Mediterranean Diet Adherence and Its Relationship to Metabolic Markers and Body Composition in Portuguese University Students.

BACKGROUND: Transitioning to university involves several changes, which might affect dietary habits. The present study aimed to assess the potential relationships involving adherence to the MedDiet, body composition, and metabolic markers within a Portuguese university sample. METHODS: A cross-sectional study involved 70 participants, 52 women, and 18 men (23.00 ± 7.00 years old and a BMI of 21.99 ± 2.79 kg/m2). The average MedDiet adherence of participants was 9.23 points, as evaluated by the 14 point validated questionnaire, with classifications of low and high (under or over 9 points, respectively). Body composition was assessed using X-ray dual densitometry (DXA), and metabolic markers were collected from capillary blood. RESULTS: Statistically significant differences in HDL cholesterol and the total/HDL cholesterol ratio were found between groups. Lower levels (p < 0.05) of visceral (VAT) and subcutaneous adipose tissue (SAT), BMI, and waist circumference were found in the higher MedDiet adherence group. Those measures were negatively correlated (p < 0.05) with the adherence scores to the MedDiet. CONCLUSION: Higher adherence to MedDiet seemed to have a favorable and important impact on lipid profiles, primarily HDL-c. A positive relationship between MedDiet adherence and body composition distribution was also described, mostly due to the influence of higher adherence to MedDiet at lower levels of VAT and SAT in Portuguese university students.

Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

The (Poly)phenol-Carbohydrate Combination for Diabetes: Where Do We Stand?

The type 2 diabetes epidemic is real and hardly coming to an end in the upcoming years. The efforts of the scientific community to develop safer and more effective compounds for type 2 diabetes based on the structure of natural (poly)phenols are remarkable and have indeed proven worthwhile after the introduction of gliflozins in clinical practice. However, low-quality reports on the antidiabetic potential of plant-derived lipophilic (poly)phenols continue to pile up in the literature. Many of these compounds continue to be published as promising functional nutrients and antidiabetic pharmaceutical leads without consideration of their Pan-Assay Interference Compounds (PAINS) profile. This evidence-based opinion article conveys the authors' perspectives on the natural (poly)phenol artillery as a valuable and reliable source of bioactive compounds for diabetes. Ultimately, in light of the already established membrane-perturbing behavior of lipophilic (poly)phenols, together with the multiple benefits that may come with the introduction of a C-glucosyl moiety in bioactive compounds, we aim to raise awareness of the importance of contemplating the shift to (poly)phenol-carbohydrate combinations in the development of functional nutrients, as well as in the early stages of antidiabetic drug discovery.

RNA Aptamer-functionalized Polymeric Nanoparticles in Targeted Delivery and Cancer Therapy: An up-to-date Review.

Cancer nanotechnology takes advantage of nanoparticles to diagnose and treat cancer. The use of natural and synthetic polymers for drug delivery has become increasingly popular. Polymeric nanoparticles (PNPs) can be loaded with chemotherapeutics, small chemicals, and/or biological therapeutics. Major problems in delivering such therapeutics to the desired targets are associated with the lack of specificity and the low capacity of PNPs to cross cell membranes, which seems to be even more difficult to overcome in multidrugresistant cancer cells with rigid lipid bilayers. Despite the progress of these nanocarrier delivery systems (NDSs), active targeting approaches to complement the enhanced permeability and retention (EPR) effect are necessary to improve their therapeutic efficiency and reduce systemic toxicity. For this, a targeting moiety is required to deliver the nanocarrier systems to a specific location. A strategy to overcome these limitations and raise the uptake of PNPs is the conjugation with RNA aptamers (RNApt) with specificity for cancer cells. The site-directed delivery of drugs is made by the functionalization of these specific ligands on the NDSs surface, thereby creating specificity for features of cancer cell membranes or an overexpressed target/receptor exposed to those cells. Despite the advances in the field, NDSs development and functionalization are still in their early stages and numerous challenges are expected to impact the technology. Thus, RNApt supplies a promising reply to the common problem related to drug delivery by NDSs. This review summarizes the current knowledge on the use of RNApt to generate functionalized PNPs for cancer therapy, discussing the most relevant studies in the area.

Updated Information of the Effects of (Poly)phenols against Type-2 Diabetes Mellitus in Humans: Reinforcing the Recommendations for Future Research.

(Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols.

Polyphenols and Their Metabolites in Renal Diseases: An Overview.

