Showing papers by "Regina Menezes published in 2020"

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

Abstract: 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 β-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 β-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 (As), 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.

Abstract: (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. 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. 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). 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.

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

Abstract: 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 11β,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.

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Abstract: 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.

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

Abstract: 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.

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

Abstract: 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 β-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 β-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.

Evaluation of Starch Hydrolysis for Glycemic Index Prediction of Rice Varieties

Abstract: Rice consumed as white cooked polished grain has been considered a high glycemic index (GI) food, particularly compared with other starchy foods. However, the GI levels of rice based food can vary among different rice types and food processing technologies. Rice GI variation can be affected by several factors, such as rice variety, the genetic background of rice as well as due to crop edaphoclimatic conditions. The main difference in rice starch composition that influences GI is the amylose content. Besides the chemical composition of rice, the gelatinization characteristics and food processing can also contribute to starch retrogradation, thus increasing the level of resistant starch with a great influence on GI. To understand the glycemic response of rice types differing in amylose and viscosity profiles, four rice samples were analyzed and compared with standard and resistant HI-MAIZE corn starches. An in vitro enzymatic starch hydrolysis procedure was applied to estimate GI. The results indicate substantial differences in the starch hydrolysis of the two corn starches. Starch hydrolysis tended to be more rapid and efficient for ‘Waxy’ and ‘Ceres’ (intermediate-amylose) rice types than for ‘Macarico’ (high-amylose rice). In addition, the data show that the Macarico variety has the lowest estimated GI and the highest retrogradation rate compared with ‘Waxy’, ‘Ceres’ and ‘Basmati’ type. The results obtained reinforce the importance of knowing amylose content and viscosity profiles for the prediction of rice glycemic responses.