hrcak mascot   Srce   HID

Pregledni rad
https://doi.org/10.17113/ftb.55.03.17.5233

Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane

Andrea Summer   ORCID icon orcid.org/0000-0002-4833-657X ; Department of Veterinary Science, University of Parma, Strada del Taglio 10, IT-43126 Parma, Italy
Paolo Formaggioni   ORCID icon orcid.org/0000-0003-0565-2422 ; Department of Veterinary Science, University of Parma, Strada del Taglio 10, IT-43126 Parma, Italy
Piero Franceschi ; Department of Veterinary Science, University of Parma, Strada del Taglio 10, IT-43126 Parma, Italy
Federica Di Frangia ; Department of Veterinary Science, University of Parma, Strada del Taglio 10, IT-43126 Parma, Italy
Federico Righi ; Department of Veterinary Science, University of Parma, Strada del Taglio 10, IT-43126 Parma, Italy
Massimo Malacarne ; 2MILC Center, University of Parma, Parco Area delle Scienze 59/A, IT-43124 Parma, Italy

Puni tekst: hrvatski, pdf (310 KB) str. 277-289 preuzimanja: 147* citiraj
APA 6th Edition
Summer, A., Formaggioni, P., Franceschi, P., Di Frangia, F., Righi, F. i Malacarne, M. (2017). Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane. Food Technology and Biotechnology, 55 (3), 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
MLA 8th Edition
Summer, Andrea, et al. "Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane." Food Technology and Biotechnology, vol. 55, br. 3, 2017, str. 277-289. https://doi.org/10.17113/ftb.55.03.17.5233. Citirano 29.10.2020.
Chicago 17th Edition
Summer, Andrea, Paolo Formaggioni, Piero Franceschi, Federica Di Frangia, Federico Righi i Massimo Malacarne. "Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane." Food Technology and Biotechnology 55, br. 3 (2017): 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
Harvard
Summer, A., et al. (2017). 'Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane', Food Technology and Biotechnology, 55(3), str. 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
Vancouver
Summer A, Formaggioni P, Franceschi P, Di Frangia F, Righi F, Malacarne M. Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane. Food Technology and Biotechnology [Internet]. 2017 [pristupljeno 29.10.2020.];55(3):277-289. https://doi.org/10.17113/ftb.55.03.17.5233
IEEE
A. Summer, P. Formaggioni, P. Franceschi, F. Di Frangia, F. Righi i M. Malacarne, "Sirevi Parmigiano Reggiano i Grana Padano kao primjeri funkcionalne hrane", Food Technology and Biotechnology, vol.55, br. 3, str. 277-289, 2017. [Online]. https://doi.org/10.17113/ftb.55.03.17.5233
Puni tekst: engleski, pdf (310 KB) str. 277-289 preuzimanja: 174* citiraj
APA 6th Edition
Summer, A., Formaggioni, P., Franceschi, P., Di Frangia, F., Righi, F. i Malacarne, M. (2017). Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano. Food Technology and Biotechnology, 55 (3), 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
MLA 8th Edition
Summer, Andrea, et al. "Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano." Food Technology and Biotechnology, vol. 55, br. 3, 2017, str. 277-289. https://doi.org/10.17113/ftb.55.03.17.5233. Citirano 29.10.2020.
Chicago 17th Edition
Summer, Andrea, Paolo Formaggioni, Piero Franceschi, Federica Di Frangia, Federico Righi i Massimo Malacarne. "Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano." Food Technology and Biotechnology 55, br. 3 (2017): 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
Harvard
Summer, A., et al. (2017). 'Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano', Food Technology and Biotechnology, 55(3), str. 277-289. https://doi.org/10.17113/ftb.55.03.17.5233
Vancouver
Summer A, Formaggioni P, Franceschi P, Di Frangia F, Righi F, Malacarne M. Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano. Food Technology and Biotechnology [Internet]. 2017 [pristupljeno 29.10.2020.];55(3):277-289. https://doi.org/10.17113/ftb.55.03.17.5233
IEEE
A. Summer, P. Formaggioni, P. Franceschi, F. Di Frangia, F. Righi i M. Malacarne, "Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano", Food Technology and Biotechnology, vol.55, br. 3, str. 277-289, 2017. [Online]. https://doi.org/10.17113/ftb.55.03.17.5233

Rad u XML formatu

Sažetak
Talijanski tvrdi kuhani sirevi, kao što su Parmigiano Reggiano i Grana Padano, imaju veliku nutritivnu vrijednost. Prema definiciji Europske Unije smatraju se funkcionalnom hranom, jer sadržavaju spojeve koji imaju specifična biološka svojstva. U ovom su preglednom radu ukratko opisani ti spojevi te njihov pozitivan učinak na zdravlje, i to u nekoliko poglavlja: proteini i peptidi, masti i lipidi, ugljikohidrati i prebiotici, probiotičke bakterije, vitamini, mineralne tvari, te sastojci mliječnih proizvoda s aktivnom ulogom u prevenciji bolesti. U uzorcima sira Parmigiano Reggiano pronađeno je nekoliko peptida s dokazanim biološkim svojstvima, npr. fosfopeptidi, koji imaju sposobnost vezivanja mineralnih tvari i funkciju prijenosnika funkcionalnih skupina, peptidi s imunomodulacijskim učinkom, te peptidi s antihipertenzijskim svojstvima i sposobnošću inibicije enzima koji konvertira angiotenzin. Među lipidima su opisane uloge konjugirane linolne kiseline i drugih masnih kiselina u siru. Također su opisani oligosaharidi s prebiotičkim svojstvima i probiotičke bakterije. Na kraju je posebno naglašena iskoristivost kalcija iz sireva, što je bitno za zdravlje kostiju.

Ključne riječi
talijanski tvrdi kuhani sirevi; funkcionalna svojstva; proteini i peptidi; masti i lipidi; ugljikohidrati i mineralne tvari; prevencija bolesti

Hrčak ID: 186539

URI
https://hrcak.srce.hr/186539

▼ Article Information



Introduction

A study conducted at the INRAN (National Research Institute for Food and Nutrition, Rome, Italy) has led to the conclusion that it is simplistic to consider milk and dairy products exclusively as sources of essential nutrients (protein, calcium and vitamins) since it has been reported that milk and dairy products contain about 2000 molecules, some of which possess a specific biological activity (1). Among dairy foods, Italian hard cooked types of cheese, such as Parmigiano Reggiano and Grana Padano, are characterised by positive nutritional qualities. In fact, these cheese types contain substances that have particular biological activities, and therefore they can be fully considered, according to the definition given by the EU, as ‘functional’ foods, which are defined as ‘foods that contain biologically active components able to improve human health or reduce the risk of disease, or otherwise produce beneficial effects on the health and welfare of the consumer’ (2). In this short review, these components and the beneficial effects related to their activities are succinctly described.

Protein and Peptides

Proteins constitute about 33% of Italian hard cooked types of cheese, presenting, from a quantitative perspective, the most important components of Parmigiano Reggiano and Grana Padano cheese. The proteins of these types of cheese are characterised by a high biological value. In fact, they contain high concentrations of all the essential amino acids. Amino acids such as isoleucine, leucine, lysine, threonine, tryptophan, valine, methionine, phenylalanine, tyrosine and histidine are present in optimal amounts and in a particularly bioavailable form (2). In particular, the high content of lysine in cheese protein is noticeable, especially if compared with that of wheat, whose protein lacks this amino acid (3).

Besides this nutritional aspect, Italian hard cooked cheese proteins also have a capacity to be assimilated relatively fast, since during ripening, a great percentage of them are hydrolysed into peptones, peptides and free amino acids by proteolytic enzymes, deriving both from milk and from the lactic acid bacteria that develop in the curd. This is similar to a predigestion, which leads to the formation of compounds with a progressively lower molecular mass until free amino acids are formed. At the end of this process, free amino acids constitute approx. 25% of total nitrogen. Moreover, these low-molecular-mass peptides and free amino acids themselves play a role in the stimulation of both acid and pepsin gastric secretion, which further increases the digestion rate of proteins (4).

Overall, Italian hard cooked types of cheese are characterised by a very varied composition of nitrogen components. Apart from a variable amount of intact casein, they contain peptides of various length and free amino acids. During digestion, these three nitrogen components undergo a different absorption (slow, accelerated and fast, respectively), allowing for a modulation in the utilisation of the protein substrate and its more efficient assimilation from the diet (5).

Bioactive peptides: general description

The primary function of milk and dairy proteins is to supply the body with fundamental amino acids and organic nitrogen adequately. However, in addition to a nutritional role, milk proteins have a physiological importance, being a source of biologically active peptides. This aspect has been studied since 1979, and numerous peptides derived from milk proteins (αs1-casein, β-casein, κ- -casein, α-lactalbumin, β-lactoglobulin, immunoglobulins, lactoferrin, phosphoglycoproteins, transferrin and serum albumin), their sequence and biological activity have been determined. Some reviews are specifically devoted to this subject (611). Bioactive peptides (consisting of 2–30 amino acid residues), encrypted in major milk proteins, are latent and inactive until they are released and activated by enzymatic proteolysis, e.g. during gastrointestinal digestion or food processing (12). After activation, they can act within the body by influencing physiological processes and modulating various biological functions (11).

As previously reported, during cheese ripening, milk caseins are first hydrolysed by the action of milk proteases, rennet proteases (only to a lesser extent in Italian hard cooked types of cheese, due to the almost complete denaturation of chymosin during the cooking phase) and the proteases and proteinases of lactic acid bacteria used as starters. The large fragments formed are then further degraded by proteolytic enzymes from the microbiota of both the whey starter and the milk. Lactic acid bacteria proteinases which, after lysis of the cell, are associated with the cell wall and intracellular peptidases are released in the curd and are responsible for the formation of small peptides and free amino acids. Digestive enzymes in the gastrointestinal tract (stomach and intestinal proteases and brush border peptidases) further hydrolyse oligopeptides, contributing to the formation of bioactive peptides (4). Thus, the enzyme-modified cheese process, mainly designed to produce flavour ingredients, may simultaneously produce bioactive peptides which are considered physiologically important (13).

