Exhaustive Overview of Dietary Plant Lectins: Prospective Importance in the Mediterranean Diet

Stillmark reported in 1888 that castor bean extracts were able to agglutinate red blood cells from different species [1]. The seed extracts were found to contain haemagglutinating proteins, defined as agglutinins. Haemagglutinins are now known as lectins, a term proposed many years ago. Lectins are a very heterogeneous group of proteins of non-immune origin and have gone through several definition steps resulting in lesser strictness over the years. Some years ago, Van Damme defined lectins as: “carbohydrate-binding proteins possessing at least one non-catalytic domain, which bind reversibly to a specific monoor oligosaccharide” [2]. The continuous discovery of new and diverse lectins with similarities found in several different classes of proteins seems to call for even less strict definitions in the future. Maybe the most accurate lectin definition would simply be: “proteins that specifically bind or cross-bind carbohydrates”. Lectins are becoming more and more interesting as components of our diet, and it is interesting to note that in the U.S. News and World Report of 2020 the Mediterranean diet has been named as the best overall healthy diet [3]. The diet is well-known for its high content of vegetables, fruits and nuts and whole grains. This review examines our current knowledge of its importance for the Mediterranean diet.


Introduction
Lectins are widespread in the plant kingdom, occurring in seeds and all kinds of vegetative tissues, and often take part in the plants defence system against predators such as insects, worms etc [4]. To prevent the plant being fed on, lectins are not very tasteful, and severely interfere with digestive processes in insects and worms. Lectins and many other low molecular weight components in foodstuffs are thus called antinutrients because they often have a negative impact on the nutritional value of diets containing them. As biologically active proteins, lectins are very seldom harmful. Some are able to modify and sometimes improve gut function and body metabolism. They can also alter health status as well [5]. Animal lectins, on the other hand, are usually secreted from the cells where they may participate in cell-cell-interactions, recognition of immune defence systems, immunoregulation and prohibition of autoimmunity [6][7][8]. Due to the homology between plant and animal lectins, it is likely that the dietary plant lectins to some extent can mimic and amplify the effects normally exerted by their lectin counterparts produced by the animals themselves.
A large number of plant, animal and microbe lectins have now been isolated [9][10][11][12][13][14][15][16][17]. Lectins are widespread in the plant kingdom (fruits, nuts, vegetables), occurring in seeds and all kinds of The number of lectins found in various parts of plants has now become extensive and in order to bring the reader up-to-date Table 1   contains an overview of lectins in vegetables, fruits, cereals, seeds and nuts, and herbs and spices. As we can see more than 100 dietary vegetables contain lectins and the number of fruits is over 55. The Heath Authorities in Western society have advised its members to adopt the principle of "5 a day", that is one should include in the daily diet five portions of vegetables, fruits, cereals and nuts etc., amounting to about 400g per day [3]. In Greece, Italy, Spain and Turkey where the Mediterranean diet is used then the risk of suffering from heart disease is reduced. It is thus evident that to ensure long-term good health the diet needs to have an adequate content of plant lectins. Table 1: Lectins in Vegetables, Fruits, Cereals, Seeds and Nuts, Flowers, Herbs and Spices.

Hyacinth bean
Lab-lab purpureus [20] Srinivas Naik et al (2014) Jack bean Canavalia ensiformis [10] Nachbar & Oppenheim (1980) Jap. red sword bean Canavalia gladiata [35] Une et al (2018) Jerusalem artichoke Helianthus tuberosus L. [ [78]. From Aricigil and Pryme [12] (see Table 1. It would seem likely that NK cells have a similar role in the immunologic surveillance against cancer in humans and that plant lectins here play a vital role [102]. There is, therefore, a strong indication of the importance of keeping the number of activated NK cells in the blood within normal limits.
Many lectins taken orally are resistant to low pH and proteolytic breakdown due to their carbohydrate shell and complex structure.