Kidney diseases constitute a worldwide public health problem, contributing to morbidity and mortality. The present study aimed to provide an overview of the published data regarding the potential beneficial effects of polyphenols on major kidney diseases, namely acute kidney injury, chronic kidney disease, diabetic nephropathy, renal cancer, and drug-induced nephrotoxicity. This study consists of a bibliographical review including in vitro and in vivo studies dealing with the effects of individual compounds. An analysis of the polyphenol metabolome in human urine was also conducted to estimate those compounds that are most likely to be responsible for the kidney protective effects of polyphenols. The biological effects of polyphenols can be highly attributed to the modulation of specific signaling cascades including those involved in oxidative stress responses, anti-inflammation processes, and apoptosis. There is increasing evidence that polyphenols afford great potential in renal disease protection. However, this evidence (especially when in vitro studies are involved) should be considered with caution before its clinical translation, particularly due to the unfavorable pharmacokinetics and extensive metabolization that polyphenols undergo in the human body. Future research should consider polyphenols and their metabolites that indeed reach kidney tissues.

Urolithin B: Two-way attack on IAPP proteotoxicity with implications for diabetes.

Introduction: Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (IAPP), or amylin, is a recognized histopathological marker of the disease. Although IAPP proteotoxicity represents an important trigger of ß-cell dysfunction and ultimately death, its exploitation as a therapeutic tool remains underdeveloped. The bioactivity of (poly)phenols towards inhibition of pathological protein aggregation is well known, however, most of the identified molecules have limited bioavailability. Methods: Using a strategy combining in silico, cell-free and cell studies, we scrutinized a unique in-house collection of (poly)phenol metabolites predicted to appear in the human circulation after (poly)phenols ingestion. Results: We identified urolithin B as a potent inhibitor of IAPP aggregation and a powerful modulator of cell homeostasis pathways. Urolithin B was shown to affect IAPP aggregation pattern, delaying the formation of amyloid fibrils and altering their size and morphology. The molecular mechanisms underlying urolithin B-mediated protection include protein clearance pathways, mitochondrial function, and cell cycle ultimately rescuing IAPP-mediated cell dysfunction and death. Discussion: In brief, our study uncovered urolithin B as a novel small molecule targeting IAPP pathological aggregation with potential to be exploited as a therapeutic tool for mitigating cellular dysfunction in diabetes. Resulting from the colonic metabolism of dietary ellagic acid in the human body, urolithin B bioactivity has the potential to be explored in nutritional, nutraceutical, and pharmacological perspectives.

Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes.

Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.

Rice Compounds with Impact on Diabetes Control.

Rice is one of the most cultivated and consumed cereals worldwide. It is composed of starch, which is an important source of diet energy, hypoallergenic proteins, and other bioactive compounds with known nutritional functionalities. Noteworthy is that the rice bran (outer layer of rice grains), a side-stream product of the rice milling process, has a higher content of bioactive compounds than white rice (polished rice grains). Bran functional ingredients such as γ-oryzanol, phytic acid, ferulic acid, γ-aminobutyric acid, tocopherols, and tocotrienols (vitamin E) have been linked to several health benefits. In this study, we reviewed the effects of rice glycemic index, macronutrients, and bioactive compounds on the pathological mechanisms associated with diabetes, identifying the rice compounds potentially exerting protective activities towards disease control. The effects of starch, proteins, and bran bioactive compounds for diabetic control were reviewed and provide important insights about the nutritional quality of rice-based foods.

Overview of Beneficial Effects of (Poly)phenol Metabolites in the Context of Neurodegenerative Diseases on Model Organisms.

The rise of neurodegenerative diseases in an aging population is an increasing problem of health, social and economic consequences. Epidemiological and intervention studies have demonstrated that diets rich in (poly)phenols can have potent health benefits on cognitive decline and neurodegenerative diseases. Meanwhile, the role of gut microbiota is ever more evident in modulating the catabolism of (poly)phenols to dozens of low molecular weight (poly)phenol metabolites that have been identified in plasma and urine. These metabolites can reach circulation in higher concentrations than parent (poly)phenols and persist for longer periods of time. However, studies addressing their potential brain effects are still lacking. In this review, we will discuss different model organisms that have been used to study how low molecular weight (poly)phenol metabolites affect neuronal related mechanisms gathering critical insight on their potential to tackle the major hallmarks of neurodegeneration.

Small Molecule Fisetin Modulates Alpha-Synuclein Aggregation.

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.

Supercritical CO2 Extraction as a Tool to Isolate Anti-Inflammatory Sesquiterpene Lactones from Cichorium intybus L. Roots.

