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Eating the right amount of quality protein also protects our immune system by: Maintaining heart health Maintaining respiratory health Speeding up recovery after exercise Improving mood and boosting resistance to anxiety and depression which can often creep up in the colder months.

How much protein should you be having per day? Where should I get my protein from? Clean Lean Protein Clean Lean Protein is such a quick, easy and healthy way to boost your daily protein intake. min read The Key to a Healthy Life - Amino Acids and Protein for Optimal Health.

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min read How To Optimise Brain Function And Health To optimise brain function we must consider the health of our second brain — the gut! These two organs work synergistically and so we need to feed the body with the right nutrients to support them. It's about consistently implementing the foundations of health and nourishing your body and mind in order to feel your best all the time.

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Lind D. Associate Professor Laurence Macia. Traditionally, however, scientists have focused on the role of dietary fibre in maintaining a healthy gut. In this first-of-its-kind study, published in Nature Communications , the team from the Charles Perkins Centre used sophisticated modelling to explore the impact of 10 diets with a different makeup of macronutrients — protein, fats and carbohydrate in mice.

They discovered that a high-protein diet changed the composition and activity of the gut microbiota. Mice fed a high protein diet increased their production of bacterial extracellular vesicles, complex cargo containing bacterial information such as DNA and protein.

The body subsequently viewed this activity as a threat and triggered a sequence of events where immune cells travelled into the gut wall. While it is too early to say if this research might translate in humans, the researchers say activation of the immune system can prove either good or bad news.

All these changes cause the growth of the inflammatory response 1. Based on the knowledge of which cells are involved in each inflammatory response pathway, it is now feasible to shed light on the effects of specific nutrients on each of these processes.

To this end, we selected to discuss the influence of certain vitamins such as: A, B1, B2, B3, B12, C, and D, minerals like: Zinc, and Selenium as well as certain amino acids such as arginine and tryptophan and some fatty acids.

Vitamin A plays an essential role in the regulation of innate and cell-mediated immunity, and antibody responsiveness through the activity of either all-trans retinoic acid, 9-cis retinoic acid or other metabolites and nuclear retinoic acid receptors Vitamin A and associated retinoid metabolites exert an important regulatory function of the immune system.

This essential role is evidenced when Vitamin A is deficient and an augmented susceptibility to infections is evident Vitamin A deficiency affects processes related to appropriate cytokines release and antibody production.

Additionally, vitamin A deficiency is associated with a reduced production of natural killer cells, monocytes or macrophages, and impaired maturation and proliferation of T- and β-lymphocytes.

Vitamin A deficiency impairs innate immunity by impeding normal regeneration of mucosal barriers damaged by infection, and by diminishing the function of neutrophils, macrophages, and natural kill cells. Vitamin A supplementation cuts down morbidity and mortality in various infectious diseases In the case of vitamin A deficiency, the integrity of the mucosal epithelium is altered, resulting in enhanced accessibility to various pathogens to the gastrointestinal tracts and other organs, being children the most affected population In children, severe vitamin A deficiency causes almost the disappearance of goblet cells present in the upper layer of the epithelial line, therefore the production of mucus by these cells is compromised, and bacterial adherence to the epithelial lining is reinforced thus becoming the major factor for the development of the bacterial disease Additionally, vitamin A deficiency is associated with diminished phagocytic activity and macrophage oxidative breakdown that takes place during the process of inflammation along with a reduction in the number of natural killer NK cells It has been demonstrated that vitamin A Tab.

Thus, vitamin A is capable of promoting the Th2 anti-inflammatory response by repression of IL and IFNγ which are synthesized by Th1 lymphocytes In addition, some studies suggest a positive relationship between vitamin A and mitogen-induced pro-inflammatory cytokine IFN-γ and anti-inflammatory cytokine IL It is important to know that retinol, retinoic acid RA , and retinal are the three forms of vitamin A.

It has been shown that RA is involved in a lot of biological activities According to Rampal et al. When it comes to hypovitaminosis in children, vitamin A administration reduces mortality caused by diarrheal diseases Vitamin A might be responsible for antitumor effects on human pancreatic cell lines In metastasis of renal carcinoma, it seems that all-trans-RA ATRA have a similar effect ATRA represents a nutrient that is required in small quantities and it is synthesized in the human body from the A vitamin In acute promyelocytic leukemia APL , ATRA is utilized as a very efficient therapeutic agent.

Furthermore, together with arsenic trioxide ATO , they are able to increase life expectancy. As a result, vitamin A is capable of reducing some negative chemotherapy effects The next question worth asking would be whether there are more nutrients involved in mediating pro- and anti-inflammatory responses.

The group of B-vitamins comprise eight water soluble vitamins in charged to carry out essential, inter-related roles for appropriate cellular functioning.

These vitamins act as efficient co-enzymes in a vast array of catabolic and anabolic enzymatic reactions and they are essential cofactors for many important cellular metabolic pathways. We therefore cannot refer to life or to cellular life without referring to the B vitamins.

However, an important aspect to be considered in terms of B vitamins, is that when it comes to the human body, an important source of vitamins B is determined by the activity of the gut microbiota except for some that may be ingested by the diet. The absorption of B vitamins takes place in two different intestinal locations, the large and small intestines.

The large intestine represents the main absorption place for most bacterial-produced B vitamins. At the same time, the small intestine represents the place where dietary B vitamins are absorbed. It is tentatively to surmise whether two specific immune responses result from the two different absorption places We surmise that the immune activities at the two specific locations are different since the population of gut immune cells are different Vitamin B1 or Thiamine Table 1 , exerts an anti-oxidative role due to its protective action on sulfhydryl groups from the surface of neutrophils.

As a result, the synthesis of cytokines from macrophages is blocked furthermore. The NF-κB pathway involved in the control of the oxidative stress, is prevented by Thiamine. This role is highlighted by suppressing the phosphorylation and catabolism of inhibitory kappa B IκB , which subsequently inhibits the nuclear translocation of the transcription factor-sensitive redox NF-κB 58 , These properties are a result of its function in maintaining an equilibrium between glycolysis and the TCA cycle The TCA energy cycle represents the main source of naïve T cells, rest macrophages, and T-regulatory cells.

Interestingly, activated T helper cells need energy from aerobic glycolysis because the amount of energy from TCA is not sufficient Due to the significant effects of thiamine on these pathways, B1 deficiencies have so significant side effects. One of the side effects is linked to the stimulation of IL-1, IL-6, and TNF-α pro-inflammatory cytokines expression and neuro-inflammation.