Most of these studies on bioactive peptides were performed on hydrolysed and digested casein or by administering milk or generic dairy products to mice. However, as stated by Korhonen and Pihlanto (14), during cheese ripening, a great variety of peptides are formed, many of which have been shown to exert biological activities. So, it is reasonable to think that many of these bioactive peptides can be produced also during the ripening of Parmigiano Reggiano and Grana Padano, mainly by lactic acid bacteria starters (15, 16). In fact, one of the very specific species of whey starters used for Grana Padano and Parmigiano Reggiano, Lactobacillus helveticus, is one of the species mainly responsible for the formation of these bioactive compounds (17, 18). Some studies (19, 20) have investigated the formation of peptides in Parmigiano Reggiano and Grana Padano cheese and/or their digested products in vitro; however, this topic needs to be studied further, with particular emphasis on biopeptide formation. As attested by Sforza et al. (20), several known bioactive peptides were found to be present in Parmigiano Reggiano cheese samples; for example, phosphopeptides derived from the N-terminal part of β-casein, known for their mineral binding capacity and vehiculation activity (21), are present in Parmigiano Reggiano cheese aged for more than 16 months.

Bioactive peptides act in the body of mammals according to mechanisms similar to hormones. The peptides introduced with dietary cheese or produced by intestinal hydrolysis can reach the target sites in the luminal side of the gastrointestinal tract or, after being absorbed into the systemic circulation, the peripheral organs (9, 10, 12, 22). These peptides may exert different beneficial physiological functions: opioid peptides are opioid receptor ligands which can modulate absorption processes in the intestinal tract; ACE-inhibitory peptides are blood pressure regulators and exert an antihypertensive effect; immunomodulating casein peptides stimulate the activities of the cells of the immune system; caseinophosphopeptides may function as carriers for different minerals, especially calcium. Many of these peptides can have two or more different biological activities (12). In the following paragraphs, the principal peptides derived from dairy protein and their biological functions are summarised, referring for a more detailed description to the specific reviews.

Opioid peptides

A number of milk protein peptides have been shown to behave like opioid receptor ligands able to address opioidergic reactions in adults or in neonates. With respect to the proteins from which they are derived, these peptides have been named α-casein exorphins or casoxin D (α-casein), β-casomorphins or β-casorphin (β-casein), casoxin or casoxin A, B or C (κ-casein), and other coming from whey proteins that can be present in cheese only in a negligible amount (α-lactorphins from α-lactalbumin, β-lactorphin from β-lactoglobulin or lactoferroxins from lactoferrin). Only casoxins and lactoferroxins display antagonistic properties; the other peptides behave like opioid receptor agonists (23).

β-Casomorphins were the first milk protein-derived opioid receptor ligands whose amino acid sequences were identified. It is thus conceivable that more information about this peptide group has been collected than about any other group of milk opioids. They were called β-casomorphins due to their morphine-like behaviour.

Teschemacher et al. (24) found that β-casomorphins arrive to the cardiovascular system after gastrointestinal digestion of milk or milk products in more than negligible amounts – at least in adult animals or humans; enzymatic degradation in the intestinal wall and in blood appears to prevent it. The authors have also described that these peptides can have a regulatory influence as ‘food hormones’, participating in the control of gastrointestinal functions in adults and neonates.

Immunomodulatory peptides

There is a substantial body of evidence according to which several of the biologically active peptides released by enzymatic hydrolysis of milk proteins are very potent immunoregulatory peptides (25), affecting cells of the immune system, and consequently the downstream immunological responses and cellular functions (25, 26).

It was demonstrated that peptides from αs1-casein (residues 194–199 and 23–34) and β-casein (residues 63–68 and 191–193) stimulate phagocytosis by murine peritoneal macrophages and consequently exert a protective effect against Klebsiella pneumoniae infection in mice after intravenous treatment (25, 2731). The peptide αs1-casein (residues 23–34) was demonstrated to be produced in Parmigiano Reggiano during ripening (19). Quantification of this peptide is not given in the paper, but its presence is attested at 6 months of ripening, probably produced by a chymosin cleavage.

The peptide isracidin (N-terminal sequence 1–23 of αs1-casein) has been found to protect mice against infections by Staphylococcus aureus and stimulate a phagocytic response in mice infected with Candida albicans (32). This peptide was found by Sforza et al. (20) in samples of Parmigiano Reggiano cheese. The authors do not give a specific quantity of this peptide, but they write that it is probably produced by a chymosin cleavage and it is the most abundant in the group of peptides whose amount is decreased during cheese ripening. A figure in the paper attests that the peptides of this group are still present, in low amounts, at 12–25 months of ripening.

β-Casomorphin-7 derived from β-casein was used as a possible immunostimulating substrate, since it is a ligand of opioid receptors that have also been found on the surface of human T-lymphocytes (3335).

β-Casokinin-10 (residues 193–202 of β-casein) and another heptapeptide from β-casein (residues 177–183), such as residues 23–34 of bovine αs1-casein, have been found to inhibit angiotensin-converting enzyme (ACE), which may act on the immune system, preventing the breakdown of bradykinin (25, 36). The latter acts as a mediator of the acute inflammatory process and is thus able to stimulate macrophages and enhance lymphocyte migration.

Regazzo et al. (37) found that β-casein (residues 193–209), a long and hydrophobic peptide composed of 17 amino acid residues, has immunomodulatory activity. This peptide was demonstrated by Sforza et al. (20) to be formed during Parmigiano Reggiano ripening and present in the cheese samples. The authors do not give a specific quantity of this peptide, but they write that it is probably produced by lactic acid bacteria proteases and that chymosin itself is responsible for its production. This peptide is not formed during the early stage of cheese production, but its amount increases during ageing and it is present in a small amount from the start to the end of the ageing period, indicating that its production continued throughout the ripening period.

Dipeptide (Tyr-Gly), which corresponds to a partial sequence in the primary structure of bovine κ-casein (residues 38–39), was used for immunotherapy of human immunodeficiency virus infection (35, 38).

Caseinophosphopeptides

Casein phosphopeptides or caseinophosphopeptides (CPPs) are a mixture of phosphorylated peptides of different molecular mass formed in vivo when casein is degraded by proteolytic enzymes in the digestive tract (39). Phosphate residues, represented as serine esters, constitute the anionic binding site for minerals such as calcium, iron and zinc and form with them soluble salts, increasing their intestinal bioavailability. Bouhallab and Bouglè (40) showed that a purified phosphopeptide (β(1–25)) exhibits a positive effect on iron bioavailability in vivo, reporting its efficiency in the absorption and availability of iron and the mechanism involved.

Numerous studies show that caseinophosphopeptides, by means of a bond with calcium, make the latter more soluble, improving its absorption and increasing its availability (41, 42). This system of passive transport is the main way of absorption of the calcium requested for bone calcification. Erba et al. (41) state that the positive effect of CPPs on passive calcium absorption seems to depend on the relative amounts of both CPPs and calcium in intestinal lumen. In that study, the ratio CPPs/Ca=15 was identified as the most efficient to increase mineral transport.

Moreover, Aimutis (43) demonstrated that CCPs can possess an anticariogenic effect, i.e. have a role in the prevention of dental caries. Tooth enamel is a polymeric substance consisting of crystalline calcium phosphate embedded in a protein matrix. Dental caries develops as a result of acidic demineralisation (calcium and phosphorus solubilisation) of tooth enamel. CPP can form nanoclusters with amorphous calcium phosphate (ACP) at the tooth surface to provide a reservoir of calcium and phosphate ions to maintain a state of supersaturation on the surface of tooth enamel. This would buffer the pH of the plaque, and also provide ions for tooth enamel remineralisation.

Recently, Cattaneo et al. (44) have found that casein phosphopeptides were released during in vitro gastrointestinal digestion of Grana Padano cheese samples aged 13, 19 and 26 months.

The ACE-inhibitory peptides

ACE-inhibitory peptides deserve special mention. They are generated by the activity of specific enzymes that cut proteins like β-casein and κ-casein (45). The angiotensin-converting enzyme, called ACE, cuts the chain of angiotensin I, which is then converted into angiotensin II. Angiotensin II acts on several mechanisms that regulate blood pressure, such as vasoconstriction, sodium reabsorption, and aldosterone release. Moreover, angiotensin II acts by degrading bradykinin, which exerts a regulatory role on vasodilation. All this leads to an increase in blood pressure. These biopeptides inhibit the function of the ACE, inducing a drop in both systolic and diastolic pressure; the same mechanism is activated by drugs belonging to the class of ACE-inhibitors.

Basiricò et al. (46) demonstrated for the first time the presence of eight different potent ACE-inhibitory peptides in Parmigiano Reggiano cheese samples and in their relative intestinal digestate. In particular, VPP, IPP, LHLPLP and HLPLP were revealed in a water-soluble extract, and their total amount was in the range of 8.46 to 21.55 mg per kg of cheese. The mass fraction of ACE-inhibitory peptides in the total peptide content of undigested water--soluble extract was 0.10 to 0.38%. After in vitro gastrointestinal digestion of this water extract, the same ACE-inhibitory peptides, along with the newly formed AYFYPEL and AYFYPE, were found. The total amount of ACE-inhibitory peptides in digested Parmigiano Reggiano samples was in the range of 1959.33 to 3122.52 mg/kg, and the mass fraction of ACE-inhibitory peptides in the total peptides in digested water-soluble extract was 13.68 to 21.81%. At the end of the digestive process, the authors found relevant amounts of LHLPLP (2483.95 mg/kg) and HLPLP (58.97 mg/kg). Other detected peptides included the newly formed AYFYPEL (6.46 mg/kg) and AYFYPE (7.34 mg/kg). Two of these peptides are Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), in the amounts of 3.97 and 2.32 mg/kg, respectively: these peptides were found by Hata et al. (47) to be responsible for a marked decrease in blood diastolic and systolic pressure in patients with blood pressure problems.