Cichorium intybus L. or chicory plants are a natural source of health-promoting compounds in the form of supplements such as inulin, as well as other bioactive compounds such as sesquiterpene lactones (SLs). After inulin extraction, chicory roots are considered waste, with most SLs not being harnessed. We developed and optimized a new strategy for SL extraction that can contribute to the conversion of chicory root waste into valuable products to be used in human health-promoting applications. In our work, rich fractions of SLs were recovered from chicory roots using supercritical CO2. A response surface methodology was used to optimize the process parameters (pressure, temperature, flow rate, and co-solvent percentage) for the extraction performance. The best operating conditions were achieved at 350 bar, 40 °C, and 10% EtOH as a co-solvent in a 15 g/min flow rate for 120 min. The extraction with supercritical CO2 revealed to be more selective for the SLs than the conventional solid-liquid extraction with ethyl acetate. In our work, 1.68% mass and a 0.09% sesquiterpenes yield extraction were obtained, including the recovery of two sesquiterpene lactones (8-deoxylactucin and 11ß,13-dihydro-8-deoxylactucin), which, to the best of our knowledge, are not commercially available. A mixture of the abovementioned compounds were tested at different concentrations for their toxic profile and anti-inflammatory potential towards a human calcineurin/NFAT orthologue pathway in a yeast model, the calcineurin/Crz1 pathway. The SFE extract obtained, rich in SLs, yielded results of inhibition of 61.74 ± 6.87% with 50 µg/mL, and the purified fraction containing 8-deoxylactucin and 11ß,13-dihydro-8-deoxylactucin inhibited the activation of the reporter gene up to 53.38 ± 3.9% at 10 µg/mL. The potential activity of the purified fraction was also validated by the ability to inhibit Crz1 nuclear translocation and accumulation. These results reveal a possible exploitable green technology to recover potential anti-inflammatory compounds from chicory roots waste after inulin extraction.

Islet amyloid polypeptide & amyloid beta peptide roles in Alzheimer's disease: two triggers, one disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide. Due to population ageing, the incidence of AD is increasing. AD patients develop cognitive decline and dementia, features for which is known, requiring permanent care. This poses a major socio-economic burden on healthcare systems as AD patients' relatives and healthcare workers are forced to cope with rising numbers of affected people. Despite recent advances, AD pathological mechanisms are not fully understood. Nevertheless, it is clear that the amyloid beta (Aß) peptide, which forms amyloid plaques in AD patients' brains, plays a key role. Type 2 diabetes, the most common form of diabetes, affects hundreds of million people globally. Islet amyloid polypeptide (IAPP) is a hormone co-produced and secreted with insulin in pancreatic ß-cells, with a key role in diabetes, as it helps regulate glucose levels and control adiposity and satiation. Similarly to Aß, IAPP is very amyloidogenic, generating intracellular amyloid deposits that cause ß-cell dysfunction and death. It is now clear that IAPP can also have a pathological role in AD, decreasing cognitive function. IAPP harms the blood-brain barrier, directly interacts and co-deposits with Aß, promoting diabetes-associated dementia. IAPP can cause a metabolic dysfunction in the brain, leading to other diabetes-related forms of AD. Thus, here we discuss IAPP association with diabetes, Aß and dementia, in the context of what we designate a "diabetes brain phenotype" AD hypothesis. Such approach helps to set a conceptual framework for future IAPP-based drugs against AD.

Assessing the Intestinal Permeability and Anti-Inflammatory Potential of Sesquiterpene Lactones from Chicory.

Cichorium intybus L. has recently gained major attention due to large quantities of health-promoting compounds in its roots, such as inulin and sesquiterpene lactones (SLs). Chicory is the main dietary source of SLs, which have underexplored bioactive potential. In this study, we assessed the capacity of SLs to permeate the intestinal barrier to become physiologically available, using in silico predictions and in vitro studies with the well-established cell model of the human intestinal mucosa (differentiated Caco-2 cells). The potential of SLs to modulate inflammatory responses through modulation of the nuclear factor of activated T-cells (NFAT) pathway was also evaluated, using a yeast reporter system. Lactucopicrin was revealed as the most permeable chicory SL in the intestinal barrier model, but it had low anti-inflammatory potential. The SL with the highest anti-inflammatory potential was 11ß,13-dihydrolactucin, which inhibited up to 54% of Calcineurin-responsive zinc finger (Crz1) activation, concomitantly with the impairment of the nuclear accumulation of Crz1, the yeast orthologue of human NFAT.

