measured experimentally. In humans this is most often performed using blood samples, although some immune biomarkers can also be measured in other accessible fluids including saliva.

It is important to note that most immunologic activity does not take place in the bloodstream but in lymphoid organs such as the spleen and lymph nodes, or in tissues such as the gut mucosa and lungs.

As a consequence of this, only the minority of immune cells are in the bloodstream at any one time. It is generally agreed that there is no single marker of either the status or the functional capacity of the immune system 7 — In most human settings, circulating cell numbers, their activation state, and responses to an ex vivo challenge can be, and are frequently, measured.

There are normal ranges for circulating immune cell numbers and immunoglobulin concentrations, but there are no normal ranges for immune cell functional responses.

Assessments of the functional capacity of the immune system can be made by:. Expert groups have summarised and evaluated a large number of immune function assays commonly used as markers in human intervention studies 9 , Markers classified as being of high suitability were vaccine-specific serum antibody concentrations, the delayed-type hypersensitivity response, vaccine-specific or total secretory immunoglobulin Ig A in saliva, and the response to attenuated pathogens.

Markers classified as being of medium suitability included natural killer cell cytotoxicity, oxidative burst of phagocytes, lymphocyte proliferation, and the cytokine pattern produced by activated immune cells.

Other markers were classified as being of low suitability. Albers et al. With regard to inflammation, the total number of leukocytes white blood cells and circulating C-reactive protein CRP concentration are regarded as valid measures and may be supported by measuring concentrations of pro- and anti-inflammatory cytokines, chemokines and lipid mediators 2 , 4 — 6.

CRP at low concentrations requires measurement kits with high sensitivity to be used. As such, CRP measured with these kits is sometimes referred to as high-sensitivity CRP; it is important to note that this does not indicate a different type of CRP but merely indicates the nature of the assay used to measure CRP.

Patterns and clusters of such markers may be more robust biomarkers of inflammatory state and inflammatory response than individual markers or small numbers of markers. Citrus fruit juices contain a wide range of micronutrients vitamins and minerals and bioactive compounds; a comprehensive nutrient composition of orange juice has been provided elsewhere Several of these micronutrients are important in immune function support 12 — 16 and citrus fruit juice is a particularly good source of two of these, vitamin C and folate.

Chanson-Rolle et al. This difference may relate to variations in production and storage. De Rycker et al. Ashchoff et al. Others report similar values for folate [e.

The main form of folate in orange juice is 5-methyl-tetrahydrofolate 22 , which is stable over normal shelf life In addition to micronutrients, citrus fruit juices contain a number of polyphenolic flavonoid compounds of relevance to the immune system.

The concentration of total polyphenols was found to be similar between commercial and home-made orange juices Hesperidin is the main polyphenol in orange juice.

Bestwick et al. Li et al. Blood orange juice contained 2. Phenolic compounds in orange juice have been noted to decline minimally during optimal low temperature storage The bioavailability of bioactives from food and beverages is important if they are to exert a physiological effect or a health benefit, although they may also act via effects on gastrointestinal microbiota.

Folate bioavailability is discussed in detail elsewhere 28 ; bioavailability varies depending upon the exact chemical form and the food matrix but can be high. The majority of an ingested dose of hesperidin or narirutin is believed to reach the colon, where they are hydrolysed by the colonic microbiota, primarily yielding their corresponding aglycones hesperetin and naringenin, which are then absorbed by colonocytes.

After conjugation with glucuronic acid or sulphate, they are released into the bloodstream 31 , Reported urinary flavanone recoveries are poor: only 4. However, a substantial portion of the flavanone aglycones is further metabolized to similarly bioavailable catabolites by the colonic microbiota Nevertheless, a considerable interindividual variability in the absorption and metabolism of citrus flavanones has been noted, most likely associated with difference in gut microbiota The availability of hesperidin from orange juice appears to be greater than for whole oranges 38 , while levels of hesperidin are three times greater in commercially-squeezed orange juice compared with home-squeezed which results in higher blood levels of hesperitin Fruits, fruit extracts and fruit juices are good sources of micronutrients and of bioactive phytochemicals.

