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Abstract Background Beneficial effects from practising a Paleolithic diet as compared to a diabetes diet on weight, waist circumference, satiety, leptin, HbA1c and glucose control in randomised controlled trial participants with type 2 diabetes could be due to lower leptin resistance. Support for this hypothesis comes from an in vitro experiment that showed that digested wheat gluten, which is excluded from a Paleolithic diet, inhibits leptin from binding to its receptor, thus indicating a possible dietary cause of leptin resistance. However, the clinical relevance of the latter finding is unclear since removal of enzyme activity from the gluten digest by heat treatment also abolished leptin binding inhibition. Assessment of leptin binding inhibition in vivo is possible by comparison of total leptin levels with those of ‘biologically active’ leptin bound to its receptor (bioLep). Objectives To assess the effects of a Paleolithic diet compared to a diabetes diet on leptin binding inhibition and to replicate our in vitro study. Methods BioLep and total leptin levels were measured in secondary analysis of fasting plasma samples from our open label random order three plus three-month long cross-over trial performed in 2005–2007, that compared a Paleolithic diet with a diabetes diet in participants with type 2 diabetes without insulin treatment (per protocol). BioLep was also measured in vitro for known recombinant leptin concentrations incubated with a series of concentrations of 10 kDa spin-filtered digested wheat gluten, with or without prior heat treatment, at 100ºC for 30 min and centrifugation. Results There was no difference between diets when comparing differences between bioLep and total leptin levels and their ratio in the 13 participants, three women and 10 men, aged 52–74 years with a mean BMI of 30 kg/m2 and a mean diabetes duration of eight years. We found no carry-over or period effect for bioLep and total leptin. In vitro, wheat gluten digest inhibited leptin binding in a dose-dependent manner but not after heat treatment. Conclusions We found no leptin binding inhibition after the Paleolithic or diabetes diet, possibly due to its abolishment from cooking-related heat treatment of wheat gluten. Trial registration Registered on 14/02/2007 at ClinicalTrials.gov Identifier: NCT00435240.

Abstract Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies.

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Abstract Background Population-based levels of the chronic low-grade systemic inflammation biomarker, C-reactive protein (CRP), vary widely among traditional populations, despite their apparent absence of chronic conditions associated with chronic low-grade systemic inflammation, such as type 2 diabetes, metabolic syndrome and cardiovascular disease. We have previously reported an apparent absence of aforementioned conditions amongst the traditional Melanesian horticulturalists of Kitava, Trobriand Islands, Papua New Guinea. Our objective in this study was to clarify associations between chronic low-grade systemic inflammation and chronic cardiometabolic conditions by measuring CRP in a Kitava population sample. For comparison purposes, CRP was also measured in Swedish controls matched for age and gender. Methods Fasting levels of serum CRP were measured cross-sectionally in ≥ 40-year-old Kitavans (N = 79) and Swedish controls (N = 83). Results CRP was lower for Kitavans compared to Swedish controls (Mdn 0.5 mg/L range 0.1—48 mg/L and Mdn 1.1 mg/L range 0.1—33 mg/L, respectively, r = .18 p = .02). Among Kitavans, there were small negative associations between lnCRP for CRP values

Sulbutiamine is a thiamine derivative developed in Japan in the mid-60’s as a beriberi treatment drug. Since then, different potential applications have been described. For instance, there is some evidence that sulbutiamine can have anti-fatigue, nootropic, and antioxidant effects, which led to its use as a sport supplement (although some authors argue it is actually a masking doping strategy). Moreover, this molecule has been proposed as a possible treatment for some microsporidial infections and even for certain types of cancer. Despite these potential effects, sulbutiamine is still a relatively unknown molecule, which justifies the present review, where we discuss its history and the existing literature on its health applications. We conclude that there is a great potential for sulbutiamine use, well beyond its first described function (to increase thiamine tissue concentration). Indeed, new mechanisms of action have been found, mainly associated with its derivatives. Nevertheless, and although the research on sulbutiamine started 50 years ago, only a limited number of studies were conducted during this time frame. As so, methodological concerns need to be addressed and new studies are necessary, especially randomized controlled trials. Only then will the full potential of this versatile molecule be identified.

