Functional efficacy of food components and non-nutrient bioactives. A case study: Phaseolus vulgaris L.

Healthy diet is generally believed to have a major influence on both the prevention and development of chronic non-communicable diseases like obesity, diabetes, cardiovascular events, cancer, and osteoporosis. Actually, most food-derived macro and micronutrients, as well as phytochemicals, are able to regulate key metabolic pathways and modulate oxidative stress and inflammatory signalling. Accordingly, interventions designed for healthy eating have become a hot topic in nutritional research and the intake of a number of food is nowadays highly recommended to get and maintain physical and mental health.1 The potential of pulses to address nutritional needs, for example, has been recently acknowledged by UN General Assembly, which declared 2016 International Year of Pulses. Although recognizing their important role in healthy diet, the full set of benefits that pulse crops can offer has not been fully characterized yet, and this results in an intriguing research opportunity. To raise awareness about the important role of pulses in healthy diets and their contribution to nutrition, we focused our attention on Phaseolus vulgaris L. (Zolfino Landraces), a small, pale yellow Tuscan bean coming from the very small mountainous region of Pratomagno, between the provinces of Arezzo and Florence.2,3 This particular variety of bean differs from the other ones for the high content of flavonoids, known for their antioxidant and chelating properties. However, it contains also a number of amphiphilic compounds, represented by saponins, whose functional activities have not been thoroughly studied yet. Being characterized by a rigid hydrophobic group, connected via glycoside bonds to hydrophilic oligosaccharide chain, these compounds are acknowledge as natural surfactants able to exert beneficial effects on blood cholesterol levels. However, investigated in depth, saponins proved also to modulate the activity of aldose reductase, a key enzyme of glucose metabolism involved in long term diabetic complications, thus opening up a novel nutritional claim for this kind of pulse

Synthetic analogues of flavonoids as novel prototypes of food supplements

Flavonoids are ubiquitous in fruits and vegetables and show many functional effects, resulting from their ability to modulate key molecular mechanisms related to cardiovascular diseases and some types of cancer. They are present in relatively high amounts in the diet of both European and American population and their intake is highly recommended for preventive health purposes. However, despite endowed with intriguing activities, flavonoids possess significant drawbacks. Actually, their functional effects occur at high, non-physiological concentrations, seldom reached in the circulation, and a clear evidence of the relationship between flavonoids consumption and health benefits still lacks. Moreover, their low solubility and stability, coupled with unfavourable pharmacokinetics properties and the ability to modulate additional and unrelated molecular targets, limit their exploitability either as food supplements or even as drug candidates. Nevertheless, they represent an excellent and logical source of inspiration for medicinal chemists, who may design synthetic analogues to achieve safer and more effective compounds. Prompted by these considerations, we developed a number of synthetic analogues of flavonoids, to obtain novel anti-oxidant, anti-inflammatory compounds as viable agents exploitable in the management of vascular dysfunctions. When tested at a concentration fully consistent with their use in vivo, our derivatives turned out to be more effective than well known flavonoids in modulating platelet reactivity and regulating key inflammatory events involved in the remodelling of vessel walls. Accordingly, they may represent novel prototypes of food supplements, exploitable to enrich the efficacy of natural flavonoids compounds

Unveiling heterogeneity: the pressing challenge to cancer diagnosis and therapy

Since the pioneering studies of Heppner and co-workers on mouse mammary cancer, the presence of heterogeneous phenotypes and genotypes within the cancer bulk has been clearly demonstrated in several types of malignancies. Different co-existing sub-populations, arising from both genetic and non-genetic variability and providing both heritable and non-heritable clones, give rise to an organized community in which not only cooperative but also conflicting interactions may set up. The resulting clonal crosstalk guarantees tumour growth, helping its spread through metastasis and the emergence of resistance to the commonly exploited anti-cancer treatments. Although aware of tumour heterogeneity, we are still far from understanding how different phenotypes and genotypes interact, thus allowing the whole community to survive therapeutic selection and/or suppression. This is why we failed so far to fine-tune a long-lasting, effective treatment for this kind of pathology. Accordingly, untangle tumour complexity is a basic and urgent challenge scientists should not work around anymore

Improving the Bioaccessibility and Bioavailability of Carotenoids by Means of Nanostructured Delivery Systems: A Comprehensive Review

Carotenoids are bioactive compounds provided by the diet playing a key role in maintaining human health. Therefore, they should be ingested daily in an adequate amount. However, even a varied and well-balanced diet does not guarantee an adequate intake, as both the bioaccessibility and bioavailability of the compounds significantly affect their absorption. This review summarizes the main results achieved in improving the bioaccessibility and bioavailability of carotenoids by means of nanostructured delivery systems, discussing in detail the available lipid-based and biopolymeric nanocarriers at present, with a focus on their formulation and functional efficiency. Although the toxicity profile of these innovative delivery systems is not fully understood, especially for long-term intake, these systems are an effective and valuable approach to increase the availability of compounds of nutritional interest

