Nutraceutical-based Integrative Medicine: Adopting a Mediterranean Diet Pyramid for Attaining Healthy Ageing in Veterans with Disabilities.

Veterans with disability represent a big burden worldwide and often require long-term rehabilitation. Unhealthy dietary and lifestyle habits, including smoke and alcohol abuse, are common in veterans. In the context of integrative medicine approaches, the "complementary and alternative medicine" has been suggested for the management of chronic diseases. However, the potential risk of interaction between herbal products, dietary supplements and drugs must be considered in veterans. The Mediterranean diet has been suggested as a natural, non-pharmacological nutraceutical for healthy ageing. Although there is a broad consensus on the positive effect of plant foods consumption, the presence of glucosinolates, flavonoids and furanocoumarins in some plant foods and beverages must be taken into consideration owing to their potential interfering with drugs metabolism and bioavailability. Albeit seasonality could ensure the maintenance of the single dose of phytochemical below that at which adverse effects in some individuals genetically predisposed or unpleasant drug interactions in diseased subjects can occur, a personalized nutrition is recommended in veterans who are under treatment for comorbidities. Furthermore, sports practice can lead veterans with motor disabilities and mental impairments to excel in some disciplines, giving rise to the phenomenon of the Paralympics and the development of "recreational therapy". Moreover, outdoor lifestyle, through vitamin D synthesis, and conviviality, improving socialization, could account for the Mediterranean lifestyle health benefits. In this work, we propose for veterans a Mediterranean Pyramid, which could be the basis for integrative medicine for veterans with disabilities, patient-centered approaches and interprofessional (including physical medicine and rehabilitation clinicians, pharmacists and nutritionists) interventions.

Non-Provitamin A and Provitamin A Carotenoids as Immunomodulators: Recommended Dietary Allowance, Therapeutic Index, or Personalized Nutrition?

Vegetables and fruits contain non-provitamin A (lycopene, lutein, and zeaxanthin) and provitamin A (ß-carotene, ß-cryptoxanthin, and α-carotene) carotenoids. Within these compounds, ß-carotene has been extensively studied for its health benefits, but its supplementation at doses higher than recommended intakes induces adverse effects. ß-Carotene is converted to retinoic acid (RA), a well-known immunomodulatory molecule. Human interventions suggest that ß-carotene and lycopene at pharmacological doses affect immune functions after a depletion period of low carotenoid diet. However, these effects appear unrelated to carotenoids and retinol levels in plasma. Local production of RA in the gut-associated lymphoid tissue, as well as the dependency of RA-induced effects on local inflammation, suggests that personalized nutrition/supplementation should be considered in the future. On the other hand, the differential effect of RA and lycopene on transforming growth factor-beta suggests that lycopene supplementation could improve immune functions without increasing risk for cancers. However, such preclinical evidence must be confirmed in human interventions before any recommendations can be made.

Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe?

Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP.

Camellia sinensis in asymptomatic hyperuricemia: A meta-analysis of tea or tea extract effects on uric acid levels.

Flavanols of Camellia sinensis exhibit uric acid (UA) lowering effect, through the modulation of both xanthine oxidase and urate excretion. In order to investigate the potential benefit of Camellia Sinenis products in asymptomatic hyperuricemia, a meta-analysis of long-term Randomized Controlled Trials (RCT) with tea or tea extract has been conducted. From 20 human intervention studies selected only 5 RCT (13 interventions) were suitable for meta-analysis (n = 472). The current "normal" range set for hyperuricemia fails to identify patients with potential metabolic disorders. Therefore on the basis of the literature data, we fixed cut-off limits for UA baseline levels of 4.5 mg/dl for women, 6.1 mg/dl for men, and 5.5 mg/dl for studies involving mixed populations. Statistically significant effects were not found, but subgroup analysis revealed that the Pooled Estimate effect was different in subjects with baseline levels under [MD (95% CI): 0.1078 (-0.0528 to 0.2684)] and over the cut-off [MD (95% CI): -0.0239 (0.3311 to 0.2833)]. However, due to the low number of RCT and to the lack of data on bioavailability, it is difficult to draw any firm conclusion and more studies are needed to establish if tea flavanols could be useful in asymptomatic hyperuricemia treatment.

Green Tea and Bone Marrow Transplantation: From Antioxidant Activity to Enzymatic and Multidrug-resistance Modulation.