Finally, neuronal death may occur due to the inhibition of CD 40 and CD 40L regulation It was observed that B1 could be used in the treatment of neurodegenerative diseases through its involvement in the suppression of the pro-oxidative activity of microglial cells Additionally, in regards to B vitamins, we should pay attention to their role in oncogenesis and more over is extremely important to clearly make a distinction between healthy and sick individuals.

Some speculations exist regarding the role of B1 in cancer due to its involvement as a cofactor in proliferation and energy pathways that are essential in the development of tumor cells. Table 1. Vitamins with pro-and anti-inflammatory effects as well as pro-tumor and anti-tumor effects.

Riboflavin, or vitamin B2 is crucial for energy metabolism through its function as a cofactor It also plays an important role as an anti-inflammatory and anti-oxidant modulator, especially in lungs 68 , Some specific aspects regarding the link between major histocompatibility complex MHC and B2 bacterial compounds are worth mentioning.

This function on the innate mucosal results in the stimulation of invariant T cells. Riboflavin and its precursors selectively activate mucosa-associated invariant T cells MAIT that represent the largest population of innate-like T cells in humans. Their synthesis as well as the link with the major histocompatibility complex through the major histocompatibility complex-protein MR1 are not fully understood.

It was observed that the activation of MAIT cells is dependent on genes that encode enzymes responsible for the formation of intermediate compounds in the synthesis of bacterial riboflavin.

These types of cells are known for their function in the inflammation and defense activity in gut mucosal due to their production of IL and IFN-γ The proliferation of neutrophils and monocytes as well as the stimulation of macrophages and neutrophils activities might be boosted by the activity of riboflavin 72 , The catabolism of inhibitory kappa B IκB is responsible for the activation of the pro-inflammatory factor Kappa B NF-κB.

Following this catabolic pathway, the inflammatory signaling pathway becomes activated. At the end of this signaling pathway, the activation of pro-inflammatory cytokines, such as TNF-α and ILs, takes place.

In this signaling process vitamin B2, act as an anti-inflammatory suppressor and it may block the activation of the NF-κB Furthermore, through the overexpression of catalase and nitric oxide synthase vitamin B2 could reduce oxidative stress Vitamin B3, niacin Table 1 is known as NADP and NAD precursor.

Similarly, to all B vitamins, it is a cofactor for a wide variety of enzymes involved in several metabolic pathways. In contrast to other B vitamin groups, human cells can synthesize NADP and NAD cofactors through independent pathways. From a biochemical point of view, niacin and the resulting cofactors are involved in redox reactions.

NAD is responsible for genomic equilibrium and epigenetic regulation may represent its mechanism of action Additionally, there is a positive correlation between high concentrations of NAD and the blockage of ROS synthesis Furthermore, NAD can be considered an anti-inflammatory micronutrient due to its inhibitory and deacetylation actions, which were observed in the NF-κB pathway Also, it has an inhibitory effect on inflammatory cytokines as well as on animal tumor cells NAD is also considered an efficient anti-inflammatory component since it induces the reduction of certain cytokines released from alveolar macrophages B12, cobalamin Table 1 affects pro- and anti-inflammatory responses.

A negative correlation has been observed between vitamin B12 and TNF-α It has been demonstrated that an increase of TNF-α induce the exhaustion of antioxidants involved in the defense against free radicals As a result, pro-inflammatory cytokines and some other pro-inflammatory compounds are activated Additionally, in these patients, the activity of NK cells is decreased Interestingly, hyperhomocysteinemia is the result of vitamin B12 deficiency 85 , leading to chronic diseases such as insulin resistance 86 and coronary heart disease 87 through the expansion of inflammatory processes.

Since vitamin B12 deficiency is associated with abnormal TNF-α activity, it can also lead to insulin resistance 88 , Regarding cancer activity, a study by Cheng et al.

In the case of lung cancer, B12 administration was not considered a risk factor On the contrary, a higher intake of B12 was considered dangerous for many types of cancer as indicated in a big meta-analysis of cancer patients Vitamin C Table 1 , is considered an essential micronutrient 93 in humans since they cannot synthesize it.

Human absorption of vitamin C is higher compared to other species that are capable to synthesized it 94 , Vitamin C is involved in the modulation of a wide variety of immune functions and play a role as a regulator of cell-signaling.

Vitamin C is also, involved in gene transcription as well as in hydroxylation reactions Through its main function as an antioxidant, it became capable to defend the body against reactive oxygen species that are the result of the activity of toxins and pollution Vitamin C is responsible for discontinuing the action of the pro-inflammatory cytokines and inhibiting the initiation of the NF-κB reaction In peripheral blood cultures that are stimulated with LPS lipopolysaccharide , after vitamin C administration, an enhancement of IL and a reduction of TNF-α and IFN-γ has been observed Moreover, as a result of ROS accumulation in microbial infections, vitamin C causes neutrophils displacement into infected sites Additionally, vitamin C might be useful as a cofactor in the synthesis pathways for vasopressin and norepinephrine in severe infections.

This has a noticeable effect on the infection response of the cardiovascular system when the pathological state represents a danger In this case, the effect is more pronounced if vitamin C is administrated in combination with vitamin E Ellulu et al.

Vitamin C is also involved in the regulation of hypoxia-inducible factor 1-alpha HIF-1α activity, which makes neutrophil viability under hypoxic conditions possible , and in this way, neutrophil apoptosis is delayed Furthermore, it is thought that vitamin C is involved in the fight against tumor cells through the increase in the number of NK cells Vitamin D, Table 1 exerts many anti-inflammatory roles since receptors to this vitamin are expressed in different organs throughout the human body.

The best known and established effects are linked to mineral and bone metabolism Wöbke et al. Vitamin D binds its receptors VDR resulting in a complex of vitamin D-VDR that may contribute to the formation of homodimer with an additional VDR or formation of a heterodimer compound with the nuclear retinoid X receptor RXR.

Also, the nuclear role is demonstrated following the formation of heterodimers with steroid hormone receptors From the immunological regulatory aspect, vitamin D can block the secretion of the pro-inflammatory cytokines IL-6 or TNFα in monocytes Additionally, the same effect has been observed in prostate cells These effects are caused by the inhibition on P MAP kinase a subclass of mitogen-activated protein kinase as a response to pro-inflammatory cytokines The results are closely related to the specificity of cells, their response, and effects of triggering factors Thus, vitamin D may be considered an anti-inflammatory micronutrient as a result of these interactions.