El sueño es un determinante fundamental en el rendimiento y la salud del deportista. En la actualidad algunos expertos la definen como la mejor estrategia de recuperación debido a sus efectos fisiológicos y restaurativos. Los deportistas deben ser alentados a dormir más horas que la población general, debido a las demandas de recuperación impuestas por el ejercicio. La presente revisión teórica busca esclarecer los factores que afectan al sueño, los efectos de éste sobre el rendimiento deportivo y la salud, así como explicar las estrategias más determinantes para mejorar la cantidad y calidad del sueño del deportista. Para ello es importante tener en cuenta los horarios de los eventos deportivos, el estrés psicosocial del deportista, el uso de dispositivos electrónicos, los viajes, el uso de sustancias estimulantes como la cafeína o la ingesta de alcohol, entre otros. Diferentes estrategias como la extensión del sueño, las siestas, estrategias de higiene del sueño y nutricionales deben ser consideradas en la mejora del sueño del deportista.

Summary: Background: Dietary compliance assessments are absent in clinical studies on Paleolithic diet. We therefore developed a ‘Paleolithic Diet Fraction’ (PDF), calculated as the fraction of intake from Paleolithic food groups, to assess compliance with Paleolithic diet in a previously reported study. Methods: 29 male patients with ischemic heart disease, impaired glucose tolerance and waist circumference > 94 cm, were randomized to a Paleolithic or Mediterranean-like diet for 12 weeks. Mean daily PDFs were calculated for dietary energy and weight for all participants using four-day weighed food records, and linear regression analysis was performed between PDF and primary outcome measures plus leptin for both diet groups combined. Results: PDFs were just above 80% for the Paleolithic diet group and around 40% for the Mediterranean-like diet group. We found associations between PDF and outcome measures of similar strength as previously reported for group differences, and an association with weight, for which no group difference was previously found. Conclusions: Calculation of PDF demonstrated a mean compliance of just above 80% in the Paleolithic diet group and association studies indicated a clinical relevance for PDF. Trial registration: ClinicalTrials.gov NCT00419497 retrospectively registered. Keywords: Paleolithic diet, Compliance, Paleolithic diet fraction, Ischemic heart disease, Type 2 diabetes, Satiety

Pedro Carrera-Bastos1, Maelan Fontes-Villalba1, James H O’Keefe2, Staffan Lindeberg1, Loren Cordain31Center for Primary Health Care Research, Faculty of Medicine at Lund University, Malmö, Sweden; 2Mid America Heart and Vascular Institute/University of Missouri-Kansas City, Kansas City, Missouri, USA; 3Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, USAAbstract: It is increasingly recognized that certain fundamental changes in diet and lifestyle that occurred after the Neolithic Revolution, and especially after the Industrial Revolution and the Modern Age, are too recent, on an evolutionary time scale, for the human genome to have completely adapted. This mismatch between our ancient physiology and the western diet and lifestyle underlies many so-called diseases of civilization, including coronary heart disease, obesity, hypertension, type 2 diabetes, epithelial cell cancers, autoimmune disease, and osteoporosis, which are rare or virtually absent in hunter–gatherers and other non-westernized populations. It is therefore proposed that the adoption of diet and lifestyle that mimic the beneficial characteristics of the preagricultural environment is an effective strategy to reduce the risk of chronic degenerative diseases.Keywords: Paleolithic, hunter–gatherers, Agricultural Revolution, modern diet, western lifestyle and diseases

Over 100 diseases have been recognized as autoimmune in nature, collectively affecting ∼20 % of the population in industrialized countries. These conditions are more prevalent among women of childbearing age, reflecting the potential association between alterations in the immune-neuroendocrine network, on the one hand, and autoimmune conditions, on the other. Prolactin (PRL), a polypeptide hormone that is primarily (but not only) secreted by the lactotrophic cells of the pituitary gland, is a critical element of the immune-neuroendocrine network. Although this hormone has several nonimmune functions, its role in regulating immune responses and affecting autoimmune inflammation is particularly enigmatic and controversial. Indeed, PRL interacts with various immune cells to bolster the body defenses, but also potentially to exacerbate autoimmune conditions. Understanding how and when PRL acts as a 'friend or foe' is crucial for unraveling its role as a potential therapeutic target in the management of autoimmune diseases (AIDs). This review therefore provides a critical overview of PRL's role in the immune system, and of the influence of this pleiotropic hormone in the development of autoimmunity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported., Methods: Fasting levels of serum total adiponectin were measured cross-sectionally in ≥40-year-old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index., Results: Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 μg/mL, range 1.0-206 μg/mL and Mdn 9.7 μg/mL, range 3.1-104 μg/mL, respectively, r = .64, p < .001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low-density lipoprotein, high-density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non-HDL cholesterol, and higher anti-PC IgG (only in Kitavans and Swedish controls combined)., Conclusion: Total adiponectin in Kitavans was significantly lower than in Swedish controls., (© 2024 The Author(s). American Journal of Human Biology published by Wiley Periodicals LLC.)