They thus remain fully active during their passage through the entire alimentary canal [103]. The surface of the mammalian gut is highly glycosylated, and the epithelium is covered by glycolipids These molecules can therefore be extremely resistant to digestive processes and are therefore not completely degraded following exposure to acid and proteolytic enzymes in the GIT. Their biological activity thus being to a large extent retained during intestinal passage. For example, >90% of phytohaemagglutinin (PHA) and >60 of Sambucus nigra (SNA) lectins in kidney bean and elderberry, respectively, were recovered in an active form [105]. Very many lectins can thus remain fully biologically and immunogenically active during their passage through the entire alimentary canal [78]. Those lectins that survive will thus be able to bind to cells present in the intestine that bear appropriate receptors [2,105]. The mammalian gut surface is highly glycosylated and the epithelium is covered by numerous glycolipids and glycoproteins. Because of their affinity for saccharides, lectins bind to epithelial membrane glycoproteins, including receptors for hormones, growth factors and cytokines, transport proteins and brush-border membrane enzymes, glycolipids, gangliosides and secreted mucins [78].
As seen in Aricigil and Pryme [12, see The GIT, through its entire length, has various levels of glycosylation. Specific lectin binding can be therefore very different in the stomach, small intestine, and large intestine [78,103].
Different lectins can also bind to the same cell surface and these can therefore exert a synergistic response. In Figure 1

Oral Immunogenicity
The function of the gut associated lymphoid tissue is to absorb minute samples of oral antigens via Peyers patches M-cells and activate the gut immune system. As lectins are able to bind to M-cells [106], their endocytosis is more extensive, which makes them more powerful immunogens than other antigens. Lectins influence the immune system by evoking local and systemic immune responses and sometimes they can induce strong allergenic reactions [107][108][109]. Mitogenic lectins are inducers of lymphocyte proliferation.
Several components of the immune system, such as mast cells, basophils, eosinophils and others produce or release cytokines and chemokines when exposed to appropriate lectins.

The Effect of Plant Lectins in Animal Model Systems and Observations Made in Humans
Research performed on plant lectins has been mainly performed on laboratory animals. It is likely that many of the interesting findings cannot be directly transferred to humans. This is a direct result of the conditions prevailing during the experiments; firstly, much larger doses have been administered than would be realistic for humans to consume, secondly, the method of application e.g.
by intragastric intubation or subcutaneous injection, is often not at all relevant in the "normal" human situation, and thirdly, in animal experiments the effects of a single given lectin have been typically studied and this is atypical for our human lifestyle where, on a balanced diet of vegetables, fruit and nuts, a series of lectins would be ingested, often during the same meal. In Table 2 we see the approximate amounts of lectin present in common foodstuffs.
It is apparent that the amounts vary considerably from the kidney bean (<500mg/50g) to the tomato (<0.05mg/50g). These values, however, are dependent on the nature of the form of preparation of the foodstuff prior to its consumption. if it injected so that it reaches the blood stream directly. Abrin and volkesein lectins are also known to be lethal toxins [2]. These, however, are present in plants that do not belong to our natural diet.
To be able to promote biological effects, lectins that are present in common foodstuffs have to be in a biologically active form and they must have the property of being able to bind to glycan receptors under the conditions that prevail in the GIT. Even though most lectins satisfy both criteria, the effects can be variable, depending on the type of lectin, its binding specificity and strength of binding [110,111]. The prevailing physiological conditions in the GIT (e.g. pH, level of bile salts, bacterial and yeast flora) will undoubtedly have an effect on binding effectivity and we can therefore expect great individual differences. IIiev et al [112] have in fact reported that the presence of a fungal community in the GIT (the so-called "mycobiome") that coexists with bacteria and greatly increases the repertoire of organisms that have the capacity to interact with the immune system of the intestine, thereby potentially having a major influence on health and disease. These workers have identified a polymorphism in the gene coding for Dectin-1 (a C-type lectin receptor) that is strongly associated with a severe form of ulcerative colitis.
Lectins that do not bind to the mucosa of the GIT, or are prevented from doing so, will be unable to induce biological effects through the mechanism indicated [12]. As mentioned earlier it is feasible, however, that some lectins may be taken up by endocytosis, are thus internalised and thereby will be in a position to promote a biological response. Such a response, however, will depend on how quickly the body is able to produce an antibody [113].