The vitamin D bound VDR becomes active and thus exerts inhibitory effects on NF-κB, which is also a heterodimer compound Additionally, some studies suggest anti-inflammatory role of D vitamin is mediated also through the inhibition of specific pro-inflammatory Th1 cell cytokines such as TNF-α, IFN-γ, IL-6, IL-2, and IL , Additionally, vitamin D is capable of increasing the concentration of cytokines such as IL, IL-4, and IL-5 as a result of an increase in the activity of Th2 cells At the same time, it may induce the amplification of Treg cells as well as a reduction of the number of Th17 cells , From a medical perspective, vitamin D has an important effect on the lung defense system against microbial pathogens.

This function represents the result of the antimicrobial peptides activation expression in monocytes, epithelial cells lining the respiratory tract, monocytes, neutrophils, and NK cells Lower levels of vitamin D in the serum are correlated with higher infection risks Particularly, the administration of vitamin D induce a decline in acute respiratory infections The anti-cancer effect of vitamin D in tumor cells is mediated by calcitriol which is the biologically active molecule of vitamin D The stimulation of apoptosis, the suppression of cancer cell proliferation, and associated delayed tumor development in cancer are the main effects mediated by calcitriol , At a molecular level, through the suppression of pro-inflammatory cytokines and prostaglandins PG activity as well as by preventing the NF-κB signaling pathway, calcitriol is considered an anti-inflammatory nutrient From this point of view, calcitriol may be used as a preventive and therapeutic agent in cancer When inflammatory cytokines are maintained at a high level, chronic inflammation takes place This process is closely linked to the action of some minerals.

In this way, it is important to test what is the role of Zinc in this essential process. The process is mediated Table 2 by the activity of several signaling pathways that are triggered due to the action of some changes produced by antigens and their metabolites.

The main compound involved in inflammatory responses as a result of its role in cell proliferation, cell apoptosis, and the release of certain cytokines like IL-6, IL-8, and IL-1β are mediated by the activity of the NF-κB factor The role of Zinc in this regard is controversial.

In vitro studies demonstrate that the zinc effects can be either anti-or-pro- inflammatory From one side the apoptosis effect is evident following the binding of the chelator and heavy metals From the other side, other studies indicate a strong relationship between the initiation of LPS-induced NF-κB and zinc Moreover, after a decline in the release of IL-1β, zinc is able to inhibit pro-inflammatory actions Furthermore, it has been reported that cytokine synthesis is dependent on Zinc status and this is closely related to chronic inflammation.

In this regard, it has been observed that obese people having low zinc plasma concentrations over-express IL-1β, IL-1α and IL-6 genes Zinc exerts beneficial effects on the proliferation and differentiation of T lymphocytes The strong relation between a high number of cytokines and the decline in zinc plasma levels in infections and trauma-associated conditions has been demonstrated in cross-sectional studies.

In patients with severe head injuries, upregulated cytokine production genes have been observed In addition, the production of cytokines is elevated in patients that are in a critical state due to their decrease in plasma zinc concentration Moreover, zinc antioxidant effects help the body to defend against reactive nitrogen species RNS and reactive oxygen species ROS Zinc also can be capable to support the integrity of skin and the mucous membrane In this regard, it was observed that deficiency of this mineral negatively impacts health by decreasing resistance to infectious diseases, dermatitis, growth diseases, and genetic disorders Another crucial micronutrient is selenium Table 2 , which is involved in the functioning of the thyroid metabolism and the cardiovascular system as well as in ensuring a functional immune system and preventing cancer.

From the cellular point of view, there are still discrepancies regarding the exact dose that may be translated into deficiency or toxicity, even if these stages do not commonly take place in the human body , It is well known that when selenium is present within the amino acid selenocysteine is able to control certain metabolic reactions that may lead to lipoxygenase synthesis that finally, can be involved in the production of inflammatory mediators , In mice, selenium, due to stimulation of T cell receptor complexes TCR activity and conversion of Th1 from T0 cells, may improve the regulation of cellular immunity Selenium can also contribute to the defense against pathogens as a result of its effects on redox signaling activities It was recently demonstrated that in COVID patients, selenium together with zinc exert a protective role and they are associated with a higher chance of survival During vaccination against COVID, it has been demonstrated that the response may increase after selenium administration as well as the increase of titers antibodies.

It is assumed that selenium may act as a cofactor in immunity response that is mediated by the vaccine Additionally, in women that are infertile as a result of polycystic ovary syndrome, to whom fertilization in vitro has been recommended, a decline in IL-1 and TNF-α gene expression was observed as a result of selenium treatment This effect suggests that selenium has an anti-inflammatory role in the human body.

Furthermore, in patients with cancer, the supplementation of selenium increased antibody titers of IgA and IgG as well as the number of neutrophils Selenium is capable to enhance the immune response of Th1 cells and the stimulation of T cells.

Selenium has a positive relationship with the number of B cells. The innate immune system may be strengthened after selenium administration. A similar effect has been observed on cellular immunity Increased titers of antibodies were measured due to selenium supplements that can cause an enhancement of vaccine effects , In the brain, both neurogenesis and hippocampal neural precursor cells are increased after selenium infusion Besides micronutrients, macronutrients, such as proteins and amino acids, also play an important role in the activity of the immune system.

Proteins are formed from amino acids that are essential in the construction of other proteins among which antibodies and cytokines that are typical proteins belonging to the immune system Arginine Table 3 contribute with the production of nitric oxide in macrophage cells.

Nitric oxide NO resulting from arginine under the action of nitric oxide synthase iNOS determines the cytotoxicity of macrophages in the fight against antigens such as pathogenic bacteria and parasites.

Moreover, M1 macrophages use arginine to produce NO Even though that arginine was initially considered a non-essential amino acid , after one decade, some papers have proven that arginine is essential for embryonic outliving, ontogenetic fetal development, and for constant hemodynamics and vascular parameters Moreover, the induction of the NF-κB pathway has been linked to the arginine degradation pathway As we presented previously, arginine through cations dependent mechanism can improve the release of insulin from pancreatic β cells.