Aim: Assess effects on waist circumference from diet with or without cereal grains and with or without long-term physical exercise., Background: Elevated waist circumference is an indicator of increased abdominal fat storage and is accordingly associated with increased cardiovascular mortality. This is likely due to the association between lifestyle-induced changes in waist circumference and cardiovascular risk factors. Reductions in waist circumference may be facilitated by diet without cereal grains combined with long-term physical exercise., Methods: Two-year randomised controlled trial with factorial trial design in individuals at increased risk of cardiovascular disease with increased waist circumference. Participants were allocated diet based on current Swedish dietary guidelines with or without cereal grains (baseline diet information supported by monthly group sessions) and with or without physical exercise (pedometers and two initial months of weekly structured exercise followed by written prescription of physical activity) or control group. The primary outcome was the change in waist circumference., Findings: The greatest mean intervention group difference in the change in waist circumference among the 73 participants (47 women and 26 men aged 23-79 years) was at one year between participants allocated a diet without cereal grains and no exercise and participants allocated a diet with cereal grains and no exercise [ M = -5.3 cm and -0.9 cm, respectively; mean difference = 4.4 cm, 4.0%, 95% CI (0.0%, 8.0%), P = 0.051, Cohen's d = 0.75]. All group comparisons in the change in waist circumference were non-significant despite the greatest group difference being more than double that estimated in the pre-study power calculation. The non-significance was likely caused by too few participants and a greater than expected variability in the change in waist circumference. The greatest mean intervention group difference strengthens the possibility that dietary exclusion of cereal grains could be related to greater reduction in waist circumference.

Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the "Suppressor Of Cytokine Signaling 1 and 3" (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the "typical western" conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.

Growing evidence supports the importance of lifestyle and environmental exposures-collectively referred to as the 'exposome'-for ensuring immune health. In this narrative review, we summarize and discuss the effects of the different exposome components (physical activity, body weight management, diet, sun exposure, stress, sleep and circadian rhythms, pollution, smoking, and gut microbiome) on immune function and inflammation, particularly in the context of the current coronavirus disease 2019 (COVID-19) pandemic. We highlight the potential role of 'exposome improvements' in the prevention-or amelioration, once established-of this disease as well as their effect on the response to vaccination. In light of the existing evidence, the promotion of a healthy exposome should be a cornerstone in the prevention and management of the COVID-19 pandemic and other eventual pandemics.

DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

Sulbutiamine is a thiamine derivative developed in Japan in the mid-60's as a beriberi treatment drug. Since then, different potential applications have been described. For instance, there is some evidence that sulbutiamine can have anti-fatigue, nootropic, and antioxidant effects, which led to its use as a sport supplement (although some authors argue it is actually a masking doping strategy). Moreover, this molecule has been proposed as a possible treatment for some microsporidial infections and even for certain types of cancer. Despite these potential effects, sulbutiamine is still a relatively unknown molecule, which justifies the present review, where we discuss its history and the existing literature on its health applications. We conclude that there is a great potential for sulbutiamine use, well beyond its first described function (to increase thiamine tissue concentration). Indeed, new mechanisms of action have been found, mainly associated with its derivatives. Nevertheless, and although the research on sulbutiamine started 50 years ago, only a limited number of studies were conducted during this time frame. As so, methodological concerns need to be addressed and new studies are necessary, especially randomized controlled trials. Only then will the full potential of this versatile molecule be identified., Competing Interests: L. Bettendorff is the Research Director of the “Fonds de la Recherche Scientifique-FNRS, Belgium. The authors declare that they have no conflicts of interest., (Copyright © 2020 Bernardo Starling-Soares et al.)