Crippa et al. (48) conducted a randomised, double- -blind, placebo-controlled study on 30 subjects suffering from hypertension, who presented pathological pressure values (maximum >140 and/or minimum >90 mm Hg). All patients received, at random, a dietary supplementation with Grana Padano (30 g daily) and placebo (obtained with flavoured bread mixed with fat and salt in the amounts equal to those of the cheese). Supplementing the diet with Grana Padano cheese resulted in a significant reduction in systolic and diastolic blood pressure.

Recently, Bernabucci et al. (49) found ACE-inhibitory activity and antihypertensive effect of naturally formed bioactive peptides in a lyophilised water-soluble extract from 32-month-aged Parmigiano Reggiano and Grana Padano. They were evaluated in undigested and in vitro digested water-soluble extracts and tested in 20 spontaneously hypertensive rats. Both Parmigiano Reggiano and Grana Padano water-soluble extracts showed a consistent ACE-inhibitory activity and IC50 value of Grana Padano water-soluble extract was lower than that of Parmigiano Reggiano. The in vitro enzymatic digestion of these water--soluble extracts did not significantly affect IC50 values.

The presence of ACE-inhibitory peptides in undigested (and also in in vitro digested in the stomach and intestine) Grana Padano samples was recently demonstrated also by Stuknytė et al. (50). The authors found the following peptides in the undigested Grana Padano samples (in mg/kg): VPP 2.76, IPP 2.49, RYLG 0.07, HLPLP 0.23, LHLPLP 0.38, in total mass fraction of ACE-inhibitory peptides of 5.93 mg/kg. After gastric digestion, the following peptides were found (in mg/kg): VPP 2.85, IPP 1.22, RYLG 1.72, HLPLP 0.71, in total mass fraction of ACE-inhibitory peptides of 6.50 mg/kg. After intestinal digestion the following peptides were found (in mg/kg): HLPLP 4.64 and LHLPLP 306, in total mass fraction of ACE-inhibitory peptides of 311 mg/kg. The authors affirm that, together with plasmin, proteinases and peptidases of Lactobacillus helveticus spp., the main lactic acid bacterium present in the whey starter added to raw milk prior to renneting, are mainly responsible for this extensive proteolysis in Grana Padano cheese.

Parmigiano Reggiano protein and glucose tolerance

In a study published in Diabetologia, Tricò et al. (51) showed that the administration of a meal composed of 50 g of Parmigiano Reggiano, a boiled egg, and 300 mL of water, 30 minutes prior the ingestion of a strong glucose load, has a hypoglycaemic effect in comparison with a control group that did not receive this meal. The authors observed that proteins co-ingested with carbohydrates exert a hypoglycaemic effect on both normal subjects and subjects with diabetes, through the enhancement of insulin secretion and a minor delay in gastric emptying.

Fat and Lipids

Milk and dairy fat is the most complex fat in the human diet, consisting of more than 400 distinct fatty acid species (52). In dairy fat, short-, medium- and long-chain fatty acids, odd-chain fatty acids, branched chain fatty acids, conjugated linoleic acids (CLA), ruminal trans fatty acids (vaccenic acid), n-3 and n-6 fatty acids are represented. Many of these fatty acids are present in our diets in significant amounts only from dairy products (53). In particular, dairy fat is a rich source of butyric acid (C4:0), CLA, cis- and trans-palmitoleic acid (C16:1), and the branched chain fatty acid phytanic acid (C20:0). Some of these are present in dairy fat only in a small percentage, but these small amounts may still be biologically relevant, alone or within the context of other fatty acids (53).

Fat is present in Italian hard cooked types of cheese from a minimum of 25.5% to a maximum of 31.4%, with a mean value of 28.4%, compatible with the definition of semi-fat cheese (4). The content of cholesterol is relatively low, amounting on average to 83–91 mg per 100 g of cheese.

Triglycerides present in Italian hard cooked types of cheese are characterised by more than 25% of medium- and short-chain fatty acids (from C4 to C10). These compounds are naturally more easily absorbed than long-chain fatty acids (they do not need lipoprotein transportation) and provide very quick energy to the organism, as they follow different ways of assimilation from long-chain fatty acids (4, 5).

Moreover, during the ripening of Italian hard cooked types of cheese, a partial lipolysis of fats occurs, which makes available a certain amount of fatty acids in a free form, facilitating their absorption (4), in analogy with the process of protein fractionation to amino acids previously described.

In a review regarding the effects of foods rich in fat on human health, Kratz et al. (53) summarised various studies (5458) demonstrating that dairy fat consumption is associated with markers of better metabolic health and that dairy fat may protect against metabolic dysfunction. Kratz et al. (53) suggested that a potential mechanism by which dairy fat may exert beneficial effects on cardiometabolic risk is the reduction of chronic inflammation and lipid peroxidation, as suggested by Wang et al. (59) in a study showing that dairy fat intake is inversely related to inflammation and oxidative stress in overweight adolescents.

White et al. (60) demonstrated that medium-chain fatty acids (and in particular capric acid) can induce the phenomenon of vasodilation in vitro and in vivo. Moreover, these compounds, along with short-chain fatty acids, can help in increasing the body antioxidant defences (61). Even phospholipids can have antioxidant properties: Franson et al. (62) reported that sphingosine directly inhibits phospholipases A2 and D. A research by Yoshida et al. (63) demonstrated an inhibitory effect of phosphatidylserine on iron-dependent lipid peroxidation. Gordon et al. (64) found that phosphorylethanoline inhibited superoxide anion, with a mechanism that was not due to inhibition of cellular superoxide generation but to scavenging of generated superoxide anion.

In the following paragraphs, some dairy fatty acids of fats or groups of dairy fatty acids that have shown particular benefits for human health are described.

Conjugated linoleic acids

The term conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid characterised by the presence of two conjugated double bonds. The CLA are present in abundance in animal products, especially in milk and cheese.

The main isomer in dairy fat is rumenic acid, cis-9, trans-11 CLA, which can represent from 79 to 94% of the total CLA of dairy fat. The other isomer frequently found in dairy fat is the trans-10, cis-12 CLA. Numerous studies have highlighted the potential health beneficial effects of these two fatty acids.

There is increasing evidence that individual isomers of CLA may have unique biological or biochemical effects. In particular, some beneficial effects of the trans-10, cis-12 CLA isomer in rodents were described. Body composition changes (reduced body fat, enhanced body water, enhanced body protein, and enhanced body ash contents) were associated with feeding the trans-10, cis-12 CLA isomer (65). The trans-10, cis-12 CLA isomer also exerts specific effects on adipocytes, in particular reducing the uptake of lipid by inhibiting the activities of lipoprotein lipase and stearoyl-CoA desaturase (66). These effects on body composition appear to be due in part to reduced fat deposition and increased lipolysis in adipocytes, possibly coupled with enhanced fatty acid oxidation in both muscle cells and adipocytes (67). Moreover, trans-10, cis- -12 CLA inhibits preadipocyte differentiation, decreasing body fat accumulation (68). Park et al. (69) indicate that CLA prevents body fat accumulation and mass gain and that their dietary administration may be more effective in protecting against fat mass regain following mass loss than a mass loss treatment.

Other beneficial effects are due to the presence of the other CLA isomer, the cis-9, trans-11 CLA. Pariza et al. (66) demonstrated that this isomer enhances growth and probably feeds efficiency in young rodents. Some other beneficial effects are due to the presence of both isomers or possibly to a synergy between them. Pariza et al. (66) showed that both the cis-9, trans-11 and trans-10, cis-12 CLA isomers appear to be active in inhibiting carcinogenesis in animal models. Ip et al. (70) showed that the anticancer efficacies of the two isomers (cis-9, trans-11 CLA and trans-10, cis-12 CLA) were very similar. With the administration of both CLA, 6 weeks after carcinogen administration in rats, the total number of premalignant lesions was reduced by 33–36%; at 24 weeks, the total number of mammary carcinomas was reduced by 35–40%. Also Masso- -Welch et al. (71) found an inhibition of angiogenesis by CLA, defined as ‘cancer chemopreventive agent’.

Antiatherogenic activity, antidiabetogenic effect and antiaggregant action, such as the capacity to stimulate bone mineralisation and immune response, regulate the allergenic responses and decrease hypertension, have also been suggested for these molecules (2). A retrospective case-control study conducted in Costa Rica demonstrated a strong inverse relationship between cis-9, trans-11 CLA in adipose tissue and the risk of myocardial infarction (72). In this study, the presence of the cis-9, trans-11 CLA acid in the adipose tissue was strongly connected to the consumption of dairy products. This suggested that CLA may play the role of protective factor when ingested by dairy products.

Prandini et al. (73) reported a content of 183 mg of cis--9, trans-11 CLA (+ trans-9, cis-11 CLA) per 100 g of Parmigiano Reggiano cheese (corresponding to 6.18 mg per g of fat) and 145 mg per 100 g of Grana Padano cheese (corresponding to 5.22 mg per g of fat), while the same authors reported a content of 37.7 mg of trans-9, trans-11 CLA (+ trans-10, trans-12 CLA) per 100 g of Parmigiano Reggiano cheese (corresponding to 1.27 mg per g of fat) and 27.2 mg per 100 g of Grana Padano cheese (corresponding to 0.98 mg per g of fat).

Prandini et al. (74) also reported a total CLA value of 385 mg per 100 g of fat in the same types of cheese, corresponding to 1.06 mg per g of cheese (for a fat content of 27.43 g/100 g). CLA content markedly depends on animal feed; in fact, in conventional Grana Padano, its content is 0.55 g per 100 g of total fatty acids, while in organic Grana Padano it is higher, 0.86 g per 100 g of total fatty acids (75).