Epigallocatechin-3-gallate (EGCG), the main flavonoid of green tea (GT), could play an active role in the prevention of oxidative-stress-related diseases, such as hematologic malignancies. Some effects of EGCG are not imputable to antioxidant activity, but involve modulation of antioxidant enzymes and uric acid (UA) levels. The latter is the major factor responsible of the plasma non-enzymatic antioxidant capacity (NEAC). However, hyperuricemia is a frequent clinical feature caused by tumor lysis syndrome or cyclosporine side effects, both before and after bone marrow transplantation (BMT). Besides this, food-drug interactions could be associated with GT consumption and could have clinical implications. The molecular mechanisms involved in the redox and drug metabolizing/transporting pathways were discussed, with particular reference to the potential role of GT and EGCG in BMT. Moreover, on reviewing data on NEAC, isoprostanes, uric acid, and various enzymes from human studies on GT, its extract, or EGCG, an increase in NEAC, without effect on isoprostanes, and contrasting results on UA and enzymes were observed. Currently, few and contrasting available evidences suggest caution for GT consumption in BMT patients and more studies are needed to better understand the potential impact of EGCG on oxidative stress and metabolizing/transporting systems.

The Peroxidation of Leukocytes Index Ratio Reveals the Prooxidant Effect of Green Tea Extract.

Despite tea increased plasma nonenzymatic antioxidant capacity, the European Food Safety Administration (EFSA) denied claims related to tea and its protection from oxidative damage. Furthermore, the Supplement Information Expert Committee (DSI EC) expressed some doubts on the safety of green tea extract (GTE). We performed a pilot study in order to evaluate the effect of a single dose of two capsules of a GTE supplement (200 mg × 2) on the peroxidation of leukocytes index ratio (PLIR) in relation to uric acid (UA) and ferric reducing antioxidant potential (FRAP), as well as the sample size to reach statistical significance. GTE induced a prooxidant effect on leukocytes, whereas FRAP did not change, in agreement with the EFSA and the DSI EC conclusions. Besides, our results confirm the primary role of UA in the antioxidant defences. The ratio based calculation of the PLIR reduced the sample size to reach statistical significance, compared to the resistance to an exogenous oxidative stress and to the functional capacity of oxidative burst. Therefore, PLIR could be a sensitive marker of redox status.

Investigation of the effects of vitamin D and calcium on intestinal motility: In vitro tests and implications for clinical treatment.

The presence of vitamin D receptors in small intestine muscle cells may lead one to think that vitamin D may act locally, influencing intracellular calcium concentration and contributing to the contraction-relaxation regulation of the intestinal smooth muscle cells. This study investigates the potential effects of vitamin D and calcium on intestinal motility using an in vitro test. Different calcium concentrations added to the tissue not pre-treated with 1,25-dihydroxycholecalciferol [1α,25(OH)2D3] produced no response at low doses (1.25 × 10-3 and 2.0 × 10-3 mol L-1) and only a very weak response at higher concentration (3.0 × 10-3 mol L-1). The addition of 1α,25(OH)2D3 (1.44 × 10-10 mol L-1) had no effect on isolated ileum motility. When calcium (3.0 × 10-3 mol L-1) was added after at least 3 hours, it evoked evident and persistent contractions for 60-90 minutes. The contractions were at about 40 % of the peak produced by acetylcholine. Thus, simultaneous intake of vitamin D and calcium might be a useful co-adjuvant in intestinal atony therapy aimed to stimulate normal gut motility in humans. These findings imply that supplemental vitamin D may be important in all cases where calcium has to be prescribed.

Association of flavonoid-rich foods and statins in the management of hypercholesterolemia: a dangerous or helpful combination?

Statins and dietary modifications are the cornerstone of hypercholesterolemia management. Although it is well known that possible adverse effect of statins can occur due to drug-drug interactions, food-drug interactions are a commonly overlooked aspect. In particular, flavonoids could interfere with statins' bioavailability through different mechanisms, such as competition with cytochrome P450 (CYP) enzymes, esterases, uridine diphosphate glucuronosyltransferases and transporters (P-glycoprotein, multi-drug resistance-associated proteins, organic anion transporting polypeptides, breast cancer-resistance protein and monocarboxylate transporters). Transporters are characterized by low substrate specificity and flavonoid- rich foods could interfere with the bioavailability of all statins at this level. On the other hand, in addition to being substrates of drug metabolism/ transport systems, flavonoids are also able to modulate gene expression of enzymes and transporters. Therefore, long-term transcriptional induction may increase the clearance of statins, despite flavonoids act as competitive inhibitors after bolus consumption. In humans, major interactions were observed between grapefruit juice and statins that are substrates of P-glycoprotein/CYP3A, but other fruit juices also affect the bioavailability of statins that are not metabolised by CYP. Even if flavonoids could play a role in the prevention of hypercholesterolemia, the question whether there's a helpful or dangerous association between flavonoid-rich foods and statins, due to the interactions between flavonoid-rich foods and statins and the potential associated adverse effects of statins, remain unanswered. Therefore, the anamnesis of patients must include detailed information about their eating habits and the present review suggests monitoring and reporting any possible case of interaction between a prescribed statin and food.