Many of these play roles in supporting the immune response, in controlling inflammation and in preventing or controlling oxidative stress which promotes inflammation and harms the immune response. In a randomised controlled trial, older people 65 to 85 years of age who consumed 5 or more portions of fruits and vegetables per day had a better response to the vaccine against pneumococcus than those consuming 2 or less portions per day Bub et al.

Both were matched for total polyphenol content although the nature of the polyphenols differed. Intervention duration was two weeks. Both juices increased lymphocyte proliferation, interleukin IL -2 production and natural killer cell activity compared with baseline. The effects of a dried encapsulated fruit and vegetable extract on immune function have been tested in several studies.

After 80 days, this extract increased lymphocyte proliferation and natural killer cell activity in older men and increased IL-2 production in those who smoked cigarettes A day randomised controlled trial in university students reported that the extract increased γδ T cells in the blood stream and resulted in fewer symptoms of the common cold γδ T cells are a distinct sub-population of T cells that are relatively uncommon but are most abundant in the gut mucosa where they contribute to the intraepithelial lymphocyte population.

They are considered to be regulatory cells that link innate and adaptive immunity. A randomised controlled trial over 28 weeks in middle-aged men reported that the encapsulated extract improved markers of oxidative stress and decreased the inflammatory marker CRP 44 ; there was also a tendency to less illness in those consuming the extract compared with the control group.

Taken together these studies indicate that fruits and vegetables, their juices and concentrates of their juices, can beneficially modify immune responses, inflammation, and oxidative stress in humans. It is well described that the post-prandial period can be accompanied by an elevation in the blood concentrations of markers of inflammation including various cytokines and adhesion molecules This post-prandial inflammation is exaggerated by meals high in sugar, total fat or saturated fat and is believed to enhance cardiovascular risk The effects of including a specific component e.

Acute effects of orange juice consumption on inflammatory markers have been evaluated in postprandial studies. In the study by Ghanim et al. Glucose promoted an increase in reactive oxygen species production by neutrophils and in activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells NFκB in mononuclear cells.

However, these effects were not seen with fructose, orange juice or saccharin. Plasma CRP declined one hour after consuming orange juice. These observations indicate that orange juice itself does not induce an acute inflammation.

Further research by this group 48 considered the effect of orange juice on the post-prandial inflammatory response induced by a high fat-high carbohydrate meal.

Adding orange juice to a standard meal reduced the post-prandial generation of reactive oxygen species by neutrophils compared with the meal plus water or the meal plus glucose. Orange juice totally mitigated the post-prandial rise in p38 mitogen-activated protein kinase MAPK , phosphorylated p38 MAPK the active form of MAPK and p47phox a subunit of NADPH oxidase responsible for reactive oxygen species production in mononuclear cells, all molecular markers of enhanced inflammation, as well as the elevation in matrix metalloproteinase MMP -9 mRNA in mononuclear cells.

Plasma MMP-9 concentration was not elevated with orange juice unlike in the other two groups, while the post-prandial elevation in toll-like receptor TLR 2 and TLR4 mRNA and protein in mononuclear cells seen with glucose did not occur with orange juice.

Endotoxemia occurred in the meal plus water and the meal plus glucose groups by not in the meal plus orange juice group. These observations suggest that orange juice mitigates the acute pro-inflammatory effects of a high fat-high carbohydrate meal.

A comparison of test meals accompanied by water, cream, glucose or orange juice confirmed the protective effects of orange juice 49 : unlike the meals with cream or glucose, the meal with orange juice did not elevate tumour necrosis factor TNF -α or IL-1β mRNA or NFκB activation in mononuclear cells.

Furthermore, unlike the meal with cream, the meal with orange juice did not elevate TLR4 mRNA or protein in mononuclear cells. Taken together, these findings suggest that inclusion of orange juice with a meal could minimize postprandial oxidative stress and inflammation.

The influence of chronic intervention with orange juice on inflammatory markers has been studied. In an uncontrolled study in 12 young adults, Sánchez-Moreno et al. In healthy overweight men, the consumption of ml orange juice daily for 4 weeks did not affect serum concentrations of several inflammatory markers CRP, IL-6, soluble intercellular adhesion molecule ICAM -1, soluble vascular cell adhesion molecule sVCAM -1 51 , although blood pressure was lowered and vascular function improved.