Other fatty acids potentially beneficial for health

Kratz et al. (53) suggested that the butyric acid at the mass fraction typical of dairy product fat (4%) can have relevant clinical effects on body mass and metabolic health. It also seems possible that butyrate consumption can have beneficial effects on chronic inflammation of the gastrointestinal tract. There is also experimental evidence (76) that butyric acid may lead to an increased synthesis of melatonin and metallothionein, one of the major antioxidant proteins of plasma. It can also stimulate the secretion of apolipoprotein A–I and apolipoprotein B-100 (77), improving the physiological homeostasis of cholesterol and plasma triglycerides. The content of butyric acid in Parmigiano Reggiano cheese was reported by Sandri et al. (78), who found a value of 59 mg per 100 g of fat at 12 months of ripening, while at 24 months of ripening the value increased to 144 mg per 100 g of fat, due to lipolysis. Malacarne et al. (79) reported a butyric acid content in Parmigiano Reggiano of 3.4 (1 month), 17.5 (6 months), 29.9 (12 months), 38.8 (18 months) and 71.0 (24 months) mg per 100 g of fat in the inner part of the wheel, while in the outer part of the wheel, where lipolysis is more accentuated, from 6 months onwards values were higher: 3.8 (1 month), 25.2 (6 months), 50.4 (12 months), 83.3 (18 months) and 123.9 (24 months) mg per 100 g of fat.

Trans-palmitoleic acid was associated with a lower incidence of diabetes (56). In particular, it should be noted that the consumption of full-fat dairy products has been directly and strongly associated with trans-palmitoleic acid levels in plasma phospholipids (56). Palmitoleic acid, in fact, plays an important role in the regulation of hepatic lipogenesis and in the adipocyte lipogenesis. Therefore, the consumption of dietary fats rich with this fatty acid can positively affect both energy homeostasis and metabolic health. These considerations may be relevant, since full-fat dairy products are one of the few dietary sources of palmitoleic acid (53). The mass fraction of trans-palmitoleic acid in Parmigiano Reggiano was reported by Castagnetti et al. (80), which was 0.08 g per 100 g of fat when cattle feed was fresh or preserved forage, while it was 0.11 g per 100 g of fat when cows were fed fresh forage with integrated extruded whole linseed flour.

Another fatty acid of potential interest is phytanic acid, a branched chain fatty acid (C20:0). This acid is characterised by a C16 chain with four methyl groups as side chains attached in positions 3, 7, 11 and 15 (81). There are a series of in vitro experiments suggesting that phytanic acid from fat of dairy products may be relevant for energy and glucose homeostasis (53). Unfortunately, so far, to our knowledge, amounts of phytanic acid in Parmigiano Reggiano or Grana Padano cheese have not been detected. A study (82) has been done on other types of cheese, less hard than Italian hard cooked cheese, as Emmental (167–303 mg per 100 g of lipids), Edam (288 mg per 100 g of lipids) and Gouda (256–265 mg per 100 g of lipids). Other studies have reported the content of phytanic acid in milk that is rather variable: Capuano et al. (83) reported an average content of 146 mg per 100 g of fat, but with oscillations between 65 and 328 mg per 100 g of fat; Schröder et al. (84) reported an average content of 116 mg per 100 g of lipids, but in organic milk the content was higher (153 mg per 100 g of lipids); Che et al. (85) registered the highest value in September (121 mg per 100 g of fat) and the lowest in May (96 mg per 100 g of fat), depending also, to a great extent, on cattle feed, being higher with pasture (21–76 mg per 100 g of fat) than with maize silage (0–48 mg per 100 g of fat) and concentrate (10–34 mg per 100 g of fat).

Carbohydrates and Prebiotics

Another important characteristic of Italian hard cooked cheese is the total absence of lactose, the main carbohydrate in milk. Lactose disappears in the early hours after the cheese making process. In fact, the fermentation of lactose into lactic acid and the subsequent acidification of the curd is one of the most important processes in the production technology of Parmigiano Reggiano DOP and Grana Padano DOP. Based on the standards of the European Commission (April 2003), Parmigiano Reggiano and Grana Padano can be defined as ‘lactose-free’ products because they contain lactose in amounts not higher than 0.10 mg per 100 kcal of product (86). The absence of lactose in ripened cheese which is ready for consumption is a very important fact for subjects who are intolerant to this sugar or for individuals who, due to an insufficiency of lactase enzyme, are unable to digest lactose. Lactose intolerance is a very common disease among Asian populations, who historically do not consume milk and dairy products and consequently suffer from lactase deficiency; Western populations suffer more often from some types of lactose malabsorption, and only occasionally of intolerance. Lactose intolerance induces a reduction in calcium ingestion, sometimes below the requirements, as a consequence of the elimination of milk and dairy products from the diet. Increasing evidence suggests that individuals with lactase deficiency can reach an adequate level of calcium intake through Italian hard cooked cheese consumption, thereby improving bone health and preventing osteoporosis (2).

Oligosaccharides with prebiotic properties

In the carbohydrate fraction of Italian hard cooked cheese, it is important to emphasise the presence of certain oligosaccharides, i.e. short-chain non-digestible carbohydrates with a possible prebiotic effect. In particular, these carbohydrates could stimulate the growth and/or activity of one or more bacterial populations in the colon, with specific health benefits. Prebiotics are defined as those food components which, resisting the acid environment of the stomach and the action of bile salts and digestive enzymes in the small intestine, reach the colon, where they selectively stimulate the multiplication of existing beneficial strains (bifidobacteria and lactobacilli) and induce local and systemic effects advantageous for the host (87, 88).

Prebiotics act as a selective substrate for fermentations, influencing the microbial activity in the intestine and the absorption of minerals, as well as stimulating the immune system (86). The oligosaccharides are also involved in many cellular recognition processes and have numerous biological activities including immunostimulatory, anti-inflammatory, antiviral and immunological function (89).

In a study carried out on a large number of samples of Parmigiano Reggiano, Coppa (87, 90) demonstrated for the first time the presence of a significant proportion of oligosaccharides, compounds which can act as prebiotics able to favour the development of intestinal ‘bifidogenic microbiota’. The analysis of the characterisation of the oligosaccharides showed the presence of several peaks (over 50), whose sequence was found to be very constant in all the examined samples (87). These peaks are considerably more numerous and substantially different from those present in the cow’s milk employed for cheese production; consequently, their presence in the final product must be linked to the action of digestive-fermentative processes that, taking place in various stages of the production, could lead to the synthesis of new oligosaccharide molecules. The mass fraction of oligosaccharides in Parmigiano Reggiano was approx. 2.5 g per 100 g.

The presence of glycosaminoglycans was also found in Parmigiano Reggiano cheese. This denomination identifies a class of natural molecules active in the regulation of primary biological activities such as, among the many, cell interaction with growth factors and regulation of blood coagulation functions, showing at the same time antithrombotic, antiviral and anti-inflammatory activity (91).

Probiotic Bacteria

To be considered a probiotic, a bacterial strain must be a normal component of human intestinal microbiota, be absolutely safe for use in human beings, be active and vital under the conditions present in the intestine, be resistant to gastrointestinal secretions (gastric juice, bile and pancreatic juice), and be able to persist, at least temporarily, in the human gut. There is experimental evidence that some of the bacteria in Italian hard cooked cheese can have probiotic functions. In particular, it has been shown that, at 12 months of ripening, in Parmigiano Reggiano, the presence of Lactobacillus rhamnosus is still detectable, even if at low levels (103–104 CFU/g), having the actual characteristics of probiotic (92). Also, Pancaldi et al. (86) emphasise the probiotic nature of Parmigiano Reggiano and its possible use in the prevention of intestinal and extraintestinal diseases at all ages, from infants to the elderly.

Vitamins

Milk and cheese belong to food that in the daily ration covers only a small proportion of the vitamin requirements. However, with reference to the values indicated by the Recommended Levels of Nutrient Intake (LARN) for adults, 100 g of Parmigiano Reggiano completely cover the need for vitamin B12 and biotin, a third of the requirement of vitamin A and B2, and from 1/5 to 1/10 of the requirements of other vitamins (4, 5).

Mineral Salts

Italian hard cooked types of cheese also contain a large amount of macrominerals (namely calcium, phosphorus, sodium and chloride) and trace elements (particularly zinc and selenium). In particular, these types of cheese are a very important source of calcium, because of both their high content of this element (1159 mg per 100 g) and its particular bioavailability. The content of calcium in these types of cheese depends also on cattle breed, the milk of Italian Brown cows being richer in calcium than that of Italian Friesian cows (93).

Calcium, vitamin D and proteins are the three main nutrients that sustain the development and maintenance of bone structure. Many reports relating to the intake of these nutrients have emphasised their importance in the prevention of bone loss and thus in the reduction of the risk of fractures in the elderly (94). Being a source of calcium and protein, dairy products could play a positive role on bone health (42). Perego et al. (95) have shown that casein phosphopeptides (produced by hydrolysis of Italian hard cooked cheese proteins, see Protein and Peptides section) can activate calcium uptake by intestinal cells. From this point of view, Italian hard cooked types of cheese can be very important foods for the skeleton bone growth: they represent an excellent source of many essential nutrients for the skeletal development and health. The presence of proteins of high biological value and highly bioavailable calcium makes these types of cheese really ‘functional foods’ for treating bone homeostasis and for the prevention of osteoporosis (42).

Recently, De Luca et al. (96) have demonstrated that gastrointestinal digestates of Grana Padano and Trentingrana cheese promote intestinal calcium uptake and extracellular bone matrix formation in vitro.

Among the trace elements, the presence of selenium and zinc in milk and Italian hard cooked cheese is of particular interest, since Se is the cofactor of glutathione peroxidase and Zn is the cofactor of the enzyme superoxide dismutase. Therefore, Se and Zn indirectly inhibit the activity of the prooxidant iron and free radical in general. Moreover, they induce the synthesis of metallothionein and activate the ornithine decarboxylase for the synthesis of polyamines (61).