An experiment with rats given parenteral nutrition, to establish whether or not PHA and peanut Arachis hypogea lectin (PNA) could reverse GIT and pancreas atrophy was performed by Jordinson et al [114]. During a period of 4 days the rats received a continuous infusion of parenteral nutrition, and the test group a daily dose of lectins in addition. The results showed that both these lectins could prevent gastrointestinal atrophy that arose as a result of parenteral nutrition. Interestingly, their effects in the GIT were specific in that PHA had greatest effect on the fundus mucosa in the ventricle and upper region of the small intestine, while PNA was most effective in the large bowel. The observed effects of these lectins were partly attributed to direct binding of the lectin to the surface membrane and partly to a local lectin-mediated liberation of growth stimulating hormones, which in turn results in an increased synthesis and uptake of polyamines. This is an interesting example where two lectins from different sources were able to act positively in concert.
That plant lectins can modify the natural composition of the microflora in the intestine has been demonstrated by directly allowing these molecules to interact with lectins and agglutinating substances. It was seen that particular bacterial species in the intestinal lumen, could result in their selective elimination. Freed [115] has shown that lectins can prevent the binding of bacteria to the brush border membrane surface by increased cell proliferation, a modification of the level of glycosylation or by occupying binding sites for bacteria.
Banwell et al [116] performed an experiment where 2 groups of rats, one being bacteria-free, were fed a PHA-containing diet for 7 days and the intestinal flora was then checked. In contrast to rats maintained under bacteria-free conditions, "normal" rats The oral feeding of PHA over time caused the normally thin and continuous mucous layer in the intestine to become thicker and uneven. Certain areas may thus lose their protection. This can theoretically lead to a weakening of the protective role that the mucous barrier plays in the intestine [115].
In parallel with the effects observed in the small intestine in rats, PHA in the diet also causes hypertrophy of the pancreas and promotes an increased secretion of digestive enzymes as a result of increased cholecystokinin (CCK) production [116][117][118]. This Pusztai et al [118] have expressed the opinion that low doses of PHA can probably be useful as a therapeutic agent for patients with chronic pancreatitis since PHA is able to stimulate growth of the pancreas. Vasconcelos and Oliveira [119] have shown that PHA, in a dose-dependent manner, can have an effect on the endocrine pancreas by interfering with the secretion of insulin.
In rats fed PHA the plasma insulin level was seen to fall while the That PHA may be useful as a dietary supplement or a therapeutic agent in order to stimulate GIT function, and in the treatment of obesity, has been suggested by Pusztai et al. [118]. First, however, it will be necessary to provide safe and effective doses in clinical trials. [120] that PHA has the property of binding to the gastric mucosa, and to parietal cells in the ventricle.

The interaction resulted in a reduction in both endogenously
and exogenously stimulated acid secretion. This has been been associated with delayed emptying of the ventricle [119]. It has been suggested that certain plant lectins, for example those present in Allium species, may have promising probiotic effects.
The presence of lectins in elderberry fruit is well known [121] and the concentration is about 10mg/kg raw fruit. Of the three elderberry lectins in the fruit there is most of the SNA-IVf type while there are decreasing amounts of SNA-1f and SNA-Vf [see Pryme and Dale [122]

Systemic Effects
A systemic effect can be caused by biologically active lectins.
This can be caused either by simulating the effects of endocrine hormones or they can bind to neuroendocrine cells in the GIT.
This can lead to secretion of peptide hormones, which in turn can modulate the endocrine system [2].
Of the five main groups of heat shock proteins (HSP), the 70kDa family is the best studied. This protein is central in cancer since it suppresses apoptosis by inhibiting the caspase chain reaction [127] and thus has the function of a survival protein. It can also enter into a strong complex with mutated tumour suppressor protein p53 [128], and effectively obstructs it from entering the nucleus where it activates transcription.
A malignant tumour can be regarded as a tumour where, following a process of selection, cells have lost the ability to commit suicide (i.e., enter apoptosis) [129]. Over-expression of HSP70 has thus been observed in malignant tumours of diverse origin and increased levels are known to be associated with poor prognosis in cancer [130][131][132]. Rohde et al [132] have shown that if HSP70 is eliminated from a cell then apoptosis is spontaneously induced.