However, clinical evaluations have shown that the beneficial effects of arginine administration are limited, probably due to the fact that it is very quickly transformed into ornithine or citrulline in epithelial cells In addition, the polyamines, compounds which are also derived from arginine degradation, are involved in balanced levels of membrane, mRNA and DNA.

Thus polyamines are capable to control the proliferation of cells In vitro , polyamines can modify the inflammatory process Furthermore, it has been demonstrated that higher concentrations of intracellular polyamines may change the in vitro cytotoxicity regulated by macrophage cells The inflammation regulation and identification of pathogens are closely related to polyamines through their binding manner to receptor-ligand complexes In an in vitro intestinal system in Caco-2 cells, arginine is able to induce the inhibition of IL-1β-mediated NF-κB pathway However, the mechanism of reducing the inflammatory pathways is still unknown.

Perhaps, it is linked to the activity of Arginase-1 Arg-1 , which, in this case, is stimulated by L-arginine as a substrate. The arginase-1 is an enzyme involved in the end of the urea cycle with the aim of forming l-ornithine and urea from l-arginine Some studies suggest that the Arg-1 has positive effects in certain inflammatory diseases through an anti-inflammatory action , In contrast, there are studies which have shown that higher metabolism of arginine in tumors cells, together with their particular environment, create conditions that are intermediary, and at the same time, crucial for the maintenance and development of cancer cells.

The result of these actions is translated into proper immunosuppression , One thing is certain, that the relationship between arginine and cancer cells is controversial. On the one hand there is data suggesting that arginine deprivation is correlated with a delay in the development of some tumor cells On the other hand, arginine can have antitumoral actions which are observed through the enhancement of immune response Furthermore, Al-Koussa et al.

In this sense, some authors suggest that arginine deprivation may downregulate the migration of cancer cells. In physiological conditions, the movement process is useful for embryonic growth and immune function. But when it comes to cancer cells, things are different. This happens since certain kinds of cancer cells can use this property with the aim to stimulate metastasis , Therefore, arginine deprivation in cancer cells is capable of reducing metastatic activity Unfortunately, the exact mechanism remains unknown.

Tryptophan Trp is clearly essential for the activity of the immune system Table 3. Since Trp is necessary for protein synthesis, it becomes to be indispensable for cell division and development Since Trp is not synthesized by the human body, it is required to be obtained from the diet Trp serves as a substrate for the biosynthesis and formation of serotonin 5-HT , kynurenine Kyn , and indoles The most useful and active Trp metabolism is the Kyn path which is related to the formation of nicotinamide adenine dinucleotide NAD and kynurenic acid.

Of course, similarly to all pathways, this type takes place due to the involvement of two types of enzymes indoleamine 2,3-dioxygenase IDO and IDO2 and tryptophan 2,3-dioxygenase TDO , Additionaly to the Trp metabolism, we brought information on its role in the regulation of inflammation through its initiators, starting with IDO, which exerts an insignificant effect on healthy and normal conditions.

Things are changed by some cytokines, including interferons which represent the result of the triggered inflammatory process The highly potent and amply used cytokine interferon-gamma IFN-γ. It is linked to the promotor-region of IDO and it is capable to express itself in many types of cells.

However, the highest expressive grade is found in dendritic cells and macrophages, but there are some other places where it was manifest such as epithelial and connective tissues — As we discussed before, inflammation and chronic immune tolerance are regulated by Trp biochemistry.

In tumor cells, an important step for metabolic reprogramming is represented by amino acids metabolism. Some authors suggest that, in the case of glioma, there is a strong link between the two because the metabolic amino acid pathway could be used as a predictor for survival as well as certain clinical characteristics As we mentioned before, amino acids and their metabolites are responsible for both controlling malignant cells as well as for changing the microenvironment.

In this way, the results are translated into the improvement of immunosuppression and malignancy state Kynurenine metabolism is capable of stimulating an oxidative stress resistance pathway, and, in this way, creating an opportunity to make changes in the tumor microenvironment that helps the development of the tumor However, another metabolite of tryptophan; 5-methoxytryptophan 5-MTP has the ability to suppress the development of tumors and the displacement of cancer cells in other tissues.

Wu et al. This type of inflammation-associated enzyme is very abundant in tumor cells and also contributes to development process of cancer Cholesterol has a key function on cellular membranes functionality, especially in the plasma membrane of the cell where it is found at higher concentrations.

Its special location at the lipid bilayer allows optimal interaction with other lipids and displays a significant role in membrane fluidity. Cholesterol points its structure mainly into the lipid bilayer leaving only the hydroxyl group facing the external environment.

Thus, the steroid rings are in close vicinity to the hydrocarbon chains of adjacent lipids Cholesterol is vital for the many physiological roles that the plasma membrane is involved. The cells keep their lipid bilayer appropriate functionality due to cholesterol molecules, otherwise, microenvironment, endocytosis, signaling pathways, as well as other functions, would be altered.

Cholesterol is involved in membrane integrity and it is responsible for receptors arrangement and bilayer fluidity , For a better understanding of the information provided later-on, we will describe the cholesterol synthesis and pathway in a schematic frame.

Cholesterol biosynthesis of is characterized by a complex pathway, nonetheless the pathways involved have been clearly elucidated Its synthesis involves more than 20 metabolic-specific actions, which include enzymatic reactions belonging to the mevalonate pathway of and additional synthesis pathway of cholesterol.

Enzymes involved in cholesterol biosynthesis are mainly detected in the membranes of the endoplasmic reticulum ER. These enzymes are the target of several molecular reactions which, closely controlled in order to not allow cellular damage , However, cholesterol is non-uniformly disseminated in the plasmalemma.

It has been observed that each pool is corresponded to an exclusive function in the plasma membrane physiology — It is clear that cholesterol equilibrium involves a transport mechanism by virtue of the concentration gradient from high concentration cholesterol places to regions where cholesterol has been lost or has a low level.

The transport of cholesterol is dependent on proteins due to its hydrophobic conformation, thus it cannot be transported through the blood. Thus cholesterol binds to different proteins and forms distinct lipoprotein compounds such as low-density LDL and high-density HDL.

As expected, regulatory mechanisms for the formation of each lipoprotein are specific The surplus of cholesterol can be transported through the efflux process or deposited as intracellular lipid droplets because of the incapacity of most human cells to efficiently degrade it.