Components of Dairy Products and Disease Prevention

The last part of the review focuses on the components of Italian hard cooked cheese that can have a role in the prevention of some diseases. In the following paragraphs, the most important experimental evidence of this is succinctly exposed.

Dairy products can reduce the occurrence of type 2 diabetes

Numerous studies have demonstrated a relationship between the consumption of dairy products, in particular of some of their constituents, and a reduction of diabetes occurrence.

Statistical studies have found that subjects who received greater amounts of dairy products within their diet decreased the risk of developing type 2 diabetes (DM2) by an average of 14% (97, 98). Also, Sluijs et al. (99) suggest that increased consumption of cheese tends to be inversely associated with the risk of diabetes.

In a large prospective study, Malik et al. (100) showed that an increased consumption of dairy products during adolescence is significantly associated with a reduced risk of type 2 diabetes in adulthood. This finding is in agreement with the results from previous studies (101, 102) performed on adults, which showed inverse associations between the intake of dairy products and type 2 diabetes. Overall, there is evidence of the beneficial effect of daily intake of dairy products on glucose homeostasis, indicating a possible beneficial effect of dairy consumption in the prevention of the development of type 2 diabetes (97).

Recent literature suggests that the fatty acids contained in dairy products can exert a potential role in preventing diabetes (56, 99, 103). In addition, dairy products are rich in calcium, vitamin D and magnesium, all constituents that may exert a protective function against diabetes (102, 104).

Some scientific studies have shown that the incidence of diabetes is inversely associated with dairy products with high fat content (56, 100, 103). Many researchers have suggested an association between the quality of fat, rather than the quantity, and diabetes risk. For example, cheese is a source of saturated fatty acids; Hu et al. (105) suggested that these fatty acids may be involved in reducing the risk of diabetes. However, based on Krachler et al. (103), the higher amount of odd-chain fatty acids in dairy products too can lead to a diabetes risk reduction. Recently, Ericson et al. (106) detected an association between the presence of short-chain saturated fatty acids, typical of dairy products, and the onset of diabetes protection. Dairy products are also the best sources of lauric acid (12:0) and myristic acid (14:0).

Dairy products can reduce symptoms of intestinal problems

Pancaldi et al. (86) presented three cases of infants suffering from various forms of intestinal problems, subjected to a special diet therapy, in order to resolve situations that would be difficult to manage using special varieties of infant formula on the market. These children were given a mixture consisting of 40 g of Parmigiano Reggiano aged for at least 36 months, 40 g of rice or corn and tapioca, 40 g of sugar, 10 g of corn oil, all added to 1 litre of water. This compound, known as NO (New Olivi, from the researcher who invented this composition), is able to provide about 60 kcal per 100 mL.

After the introduction of the food based on Parmigiano Reggiano cheese, all cases showed a rapid and progressive relief of symptoms. In fact, Italian hard cooked types of cheese have a high concentration of easily absorbable amino acids and oligopeptides, similar to that of protein hydrolysates. As for the lipid component, medium- and short-chain fatty acids are directly absorbed in the intestine and immediately employed as a significant source of energy. The use of Italian hard cooked cheese as food therapy is appropriate not only for their high nutritional value, but also for their characteristics as functional food, which produce beneficial effects on the gastrointestinal tract. Moreover, their efficacy in pathological conditions is further increased by the prebiotic and probiotic effects resulting from oligosaccharides and by the natural bacterial microbiota present in the Italian hard cooked cheese mass.

Dairy products can have a beneficial role in metabolic syndrome

Dairy products as Italian hard cooked cheese may have a beneficial role also in the alleviation of metabolic syndrome (98). This syndrome is a cluster of risk factors for increased mortality, including obesity, altered glucose homeostasis, hypertension and atherogenic dyslipidaemia. Individuals with metabolic syndrome often suffer from a chronic inflammatory state.

Dairy products can regulate blood pressure

Epidemiological studies suggest that the consumption of dairy products may be associated with a 13% reduction of the risk of high blood pressure (98, 107). The content of calcium and vitamin D, as well as some peptides of milk (see the ACE-inhibitory peptides section), may exert a beneficial effect on blood pressure by inhibiting ACE, which modulates the endothelial function (108, 109).

Dairy products can prevent cardiovascular diseases

Warensjö et al. (55) reported an inverse association between the intake of fat from dairy products and the risk factors for cardiovascular diseases including triglycerides, total cholesterol, and insulin in the serum during fasting. A possible explanation may be that the intake of dairy fat reduces the risk of myocardial infarction through a mechanism which involves the reduction of fat and triglycerides, and improves metabolic health.

Dairy products can prevent insurgence of colon cancer

Perego et al. (110) showed that casein phosphopeptides derived from dairy foods can prevent insurgence of colon cancer, protecting differentiated intestinal cells from calcium overload toxicity and prevent their apoptosis, favouring proliferation while inducing apoptosis in undifferentiated tumour cells.

Conclusions

In this review, the functional properties of Italian hard cooked types of cheese were described, highlighting the effects of each component on human health. It appears that there are many important benefits related to the dietary intake of the components of these types of cheese, making these products truly valuable functional foods.

In particular, proteins in Italian hard cooked types of cheese possess biological properties attributable to potentially bioactive peptide sequences; these peptides, hidden and inactive in the primary protein structure, may be released and activated by proteolytic processes during the technological treatment or during gastrointestinal digestion and act in the body by influencing physiological processes and modulating various biological functions. In particular, several ACE-inhibitory peptides were found in Parmigiano Reggiano cheese samples and in their relative intestinal digestate. In particular, VPP, IPP, LHLPLP and HLPLP were revealed in water-soluble extract, while after in vitro gastrointestinal digestion of this water extract, the same ACE-inhibitory peptides along with the newly formed AYFYPEL and AYFYPE were found. Some of these peptides are responsible for a marked decrease in blood diastolic and systolic pressure in patients with blood pressure problems.

As far as lipid fraction is concerned, Italian hard cooked cheese can be an important source of fatty acids, which appear to be particularly beneficial to human health. Many of them are present in significant amounts only in dairy products. In particular, Italian hard cooked cheese fat is a source of butyric acid (C4:0) (30–140 mg per 100 g of fat, depending on cheese ripening), CLA (385 mg per 100 g of fat, corresponding to 1.06 mg per g of cheese, but variable according to cattle feed), trans-palmitoleic acid (tC16:1) (0.08–0.11 mg per 100 g of fat, depending on cattle feed), and possibly also the branched chain fatty acid phytanic acid (C20:0), but in this case the presence in Italian hard cooked cheese, attested for other types of cheese, needs confirmation. CLA may have unique and precious biological or biochemical effects: in particular, body composition changes (reduced body fat, enhanced body water, enhanced body protein, and enhanced body ash contents) were associated with CLA. They exert specific effects on adipocytes too, in particular reducing the uptake of lipid by inhibiting the activities of lipoprotein lipase and stearoyl-CoA desaturase; moreover, CLA can prevent body fat accumulation and mass gain. Butyric acid can have relevant clinical effects on body mass and metabolic health and can have beneficial effects on chronic inflammatory conditions of the gastrointestinal tract. Trans-palmitoleic acid was associated with a lower incidence of diabetes, and phytanic acid may be relevant for energy and glucose homeostasis.

Italian hard cooked types of cheese are also characterised by the presence of certain oligosaccharides, i.e. short-chain non-digestible carbohydrates, with a possible prebiotic effect, which could stimulate the growth and/or the activity of one or more bacteria in the colon, with specific health benefits and numerous biological activities such as immunostimulant, anti-inflammatory, antiviral and immunological.

There is experimental evidence that some of the bacteria in the Parmigiano Reggiano cheese ripened for 12 months are still present, even if at low levels, and can have probiotic functions. Vitamins are also present in Italian hard cooked cheese, even if some of them do not completely cover the recommended levels of nutrients (LARN) indicated by Italian Society of Human Nutrition (SINU).

Italian hard cooked cheese also contains a large amount of macrominerals (calcium, phosphorus, sodium, chloride) and trace elements (particularly zinc and selenium). The particularly high content and bioavailability of calcium, together with the presence of vitamin D and specific proteins, make these types of cheese really ‘functional foods’ for bone homeostasis and for the prevention of osteoporosis.

Among all these properties, two in particular seem to be of great interest: the ability to keep blood pressure regulated, thanks to ACE-inhibitory peptides, and the possibility of these types of cheese to act as foods rich in bioavailable calcium, especially for countries such as Asia, where osteoporosis in menopause is an increasingly important issue. This evidence needs to be highlighted to counteract the negative impact of the smear campaign against animal foods that are publicised to exert negative influence on human health.

References

1 

Guimont C, Marchall E, Girardet JM, Linden G, Otani H. Biologically active factors in bovine milk and dairy byproducts: influence on cell culture. Crit Rev Food Sci Nutr. 1997;37:393–410. DOI: http://dx.doi.org/10.1080/10408399709527780 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9227891

2 

Cannella C, Pizzoferrato L. Dossier: Parmigiano Reggiano: a naturally functional product. Rome, Italy: National Research Institute for Food and Nutrition (INRAN); 2008. Available from: storage.parmigiano-reggiano.it/file/Dossier_PR_20100222_ 1–27.pdf (in Italian).

3 

Millward DJ, Jackson AA. Protein/energy ratios of current diets in developed and developing countries compared with a safe protein/energy ratio: implications for recommended protein and amino acid intakes. Public Health Nutr. 2004;7:387–405. DOI: http://dx.doi.org/10.1079/PHN2003545 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15153271

4 

Garini L, Verduci E, Scaglioni S, Bernasconi S. Nutrition in childhood. Update on nutritional aspects of Parmigiano-Reggiano cheese. Proceedings of the conference Acquisitions related to the nutritional value of Parmigiano-Reggiano cheese; 2008 March 8; Reggio Emilia, Italy; 2008. pp. 7–56 (in Italian).