Inhibition of HSP70 synthesis would therefore appear to be a novel and promising approach for treatment of human cancers, including those that show resistance to standard forms of therapy [133].
Pryme et al [100] have demonstrated that PHA, when added to the diet of mice, results in a great reduction in HSP70 levels in NHL cells growing intraperitoneally in mice. Briefly, two groups of mice were injected intraperitoneally with NHL cells; one group was maintained on a lectin-free diet while the second group was fed a diet containing PHA (7mg/g diet). On days 2, 3, 4 and 7 after injection mice were sacrificed and the peritoneal cavity was washed extensively with PBS to recover the tumour cells. Extracts were prepared from the harvested cells. Following electrophoresis and Western blotting to visualize HSP70, band intensity was determined and plotted as a function of duration of feeding PHA.
The results showed that when a PHA-containing diet was fed to mice injected with NHL cells then a drastic reduction occurred in HSP70 levels in a time-dependent manner. After two days of feeding PHA the HSP70 level was already reduced by about 65%. Two days later the level had decreased to 10% of that expressed in NHL cells growing in mice fed a lectin-free diet. Seven days after injection HSP70 was virtually non-detectable.
What is striking with these observations is that the effect is seen after dietary intake of a normal plant protein. It would seem unlikely that PHA merely diffuses from the gut lumen into the intraperitoneal cavity since the molecule is a large 118 kDa protein [134]. As described earlier (and shown in Figure 1 The consequences may be of extreme interest since it is evident here that a single dietary lectin is capable of inducing a response in the body that is detrimental to the growth of cancer cells.
Using a lectin-containing extract derived from Korean mistletoe Yoon et al [135] observed an anti-metastatic effect in a series of tumours where anti-angiogenic mechanisms were involved. In later experiments an induction of apoptosis was reported in tumours [136]. Similarly, using a purified lectin from Korean mistletoe, it was shown that mechanisms involving anti-angiogenesis and apoptosis were involved in reducing growth of a B16-BL6 melanoma in mice.
Yoon et al [137] have described that the anti-tumour effect of the Korean mistletoe lectin can be attributed to the activation of both macrophages and NK cells. There are, therefore, a series of recent observations clearly indicating that the administration of plantderived lectins can be beneficial in reducing tumour growth [138][139][140][141].
Even though mistletoe is not recognised today as a normal constituent of our diet, the plant was used widely in ancient times in folk medicine. This probably led to the development of receptors in the GIT having the property of binding mistletoe lectins. This could perhaps explain why ML-2 has been shown to bind to the FAE and VE areas in human Peyers patches (Table 1.4
Industrially processed food forms an increasing part of everyday life. The means by which such food is prepared will often result in a loss (degradation, denaturation etc.) of biologically active molecules e.g., lectins. As mentioned above lectins can have extremely important functions and their "removal" from the diet would therefore not be desirable. A person closely following the blood type diet would probably eat lower amounts of processed food than non-followers, meaning that their diet would have a higher active lectin content. This may then afford an explanation for some of the positive effects that D Ádamo has described [142]. The The future for lectins would seem to be promising. This further emphasises that a healthy diet should include large amounts of raw vegetables, fruit and nuts. In this way we can ensure a rich availability of these biologically active molecules that by all accounts exhibit beneficial effects on our well-being. What we need to know, however, is the stability of lectins under gastric and duodenal environments. For example, the elderberry lectins were shown by Jiménez et al [123] to be refractory to these conditions. chains, it would therefore be incorrect to assume that PHA and ML-1-induced effects [95][96][97][98][99][100] will necessarily be characteristic for other lectins that we consume. A major reason for the frequent use of PHA is its availability since it amounts to 1-10g/kg raw kidney beans [111], thus representing a major protein in the bean. This is in contrast to lectins for example in onion, tomato, rice and banana where the concentration is <0.01g/kg raw material [111].
