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Oxidative stress is involved in endothelial dysfunction, the key player in the development of vascular events. Flavanols, the major antioxidants in cocoa have been related to vascular protection and lower cardiovascular risk. However, the bioavailability of cocoa flavanols is very low and their bioactivity in vivo seems to be greatly mediated by the derived phenolic metabolites formed by intestinal microbiota. Hence, we investigated whether microbial-derived flavanol metabolites 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3-dihydroxybenzoic acid (DHBA), 3-hydroxyphenylpropionic acid (HPPA) and a mix of them could influence endothelial function and prevent oxidative stress in human endothelial cells (Ea.hy926). Our results revealed that a mixture of flavanol colonic metabolites significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. By using specific inhibitors, we also established the participation of the adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) in eNOS activation. Likewise, flavanol metabolite mix protected against oxidative stress-induced endothelial dysfunction and cell death by preventing increased ROS generation and activation of signaling pathways related to oxidative stress. We concluded that flavanol colonic metabolites could exert beneficial effects in endothelial cells and prevent oxidative stress-induced vascular dysfunction. [ABSTRACT FROM AUTHOR]

Prevention of diabetes through the diet has recently received an increasing interest, and polyphenolic compounds, such as flavanols, have become important potential chemopreventive natural agents due to their proved benefits on health, with low toxicity and cost. Tea, red wine and cocoa are good sources of flavanols and these highly consumed foods might contribute to prevent diabetes. In this regard, there is increasing evidence for a protective effect of tea, red wine and cocoa consumption against this disorder. This review summarizes the available epidemiological and interventional human studies providing evidence for and against this effect. Overall observational data suggest a benefit, but results are still equivocal and likely confounded by lifestyle and background dietary factors. The weight of data indicate favourable effects on diabetes risk factors for tea, red wine and cocoa intake, and a number of plausible mechanisms have been elucidated in human studies. However, despite the growing evidence it remains uncertain whether tea, red wine and cocoa consumption should be recommended to the general population or to patients as a strategy to reduce the risk of diabetes. [ABSTRACT FROM AUTHOR]

Highlights: [•] Microbial metabolites DHPAA and HPPA have potential anti-diabetic benefits. [•] DHPAA and HPPA potentiate glucose-stimulated insulin secretion. [•] DHPAA and HPPA protect beta cells against citotoxicity induced by oxidative stress. [•] DHPAA and HPPA promote survival and function of beta cells via ERKs and PKC pathways. [ABSTRACT FROM AUTHOR]

Cocoa is a source of flavanols, and these phenolic compounds exert beneficial effects on health and aging, and reduce the risk of suffering chronic diseases (cardiovascular diseases, metabolic disorders, cancer). An increasing body of evidence has emerged to suggest that cocoa flavanols potentially are important chemopreventive natural agents. This review summarizes human studies from the past two decades, providing data related to the effects derived from cocoa intake on health and disease. Most human studies have reported beneficial effects of cocoa consumption on health and chronic diseases; however, outcomes are not unequivocal. Review of human studies enable to identify different mechanisms of action for cocoa, although they are not fully understood at present. In addition, it remains unclear whether cocoa consumption should be recommended to healthy subjects or to patients and what is the appropriate dosage or duration of cocoa consumption. Elucidation of information regarding these crucial issues could lead to cocoa use as an approach for decreasing the risk of certain chronic diseases, as well as improving health and quality of life. - Most epidemiologic and interventional studies report benefits of cocoa intake on health. - Human studies mostly state protective effects of cocoa intake against chronic diseases. - Large controlled trials with longer follow-ups are needed to verify equivocal findings. - Well-designed studies in cells and animals will help to clarify cocoa molecular mechanisms. - Further human studies are needed before recommending specific cocoa dosages for the population. [ABSTRACT FROM AUTHOR]