Healthy aging depends on a complex gene-environment network that is ultimately reflected in the expression of different proteins. We aimed to perform a comparative analysis of the plasma proteome of healthy centenarians (n=9, 5 women, age range 100-103 years) with a notably preserved ambulatory capacity (as a paradigm of 'successful' aging), and control individuals who died from a major age-related disease before the expected life expectancy (n=9, 5 women, age range: 67-81 years), and while having impaired ambulatory capacity (as a paradigm of 'unsuccessful' aging). We found that the expression of 49 proteins and 86 pathways differed between the two groups. Overall, healthy centenarians presented with distinct expression of proteins/pathways that reflect a healthy immune function, including a lower pro-inflammatory status (less 'inflammaging' and autoimmunity) and a preserved humoral immune response (increased B cell-mediated immune response). Compared with controls, healthy centenarians also presented with a higher expression of proteins involved in angiogenesis and related to enhanced intercellular junctions, as well as a lower expression of proteins involved in cardiovascular abnormalities. The identification of these proteins/pathways might provide new insights into the biological mechanisms underlying the paradigm of healthy aging.

Endotoxemia-induced inflammation has been associated with insulin resistance and atherosclerosis, ultimately increasing the risk of coronary heart disease. Increased intestinal permeability is an important event leading to endotoxemia. This study aims to elucidate the possible association between endotoxin (lipopolysaccharide) and zonulin (a biomarker of intestinal permeability) levels and the risk of coronary heart disease, and thus healthy aging. Serum levels of zonulin, lipopolysaccharide and soluble CD14 (a protein that binds lipopolysaccharide) were measured in disease-free centenarians, young healthy controls and patients with precocious acute myocardial infarction. Disease-free centenarians had significantly lower levels of serum zonulin ( P <0.01) and lipopolysaccharide ( P <0.001) than young patients with acute myocardial infarction, and had significantly lower concentrations of serum lipopolysaccharide than young healthy controls ( P <0.05). No significant differences were found for soluble CD14 between groups. Our findings may stimulate further research into the role played by intestinal permeability and endotoxemia not only in coronary heart disease but also in lifespan modulation., Competing Interests: Conflict of Interest The authors have no financial, personal or other potential conflicts of interest to declare.

Milk is rich in miRNAs that appear to play important roles in the postnatal development of all mammals. Currently, two competing hypotheses exist: the functional hypothesis, which proposes that milk miRNAs are transferred to the offspring and exert physiological regulatory functions, and the nutritional hypothesis, which suggests that these molecules do not reach the systemic circulation of the milk recipient, but merely provide nutrition without conferring active regulatory signals to the offspring. The functional hypothesis is based on indirect evidence and requires further investigation. The nutritional hypothesis is primarily based on three mouse models, which are inherently problematic: 1) miRNA-375 KO mice, 2) miRNA-200c/141 KO mice, and 3) transgenic mice presenting high levels of miRNA-30b in milk. This article presents circumstantial evidence that these mouse models may all be inappropriate to study the physiological traffic of milk miRNAs to the newborn mammal, and calls for new studies using more relevant mouse models or human milk to address the fate and role of milk miRNAs in the offspring and the adult consumer of cow's milk.

Background: We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study., Methods: In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m(2); diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records., Results: Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen's d = -1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), -2.3 (-5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed., Conclusions: Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet., Trial Registration: ClinicalTrials.gov NCT00435240.

Background: Breastfeeding has protective effects for the development of allergies and atopy. Recent evidence underlines that consumption of unboiled farm milk in early life is a key factor preventing the development of atopic diseases. Farm milk intake has been associated with increased demethylation of FOXP3 and increased numbers of regulatory T cells (Tregs). Thus, the questions arose which components of farm milk control the differentiation and function of Tregs, critical T cell subsets that promote tolerance induction and inhibit the development of allergy and autoimmunity., Findings: Based on translational research we identified at least six major signalling pathways that could explain milk's biological role controlling stable FoxP3 expression and Treg differentiation: (1) via maintaining appropriate magnitudes of Akt-mTORC1 signalling, (2) via transfer of milk fat-derived long-chain ω-3 fatty acids, (3) via transfer of milk-derived exosomal microRNAs that apparently decrease FOXP3 promoter methylation, (4) via transfer of exosomal transforming growth factor-β, which induces SMAD2/SMAD3-dependent FoxP3 expression, (5) via milk-derived Bifidobacterium and Lactobacillus species that induce interleukin-10 (IL-10)-mediated differentiation of Tregs, and (6) via milk-derived oligosaccharides that serve as selected nutrients for the growth of bifidobacteria in the intestine of the new born infant., Conclusion: Accumulating evidence underlines that milk is a complex signalling and epigenetic imprinting network that promotes stable FoxP3 expression and long-lasting Treg differentiation, crucial postnatal events preventing atopic and autoimmune diseases.