The deposition of lipid droplet plaques in the bloodstream causes the release of inflammatory cytokines which create later an inflammatory process. The consequence of this event is associated with inflammation triggered by the cytokine interleukin-1β IL-1β Furthermore, IL-1β is considered an important marker in the inflammatory process The cholesterol signaling pathway plays a role in the immune response we therefore will highlight these pathways.

Sterol response element-binding protein SREBP exerts an essential role in the signaling pathway of cholesterol Figure 3. Normally, these proteins are located in the membrane of the ER, which is capable of binding with additional two complex proteins such as the cleavage-activating protein and generating SCAP and the insulin-inducible genes INSIGs The shift of SCAP from ER to the Golgi apparatus plays a key role in its activity.

SREBPs proteins are composed of three variants SREBP1a, SREBP1c, and SREBP2, being the latter the most important SREBP2 is a protein complex structure that seems to be capable to regulate the expression of all the enzymes that are involved in cholesterol biosynthesis Its most important activity is its specific response to high concentration of sterols which are able to efficiently induce a decrease in cholesterol synthesis.

SREBP2 fulfills its function when the sterols concentration decrease. This change in sterol concentration due to SREBP2 activity will generate afterward the shifting the complex SCAP from ER to the Golgi apparatus In this organelle, the SCAP molecule is changed Once the SCAP reaches the Golgi apparatus, proteases sit 1 and 2 cut this complex Figure 3.

As a result, the transcription factor TF is created and stimulated Then the TF enters the nucleus where it is responsible for the regulation of the cholesterol synthetic pathway enzymes All these pathways may stimulate the flux of cholesterol biosynthesis , Figure 3. Schematic frame of cholesterol biosynthesis.

In the signaling pathway of cholesterol, sterol response element-binding protein SREBP2 has an essential role. SREBP2 is located in RE, where it forms a complex with the protein like cleavage-activating protein and generating SCAP ; Its most important activity is to reduce the cellular cholesterol concentration when this is higher.

Then, SCAP is shifted from ER to the Golgi apparatus. Once SCAP reaches the Golgi apparatus, proteases sit 1 and 2 digest this complex and subsequently, the transcription factor TF is formed and is activated Then, TF moves into the nucleus where it becomes active and control the transcription of the enzymes of cholesterol biosynthetic pathway.

Additionally, it is important to mention that all cholesterol associated pathways involving synthesis, influx, efflux, and esterification take place through mechanisms closely related to each other allowing well-adjusted whole mechanistic biochemical pathways.

All these tightly controlled mechanisms highlight the crucial role of cholesterol in life span, and clarify the potential risks when the concentrations are diverted from the optimal range. In this regards, Luo et al. Moreover, in several diseases such as various types of cancer, infections and allergies, cholesterol biochemical equilibrium is severely altered through inflammation-associated consequences.

Regarding the relationship between cholesterol and macrophages, counter-regulatory mechanisms oppose macrophage inflammation and at the same time cholesterol cellular accumulation.

When the concentration of cellular cholesterol increases, specific sterols are formed. With their help, the transcription factors liver X receptor LXR —retinoid X receptor RXR are activated. These heterodimers have anti-inflammatory roles, including controlling the expression of ATP-binding cassette transporters ABC transporters , which are ABC subfamily A member 1 ABCA1 and ABCG1.

They are also involved in stimulating the efflux of cholesterol from macrophages. In this way, they can suppress the activation of TLR signaling given by the increased intracellular cholesterol concentration.

When TLRs are activated, LXR genes are inhibited, thus decreasing the cholesterol efflux from macrophages. Activation of cholesterol efflux by ABCA1 and ABCG1 is via apolipoprotein A1 APOA1 , forming HDL and initiating the process of transporting cholesterol back to the liver via blood vessels and lymphatics.

Therefore, as a way of amplifying the inflammatory response, the immune system can alter cholesterol homeostasis When the control of cholesterol biosynthesis is disturbed resulting in high cholesterol levels it can be translated into metabolic diseases such as atherosclerosis and dyslipidemia Figure 4.

In some of these cases, both the innate and the adaptive immune functions have the ability to regulate this phenomenon In this way, ApoB-containing lipoproteins are originated immediately after atherosclerosis damages. These are generated, developed and stored in the endothelial compartment Interestingly, these molecules exert pro-inflammatory effects through acetylation, oxidation, and especially induce aggregation with additional molecules The modifications provoked by the accumulation of ApoB-containing lipoproteins Figure 4 in endothelial location results in the growth of adherence, hold, and mobility in this place of immune cells In summary, the inflammation is supported through the generation of ROS and certain cytokines such as TNF α, IL6, and IL 1β , At the same time, Th17 and Th1 are involved in the pro-inflammatory process , Figure 4.

Cholesterol rate in the modulation of immune function. Polyunsaturated fatty acids PUFAs are essential fatty acids that contain more than one double bond in their backbone. PUFAs are divided into two main groups: omega-3 and omega The structural chemical difference between the two groups is represented by the location of the cis double bonds Together with cholesterol, PUFAs are essential for cell membrane integrity, development and maintenance in the homeostasis of cell function.

Moreover, they are used by certain structures in cells and they stimulate cell proliferation In this way, the sensitivity of the immune function can be modified The most representative polyunsaturated fatty acids are eicosapentaenoic acid EPA , alpha-linolenic acid ALA , and docosahexaenoic acid DHA , all defined as omega-3 fatty acids They are very intensively studied since they are involved in many essential vital activities and more interestingly in immunomodulation pathways.

In addition, the ALA is important due to the fact that it is a precursor of other fatty acids Omega-3 PUFAs have a role in immunomodulation by decreasing pro-inflammatory eicosanoids. They represent a substrate for AA cascade enzymes, in this way certain prostanoids and leukotrienes are produced.

Some lipid mediators such as maresins have omega-3 PUFAs as precursors. They promote the ending of the inflammatory process In human breast cancer cells ALA produce inhibition of cell proliferation and activate apoptosis In diabetic rats, ALA increases insulin sensitivity and restored lipid and glucose metabolic abnormalities ALA is considered essential because it cannot be synthesized by the human body.

In these regards, from the omega-6 group, an essential is considered linoleic acid LA. Following LA ingestion, this fatty acid is quickly converted into arachidonic acid ARA , which is responsible for the fluidity as well as the flexibility of the cell membrane.