The orange juice intervention modulated the expression of 3, genes many of which are involved in chemotaxis, adhesion, and cell infiltration Buscemi et al. Endothelial function, which was measured as flow-mediated dilation, significantly improved in these subjects.

Asgary et al. In another study, ml orange juice daily for 8 weeks lowered circulating CRP and raised IL, but did not affect IL-4, IL, TNF-α or interferon IFN -γ, in both normal weight and overweight adults A second study with the same design ml red fleshed orange juice daily for 8 weeks also reported a reduction in CRP concentration in both normal weight and overweight individuals Patients with hepatitis C who consumed ml of orange juice daily for 8 weeks showed a reduction in plasma CRP concentration, although the starting value was higher than in the control group A recent meta-analysis of the effects of orange juice on risk factors for cardiovascular disease reported that orange juice significantly decreased CRP levels 7 trials; weighted mean difference: The greater effect of shorter than 8 week durations is perhaps counterintuitive but may be explained by loss of compliance in longer duration studies.

Whilst a number of studies have investigated the effect of orange juices on inflammation, there are almost no studies of the effects on markers of innate or acquired immunity beyond inflammation. Perche et al. The three treatments were ml orange juice daily, ml isocaloric control drink daily or ml of the control drink plus mg hesperidin in capsules daily.

There was no effect on blood immune cell phenotypes, the percentage of T cells and B cells activated with an immune stimulant ex vivo, ex vivo production of IL-2 and IL-4 by stimulated leukocytes, natural killer cell activity, or reactive oxygen species production by stimulated neutrophils. It is important to note that this study was conducted in healthy men and that it may be difficult to show improvements in immune function in healthy individuals.

Vitamin C is an essential nutrient that acts primarily as a water-soluble antioxidant. It is a cofactor for a number of enzymes including the lysyl and prolyl hydroxylases required for stabilization of the tertiary structure of collagen.

Hence, vitamin C is vital for maintaining epithelial integrity. Severe vitamin C deficiency results in scurvy, which is potentially fatal. Scurvy is characterized by weakening of collagenous structures, resulting in poor wound healing, and impaired immunity; individuals with scurvy are highly susceptible to potentially fatal infections such as pneumonia Cells of the immune system actively accumulate vitamin C against a concentration gradient, resulting in cellular concentrations that can be up to or times those seen in plasma 62 — For example, neutrophils can accumulate vitamin C to achieve intracellular concentrations of 1 mM or more 62 , This suggests that vitamin C is of some importance to immune cells.

Vitamin C has anti-inflammatory effects, in part because of its role as an antioxidant, and also has roles in several aspects of immunity, including leucocyte migration to sites of infection, phagocytosis and bacterial killing, natural killer cell activity, T lymphocyte function and antibody production.

There are a number of comprehensive reviews of the role of vitamin C in immunity and host susceptibility to infection 66 , Vitamin C is actively accumulated into epidermal and dermal cells via sodium-dependent vitamin C transporters, suggesting that it has important functions within the skin.

The effects of scurvy demonstrate the key role of vitamin C in maintaining barrier integrity. Vitamin C promotes collagen gene expression in fibroblasts 68 — 72 and promotes fibroblast proliferation and migration which is essential for tissue remodelling and wound healing 73 , Vitamin C intervention studies in humans have shown enhanced vitamin C uptake into skin cells 75 , 76 and enhanced oxidant scavenging activity of the skin 76 , The elevated antioxidant status of the skin following vitamin C supplementation could potentially protect against oxidative stress induced by UV irradiation and environmental pollutants 78 , Although cells of the immune system contain high concentrations of vitamin C, these can be decreased upon cellular stimulation, resulting in a loss of antioxidant protective mechanisms.

An altered balance between oxidant generation and antioxidant defences can lead to changes in multiple signalling pathways, with the pro-inflammatory transcription factor NFκB playing a central role Figure 2.