Heterologous Expression of Immature Forms of Human Islet Amyloid Polypeptide in Yeast Triggers Intracellular Aggregation and Cytotoxicity.

Diabetes is a major public health issue that has attained alarming levels worldwide. Pancreatic aggregates of human islet amyloid polypeptide (IAPP) represent a major histopathological hallmark of type 2 diabetes. IAPP is expressed in ß-cells as pre-pro-IAPP (ppIAPP) that is first processed to pro-IAPP (pIAPP) and finally to its mature form (matIAPP), being released upon glucose stimulation together with insulin. Impairment and overload of the IAPP processing machinery seem to be associated with the accumulation of immature IAPP species and the formation of toxic intracellular oligomers, which have been associated with ß-cell dyshomeostasis and apoptosis. Nevertheless, the pathological importance of these immature IAPP forms for the assembly and cytotoxicity of these oligomers is not completely understood. Here, we describe the generation and characterization of unprecedented Saccharomyces cerevisiae models recapitulating IAPP intracellular oligomerization. Expression of green fluorescent protein (GFP) fusions of human ppIAPP, pIAPP, and matIAPP proved to be toxic in yeast cells at different extents, with ppIAPP exerting the most deleterious effect on yeast growth and cell viability. Although expression of all IAPP constructs induced the formation of intracellular aggregates in yeast cells, our data point out the accumulation of insoluble oligomeric species enriched in immature ppIAPP as the trigger of the high toxicity mediated by this construct in cells expressing ppIAPP-GFP. In addition, MS/MS analysis indicated that oligomeric species found in the ppIAPP-GFP lysates contain the N-terminal sequence of the propeptide fused to GFP. These models represent powerful tools for future research focused on the relevance of immature forms in IAPP-induced toxicity. Furthermore, they are extremely useful in high-throughput screenings for genetic and chemical modulators of IAPP aggregation.

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases.

Plants are a reservoir of high-value molecules with underexplored biomedical applications. With the aim of identifying novel health-promoting attributes in underexplored natural sources, we scrutinized the diversity of (poly)phenols present within the berries of selected germplasm from cultivated, wild, and underutilized Rubus species. Our strategy combined the application of metabolomics, statistical analysis, and evaluation of (poly)phenols' bioactivity using a yeast-based discovery platform. We identified species as sources of (poly)phenols interfering with pathological processes associated with redox-related diseases, particularly, amyotrophic lateral sclerosis, cancer, and inflammation. In silico prediction of putative bioactives suggested cyanidin-hexoside as an anti-inflammatory molecule which was validated in yeast and mammalian cells. Moreover, cellular assays revealed that the cyanidin moiety was responsible for the anti-inflammatory properties of cyanidin-hexoside. Our findings unveiled novel (poly)phenolic bioactivities and illustrated the power of our integrative approach for the identification of dietary (poly)phenols with potential biomedical applications.

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases.

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A-D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13Δ mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13Δ cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure-activity relationship and molecular mechanisms underlying the action of luteolin were characterized. The FET4 gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13Δ, pointing out the importance of iron in response to SDS stress. The growth defect of vps13Δ in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13Δ may help to better understand VPS13A-D-dependent pathogenesis and to develop novel therapeutic strategies.

Islet Amyloid Polypeptide: A Partner in Crime With Aß in the Pathology of Alzheimer's Disease.

Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, is a hormone produced by pancreatic ß-cells. It contributes to the maintenance of glucose physiological levels namely by inhibiting insulin and glucagon secretion as well as controlling adiposity and satiation. IAPP is a highly amyloidogenic polypeptide forming intracellular aggregates and amyloid structures that are associated with ß-cell death. Data also suggest the relevance of unprocessed IAPP forms as seeding for amyloid buildup. Besides the known consequences of hyperamylinemia in the pancreas, evidence has also pointed out that IAPP has a pathological role in cognitive function. More specifically, IAPP was shown to impair the blood-brain barrier; it was also seen to interact and co-deposit with amyloid beta peptide (Aß), and possibly with Tau, within the brain of Alzheimer's disease (AD) patients, thereby contributing to diabetes-associated dementia. In fact, it has been suggested that AD results from a metabolic dysfunction in the brain, leading to its proposed designation as type 3 diabetes. Here, we have first provided a brief perspective on the IAPP amyloidogenic process and its role in diabetes and AD. We have then discussed the potential interventions for modulating IAPP proteotoxicity that can be explored for therapeutics. Finally, we have proposed the concept of a "diabetes brain phenotype" hypothesis in AD, which may help design future IAPP-centered drug developmentstrategies against AD.