Free ARA is involved in the modulation of ion channels, enzymes, and receptors through stimulation or suppression of their function Free unesterified ARA exerts antitumoral activity in vitro as well in vivo. It can be used as an anti-cancer drug.

Moreover, ARA can cause the death of tumor cells through the suppression of proliferation determining in this way, the death via stimulation of neutral sphingomyelinase nSMase mechanism Omega-3, as well as omega-6, participate in immunomodulation.

According to Simonetto et al. Omega-3 from the PUFAs group is involved in anti-inflammatory reactions through the inhibition of ARA from the membrane, which is the main precursor for pro-inflammatory eicosanoids They are capable to modulate immune and inflammatory responses through intensity and duration.

On the one hand, pro-inflammatory effects are linked to fever, vasodilatation and intensification of pain. On the other hand, they could have anti-inflammatory effects by blocking natural killer activity and lymphocyte proliferation.

Also, they are capable to inhibit IL-6, IL-2, and TNF-α However, most importantly is the ratio between the 2 groups of PUFAs. She additionally concluded that a lower ratio is associated with a general decrease in very common chronic diseases in the Western society As mentioned throughout all this review, there is a strong and dynamic link between nutrition and immune function, as a direct consequence of the modulation of the immune function through the pro-inflammatory and anti-inflammatory effects of certain nutrients including cholesterol who exerts a crucial impact in these complex biological settings and holds a great capacity to regulate immune function, tightly related to its concentration.

Certain micronutrients mentioned in this review: A, B1, B2, B3, B12, C, and D vitamins and minerals such as Zinc, and Selenium affect innate as well as adaptive immunity specifically through genetic, biochemical, and signaling pathways.

All these may be translated into the modulation of proliferation, cell division, cell mobilization, and physiology of immune cells. Additionally, we provide evidence that some macro-nutrients such as tryptophan, arginine, cholesterol and PUFAs may be involved in the prevention and therapy of some immune-related diseases.

Also, is very important to note that some vitamins such as A and D are fat soluble That is why when we consume fat-free light products, we are practically deprived of fat-soluble vitamins and the immune function can be affected. So, western diets should contain the accurate class of healthy fats, such as PUFAs, in a correct ratio, otherwise the edible products become poor in nutrients.

A good example is the Mediterranean diet. In addition, the fats are much more satiating and give food a much better taste We highlight the difference in response to micro- and macro nutrients between healthy and sick population.

We provided evidence that the response in pathophysiologic stages are very different to normal physiologic stages additionally to interindividual variations.

As a result, the immune response is different and variable 11 , , We also presented some evidences and speculations on the roles of some vitamins, as well as certain amino acids, in cancer patients, due to their involvement as cofactors in proliferation and energy-related pathways finally leading to the development of tumor cells.

We foresee that further research needs to be done in order to clearly distinguish the possible oncogenic effects of thiamin, cobalamin, and arginine 58 , We additionally provide evidence that the inflammatory responses in general, and the changes in immune functions are modified by the lack of an accurate cholesterol metabolism.

The alterations in the cholesterol biosynthetic pathway may have both positive and negative immune health-related repercussions.

Alterations in the cholesterol biosynthetic pathway may directly impinge and interfere with antimicrobial responses, as well as with antiviral effects Thus, an immediate action is required in order to adjust the cholesterol metabolism.

Moreover, we refer to the bioavailability of macro- and micro nutrients from food. We ask whether foods contain enough amounts of macro- and micro nutrients. Does the soil and then the foods today still have the same nutritional value as before for example in fruits and vegetables?

These led us to question under what conditions can artificial supplementation with macro or micronutrients be done? And how should be done? Should they be taken alone or as a complex?

The question is the synergistic and complementary action of taking supplements of vitamin complexes, results in a better or worst outcome? We surmise that the administration of nutrients micro and macro would exert distinct effects on each person. We know that each individual is different, and thus their immune responses will differ from each other.

To add more complexity, we referred also to the absorption capability of nutrients in the different compartments of the digestive system. We finally provided evidence that for each stage of the immune process, both micro and macronutrients are needed for the proper functioning of this important system.

If our diets lack the adequate amounts of dietary proteins the amino acids required for producing antibodies will also be less. Immune system cannot be strengthened in a day, it is an ongoing process. And protein is a major contributor towards building and boosting immune system.

Only few take in to account the role that a strong immunity plays during such times. Interesting revelations from a recent study called the Protein Paradox study indicate that most Indian households may not have the slightest idea of why one should consume protein or that one of its core function is building immunity.

Moreover, the study claims that the respondents could not even correctly identify more than 3 protein rich food ingredients from a list of over 20 food items which included 11 basic protein rich foods. In fact, this study finally revealed that Indian households may carry certain misconceptions may have directly contributed to the gradually declining protein intake of the country and the existing protein deficiency in India.

News Opinions Interviews Videos Reports Events. Sustainability Poshan MILLETS. A positive effect of vitamin D on the augmentation of salivary immune responses was also found during stressful military training in healthy subjects, who showed higher salivary secretory immunoglobulin A and cathelicidin secretion rates indices of mucosal immunity after vitamin D supplementation An anti-inflammatory effect of vitamin D was also found in patients with ulcerative colitis, who showed a significant decrease in serum proinflammatory cytokine levels TNF-α, IFN-γ, and IL12p70 Vitamin E is another micronutrient with potent immunomodulatory activity.

Supplementation of vitamin E and a tocotrienol-rich fraction in healthy subjects has been associated with regulation of gene expression and molecular signaling pathways related to immune response, response to stress, stimuli, hypoxia, bacteria, and complement.

A possible antioxidant and anti-inflammatory activity of vitamin E through the downregulation of signaling pathways related to apoptosis, NF-κB kinase, the cascade of extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2 has been indicated A beneficial effect of co-administration of nutrients and therapeutic medications in diseases was suggested in a randomized controlled trial investigating the effect of vitamin E on liver histology in patients with nonalcoholic steatohepatitis NASH and type 2 diabetes, where the combined treatment of vitamin E and pioglitazone improved steatosis and inflammation in patients leading to resolution of NASH Supplementation of B9 in patients with mild cognitive impairment improved cognitive function, which was associated with a reduction in peripheral inflammatory cytokines Regarding the effects of trace element supplementation on immune function and disease, zinc supplementation in patients with HIV showed potency in lowering markers of systemic inflammation, monocyte activation, and microbial translocation Serum zinc and selenium levels have also been reported as predictive markers of survival in COVID patients, with reference ranges of these trace elements associated with high-survival probability, highlighting the need for further evaluation of their supplementation effects in the disease Prenatal and postnatal zinc supplementation has been shown to improve T cell-dependent antibody responses to hepatitis B vaccination in infants Co-administration of zinc and magnesium in patients with polycystic ovary syndrome significantly decreased serum high-sensitivity C-reactive protein, a marker of inflammation, and downregulated proinflammatory IL-1 and TNF-α cytokines Moreover, selenium supplementation in healthy individuals improves their response to vaccination and increases their antibody titers , , indicating a potent role of micronutrients as cofactors in vaccine-mediated immunity.