Effect of cocoa products and flavanols on platelet aggregation in humans: a systematic review.

Previous evidence suggested an active role of cocoa products and flavanols in modulating platelet aggregation. However, cocoa flavanols are characterized by a low bioavailability that can deeply affect their presence in biological fluids and raise questions on their biological effect in humans. We performed a systematic search on Medline, Embase, Cochrane and ProQuest databases, until April 2015, on the effect of cocoa products on platelet aggregation in human intervention studies. We identified 13 interventions, of which only five involved repeated administration. Different effects were observed on the basis of the platelet aggregation test used, whereas neither a longer duration of treatment nor a higher dose was associated with a higher inhibition of platelet aggregation. In conclusion, the reviewed results suggest that consumption of cocoa products in bolus administration positively affects platelet aggregation in both healthy subjects and diseased patients. On the other hand, more evidence is required in order to assess the effect of long-term cocoa product ingestion and to identify the bioactive components involved.

Flavonoids at the pharma-nutrition interface: Is a therapeutic index in demand?

The consumption of flavonoid-rich foods could have beneficial effects on health. However, different classes of flavonoids have different effect on disease risk and the relationship between flavonoid intake and risk of disease appeared to be non-linear. Furthermore, contrarily to vitamins, there are no symptoms of deficiency for flavonoids; therefore, our body treats them like other xenobiotics. Therefore, a therapeutic index should be determined. Despite flavonoids are at the pharma-nutrition interface, drugs and foods are subject to different regulatory frameworks and there is no recommended daily allowance (RDA) for flavonoids. Relatively little is known about the efficacy, safety and underlying mechanisms of these bioactive compounds, especially when taken in concert with drugs. Flavonoids could act both as drugs and pro-drugs with pharmacological and toxicological promiscuity. Due to the low bioavailability, the gastrointestinal tract could be the primary target of flavonoids and metabolites. Different effects have been observed after acute and chronic consumption and bioavailability and bioactivity have high inter-individual variability. Furthermore, the difficulties in the design and in the interpretation of human intervention studies make difficult the establishment of a therapeutic index for flavonoids. Probably the concept of 'personalized nutrition' previously proposed could be the better approach. However, despite more studies are needed in order to establish a therapeutic index for each flavonoid subclasses, at the moment RDA of total flavonoids could be between 250-400 mg/d, respecting the seasonality of food sources.

Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention?

The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment.

In vitro relaxant and spasmolytic effects of constituents from Viburnum prunifolium and HPLC quantification of the bioactive isolated iridoids.

ETHNOPHARMACOLOGICAL RELEVANCE: Viburnum prunifolium is a North America shrub used in ethnomedicine because of its spasmolytic, sedative, and anti-asthmatic properties. AIM OF THE STUDY: Contrasting results were reported in past literature about the active principles of this plant. Our aim was to clarify this matter by evaluating the relaxant and spasmolytic activities of the main constituents obtained from the drug. MATERIALS AND METHODS: The pharmacological assays were carried out on rabbit jejunum spontaneous contractions and on guinea-pig carbachol-precontracted trachea. RESULTS: Cumulative concentration (1-100 microg/ml) of Viburnum prunifolium methanolic extract (MeOH extract), its purified fractions soluble in ethylacetate (EtOAc fraction) and in n-butanol (BuOH fraction), and the iridoid glucosides (2 x 10(-5) to 4 x 10(-4)M): 2'-O-acetyldihydropenstemide (1), 2'-O-trans-p-coumaroyldihydropenstemide (2), 2'-O-acetylpatrinoside (3), and patrinoside (4), isolated from EtOAc fraction (1 and 2) and BuOH fraction (3 and 4), induced both relaxant effect of rabbit jejunum spontaneous contractions and spasmolytic effect on guinea-pig carbachol (5.5 x 10(-7)M)-precontracted trachea. Propranolol (10(-6)M) antagonised all Viburnum prunifolium tested components relaxant and spasmolytic effects. At non-relaxing concentrations (0.5 microg/ml), MeOH extract and its fractions induced a potentiating effect of isoprenaline cumulative concentrations also in both isolated tissues. CONCLUSION: In both tissues, the order of potency was EtOAc fraction>BuOH fraction>MeOH extract and 1>2>3>4 suggesting that the major iridoids of EtOAc fraction may be considered among the most active compounds. HPLC analysis of the bioactive iridoids indicates that 1 and 2 are present for 7.38% and 14.90% in EtOAc fraction, and 3 and 4 for 18.47% and 8.86% in BuOH fraction. By comparing the values of EC(50) of the fractions and compounds isolated from them, we may assume that the iridoids play a significant role in the biological activity of the corresponding fractions.