Improving the Bioaccessibility and Bioavailability of Carotenoids by Means of Nanostructured Delivery Systems: A Comprehensive Review

Carotenoids are bioactive compounds provided by the diet playing a key role in maintaining human health. Therefore, they should be ingested daily in an adequate amount. However, even a varied and well-balanced diet does not guarantee an adequate intake, as both the bioaccessibility and bioavailability of the compounds significantly affect their absorption. This review summarizes the main results achieved in improving the bioaccessibility and bioavailability of carotenoids by means of nanostructured delivery systems, discussing in detail the available lipid-based and biopolymeric nanocarriers at present, with a focus on their formulation and functional efficiency. Although the toxicity profile of these innovative delivery systems is not fully understood, especially for long-term intake, these systems are an effective and valuable approach to increase the availability of compounds of nutritional interest

Hemp (Cannabis sativa L.) flour: an active ingredient for the formulation of nutritious, flavorful and affordable foods.

Hemp (Cannabis sativa L.) flour is obtained as a byproduct of hemp oil processing. Considered so far a food waste, it represents a significant source of nutritionally relevant compounds. Actually, besides being high in fibres and micronutrients, hemp flour is characterized by a peculiar protein content, devoid of prolamins, which allows it to be tolerated by people who suffer from celiac disease or by those who are sensitive to gluten. Moreover, the lipid profile includes high and well-balanced omega-6 and omega-3 fatty acids and the calorie content is lower if compared to the more refined wheat flour. Significantly, hemp flour is high in polyphenolic compounds, which provide the product with a relevant anti-oxidant efficacy. Altogether, the chemical composition makes this flour a well balance ingredient having the potential to be used as an active component for the formulation of foods

N-(aroyl)-N-(arylmethyloxy)-α-alanines: selective inhibitors of aldose reductase

Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications

Synthesis and functional evaluation of novel aldose reductase inhibitors bearing a spirobenzopyran scaffold

Background: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. Objectives: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. Results: Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. Conclusion: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs

A 2,3-diphenylpyrido[1,2-a] pyrimidin-4-one derivative inhibits specific angiogenic factors induced by TNF-\u3b1

Low-grade chronic inflammation is a key process of angiogenesis in tumour progression. We investigated whether a synthetic analogue of apigenin, the 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one (called DB103), interfered with the mechanisms involved in the angiogenic process induced by the inflammatory cytokine tumour necrosis factor (TNF\u3b1). In endothelial cells, DB103 but not apigenin reduced the TNF\u3b1-induced oxidative stress. DB103 inhibited the activation of ERK1/2 but not JNK, p38 and Akt kinases, while apigenin was not so selective because it inhibited essentially all examined kinases. Similarly, apigenin inhibited the TNF\u3b1-induced transcription factors CREB, STAT3, STAT5 and NF-kB, while DB103 acted only on NFinhibited the induced-release of angiogenic factors such as monocyte chemotactic protein-1, interleukin-6 (IL-6) and angiopoietin-2 but not IL-8, while apigenin reduced the IL-6 and IL-8 release. DB103 revealed a better ability than apigenin to modulate proangiogenic responses induced by an inflammatory microenvironment

INDOLE AMIDE DERIVATIVES: SYNTHESIS, STUCTURE-ACTIVITY RELATIONSHIPS AND MOLECULAR MODELLING STUDIES OF A NEW SERIES OF HISTAMINE H1-RECEPTOR ANTAGONISTS.

A number of indole amide derivatives bearing a basic side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well-known antihistamines, were prepared and tested for their H1-antihistaminic activity. The 1-benzyl-3-indolecarboxamides 32–42 showed antihistaminic (H1) activity (pA2 6–8); the 3-indolylglyoxylylamides 7–16 and the 2-indolecarboxamides 48–56 showed little or no activity. Insertion of the basic side chain of the active 3-indolecarboxamide derivatives into a piperazine ring (compounds 57–59) led to a dramatic loss of activity. All the active compounds proved to be competitive antagonists, since the values of the regression slope were not statistically different from 1. The most active compounds, 32, 33, 38–41, were also tested both in vitro for their anticholinergic activity and in vivo for their ability to antagonize histamine-induced cutaneous vascular permeability in rats. The biological results and the structure–activity relationships of the novel compounds are discussed in the light of molecular modelling studies, taking the molecule of astemizole as a model, and referring to proposed H1-receptor pharmacophore model