The focus of this paper is to explore better strategies for optimising bone strength and reducing risk of fracture, while at the same time decreasing risk of cardiovascular disease. The majority of Americans do not consume the current recommended dietary allowance for calcium, and the lifetime risk of osteoporosis is about 50%. However, traditional mononutrient calcium supplements may not be ideal. We comprehensively and systematically reviewed the scientific literature in order to determine the optimal dietary strategies and nutritional supplements for long-term skeletal health and cardiovascular health. To summarise, the following steps may be helpful for building strong bones while maintaining soft and supple arteries: (1) calcium is best obtained from dietary sources rather than supplements; (2) ensure that adequate animal protein intake is coupled with calcium intake of 1000 mg/day; (3) maintain vitamin D levels in the normal range; (4) increase intake of fruits and vegetables to alkalinise the system and promote bone health; (5) concomitantly increase potassium consumption while reducing sodium intake; (6) consider increasing the intake of foods rich in vitamins K1 and K2; (7) consider including bones in the diet; they are a rich source of calcium-hydroxyapatite and many other nutrients needed for building bone.

Milk protein intake has recently been suggested to improve metabolic health. This Perspective provides evidence that metabolic effects of milk protein intake have to be regarded in the context of the individual's pre-existing metabolic and exercise status. Milk proteins provide abundant branched-chain amino acids (BCAAs) and glutamine. Plasma BCAAs and glutamine are increased in obesity and insulin resistance, but decrease after gastric bypass surgery resulting in weight loss and improved insulin sensitivity. Milk protein consumption results in postprandial hyperinsulinemia in obese subjects, increases body weight of overweight adolescents and may thus deteriorate pre-existing metabolic disturbances of obese, insulin resistant individuals.

Dietary lipids may affect sperm membrane structure, fluidity and its susceptibility to oxidative phenomena which may lead to altered sperm viability and proper binding to eggs. Given the recently demonstrated beneficial effects of fish oil diets on turkey fertility and embryo viability, the aim of this study was to test a caviar-derived marine product on spermatogenesis and sperm quality. Sixty mice were divided into four different groups and fed for 3 weeks with normal chow (group A), added with LD-1227 at the dosage of either 5 mg/day (B1) or 10 mg/day (B2) while Group C received standard chow added with 10 mg of a DHA-rich mixture. At sacrifice tests/body weight ration and spermatogenesis was checked. No toxicity, histological sign or body or testes growth abnormality was noted, irrespective of the treatment. As compared to control, all supplements showed to increase sperm counting and motility although the effect of LD-1227 10 mg was significantly higher than DHA alone (p<0.05). Viability was improved by DHA (p<0.05) but not by low LD-1227 dosage while higher dosage performed better than DHA (p<0.05). Morphology was unaffected by any of the employed supplements. Taken altogether, these data suggest that LD-1227 has a remarkable effect on quali-quantitative parameters of spermiogenesis, some of them being more effective than high dosage DHA. These findings may prove to be of interest in clinical practice. (www.actabiomedica.it).

Alkylglycerols have shown immune stimulant and adjuvant activity in several studies and the aim of the present research was to assess in particular the effect of shark liver-derived alkylglycerols on gut immune system. C57BL/6 mice, fed under specific pathogen free conditions, were randomly divided into two groups: (a) fed normal laboratory food or (b) added with alkylglycerols (2 mg/day/mouse) for 3 weeks. Intraepithelial lymphocytes (IEL) were retrieved from the small intestine and tested for NK and tumor cytotoxicity. Lymphocytes from liver, spleen and IEL were also assessed as for their counting and phenotypic characterization. Under supplementation with alkylglycerols, the number of lymphocytes yielded by the small intestine increased by to almost 40%. Moreover, the ratio of CD8alphabeta+TCRalphabeta+ cells/CD8alphaalpha+TCRalphabeta+ cells remarkably increased. In parallel with this reshaping in the distribution of lymphocyte subsets, tumor cytotoxicity of IEL against P815 cells and cytokine production from circulating lymphocytes were also enhanced. These data show that phylogenetically developed lymphocytes (CD8alphabeta, TCRalphabeta+) were significantly activated by the oral administration of alkylglycerols. The present results indicate that purified alkylglycerols might have such significant potential via the enhancement of intestinal immunity, especially in the small intestine.