An anti-inflammatory effect of selenium was also demonstrated in infertile women with polycystic ovary syndrome who were candidates for in vitro fertilization, who showed a decrease in gene expression of the proinflammatory cytokines IL-1 and TNF-α after selenium supplementation A positive influence of selenium administration on immunity in cancer was observed, as patients with lymphomas and solid tumors who received selenium showed a significant increase in neutrophils and IgG and IgA antibody titers Deficiencies in micronutrients such as vitamins A, B12, C, folic acid, riboflavin, iron, zinc, and selenium can increase immunosenescence, particularly susceptibility to infection and progression of inflammation Vitamin A deficiency has been shown to decrease the number of NK cells and impair their activity, impair the ability of neutrophils and macrophages to undergo phagocytosis, impair the growth and differentiation of B cells, decrease the number of T cells and limit their distribution Vitamin B2 deficiency has been associated with obesity-associated chronic inflammation.

Experiments with mouse adipocytes showed that B2 deficiency resulted in stimulation of the proinflammatory NF-κB signaling pathway and increased levels of IL-1, TNF-α and ROS Vitamin B12 plays an immunomodulatory role in cellular immunity , and its deficiency has been associated with upregulation of proinflammatory TNF-α in macrophages from Bdeficient mice and a decrease in IL-6 levels in Bdeficient rats, conditions that reversed in both animal models after increasing B12 supplementation — Deficiencies of certain trace elements have also been shown to have negatively affect the number and function of immune cells, leading to dysregulation of immune homeostasis.

Zinc deficiency leads to thymic atrophy, decreased number and activity of lymphocytes, altered cytokine production, increased oxidative stress, and inflammation and is also associated with autoimmune and inflammatory diseases by affecting Th cell polarization by promoting differentiation of Th0 cells into proinflammatory Th17 cells, accompanied by loss of Treg function In mice, it has been shown that selenium deficiency leads to a decrease in B cell count However, excessive selenium intake can be counterproductive, as infectious microorganisms can utilize this nutrient in their biochemical processes Copper deficiency is associated with a reduction in the number and antimicrobial function of neutrophils and also with a reduction in the IL-2 secretion of T cells with consequent reduction in T cell proliferation Abnormalities in Th and Tc cell numbers and function have been reported in patients with hereditary hemochromatosis, which is characterized by low iron stores Iron deficiency is associated with weakened cellular immunity, decreased numbers of neutrophils and their phagocytic activity, lower levels of IL-6 and IgG antibodies , The effects of macronutrients on the immune system are summarized in Table 2.

Macronutrients, including proteins, carbohydrates, and fatty acids, provide tissues with the energy necessary for their development and function Immunomodulation by macronutrients has been studied in experimental animals and in human intervention studies by testing the effect of their intake on immunological outcomes.

Proteins represent important macronutrients for the immune system, considering that amino acids are essential for the synthesis of immune proteins, including cytokines and antibodies that mediate immune responses Metabolic degradation of certain amino acids tryptophan, arginine leads to the production of chemical substrates involved in biological processes The degradation of arginine has been associated with the induction of the non-canonical NF-κB pathway and the regulation of gene transcription in the context of immune tolerance Metabolism of arginine and methionine also leads to the synthesis of polyamines, which are organic compounds that regulate cell proliferation through their role in maintaining DNA, mRNA, and cell membrane stability; polyamines have been linked to the induction and regulation of inflammation and pathogen recognition by affecting receptor-ligand binding.

Degradation of methionine leads to the synthesis of glutathione, an antioxidant organic compound involved in the prevention of oxidative stress, regulation of NK and T cell cytotoxicity and macrophage activity, and activation of T cells Amino acids exert multiple roles in the immune system, including regulation of the activation of adaptive and innate immune cells B and T cells, NK cells, macrophages , proliferation of lymphocytes, and production of antibodies, cytokines, and cytotoxic factors , Hydrolysates or bioactive peptides released by gastrointestinal digestion have been reported to have antioxidant activities, increase killing activity of NK cells, increase phagocytic activity of macrophages, and increase the size of lymphocyte populations, antibody and cytokine production Studies in pigs and the fruit fly Drosophila melanogaster, showed that high dietary protein intake has a positive effect on intestinal cellular and humoral immunity, associated with increased expression of antimicrobial peptides On the other hand, low protein diet has been reported to induce immunity against tumor cells in mice.

Specifically, a decrease in protein content and the associated decrease in amino acids cause ER stress, which leads to the activation of T cells that secrete proinflammatory cytokines A positive effect of a high-protein diet on the modulation of inflammatory immune responses was demonstrated in an intervention study of type 2 diabetics who were fed a diet high in animal or plant protein for 6 weeks.

After this period, they had reduced levels of the proinflammatory adipokines chemerin and progranulin regardless of protein source Overweight and obese adults who followed an energy-restricted diet with either normal or high protein achieved weight loss accompanied by significant decreases in proinflammatory monocyte subpopulations, plasma lipids, and lipoproteins An important aspect of the effect of macronutrients on the immune system is their involvement in immune recognition.

Carbohydrates represent common cell surface molecules that can be recognized as antigens by TLRs. Glycolipids, zwitterionic polysaccharides and glycopeptides can be presented to γδ and αβ T-cells either through endosomal pathways or extracellular receptors Glycoproteins and glycolipids can bind to glycan-binding proteins such as lectins and antibodies, regulating cell adhesion during leukocyte migration and immunity to infection through recognition of carbohydrates contained in the membrane of pathogens In addition, carbohydrates participate in enzymatic processes of protein glycosylation that generate important functional biopolymers.