Winge et al [113] performed a small pilot study to evaluate whether or not a mistletoe lectin-containing preparation taken orally by adults was able to modulate the immune system. Eight It was thus evident that in order to "prime" the immune system almost a third of the individuals had to take the lectin preparation for a period of three months in order to bring their NK cell levels within the normal range [113]. Keeping the NK cell level at normal values is not only imperative for maintaining an effective first line attack against for example, virus infections, but importantly it was shown many years ago that in animals exhibting low NK cell levels then there is an increased risk for the development of both spontaneous and experimental tumours [143,144]. In addition, Yoon et al [137] showed that the prophylactic effect of a Korean mistletoe lectincontaining extract on tumour metastasis was mediated through the enhancement of the activity of NK cells. Takeda and Okumura [102] have reviewed a series of studies that have clearly identified a major role for NK cells in immune-surveillance.
The results presented here demonstrate that mistletoe lectins taken orally are effective as immunomodulators and thus a mistletoe preparation does not have to be injected (e.g. subcutaneously) in order to modulate the immune system in humans. The lectin-enriched mistletoe preparation described here appeared to effectively function as an immuno-stimulating dietary supplement for the healthy individuals who took part in the study.
Of special interest was the increase in activated NK cells that was observed in several of the individuals who participated in the study. This is in line with Takeda and Okumura [102] who state that toll-like receptors and receptors to lectins, including those from mistletoe, are among the most likely candidates responsible for NK cell activation. It is interesting to note that lectins, also those from mistletoe, have recently been regarded as having great potential as anticancer agents [14]. In conclusion the mistletoe preparation described here, can be envisaged as a useful dietary supplement in order to stimulate the immune system in subjects where this would be beneficial e.g. in immunodeficiency. Such a preparation could also be beneficial for the public at large in order to "prime" the immune system such that, for example, the unpleasant effects of common colds and flu may be greatly reduced. In addition, the body will in general be more suited to combat other types of bacterial or viral infection, and, furthermore, be able to operate more effectively in the inactivation/destruction of abnormal cells in the body (e.g. cells of precancerous nature, or even tumour cells themselves). Antibodies to mistletoe lectins have been detected in humans after subcutaneous administration [150][151][152]. We show here that the consumption of a mistletoe lectin preparation by adult's results in the induction of antibody production against mistletoe lectins.
After drinking the preparation for 84 days all 8 individuals were observed to have produced ML antibodies. This is in line with previous observations where oral presentation of ML to mice resulted in the appearance of specific serum IgG and IgA antibody after three oral doses [108]. As expected different epitopes were detected since ML-I antibodies cross-react, for example with ML-III.
There are many dietary supplement preparations commercially available where claims are made that they are immunostimulatory when taken orally. Documentation of these claims, however, is in on the whole sadly lacking. In this study two lines of convincing evidence were presented that the mistletoe preparation described has potent immuno-stimulatory properties, firstly, four cell types of the immune system showed marked proliferation, and secondly, all individuals produced antibodies to the lectins present.
By using the oral, as opposed to the subcutaneous route, the possibility of an allergic reaction is reduced and a much more far-reaching, long-term effect is observed [153]. About 80% of immunoreactive tissue in the body is associated with the gastrointestinal tract. Following consumption of mistletoe lectins, they work by binding to specific galactose/N-acetylglucosamine receptors on M-cells of Peyer's patches associated with the MALT/ GALT system [78]. Subepithelial lymphoid follicles provide the most important sites for antigen sampling in the small intestine and constitute an effector mechanism for secretory immune responses of GALT [154]. The importance of this mechanism is two-fold, firstly an immune response is vital such that protection of host tissues against invading microorganisms can operate, and secondly that the extent of an infection can be curtailed as much as possible [155]. Lymphoid follicles are overlayed by the follicle-associated epithelium (FAE) that includes a number of cell types such as lymphocytes, enterocytes, goblet cells, M-cells and pre-M-cells [156]. In studies on specimens of human small intestine containing Peyer's patches Sharma et al [78] showed by histochemistry that mistletoe lectin bound to both enterocytes and M-cells of the FAE.
It is therefore evident that the surface of the small intestine in humans contains receptors that bind mistletoe lectins (see Table 3 in Sharma et al [78]).
Following binding to receptors lectins causing a release of signal molecules to the blood and these are then able to stimulate the immune system and also induce an anti-angiogenic response [113].