Abstract Glucotoxicity (high levels of glucose) is a major cause in the pathogenesis of diabetes. Evidences indicate that (-)-epicatechin (EC) and colonic metabolites derived from flavonoid intake could possess antidiabetic effects, but the mechanisms for their preventive activities related to glucose homeostasis and insulin signalling in the kidney remain largely unknown. This work is aimed to investigate the effect of EC and main colonic phenolic acids derived from flavonoid intake, i.e. 2,3-dihydroxybenzoic-acid, 3,4-dihydroxyphenylacetic-acid (DHPAA) and 3-hydroxyphenylpropionic-acid, on insulin signalling, and glucose production and uptake in renal tubular proximal NRK-52E cells treated with high glucose. Pre-treatment with EC or DHPAA prevented the decreased tyrosine-phosphorylated and total levels of IR caused by high glucose. EC and DHPAA pre-treatment also avoided the inactivation of the PI3K/AKT pathway and AMPK, and the elevation of PEPCK levels induced by high glucose. Additionally, EC and DHPAA pre-treatment alleviated the altered glucose uptake and production caused by high glucose, although this protective effect was abrogated when AKT and AMPK were inhibited. These results suggest EC and DHPAA prevent or delay a potential dysfunction of NRK-52E cells treated with high glucose through the attenuation of the insulin signalling blockade and the modulation of glucose homeostasis via AKT and AMPK. Graphical abstract Image 1 Highlights • EC and DHPAA avert the insulin signalling blockage induced by a high dose of glucose in NRK-52E cells. • EC and DHPAA prevent the inhibition of AMPK caused by glucotoxicity in NRK-52E cells. • EC and DHPAA protect NRK-52E cells against the enhanced levels of PEPCK caused by glucotoxicity. • EC and DHPAA protect NRK-52E functionality by modulating glucose production and uptake via AKT and AMPK. [ABSTRACT FROM AUTHOR]

Abstract: Prevention of cancer through the diet is receiving increasing interest, and cocoa because of its polyphenolic compounds has become an important potential chemopreventive and therapeutic natural agent. Cocoa and its main polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. Cocoa flavonoids have been demonstrated to influence several important biological functions in vitro and in vivo by their free radical scavenging ability or through the regulation of signal transduction pathways to stimulate apoptosis and to inhibit inflammation, cellular proliferation, apoptosis, angiogenesis and metastasis. Nevertheless, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of the potential chemopreventive activity of cocoa and its polyphenolic components by summarizing cell culture and animal models studies, as well as interventional and epidemiological studies on humans. [Copyright &y& Elsevier]

Abstract: Phloroglucinol is an ubiquitous secondary metabolite encountered in a free state or polymerised as phlorotannins in brown macroalgae, and present in higher plants. FRAP and TEAC assays measured the antioxidant properties of phloroglucinol in non-biological conditions. Additionally, the biological effects of phloroglucinol (4–400μM) were scrutinised using cellular oxidative stress markers, such as the generation of ROS, antioxidant defences (concentration of GSH and activities of GPx, GR and GST), and levels of MDA as a marker for lipid peroxidation. The direct effect was assessed immediately after an incubation period, whereas for the protective effect, the incubation period was followed by 3-h treatment with the pro-oxidant t-BOOH. The results indicated that despite having a higher radical scavenging capacity than Trolox after 30min, phloroglucinol was not a suitable antioxidant standard for phlorotannins. Regarding the biological effects, phloroglucinol had no impact on cell viability, reduced levels of ROS and increased antioxidant defences in the direct treatment for most concentrations. The results of the protective effect were mitigated as phloroglucinol failed to protect from ROS generation but evoked a significant recovery of the stress-altered cellular antioxidant defences to restful conditions. Additionally, MDA levels were greatly reduced, preventing a radical chain oxidation. [Copyright &y& Elsevier]

Hyperglycaemia induces a vascular inflammatory process that is a critical event in cardiovascular disease in type 2 diabetes. Cocoa and its flavanols have been widely investigated for its antioxidant and anti-inflammatory properties, and several clinical and pre-clinical studies support their vascular benefits. However, the effects of cocoa flavanols on vascular inflammation in diabetes remains to be elucidated. Herein, we evaluated the anti-inflammatory effect of a cocoa-rich diet on the aortas of Zucker diabetic fatty (ZDF) rats. Moreover, the potential role of flavanol-derived colonic metabolites to modulate the adhesion and inflammatory processes were also evaluated using TNF-α-stimulated endothelial cells. Results demonstrate that cocoa attenuates the levels of phospho-p65-nuclear factor-kappaB (NF-κB) and the expression of inflammatory factors including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase in the aortas of ZDF rats. Experiments with endothelial cells further confirm that a mix of flavanol-derived colonic metabolites effectively down-regulate the levels of p-p65-NF-κB and the cell adhesion molecules ICAM-1 and VCAM-1, preventing thus the increase of monocyte-endothelial adhesion induced by TNF-α. These novel data provide the first evidence of the relevant role of cocoa and their flavanol-derived metabolites to avoid the development of endothelial inflammation and diabetic complications. • Cocoa rich diet prevent hyperglycaemia-induced arterial inflammation in diabetic rats. • Cocoa intake reduces p-p65-NF-κB, ICAM-1, VCAM-1 and iNOS levels in diabetic aortas. • Flavanol-derived gut metabolites protect endothelial cells against inflammation. • Flavanol colonic metabolites inhibit monocyte-endothelial adhesion induced by TNF-α. [ABSTRACT FROM AUTHOR]