Oxidants can activate NFκB leading to continued synthesis of oxidative species and other inflammatory mediators 80 Figure 2. Vitamin C can diminish both oxidant generation and NFκB activation 81 and can modulate inflammation through redox-sensitive cell signalling pathways 82 , 83 or by directly protecting important structural components of the cell from damage In accordance with these proposed anti-inflammatory actions, vitamin C can modulate production of inflammatory cytokines.

For example, it decreased lipopolysaccharide-induced production of TNF-α and IFN-γ, and increased anti-inflammatory IL production, by human lymphocytes in culture Vitamin C treatment reduced activation of microglial cells and decreased the synthesis of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β Addition of vitamin C to peripheral blood monocytes isolated from patients with pneumonia decreased the generation of the pro-inflammatory cytokines TNF-α and IL-6 These findings are all consistent with an anti-inflammatory action of vitamin C.

Chemotaxis describes the movement of immune cells into infected tissues which is an early step in innate immunity. Neutrophils express many receptors for different chemo-attractants, enabling them to sense and rapidly respond to signals indicating infection or tissue damage Leukocytes from vitamin C deficient guinea pigs show impaired chemotactic responses 91 — Studies with large doses of vitamin C in patients with recurrent infections and impaired leukocyte chemotaxis showed restoration of chemotaxis 95 — Supplementation of healthy volunteers with vitamin C has also been shown to enhance neutrophil chemotactic ability 84 , — Phagocytosis is the process of engulfing pathogens which are subsequently destroyed within intracellular vacuoles, in part by the oxidative burst.

Vitamin C maintains or enhances natural killer cell activity , Like phagocytes, B and T lymphocytes accumulate vitamin C to high levels via specific transporters , Jacob et al.

Vitamin C seems to be important in the differentiation and maturation of immature T cells , , effects which may relate to epigenetic modifications — In vitro studies have indicated that incubation of lymphocytes with vitamin C promotes T lymphocyte proliferation 85 , and increases antibody production Treatment of guinea pigs with vitamin C increased T cell proliferation and enhanced antibody levels during immunization , Vitamin C clearly has benefits in supporting barrier function and both innate and acquired immunity.

Furthermore, incubation of virus-infected human and murine fibroblasts with vitamin C enhanced generation of anti-viral IFNs 89 , — A major symptom of scurvy is increased susceptibility to infections, particularly of the respiratory tract, with pneumonia being one of the most frequent complications of scurvy and a major cause of death 61 , This suggests that vitamin C likely has a role in protecting against infections, particularly of the respiratory tract.

Significant decreases in leukocyte vitamin C levels occur during common cold episodes, with levels returning to normal following the infection — , indicating that vitamin C is utilized during a common cold infection.

A meta-analysis of randomised controlled trials RCTs identified that vitamin C did not affect incidence of the common cold in the general population 24 RCTs but decreased incidence in people under heavy short-term physical stress 5 RCTs Vitamin C shortened the duration of the common cold in all studies 31 RCTs , in adults 13 RCTs and in children 10 RCTs and decreased the severity of colds Plasma vitamin C concentrations are reduced in patients with acute respiratory infections, such as pulmonary tuberculosis and pneumonia , There was also a positive effect on the chest X-ray, temperature, and erythrocyte sedimentation rate A meta-analysis of 3 RCTs reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with low dietary intakes Folate is essential for the synthesis of RNA and DNA and consequently for cell division, protein synthesis and tissue growth.

It is not a surprise therefore that folate is required for the immune system to function. In common with other B vitamins, folate vitamin B9 is involved in intestinal immune regulation , , thus contributing to gut barrier function.

In fact, folate is essential for the survival of regulatory T cells in the small intestine wall , suggesting it plays a role in preventing adverse immune responses at that site.

Regulatory T cells express high levels of folate receptor 4 FR4 and administration of anti-FR4 antibody to mice results in specific reduction in the regulatory T cell population , indicating that the folate-FR4 axis is required for regulatory T cell maintenance.

In vitro culture of regulatory T cells in folate-restricted conditions impaired cell survival, with decreased expression of anti-apoptotic bcl2 molecules, although naïve T cells retained the ability to differentiate into regulatory T cells , ; this suggests that folate is a survival factor for regulatory T cells.