Helper cells show a fast initial response, whereas cells involved
in immuno-memory show a slower but prolonged increase. This, however, was as expected since populations of memory cells are quite stable and do not need to be activated to have an impact on the immune system as do the helper cells.
Interestingly, it was observed that the individuals who in general showed the weakest reaction were those who had initial values above normal limits, whilst those who demonstrated the highest response had values below normal at the onset of the study.
The results suggest that the higher the starting (normal) values, the lower the response and vice versa, which is in agreement with other observations [102].
Although present in many foodstuffs of plant origin [14] lectins are denatured by heat treatment and thus cooking, frying etc. will reduce their immune-stimulating potential virtually to zero. Since there are many lectins which have specific receptors in the human small intestine [78] it is evident that our diet needs to contain a certain quantity of these molecules in an active form in order for them to trigger the immune system. Modern diets unfortunately provide limited amounts of active plant lectins, perhaps insufficient to achieve high-level immunosurveillance. This will mean that we will be more prone to infections and other disorders.
It has been shown that obese and diabetic patients have a greater susceptibility to develop cancer than lean and nondiabetic individuals. Furthermore, it is well known that a diet rich in saturated fats and red meats and at the same time low in fresh fruits, vegetables, and whole grains favours an increased risk of cancer. According to the United States National Institutes of Health "12 servings of fruits and vegetables a day" can prevent the development of common diseases, including cancer [38].
In their paper Su and Tang [25] measured the lectin content in 20 non-cooked fruit and vegetable extracts (50 g amounts).
Based on relative lectin levels (as measured by haemagglutination activity), what was surprising was the large differences observed: Lectins are also ubiquitous in our food supply, mainly in legumes, like beans and soybean which can vary greatly in lectin content. Other legumes may contain 20g of lectin per 100g of flour.
These include cereal type foods (187.2μg of lectin/g) and texturized protein flour (53μg lectin/g) [32]. In addition to legumes, other foods may contain considerable amounts of lectins, like the cereal amaranth (8.3%), corn (0.8%) [157]. On the other hand, meat substitutes are free in active lectin content, and extremely low levels are found in bakery products [157].

The Mediterranean Diet
If we consider a newly prepared salad that contains perhaps 10 fresh ingredients (Table 2), then the spectrum of lectins that we would be exposed to during the course of a meal, would be wide (up to 50). Perhaps the success of the Mediterranean-type diet (MedDiet), rich in plant-based material, that is now highly aclaimed for its positive effect on health, is at least in part due to a rich and varied lectin content. For the third year in a row the MedDiet has been claimed by the U.S. News and World Report as the world´s best healthy diet [3]. In this class of diet, which has a high content of fruits, nuts, vegetables and whole grains, one can find >200 individual components that are rich in these foodstuffs ( Table 1).
The MedDiet has been looked at in many studies for its favourable effects on health, and professionals at the Mayo Clinic, where claims that the risk of developing cancer, Parkinson´s and Alzheimers disease, and cardiovascular disease, have been put forward [158].
The MedDiet sails up as the brain's favourite food. A number of observational and intervention studies have shown that the MedDiet best protects the brain and prevents cognitive failure [159][160][161]. This diet consists of many unsaturated fats from olive oil, nuts and seeds, more fish and seafood, more legumes, fruit and vegetables and less grain. Around the Mediterranean they drink red wine and water for meals, not milk. They eat some dairy products in everyday life, such as sour yogurt, fresh kefir and flavoured and often unpasteurized cheeses. These are, however, extremely low in lectins. They do not eat large amounts of meat on the grill, but just stick to portions of well-ripened Parma and Serrano ham, and eat vegetables and fruit. On cool evenings, they can heat up soups of squash, broccoli, and peas, mixed with plenty of fish, and Parmesan and olives. Fresh vegetables and fruits are frozen in season and ensure good health during a cold winter.