5 

Strata A. Parmigiano-Reggiano cheese nutritional and dietary aspects. In: Parma, Capitale Alimentare N. 23. Parma, Italy: S.I.G.E.P. snc, Società Iniziative Grafiche Editoriali – Pubblicitarie; 1989;23:10–8 (in Italian, English, French, German).

6 

Schlimme E, Meisel H. Bioactive peptides derived from milk proteins. Structural, physiological and analytical aspects. Nahrung. 1995;39:1–20. DOI: http://dx.doi.org/10.1002/food.19950390102 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/7898574

7 

Clare DA, Swaisgood HE. Bioactive milk peptides: a prospectus. J Dairy Sci. 2000;83:1187–95. DOI: http://dx.doi.org/10.3168/jds.S0022-0302(00)74983-6 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10877382

8 

Shah NP. Effects of milk-derived bioactives: an overview. Br J Nutr. 2000;84 Suppl 1:S3–10. DOI: http://dx.doi.org/10.1017/S000711450000218X PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11242440

9 

Meisel H. Multifunctional peptides encrypted in milk proteins. Biofactors. 2004;21:55–61. DOI: http://dx.doi.org/10.1002/biof.552210111 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15630170

10 

Meisel H. Biochemical properties of peptides encrypted in bovine milk proteins. Curr Med Chem. 2005;12:1905–19. DOI: http://dx.doi.org/10.2174/0929867054546618 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16101509

11 

Stefanucci A, Mollica A, Macedonio G, Zengin G, Ahmed AA, Novellino E. Exogenous opioid peptides derived from food proteins and their possible uses as dietary supplements: a critical review. Food Rev Int. 2016;32:1–17. DOI: http://dx.doi.org/10.1080/87559129.2016.1225220

12 

Meisel H, Bockelmann W. Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties. Antonie Van Leeuwenhoek. 1999;76:207–15. DOI: http://dx.doi.org/10.1023/A:1002063805780 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10532380

13 

Haileselassie SS, Lee BH, Gibbs BF. Purification and identification of potentially bioactive peptides from enzyme-modified cheese. J Dairy Sci. 1999;82:1612–7. DOI: http://dx.doi.org/10.3168/jds.S0022-0302(99)75389-0 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10480087

14 

Korhonen H, Pihlanto A. Bioactive peptides: production and functionality. Int Dairy J. 2006;16:945–60. DOI: http://dx.doi.org/10.1016/j.idairyj.2005.10.012

15 

Silva SV, Malcata FX. Caseins as source of bioactive peptides. Int Dairy J. 2005;15:1–15. DOI: http://dx.doi.org/10.1016/j.idairyj.2004.04.009

16 

Phelan M, Aherne A, FitzGerald RJ, O’Brien NM. Casein-derived bioactive peptides: biological effects, industrial uses, safety aspects and regulatory status. Int Dairy J. 2009;19:643–54. DOI: http://dx.doi.org/10.1016/j.idairyj.2009.06.001

17 

Matar C, Valdez JC, Medina M, Rachid M, Perdigòn G. Immunomodulating effects of milks fermented by Lactobacillus helveticus and its non-proteolytic variant. J Dairy Res. 2001;68:601–9. DOI: http://dx.doi.org/10.1017/S0022029901005143 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11928956

18 

Stuknyte M, De Noni I, Guglielmetti S, Minuzzo M, Mora D. Potential immunomodulatory activity of bovine casein hydrolysates produced after digestion with proteinases of lactic acid bacteria. Int Dairy J. 2011;21:763–9. DOI: http://dx.doi.org/10.1016/j.idairyj.2011.04.011

19 

Addeo F, Chianese L, Salzano A, Sacchi R, Cappuccio U, Ferranti P, et al. Characterization of the 12% trichloroacetic acid-insoluble oligopeptides of Parmigiano-Reggiano cheese. J Dairy Res. 1992;59:401–11. DOI: http://dx.doi.org/10.1017/S0022029900030673

20 

Sforza S, Cavatorta V, Lambertini F, Galaverna G, Dossena A, Marchelli R. Cheese peptidomics: a detailed study on the evolution of the oligopeptide fraction in Parmigiano-Reggiano cheese from curd to 24 months of aging. J Dairy Sci. 2012;95:3514–26. DOI: http://dx.doi.org/10.3168/jds.2011-5046 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/22720910

21 

Ferraretto A, Signorile A, Gravaghi C, Fiorilli A, Tettamanti G. Casein phosphopeptides influence calcium uptake by cultured human intestinal HT-29 tumor cells. J Nutr. 2001;131:1655–61. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11385049

22 

Kitts DD, Weiler K. Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des. 2003;9:1309–23. DOI: http://dx.doi.org/10.2174/1381612033454883 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12769739

23 

Teschemacher H. Opioid receptor ligands derived from food proteins. Curr Pharm Des. 2003;9:1331–44. DOI: http://dx.doi.org/10.2174/1381612033454856 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12769741

24 

Teschemacher H, Koch G, Brantl V. Milk protein-derived opioid receptor ligands. Biopolymers. 1997;43:99–117. DOI: http://dx.doi.org/10.1002/(SICI)1097-0282(1997)43:2<99::AID-BIP3>3.0.CO;2-V PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9216246

25 

Gill HS, Doull F, Rutherfurd KJ, Cross ML. Immunoregulatory peptides in bovine milk. Br J Nutr. 2000;84 Suppl 1:S111–7. DOI: http://dx.doi.org/10.1017/S0007114500002336 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11242455

26 

Coste M, Tomé D. Milk peptides with physiological activities. II. Opioid and immunostimulating peptides derived from milk proteins. Lait. 1991;71:241–7. DOI: http://dx.doi.org/10.1051/lait:1991218

27 

Migliore-Samour D, Jollès P. Casein, a prohormone with an immunomodulating role for the newborn? Experientia. 1988;44:188–93. DOI: http://dx.doi.org/10.1007/BF01941703 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/3280338

28 

Migliore-Samour D, Floch F, Jollès P. Biologically active casein peptides implicated in immunomodulation. J Dairy Res. 1989;56:357–62. DOI: http://dx.doi.org/10.1017/S0022029900028806 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/2668358

29 

Jollès P, Fiat AM, Migliore-Samour D, Drouet L, Caen J. Peptides from milk proteins implicated in antithrombosis and immunomodulation. In: Renner B, Sawatzki G, editors. New perspectives in infant nutrition, symposium Antwerp. New York, NY USA: Thieme Publishing Group; 1992. pp. 160–72.

30 

Fiat AM, Migliore-Samour D, Jollès P, Drouet L. Bal dit Sollier C, Caen J. Biologically active peptides from milk with emphasis on two examples concerning antithrombotic and immunomodulating activities. J Dairy Sci. 1993;76:301–10. DOI: http://dx.doi.org/10.3168/jds.S0022-0302(93)77351-8 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/8436680

31 

Meisel H. Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers. 1997;43:119–28. DOI: http://dx.doi.org/10.1002/(SICI)1097-0282(1997)43:2<119::AID-BIP4>3.0.CO;2-Y PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9216247

32 

Lahov E, Regelson W. Antibacterial and immunostimulating casein-derived substances from milk: casecidin, isracidin peptides. Food Chem Toxicol. 1996;34:131–45. DOI: http://dx.doi.org/10.1016/0278-6915(95)00097-6 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/8603791

33 

Wybran J, Appelboom T, Famaey JP, Govaerts A. Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J Immunol. 1979;123:1068–70. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/224107

34 

Faith RE, Liang HJ, Murgo AJ, Plotnikoff NP. Neuroimmunomodulation with enkephalins: enhancement of human natural killer (NK) cell activity in vitro. Clin Immunol Immunopathol. 1984;31:412–8. DOI: http://dx.doi.org/10.1016/0090-1229(84)90093-X PubMed: http://www.ncbi.nlm.nih.gov/pubmed/6713744

35 

Kayser H, Meisel H. Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins. FEBS Lett. 1996;383:18–20. DOI: http://dx.doi.org/10.1016/0014-5793(96)00207-4 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/8612782

36 

Maruyama S, Mitachi H, Awaya J, Kurono M, Tomizuka N, Suzuki H. Angiotensin I-converting enzyme inhibitory activity of the C-terminal hexapeptide of αs1-casein. Agric Biol Chem. 1987;51:2557–61. DOI: http://dx.doi.org/10.1080/00021369.1987.10868415

37 

Regazzo D, Mollé D, Gabai G, Tomé D, Dupont D, Leonil J, et al. The (193–209) 17-residues peptide of bovine β-casein is transported through Caco-2 monolayer. Mol Nutr Food Res. 2010;54:1428–35. DOI: http://dx.doi.org/10.1002/mnfr.200900443 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/20397193

38 

Hadden JW. Immunotherapy of human immunodeficiency virus infection. Trends Pharmacol Sci. 1991;12:107–11. DOI: http://dx.doi.org/10.1016/0165-6147(91)90517-V PubMed: http://www.ncbi.nlm.nih.gov/pubmed/2053187

39 

Meisel H, Frister H. Chemical characterization of bioactive peptides from in vivo digests of casein. J Dairy Res. 1989;56:343–9. DOI: http://dx.doi.org/10.1017/S0022029900028788 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/2760300

40 

Bouhallab S, Bouglè D. Biopeptides of milk: caseinophosphopeptides and mineral bioavalability. Reprod Nutr Dev. 2004;44:493–8. DOI: http://dx.doi.org/10.1051/rnd:2004053 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15636166

41 

Erba D, Ciappellano S, Testolin G. Effect of the ratio of casein phosphopeptides to calcium (w/w) on passive calcium transport in the distal small intestine of rats. Nutrition. 2002;18:743–6. DOI: http://dx.doi.org/10.1016/S0899-9007(02)00829-8 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12297210