Consistent with these findings, dietary deficiency of folate results in reduction of the regulatory T cell population in the small intestine of mice , Since regulatory T cells play an important role in the prevention of excessive immune responses , mice fed a folate-deficient diet exhibit increased susceptibility to intestinal inflammation Some commensal intestinal bacteria convert folate to 6-formylpterin which may suppress excess mucosal associated invariant T cell responses and prevent excessive allergic and inflammatory responses — Folate deficiency in experimental animals also causes systemic immune effects such as thymus and spleen atrophy and lower circulating T lymphocyte numbers: lymphocyte proliferation is also reduced in folate deficiency However, the phagocytic and bactericidal capacity of neutrophils appear unchanged Folate deficient culture medium resulted in an immature phenotype of murine bone marrow derived dendritic cells that produced less IL and pro-inflammatory cytokines in response to LPS This aberrant maturation of dendritic cells resulted in reduced ability to induce helper T cell responses with low production of cytokines including IL-2, IFN-γ and IL Folate deficiency in mice resulted in poor dendritic cell and spleen cell responses cytokine production and altered T cell phenotypes , while folate deficiency in rats or mice impairs antibody production , Thus, studies in experimental animals demonstrate that folate is essential for the immune system to function properly.

Rather less is known about the influence of variations in folate intake or status in human populations and immune outcomes. Congenital isolated malabsorption of folic acid is associated with impairment of both cellular and humoral immunity, and increased infections , while suppressed T cell mediated immunity in patients with megaloblastic anaemia with folate deficiency was reversed by folate treatment Critically ill patients with lower folate status had poorer neutrophil phagocytosis than those with higher folate status Likewise malnourished patients with lower folate status had poorer neutrophil function phagocytosis, bacterial killing than those with higher folate status and the impaired phagocytosis was corrected by folic acid supplementation Furthermore, the impairment in phagocytosis could be corrected by adding folic acid to the medium of the cultured neutrophils These studies indicate that having sufficient folate is important for the human immune system to function.

Hara et al. An intervention with high dose folic acid 1. Plasma levels of a number of proteins related to immunity were positively associated with folate status both prior to and following intervention Folic acid supplementation increased plasma concentrations of a number of immune-related proteins, including IgM C chain and complement 3 Folate has been a component of several micronutrient mixtures or nutritional supplements that have been reported to increase some, though not all, immune biomarkers — , including those associated with anti-viral defence , , and to decrease infections , , although the effects observed cannot, of course, be ascribed to folate.

It is also important to note that some studies of micronutrient mixtures that include folate do not show improvements in immune outcomes , Nevertheless, it seems clear from the literature that an adequate folate intake and status is required to support the human immune system.

Hesperetin is the aglycone of hesperidin Figure 3. The anti-inflammatory effects of hesperetin and hesperidin have been examined in several cell culture studies [reviewed by Chanet et al. Hesperetin decreased production of TNF-α by lipopolysaccharide-stimulated macrophages in a concentration dependent manner , ; IL-6 production was not affected Hesperitin did not affect expression of the inhibitory subunit of NFκB or inducible nitric oxide synthase in these cells following lipopolysaccharide stimulation and only modestly affected nitric oxide production Increased adhesion of monocytes to endothelial cells and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment were reduced by pretreatment with hesperetin Both hesperetin and hesperidin deceased expression of the adhesion molecule VCAM-1 in TNF-stimulated endothelial cells , and decreased monocyte adhesion to endothelial cells , Hesperidin also reduced ICAM-1 expression on endothelial cells cultured in high glucose concentrations , an effect associated with reduced phosphorylation of the p38 MAPK.

Hesperitin decreased IL-1β-induced MMP-3 and IL-6 production by cultured human synovial cells, which was linked to reduced activation of c-Jun N-terminal kinase Feeding hesperidin to mice for 6 weeks prior to undergoing irradiation resulted in lower concentrations of serum IL-1β, IL-6, and TNF-α compared to the control irradiated group This study suggests that hesperidin may enhance immunocompetence and decrease irradiation-induced inflammation in mice.