A large study published in the British Medical Journal showed that a MedDiet with extra fat and nuts posed a much lower risk of dementia than lean diets. A total of 969 elderly (44.6% men aged 74.6 +/-5.7 years) participated in the study. They were cognitively tested and randomized to a MedDiet with 1 liter of extra virgin olive oil per week or a MedDiet with 30 g unsalted nuts a day (15 g walnuts, 7.5 g hazelnuts and 7.5 g almonds). The control group received low-fat diets. After 6.5 years of mapping, 522 elderly persons underwent thorough neuropsychological mapping. Both MedDiet groups had far better cognitive function than those fed the lean diet [162]. The diets of olive oil and nuts worked independently of age, educational level, strain of cognitive failure in the family, dementia, cardiovascular disease, physical activity and caloric intake. The researchers explain the effect as being due to reduced inflammation and less oxidative stress. They also explain some of the effects of the MedDiet in the so-called PREDIMED study with a sharp reduction in oxidative stress using antioxidants from both red wine, espresso, extra virgin olive oil, olives, nuts and polyphenol-rich vegetables.
The rest they add to a muffled inflammation throughout the body.
At the same time, it is generally agreed that a Western diet rich in refined carbohydrates weakens the brain, especially the memory pathways. At the same time, scientists agree that a Western diet rich in refined carbohydrates weakens the brain, especially the memory pathways. This diet produces a malfunctioning hippocampus, and the result is impaired learning and memory.
Most experiments with lectins conducted in animals have used high doses and these have in general been conducted over relatively short periods of time. We know virtually nothing about long-term effects of exposure. It would be extremely problematical and practically difficult to test the health-related effects of plant lectins in humans. It is not such that we ingest a single type of lectin. Plant lectins are widespread in diets consisting of raw vegetables, grains, fruit and nuts and have therefore been consumed by mankind for thousands of years. From Table 1 it is evident that our food contains more than 200 lectins. The fact that fruits, vegetables and nuts can contain up to 5 different lectins means that the true number we ingest is perhaps close to 1000.
As mentioned earlier the MedDiet provides a rich source of lectins, and persons that live for example in Greece, Italy, France and Spain are thus continually exposed to a wide variety of lectins.
Their general health would appear not to be inferior to that in northern Europe, in contrast perhaps superior. One is thus tempted to conclude that a diet rich in lectins is highly advisable. For example, van Buul and Brouns [162] showed that consumption of cereals and whole grain products was associated with significantly reduced risks of cardiovascular disease, type-2 diabetes and some cancer types, where wheat germ agglutinin (WGA) is an important constituent.
In general, potential hazards of dietary lectins would appear to be unfounded. Scientific evidence currently accumulating clearly indicates that lectins are in fact important constituents of our diet, and will in due course be acknowledged as such along with the already well-accepted vitamins, minerals, trace elements, 3 and 6omega fatty acids, antioxidants and fibre etc [163].
Interestingly, data presented by Rissanen et al [164] have shown that a high intake of fruit, berries and vegetables is associated with reduced risk of mortality in middle-aged Finnish men. These findings would indicate that diets rich in plant-derived foods (i.e. lectin-enriched) can promote longevity. Beattie [165] have similarly concluded that there is considerable evidence that an adequate consumption of fruit and vegetables is advisable. This is to prevent the occurence of a series of chronic diseases such as stroke, several cancers, and heart disease. More specifically Brennan et al [166] have provided data that strongly suggest a substantial protective effect on the consumption of cruciferous vegetables on lung cancer.
Thole et al [167] have shown that elderberry fruits have a major chemopreventive effect on cancer development, while Pryme and Dale [122] in their review reported on the positive effect of elderberry lectins on gastrointestinal disorders.

Conclusions
There are still many unanswered questions concerning possible effects of plant lectins in our diet on general health.
Results published in the literature cannot in any way be interpreted such that there are indications enabling us to suspect that dietary lectins give rise to disease. On the contrary the fact that health authorities worldwide promote the "5 a day" (or even "7 a day") principle, namely that we should include a minimum of 5 portions of vegetables, fruit and nuts (i.e. lectin-containing foodstuffs) in our daily diet would clearly indicate that there are health-benefits associated with increased lectin intake. However, taken together there is little doubt that more intensive research efforts are required in order to be able to draw firm conclusions regarding potential health-promoting effects of dietary lectins. A major task will be to establish satisfactory scientific guidelines to pursue such studies and interpret results. It is evident that we are only at the very beginning with respect to gaining an understanding of the importance of lectins in our food with relation to health and nutrition [168][169][170].