Glycosylated peptides act as glycoantigens that influence the binding of antigen presentation proteins of the HLA-I and HLA-II systems and subsequent T-cell recognition of antigenic peptides.

Glycoantigens processed through intracellular pathways in APCs are presented to Th, Tc and NKT cells and modulate their activation and cytokine production Another study reported that carbohydrate intake by athletes was associated with a more balanced number of immune cells in the blood, decreased phagocytic activity of monocytes and granulocytes, and decreased ROS and inflammatory cytokine levels A low-carbohydrate, high-fat diet with or without after-meal walks in patients with type 2 diabetes improved glucose control and fasting pro-insulin levels and significantly decreased phosphorylated c-Jun N-terminal kinase in peripheral blood mononuclear cells, which is a marker of cellular inflammation Fatty acids provide an important source of energy, are components of the cell membrane, and modulate cell function by acting as signaling molecules that can regulate gene expression They can also influence immune cell functions by serving as precursors for the synthesis of lipid compounds involved in the regulation of immune responses and inflammatory pathways , Metabolic derivatives of fatty acids, including eicosapentaenoic acid EPA and docosahexaenoic acid DHA , are precursors for anti-inflammatory molecules that contribute to monocyte recruitment to sites of inflammation, where they engulf and remove apoptotic neutrophils Fatty acids regulate the phagocytic activity of macrophages, infiltration of DCs into lymph nodes and activation of mast cells , They also cross-react with the peroxisome proliferation activation receptor and TLRs , Fatty acids can have a dual effect on the regulation of inflammation, depending on whether or not double bonds are present between the individual carbon atoms unsaturated and saturated fatty acids.

Saturated fatty acids have been shown to stimulate in vitro and in vivo the intracellular macromolecular complex Nod-like receptor protein 3 NLRP3 inflammasome, which promotes the production of the proinflammatory cytokines IL-1β and IL, whereas unsaturated fatty acids exert an inhibitory effect on the NLRP3 inflammasome by limiting the activity of the transcription factor NF-κB , an observation that could be taken into account in clinical nutrition studies to attenuate inflammatory conditions in diseases.

The concentration of fatty acids is a factor that may influence their effect on immune cells. Low concentrations of free fatty acids induce T cell proliferation and cytokine production, whereas high concentrations of free fatty acids cause mitochondrial membrane dysfunction, leading to activation of apoptotic pathways and cell death Fatty acids, as components of lipid rafts in the cell membrane, can modulate cell signaling, which affects immune cell function, considering that lipid rafts have been shown to contribute to Th cell activation Metabolic derivatives of omega-3 fatty acids have also been shown to prevent the differentiation of Th0 cells into proinflammatory Th cells and decrease the secretion of proinflammatory cytokines IL-2, IFN-γ, TNF-α, IL by Th and Tc cells Contradictions exist regarding the effects of omega-3 fatty acids on B cell activation, as in vitro cultures of B cells isolated from the spleens of mice showed no change in the expression of B cell activation markers, whereas in vivo assessment of B cell activation in mice fed a fatty acid-enriched diet showed increased levels of the activation markers CD69, MHC-II, and CD11c — However, DHA and EPA stimulate IgM production by B cells by increasing the number of antibody-producing cells , An anti-atherosclerotic effect of omega-3 fatty acids has been suggested, as they have been shown to decrease the expression of adhesion molecules by endothelial cells, thereby affecting the migration of leukocytes from the bloodstream into tissues and the subsequent formation of inflammatory foam cells In a study of children, polyunsaturated fatty acids were shown to reduce the risk of allergic diseases asthma, rhinitis, and aeroallergen sensitization It has been shown that intake of short-chain fatty acids in multiple sclerosis patients or healthy controls promotes the differentiation of Th0 cells into Tregs with increased suppressive capacity A positive effect of fatty acids on immunity and inflammation has also been demonstrated in breast cancer patients who followed an enriched fish oil diet, including DHA and EPA, resulting in the maintenance of Th cell and serum hsCRP levels, indicating a positive contribution of fatty acids to immune system function and inflammatory response Omega-3 fatty acids have shown a positive effect on attenuating inflammation in patients with chronic kidney disease, as their supplementation resulted in increased production of LTB5 and specialized proresolving lipid mediators, which mediate the resolution of inflammation, and decreased levels of myeloperoxidase, an inflammatory mediator secreted by neutrophils A significant decrease in the levels of proinflammatory cytokines ILA and TNF-α was observed in patients with asthma who received a daily capsule of DHA and EPA, indicating a potent role of fatty acids as a complementary approach in the treatment of this disease Macro- and micronutrients exert critical and diverse roles in both innate and adaptive immunity by regulating the proliferation, function, and activity of various types of immune cells, as well as their interactions and signal transduction associated with inflammatory responses.

Micronutrient deficiencies and malnutrition are common in most countries of the world, highlighting the need for well-organized nutritional care for the general population to prevent disease.

Nutritional care of cancer patients undergoing chemotherapy or radiotherapy is a challenge to improve the efficacy and outcomes of cancer treatment and limit disease progression A detailed study of the effect of nutrients on the immune system is an important goal of nutritional immunology Molecular signaling of specific micronutrients is being studied to find drug targets for specific diseases associated with micronutrient deficiency, such as targeting the zinc transporter to treat insulin resistance in type 2 diabetes Studies are being conducted to investigate the effects of specific dietary interventions on human disease progression and chronic inflammation Diets containing nutrients with anti-inflammatory properties have been shown to reduce the risk of depression and attenuate the severity of depression symptoms The study of food consumption in overweight adolescents has revealed the existence of a unique dietary profile in this group associated with obesity The role of nutrition in the management of the severity of COVID and the recovery of surviving patients is currently under investigation; in particular, supplementation of vitamins C, D and zinc to improve patient health, restore immune homeostasis, and reduce the risk of infection for healthy individuals, and probiotics to improve gastrointestinal symptoms in COVID patients The field is open for further studies that will help to clarify the biological role of food metabolites in the physiology of the organism and especially the immune system, as well as the association of specific dietary nutrients with the pathogenesis of diseases.

AM and CT conceived and coordinated the study. ET and AM did the literature search and analysis and wrote the manuscript. AM and CT were responsible for the revision of the manuscript for important intellectual content.

All authors contributed to the article and approved the submitted version. Τhe publication of this article has been financed by the Research Committee of the University of Patras. 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.

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