Combined effect of interventions with pure or enriched mixtures of (poly)phenols and anti-diabetic medication in type 2 diabetes management: a meta-analysis of randomized controlled human trials.

PURPOSE: (Poly)phenols have been reported to confer protective effects against type 2 diabetes but the precise association remains elusive. This meta-analysis aimed to assess the effects of (poly)phenol intake on well-established biomarkers in people with type 2 diabetes or at risk of developing diabetes. METHODS: A systematic search was conducted using the following selection criteria: (1) human randomized controlled trials involving individuals with prediabetes and type 2 diabetes; (2) one or more of the following biomarkers: glucose, glycated haemoglobin (HbA1c), insulin, pro-insulin, homeostatic model assessment of insulin resistance (HOMA-IR), islet amyloid polypeptide (IAPP)/amylin, pro-IAPP/pro-amylin, glucagon, C-peptide; (3) chronic intervention with pure or enriched mixtures of (poly)phenols. From 488 references, 88 were assessed for eligibility; data were extracted from 27 studies and 20 were used for meta-analysis. The groups included in the meta-analysis were: (poly)phenol mixtures, isoflavones, flavanols, anthocyanins and resveratrol. RESULTS: Estimated intervention/control mean differences evidenced that, overall, the consumption of (poly)phenols contributed to reduced fasting glucose levels (- 3.32 mg/dL; 95% CI - 5.86, - 0.77; P = 0.011). Hb1Ac was only slightly reduced (- 0.24%; 95% CI - 0.43, - 0.044; P = 0.016) whereas the levels of insulin and HOMA-IR were not altered. Subgroup comparative analyses indicated a stronger effect on blood glucose in individuals with diabetes (- 5.86 mg/dL, 95% CI - 11.34, - 0.39; P = 0.036) and this effect was even stronger in individuals taking anti-diabetic medication (- 10.17 mg/dL, 95% CI - 16.59, - 3.75; P = 0.002). CONCLUSIONS: Our results support that the consumption of (poly)phenols may contribute to lower glucose levels in individuals with type 2 diabetes or at risk of diabetes and that these compounds may also act in combination with anti-diabetic drugs.

RNA-seq, de novo transcriptome assembly and flavonoid gene analysis in 13 wild and cultivated berry fruit species with high content of phenolics.

BACKGROUND: Flavonoids are produced in all flowering plants in a wide range of tissues including in berry fruits. These compounds are of considerable interest for their biological activities, health benefits and potential pharmacological applications. However, transcriptomic and genomic resources for wild and cultivated berry fruit species are often limited, despite their value in underpinning the in-depth study of metabolic pathways, fruit ripening as well as in the identification of genotypes rich in bioactive compounds. RESULTS: To access the genetic diversity of wild and cultivated berry fruit species that accumulate high levels of phenolic compounds in their fleshy berry(-like) fruits, we selected 13 species from Europe, South America and Asia representing eight genera, seven families and seven orders within three clades of the kingdom Plantae. RNA from either ripe fruits (ten species) or three ripening stages (two species) as well as leaf RNA (one species) were used to construct, assemble and analyse de novo transcriptomes. The transcriptome sequences are deposited in the BacHBerryGEN database (http://jicbio.nbi.ac.uk/berries) and were used, as a proof of concept, via its BLAST portal (http://jicbio.nbi.ac.uk/berries/blast.html) to identify candidate genes involved in the biosynthesis of phenylpropanoid compounds. Genes encoding regulatory proteins of the anthocyanin biosynthetic pathway (MYB and basic helix-loop-helix (bHLH) transcription factors and WD40 repeat proteins) were isolated using the transcriptomic resources of wild blackberry (Rubus genevieri) and cultivated red raspberry (Rubus idaeus cv. Prestige) and were shown to activate anthocyanin synthesis in Nicotiana benthamiana. Expression patterns of candidate flavonoid gene transcripts were also studied across three fruit developmental stages via the BacHBerryEXP gene expression browser (http://www.bachberryexp.com) in R. genevieri and R. idaeus cv. Prestige. CONCLUSIONS: We report a transcriptome resource that includes data for a wide range of berry(-like) fruit species that has been developed for gene identification and functional analysis to assist in berry fruit improvement. These resources will enable investigations of metabolic processes in berries beyond the phenylpropanoid biosynthetic pathway analysed in this study. The RNA-seq data will be useful for studies of berry fruit development and to select wild plant species useful for plant breeding purposes.