In a placebo controlled human trial with a crossover design conducted in 24 men and women aged 21 to 65 years with metabolic syndrome, hesperidin mg daily for 3 weeks resulted in significantly lowered plasma concentrations of CRP, serum amyloid A and sE-selectin In another human study, mg hesperidin daily for 4 weeks modified the gene expression profile of white blood cells 52 ; hesperidin intake modulated the expression of 1, genes many of which are involved in chemotaxis, adhesion, and cell infiltration.

Naringenin is the aglycone of naringin and narirutin Figure 3. The anti-inflammatory effects of naringenin have been examined in several cell culture and animal feeding studies [reviewed by Chanet et al.

In cell culture experiments, naringenin has been shown to decrease expression of inducible nitric oxide synthase and cyclooxygenase-2 and to decrease production of TNF-α, IL-1β, IL-6 and prostaglandin E 2 by lipopolysaccharide-stimulated macrophages , Naringenin also reduced expression of inducible nitric oxide synthase and cyclooxygenase-2 and decreased production of prostaglandin E2 and expression of mRNA for TNF-α, IL-1β and monocyte chemoattractant peptide 1 by BV2 microglial cells in culture Naringenin also decreased expression of the adhesion molecule VCAM-1 in TNF-stimulated endothelial cells and decreased monocyte adhesion to endothelial cells Such effects appear to relate to deceased activation of the pro-inflammatory transcription factor NFκB , , and of MAPKs Inclusion of naringenin in the diet of rabbits fed a high cholesterol diet reduced expression of VCAM-1 and monocyte chemoattractant peptide 1 in the aortic arch Naringin has also been studied in vitro and in animal feeding studies.

Naringin deceased expression of the VCAM-1 in TNF-stimulated endothelial cells Naringin also reduced ICAM-1 expression on endothelial cells cultured in high glucose concentrations , an effect associated with reduced phosphorylation of the p38 MAPK.

Inclusion of naringin in the diet of rabbits fed a high cholesterol diet reduced expression of VCAM-1 and MCP-1 in the aortic arch and reduced expression of ICAM-1 on endothelial cells Inclusion of naringin in the diet of mice fed a high cholesterol diet reduced blood levels of sICAM-1 and sE-selectin Dietary naringin lowered serum TNF-α concentration and increased serum adiponectin in mice ref a high fat diet Dietary naringin dose-dependently decreased serum concentrations of TNF-α, IL-6 and CRP and increased adiponectin concentration in diabetic rats fed a high fat diet compared with diabetic control rats In this same study, naringen increased liver and kidney expression of the anti-inflammatory transcription factor peroxisome proliferator activated receptor-γ and of heat shock protein and and decreased liver, kidney, and pancreas expression of NFκB Narirutin and naringin both decreased nitric oxide production by lipopolysaccharide-stimulated macrophages and decreased CRP release from incubated rat aortic vascular ring These data suggest that naringenin and its glycosides naringin and narirutin may have similar anti-inflammatory effects.

Beyond effects supporting immune function and controlling inflammation, bioactives present in citrus fruit juices may have direct anti-viral effects; these have been highlighted in the context of infection with systemic acute respiratory syndrome coronavirus SARS-CoV -2 and the disease that this virus causes, coronavirus disease discovered in COVID Using in silico modelling it was identified that hesperidin can bind with ACE2 and in doing so may make the ACE2-SARS-CoV-2 spike protein structure unstable — Through this action it is proposed that hesperidin could block SARS-CoV-2 from entering host cells and so could prevent the infection.

Hesperidin has also been shown to prevent replication of several viruses including the influenza virus acting through activation of immune-supporting MAPK pathways and in mice it prevented the spread of influenza virus Both hesperidin and hesperetin are able to inhibit key proteases involved in coronavirus replication , As reviewed by Tutunchi naringenin exerts similar actions suggesting it too could inhibit viral entry into host cells and subsequent viral replication.

It includes barrier functions and capabilities for recognition and elimination of pathogens and for immunologic memory. One component of the immune response is inflammation which is designed to create a hostile environment to pathogens. Generation of oxidative stress is part of the inflammatory response and, in turn, oxidative stress can induce inflammation.

