Phenolic Compounds as Preventive and Therapeutic Agents in Diabetes-Related Oxidative Stress, Inflammation, Advanced Glycation End-Products Production and Insulin Sensitivity.

Diabetes mellitus and its complications represent an extremely concerning health problem across the world. The extraordinary worldwide increase of the disease incidence highlights a challenging need for the development of new, safe, effective, and affordable therapeutic approaches. This complex disease, characterized by high blood sugar levels, involves numerous pathogenic processes in its etiology. Even though the molecular mechanisms behind are not clear, it is broadly recognized that oxidative stress, the accumulation of advanced glycation end-products (AGEs) and inflammation are implicated in the development, the progression and the related complications of the disease. In this regard, phenolic compounds represent a valuable therapeutic perspective. Thus, this review is focused on the role of phenolic compounds in diabetes-related oxidative stress, AGEs production and inflammation. In particular, we summarized recent results of in vitro and in vivo studies concerning antioxidant and antiglycative properties of phenolic compounds and also the modulation of activity on inflammation and inflammation-related pathways relevant in diabetes, namely arachidonic acid, nuclear factor-κB, mitogen-activated protein kinases and phosphatidylinositol 3­kinase/protein kinase B signaling pathways, were described. Highlighting thus the anti-diabetic potential of phenolic compounds in the development of preventive or therapeutic strategies for the management of diabetes and its related complications.

Chemical Composition of Hazelnut Skin Food Waste and Protective Role against Advanced Glycation End-Products (AGEs) Damage in THP-1-Derived Macrophages.

Glycation and the accumulation of advanced glycation end-products (AGEs) are known to occur during aging, diabetes and neurodegenerative diseases. Increased glucose or methylglyoxal (MGO) levels in the blood of diabetic patients result in increased AGEs. A diet rich in bioactive food compounds, like polyphenols, has a protective effect. The aim of this work is to evaluate the capacity of hazelnut skin polyphenolic extract to protect THP-1-macrophages from damage induced by AGEs. The main polyphenolic subclass was identified and quantified by means of HPLC/MS and the Folin-Ciocalteu method. AGEs derived from incubation of bovine serum albumin (BSA) and MGO were characterized by fluorescence. Cell viability measurement was performed to evaluate the cytotoxic effect of the polyphenolic extract in macrophages. Reactive oxygen species' (ROS) production was assessed by the H2-DCF-DA assay, the inflammatory response by real-time PCR for gene expression, and the ELISA assay for protein quantification. We have shown that the polyphenolic extract protected cell viability from damage induced by AGEs. After treatment with AGEs, macrophages expressed high levels of pro-inflammatory cytokines and ROS, whereas in co-treatment with polyphenol extract there was a reduction in either case. Our study suggests that hazelnut skin polyphenol-rich extracts have positive effects and could be further investigated for nutraceutical applications.

Rhus Coriaria L. Extract: Antioxidant Effect and Modulation of Bioenergetic Capacity in Fibroblasts from Parkinson's Disease Patients and THP-1 Macrophages.

Sumac, Rhus coriaria L., is a Mediterranean plant showing several useful properties, such as antioxidant and neuroprotective effects. Currently, there is no evidence about its possible neuroprotective action in Parkinson's disease (PD). We hypothesized that sumac could modulate mitochondrial functionality in fibroblasts of familial early-onset PD patients showing PARK2 mutations. Sumac extract volatile profile, polyphenolic content and antioxidant activity have been previously characterized. We evaluated ROS and ATP levels on sumac-treated patients' and healthy control fibroblasts. In PD fibroblasts, all treatments were effective in reducing H2O2 levels, while patients' ATP content was modulated differently, probably due to the varying mutations in the PARK2 gene found in individual patients which are also involved in different mitochondrial phenotypes. We also investigated the effect of sumac extract on THP-1-differentiated macrophages, which show different embryogenic origin with respect to fibroblasts. In THP-1 macrophages, sumac treatment determined a reduction in H2O2 levels and an increase in the mitochondrial ATP content in M1, assuming that sumac could polarize the M1 to M2 phenotype, as demonstrated with other food-derived compounds rich in polyphenols. In conclusion, Rhus coriaria L. extracts could represent a potential nutraceutical approach to PD.

Phytochemical Characterization of Rhus coriaria L. Extracts by Headspace Solid-Phase Micro Extraction Gas Chromatography, Comprehensive Two-Dimensional Liquid Chromatography, and Antioxidant Activity Evaluation.

Rhus coriaria L. (Anacardiaceae), commonly known as sumac, has been used since ancient times for many different applications, and nowadays is used mostly as a spice obtained from its in the Mediterranean and the Middle ground fruits and employed for flavoring and garnishing food, predominantly Eastern regions. Traditionally, sumac has been also used in popular medicine for the treatment of many ailments including hemorrhoids, wound healing, diarrhea, ulcers, and eye inflammation. Sumac drupes are indeed rich in various classes of phytochemicals including organic acids, flavonoids, tannins, and others, which are responsible of their powerful antioxidant capacity, from which treatment of many common diseases such as cardiovascular disease, diabetes, and cancer could benefit. In this work we evaluated the influence of fruit ripeness, conservation, and processing. To this aim, a phytochemical characterization of six different samples of Rhus coriaria L. was carried out. Specifically, headspace solid-phase micro extraction gas chromatography coupled to mass spectrometry and comprehensive two-dimensional liquid chromatography coupled to photodiode array and mass spectrometry detection, were employed. A total of 263 volatile compounds, including terpene hydrocarbons, acids, and aldehydes, as well as 83 polyphenolic compounds, mainly gallic acid derivatives, were positively identified. All samples showed a significant antioxidant activity by means of oxygen radical absorbance capacity, in line with their polyphenolic content and composition. Such findings set a solid ground to support the utilization of this plant as an attractive target for novel nutraceutical approaches and for drug discovery.

Antioxidant and Antiglycation Effects of Polyphenol Compounds Extracted from Hazelnut Skin on Advanced Glycation End-Products (AGEs) Formation.

The advanced glycation end-products (AGEs) arise from non-enzymatic reactions of sugar with protein side chains, some of which are oxido-reductive in nature. Enhanced production of AGEs plays an important role in the pathogenesis of diabetic complications as well as in natural aging, renal failure, oxidative stress, and chronic inflammation. The aim of this work is to study antiglycation effects of polyphenol compounds extracted by hazelnut skin that represents an example of polyphenols-rich food industry by-product, on AGEs formation. AGEs derived from incubation of bovine serum albumin (BSA) and methylglyoxal (MGO) were characterized by fluorescence. The phenolics identification and total polyphenol content in hazelnut skin extracts were analyzed by HPLC-MS and the Folin-Ciocalteu method, respectively. Antioxidant efficacy was evaluated by monitoring total antioxidant activity to assess the ABTS radical scavenging activity of samples by TEAC assay and oxygen radical absorbance capacity (ORAC) assay, expressed as millimoles of Trolox equivalents per gram of sample. Data here presented suggest that phenolic compounds in hazelnut skin have an inhibitory effect on the BSA-AGEs model in vitro, and this effect is concentration-dependent. The putative role of the hazelnut skin antioxidative properties for hindering AGEs formation is also discussed. Because of AGEs contribution to the pathogenesis of several chronic diseases, foods enriched, or supplements containing natural bioactive molecules able to inhibit their production could be an interesting new strategy for supporting therapeutic approaches with a positive effect on human health.