42 

Pampaloni B, Bartolini E, Brandi ML. Parmigiano-Reggiano cheese and bone health. Clin Cases Miner Bone Metab. 2011;8:33–6. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/22461827

43 

Aimutis WR. Bioactive properties of milk proteins with particular focus on anticariogenesis. J Nutr. 2004;134:989S–95S. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15051859

44 

Cattaneo S, Stuknytė M, Ferraretto A, De Noni I. Impact of the in vitro gastrointestinal digestion protocol on casein phosphopeptide profile of Grana Padano cheese digestates. Lebensm Wiss Technol. 2017;77:356–61. DOI: http://dx.doi.org/10.1016/j.lwt.2016.11.069

45 

Pripp AH. Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized controlled trials. Food Nutr Res. 2008;52:1641. DOI: http://dx.doi.org/10.3402/fnr.v52i0.1641 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19109662

46 

Basiricò L, Catalani E, Morera P, Cattaneo S, Stuknytė M, Bernabucci U, et al. Release of angiotensin converting enzyme-inhibitor peptides during in vitro gastrointestinal digestion of Parmigiano Reggiano PDO cheese and their absorption through an in vitro model of intestinal epithelium. J Dairy Sci. 2015;98:7595–601. DOI: http://dx.doi.org/10.3168/jds.2015-9801 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26364103

47 

Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T. A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr. 1996;64:767–71. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/8901799

48 

Crippa G, Zabzuni D, Bravi E, Cicognini FM, Bighi E, Rossi F. Randomized, double-blind, placebo-controlled, cross-over study on the antihypertensive effect of dietary integration with Grana Padano DOCG cheese. J Am Soc Hypertens. 2016;10 Suppl:e6. DOI: http://dx.doi.org/10.1016/j.jash.2016.03.014

49 

Bernabucci U, Catalani E, Basiricò L, Morera P, Nardone A. In vitro ACE-inhibitory activity and in vivo antihypertensive effects of water-soluble extract by Parmigiano Reggiano and Grana Padano cheeses. Int Dairy J. 2014;37:16–9. DOI: http://dx.doi.org/10.1016/j.idairyj.2014.02.009

50 

Stuknytė M, Cattaneo S, Masotti F, De Noni I. Occurrence and fate of ACE-inhibitor peptides in cheeses and in their digestates following in vitro static gastrointestinal digestion. Food Chem. 2015;168:27–33. DOI: http://dx.doi.org/10.1016/j.foodchem.2014.07.045 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25172679

51 

Tricò D, Baldi S, Tulipani A, Frascerra S, Macedo MP, Mari A, et al. Mechanisms through which a small protein and lipid preload improves glucose tolerance. Diabetologia. 2015;58:2503–12. DOI: http://dx.doi.org/10.1007/s00125-015-3710-9 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26224101

52 

Jensen RG. The composition of bovine milk lipids: January 1995 to December 2000. J Dairy Sci. 2002;85:295–350. DOI: http://dx.doi.org/10.3168/jds.S0022-0302(02)74079-4 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11913692

53 

Kratz M, Baars T, Guyenet S. The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease. Eur J Nutr. 2013;52:1–24. DOI: http://dx.doi.org/10.1007/s00394-012-0418-1 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/22810464

54 

Pereira MA, Jacobs DR Jr, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS. Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study. JAMA. 2002;287:2081–9. DOI: http://dx.doi.org/10.1001/jama.287.16.2081 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11966382

55 

Warensjö E, Jansson JH, Berglund L, Boman K, Ahrén B, Weinehall L, et al. Estimated intake of milk fat is negatively associated with cardiovascular risk factors and does not increase the risk of a first acute myocardial infarction. A prospective case-control study. Br J Nutr. 2004;91:635–42. DOI: http://dx.doi.org/10.1079/BJN20041080 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15035691

56 

Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, et al. Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. Ann Intern Med. 2010;153:790–9. DOI: http://dx.doi.org/10.7326/0003-4819-153-12-201012210-00005 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21173413

57 

Warensjö E, Jansson JH, Cederholm T, Boman K, Eliasson M, Hallmans G, et al. Biomarkers of milk fat and the risk of myocardial infarction in men and women: a prospective, matched case-control study. Am J Clin Nutr. 2010;92:194–202. DOI: http://dx.doi.org/10.3945/ajcn.2009.29054 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/20484449

58 

Sonestedt E, Wirfält E, Wallström P, Gullberg B, Orho-Melander M, Hedblad B. Dairy products and its association with incidence of cardiovascular disease: the Malmö diet and cancer cohort. Eur J Epidemiol. 2011;26:609–18. DOI: http://dx.doi.org/10.1007/s10654-011-9589-y PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21660519

59 

Wang H, Steffen LM, Vessby B, Basu S, Steinberger J, Moran A, et al. Obesity modifies the relations between serum markers of dairy fats and inflammation and oxidative stress among adolescents. Obesity (Silver Spring). 2011;19:2404–10. DOI: http://dx.doi.org/10.1038/oby.2011.234 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21779090

60 

White RP, El-Bauomy AM, Wood WB. Capric acid as a potent dilator of canine vessels in vitro and in vivo. Gen Pharmacol. 1991;22:741–8. DOI: http://dx.doi.org/10.1016/0306-3623(91)90089-O PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1936910

61 

Cestaro B. For a stainless life. Nutritional benefits of milk and dairy products. Milano, Italy: Etaslibri RCS Medicina; 1994 (in Italian).

62 

Franson RC, Harris LK, Ghosh SS, Rosenthal MD. Sphingolipid metabolism and signal transduction: inhibition of in vitro phospholipase activity by sphingosine. BBA – Mol. Biochim Biophys Acta. 1992;1136:169–74. DOI: http://dx.doi.org/10.1016/0167-4889(92)90253-8 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1504102

63 

Yoshida K, Terao J, Suzuki T, Takama K. Inhibitory effect of phosphatidylserine on iron-dependent lipid peroxidation. Biochem Biophys Res Commun. 1991;179:1077–81. DOI: http://dx.doi.org/10.1016/0006-291X(91)91929-7 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1898388

64 

Gordon LI, Weiss D, Prachand S, Weitzman SA. Scavenging of superoxide anion by phosphorylethanolamine: studies in human neutrophils and in a cell free system. Free Radic Res Commun. 1991;15:65–71. DOI: http://dx.doi.org/10.3109/10715769109049126 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1663067

65 

Park Y, Storkson JM, Albright KJ, Liu W, Pariza MW. Evidence that the trans-10,cis-12 isomer of conjugated linoleic acid induces body composition in mice. Lipids. 1999;34:235–41. DOI: http://dx.doi.org/10.1007/s11745-999-0358-8 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10230716

66 

Pariza MW, Park Y, Cook ME. The biologically-active isomers of conjugated linoleic acid. Prog Lipid Res. 2001;40:283–98. DOI: http://dx.doi.org/10.1016/S0163-7827(01)00008-X PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11412893

67 

Park Y, Albright KJ, Liu W, Storkson JM, Cook ME, Pariza MW. Effect of conjugated linoleic acid on body composition in mice. Lipids. 1997;32:853–8. DOI: http://dx.doi.org/10.1007/s11745-997-0109-x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9270977

68 

Kang K, Liu W, Albright KJ, Yeonhwa P, Pariza MW, editors. -10,cis-12 CLA inhibits differentiation of 3T3-L1 adipocytes and decreses PPARγ expression. Biochem Biophys Res Commun. 2003;303:795–9. DOI: http://dx.doi.org/10.1016/S0006-291X(03)00413-3 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12670481

69 

Park Y, Albright KJ, Storkson JM, Liu W, Pariza MW. Conjugated linoleic acid (CLA) prevents body fat accumulation and weight gain in an animal model. J Food Sci. 2007;72:S612–17. DOI: http://dx.doi.org/10.1111/j.1750-3841.2007.00477.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/17995628

70 

Ip C, Dong Y, Ip MM, Banni S, Carta G, Angioni E, et al. Conjugated acid isomers and mammary cancer prevention. Nutr Cancer. 2002;43:52–8. DOI: http://dx.doi.org/10.1207/S15327914NC431_6 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12467135

71 

Masso-Welch PA, Zangani D, Ip C, Vaughan MM, Shoemaker S, Ramirez RA, et al. Inhibition of angiogenesis by the cancer chemopreventive agent conjugated linoleic acid. Cancer Res. 2002;62:4383–9. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12154044

72 

Smit LA, Baylin A, Campos H. Conjugated linoleic acid in adipose tissue and risk of myocardial infarction. Am J Clin Nutr. 2010;92:34–40. DOI: http://dx.doi.org/10.3945/ajcn.2010.29524 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/20463040

73 

Prandini A, Geromin D, Conti F, Masoero F, Piva A, Piva G. Survey on the level of conjugated linoleic acid in dairy products. Ital J Food Sci. 2001;13:243–53.