Hence, an immune response which is appropriate to the challenge and involves controlled inflammation that is self-resolving is optimal. Limitation of oxidative stress is one means of controlling inflammation, hence, antioxidants are often also anti-inflammatory.

Nutrition is one of many determinants of the immune response 1 , 12 — 16 including the inflammatory component 4 — 6. Micronutrients vitamins and minerals are especially important for supporting normal immune response 1 , 12 — 16 and plant polyphenols have also emerged as having important roles, not only in helping to control oxidative and inflammatory stress, but also in supporting the activities of the cellular aspects of innate and acquired immunity.

Vitamin C and folate both have roles in sustaining the integrity of immunological barriers including the skin and internal mucosal linings Figure 4 , while vitamin C is an antioxidant and helps to control inflammation Figure 4.

As described earlier, both vitamin C and folate support the function of many types of immune cell including phagocytes, natural killer cells, T-cells, and B-cells Figure 4.

The Nutrient Reference Values for vitamin C and folate are 80 mg and μg respectively. Hesperidin is a glycoside of hesperetin and narirutin and naringin are glycosides of naringenin Figure 3. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been demonstrated to have anti-inflammatory effects, mainly demonstrated in cell culture and some animal studies; all seem to act, at least in part, through inhibiting activation of the pro-inflammatory transcription factor NFκB.

Human trials of hesperidin in people with metabolic syndrome or type-2 diabetes reported reductions in inflammatory markers, including CRP. Hesperidin modified gene expression in white blood cells with significant overlap of the genes modified with those modified by orange juice Thus, citrus fruit juices contain a mix of components that control oxidative stress and inflammation, and support the immune system.

In the context of human trials, orange juice has been most widely explored, although specific trials on immunity are scarce. Orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal Consuming orange juice daily for a period of weeks reduced markers of inflammation, including CRP, as confirmed through a recent meta-analysis One human intervention trial with orange juice failed to find effects on markers of innate or acquired immunity 60 ; however this trial studied healthy middle aged men and it may be that groups vulnerable to declines in immune function, such as the elderly, may be a better option for this type of trial.

Despite the findings of the latter study, in general the effects of orange juice, especially with regard to inflammation, are consistent with those of its component bioactives. A newly emerging topic, driven largely by the SARS-CoV-2 pandemic, is whether polyphenols from orange juice have direct anti-viral effects.

Furthermore in vitro studies identify that hesperidin, hesperetin and naringenin can restrict viral replication acting through inhibition of key enzymes involved in this process — Whether these effects occur in infected humans at intakes and circulating concentrations of these bioactives consistent with normal fruit juice consumption is uncertain.

In this context a clinical trial of hesperidin in people newly infected with SARS-CoV-2 has been registered In summary, micronutrients and other bioactives present in citrus fruit juices have established plausible pathways for controlling oxidative stress and inflammation and for supporting innate and acquired immune responses.

Trials in humans demonstrate that orange juice reduces inflammation, while its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups, such as older people.

Figure 4 Summary of the effects of orange juice bioactives on different aspects of inflammation and immunity. Vitamin C and folate support barrier function, T cell mediated immunity and B cell mediated immunity.

Vitamin C, folate, hesperidin and its aglycone hesperetin, and narirutin and naringin and their aglycone naringenin all reduce inflammation. The first draft of the article was prepared by PC. EM provided comment.

All authors contributed to the article and approved the submitted version. The University of Southampton received funds from a consortium of orange producers, juice manufacturers and packaging companies based in Europe and Brazil under the umbrella of the European Fruit Juice Association AIJN.

The funders had no influence on the content of the article nor on the decision of where to publish. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ACE, angiotensin converting enzyme; COVID, coronavirus disease discovered in ; CRP, C-reactive protein; FR4, folate receptor 4; ICAM, intercellular adhesion molecule; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MAMP, microbe-associated molecular pattern; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; SARS-CoV-2, systemic acute respiratory distress syndrome coronavirus 2; TLR, toll-like receptor; TNF, tumour necrosis factor; VCAM, vascular cell adhesion molecule.

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