74 

Prandini A, Sigolo S, Tansini G, Brogna N, Piva G. Different level of conjugated linoleic acid (CLA) in dairy products from Italy. J Food Compos Anal. 2007;20:472–9. DOI: http://dx.doi.org/10.1016/j.jfca.2007.03.001

75 

Prandini A, Sigolo S, Piva G. Conjugated linoleic acid (CLA) and fatty acid composition of milk, curd and Grana Padano cheese in conventional and organic farming systems. J Dairy Res. 2009;76:278–82. DOI: http://dx.doi.org/10.1017/S0022029909004099 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19445826

76 

Liu J, McKim JM, Liu YP, Klaassen CD. Effects of butyrate homologues on metallothionein induction in rat primary hepatocyte cultures. In Vitro Cell Dev Biol. 1992;28A:320–6. DOI: http://dx.doi.org/10.1007/BF02877055 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1597404

77 

Kaptein A, Roodenburg L, Princen HMG. Butyrate stimulates the secretion of apolipoprotein A–I and apolipoprotein B-100 in Hep G2 cells by different mechanisms. Clin Biochem. 1992;25:317–9. DOI: http://dx.doi.org/10.1016/0009-9120(92)80005-2 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1337018

78 

Sandri S, Fossa E, Pecorari M, Summer A, Mariani P. Observations on the lipolysis progress during the ageing of Parmigiano-Reggiano cheese. Sci Tecn Latt-Cas. 1997;48:243–52. [in Italian]

79 

Malacarne M, Summer A, Franceschi P, Formaggioni P, Pecorari M, Panari G, et al. Free fatty acid profile of Parmigiano-Reggiano cheese throughout ripening: comparison between the inner and outer regions of the wheel. Int Dairy J. 2009;19:637–41. DOI: http://dx.doi.org/10.1016/j.idairyj.2009.04.004

80 

Castagnetti GB, Delmonte P, Melia S, Gori A, Losi G. The effect of extruded whole linseed flour intake on the variation of CLA (conjugated linoleic acid) content in milk and OFA (oxidized fatty acids) in the cheese obtained: the case of Reggiana cattle. Sci Tecn Latt-Cas. 2007;58:363–82. [in Italian]

81 

Verhoeven NM, Jakobs C. Human metabolism of phytanic acid and pristanic acid. Prog Lipid Res. 2001;40:453–66. DOI: http://dx.doi.org/10.1016/S0163-7827(01)00011-X PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11591435

82 

Vetter W, Schröder M. Concentrations of phytanic acid and pristanic acid are higher in organic than in conventional dairy products from the German market. Food Chem. 2010;119:746–52. DOI: http://dx.doi.org/10.1016/j.foodchem.2009.07.027

83 

Capuano E, Elgersma A, Tres A, van Ruth SM. Phytanic and pristanic acid content in Dutch farm milk and implications for the verification of the farming management system. Int Dairy J. 2014;35:21–4. DOI: http://dx.doi.org/10.1016/j.idairyj.2013.10.003

84 

Schröder M, Lutz NL, Tangwan EC, Hajazimi E, Vetter W. Phytanic acid concentrations and diastereomer ratios in milk fat during changes in the cow’s feed from concentrate to hay and back. Eur Food Res Technol. 2012;234:955–62. DOI: http://dx.doi.org/10.1007/s00217-012-1710-2

85 

Che BN, Kristensen T, Nebel C, Dalsgaard TK, Hellgren LI, Young JF, et al. Content and distribution of phytanic acid diastereomers in organic milk as affected by feed composition. J Agric Food Chem. 2013;61:225–30. DOI: http://dx.doi.org/10.1021/jf304079r PubMed: http://www.ncbi.nlm.nih.gov/pubmed/23210769

86 

Pancaldi M, Mariotti I, Balli F. Intestinal inflammation in nursing infants: different causes and a single treatment… but of protected origin. Acta Biomed. 2008;79:144–50. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18788512

87 

Coppa GV. Biochemical characterisation of the carbohydrate content in the Parmigiano Reggiano cheese at different ripening times. Proceedings of the Conference Acquisitions related to the nutritional value of Parmigiano-Reggiano cheese; 2008 March 8; Reggio Emilia, Italy; 2008. pp. 57–66 (in Italian).

88 

Morelli L, Soldi S. In vitro study of the prebiotic potentials of Parmigiano-Reggiano cheese at different stages of ripening. Proceedings of the Conference Acquisitions related to the nutritional value of Parmigiano Reggiano cheese; 2008 March 8; Reggio Emilia, Italy; 2008. pp. 67–72 (in Italian).

89 

Saksena R, Deepak D, Khare A, Sahai R, Tripathi LM, Srivastava VML. A novel pentasaccharide from immunostimulant oligosaccharide fraction of buffalo milk. Biochim Biophys Acta. 1999;1428:433–45. DOI: http://dx.doi.org/10.1016/S0304-4165(99)00089-6 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10434063

90 

Coppa GV. Oligosaccharides: potential prebiotics of Parmigiano-Reggiano. Pediatria Preventiva & Sociale. 2011;2:154–5. [in Italian]

91 

Casu B, Lindahl U. Structure and biological interactions of heparin and heparan sulfate. Adv Carbohydr Chem Biochem. 2001;57:159–206. DOI: http://dx.doi.org/10.1016/S0065-2318(01)57017-1 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11836942

92 

Succi M, Tremonte P, Reale A, Sorrentino E, Grazia L, Pacifico S, et al. Bile salt and acid tolerance of Lactobacillus rhamnosus strains isolated from Parmigiano Reggiano cheese. FEMS Microbiol Lett. 2005;244:129–37. DOI: http://dx.doi.org/10.1016/j.femsle.2005.01.037 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15727832

93 

Malacarne M, Summer A, Fossa E, Formaggioni P, Franceschi P, Pecorari M, et al. Composition, coagulation properties and Parmigiano-Reggiano cheese yield of Italian Brown and Italian Friesian herd milks. J Dairy Res. 2006;73:171–7. DOI: http://dx.doi.org/10.1017/S0022029905001688 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16476179

94 

Bonjour JP, Benoit V, Pourchaire O, Rousseau B, Souberbielle JC. Nutritional approach for inhibiting bone resorption in institutionalized elderly women with vitamin D insufficiency and high prevalence of fracture. J Nutr Health Aging. 2011;15:404–9. DOI: http://dx.doi.org/10.1007/s12603-011-0003-y PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21528169

95 

Perego S, Zabeo A, Marasco E, Giussani P, Fiorilli A, Tettamanti G, et al. Casein phosphopeptides modulate calcium uptake and apoptosis in Caco2 cells through their interaction with the TRPV6 calcium channel. J Funct Foods. 2013;5:847–57. DOI: http://dx.doi.org/10.1016/j.jff.2013.01.032

96 

De Luca P, Bruschi S, Maggioni M, Stuknytė M, Cattaneo S, Bottani M, et al. Gastrointestinal digestates of Grana Padano and Trentingrana cheeses promote intestinal calcium uptake and extracellular bone matrix formation in vitro. Food Res Int. 2016;89:820–7. DOI: http://dx.doi.org/10.1016/j.foodres.2016.10.008 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/28460984

97 

Tong X, Dong JY, Wu ZW, Li W, Qin LQ. Dairy consumption and risk of type 2 diabetes mellitus: a meta-analysis of cohort studies. Eur J Clin Nutr. 2011;65:1027–31. DOI: http://dx.doi.org/10.1038/ejcn.2011.62 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21559046

98 

Da Silva MS, Rudkowska I. Dairy products on metabolic health: current research and clinical implications. Maturitas. 2014;77:221–8. DOI: http://dx.doi.org/10.1016/j.maturitas.2013.12.007 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/24445013

99 

Sluijs I, Forouhi NG, Beulens JWJ, van der Schouw YT, Agnoli C, Arriola L, et al. The amount and type of dairy product intake and incident type 2 diabetes: results from the EPIC-InterAct Study. Am J Clin Nutr. 2012;96:382–90. DOI: http://dx.doi.org/10.3945/ajcn.111.021907 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/22760573

100 

Malik VS, Sun Q, van Dam RM, Rimm EB, Willett WC, Rosner B, et al. Adolescent dairy product consumption and risk of type 2 diabetes in middle-aged women. Am J Clin Nutr. 2011;94:854–61. DOI: http://dx.doi.org/10.3945/ajcn.110.009621 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21753066

101 

Tremblay A, Gilbert JA. Milk products, insulin resistance syndrome and type 2 diabetes. J Am Coll Nutr. 2009;28:91S–102S. DOI: http://dx.doi.org/10.1080/07315724.2009.10719809 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19571167

102 

Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017–29. DOI: http://dx.doi.org/10.1210/jc.2007-0298 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/17389701

103 

Krachler B, Norberg M, Eriksson JW, Hallmans G, Johansson I, Vessby B, et al. Fatty acid profile of the erythrocyte membrane preceding development of type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2008;18:503–10. DOI: http://dx.doi.org/10.1016/j.numecd.2007.04.005 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18042359

104 

Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K, Boeing H. Fiber and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis. Arch Intern Med. 2007;167:956–65. DOI: http://dx.doi.org/10.1001/archinte.167.9.956 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/17502538

105 

Hu FB, van Dam RM, Liu S. Diet and risk of type II diabetes: the role of types of fat and carbohydrate. Diabetologia. 2001;44:805–17. DOI: http://dx.doi.org/10.1007/s001250100547 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11508264

106 

Ericson U, Hellstrand S, Brunkwall L, Schulz CA, Sonestedt E, Wallstrom P, et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. Am J Clin Nutr. 2015;101:1065–80. DOI: http://dx.doi.org/10.3945/ajcn.114.103010 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25832335

107 

Ralston RA, Lee JH, Truby H, Palermo CE, Walker KZ. A systematic review and meta-analysis of elevated blood pressure and consumption of dairy foods. J Hum Hypertens. 2012;26:3–13. DOI: http://dx.doi.org/10.1038/jhh.2011.3 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21307883

108 

Ascherio A, Hennekens C, Willett WC, Sacks F, Rosner B, Manson J, et al. Prospective study of nutritional factors, blood pressure, and hypertension among US women. Hypertension. 1996;27:1065–72. DOI: http://dx.doi.org/10.1161/01.HYP.27.5.1065 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/8621198

109 

Jauhiainen T, Korpela R. Milk peptides and blood pressure. J Nutr. 2007;137:825S–9S. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/17311982

110 

Perego S, Cosentino S, Fiorilli A, Tettamanti G, Ferraretto A. Casein phosphopeptides modulate proliferation and apoptosis in HT-29 cell line through their interaction with voltage-operated L-type calcium channels. J Nutr Biochem. 2012;23:808–16. DOI: http://dx.doi.org/10.1016/j.jnutbio.2011.04.004 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21840696


This display is generated from NISO JATS XML with jats-html.xsl. The XSLT engine is libxslt.

[engleski]

Posjeta: 708 *