Glucotoxicity (high levels of glucose) is a major factor in the pathogenesis of diabetic kidney disease. Cocoa has anti-diabetic effects by lowering glucose levels. However, whether cocoa exerts beneficial effects on the renal cortex glucose homeostasis and the molecular mechanisms responsible for this possible protective activity remain largely unknown. Thus, the potential anti-diabetic properties of cocoa on insulin signalling, glucose transporters and gluconeogenic enzymes were evaluated in the renal cortex of Zucker Diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker Lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed decreased body weight gain, glucose and insulin levels, improved glucose tolerance, insulin resistance and structural alterations in renal cortex. Moreover, cocoa-rich diet ameliorated insulin resistance by reverting decreased tyrosine-phosphorylated-insulin receptor levels and by preventing the inactivation of glycogen synthase kinase-3/glycogen synthase pathway (GSK-3/GS) in the renal cortex of ZDF-Co rats. Cocoa antihyperglycaemic effect also appeared to be mediated through the diminution of phosphoenolpyruvate-carboxykinase (PEPCK), glucose-6-phosphatase (G-6-Pase), sodium-glucose-co-transporter-2 (SGLT-2), and glucose-transporter-2 (GLUT-2) levels in ZDF-Co rat's renal cortex. These findings demonstrate that cocoa alleviates renal injury by contributing to maintain the glucose homeostasis in type 2 diabetic ZDF rats. Image 1 • Cocoa intake improves glucose tolerance and alleviates insulin resistance in ZDF rats. • Cocoa-enriched diet protects against structural diabetes-induced changes in the renal cortex of ZDF rats. • Cocoa intake averts the insulin signalling blockage in the renal cortex of ZDF rats. • Cocoa improves the enhanced levels of gluconeogenic enzymes in the renal cortex of ZDF rats. • Cocoa-enriched diet avoids the increased content of glucose transporters in the renal cortex of ZDF rats. [ABSTRACT FROM AUTHOR]

Highlights: [•] EC and CPE prevent insulin signalling blockage by modulating IR/IRS levels in HepG2. [•] EC and CPE restrain the inhibition of PI3K/AKT and AMPK caused by high glucose. [•] EC and CPE protect HepG2 cells against diminished levels of GLUT2 caused by high glucose. [•] EC and CPE protect HepG2 functionality by modulating glucose production and uptake. [•] EC and CPE protect HepG2 functionality by regulating glycogen content. [Copyright &y& Elsevier]

Highlights: [•] SeCys protects HepG2 cells against MeHg-induced cell damage. [•] SeCys prevents MeHg-induced alteration of the redox status. [•] MeHg modulates MAPK proteins to induce apoptosis and cell death. [•] SeCys alters MAPK modulation induced by MeHg to prevent cell damage. [ABSTRACT FROM AUTHOR]

Abstract: A series of nitroderivatives has been synthetized from natural and synthetic olive oil phenols to increase the assortment of compounds with a putative effect against Parkinson disease. Before considering the potential therapeutical and nutraceutical applications of the new compounds it was critical to assess any cytotoxic effects in the liver. The precursor compounds of the nitroderivatives have shown oxidative stress protective effects, therefore we also assessed if the new compounds counteracted oxidative stress. The antioxidant activity of nitrohydroxytyrosol (NO-HTy), nitrohydroxytyrosyl-acetate (NO-HTy-A) and ethyl-nitrohydroxytyrosyl-ether (NO-HTy-E) at 5–20μM for 20h, as well as the protective effects of the nitroderivatives after 20h against oxidative stress induced by tert-butylhydroperoxide (t-BOOH), were assessed in HepG2 cells. Direct treatment with the three nitroderivatives decreased ROS generation compared to the control and NO-HTy at 20μM also increased glutathione peroxidase (GPx) activity (p <0.001). Pretreatment with the three nitroderivatives at 5–20μM counteracted t-BOOH cell damage by decreasing ROS generation (p<0.001) and malondialdehyde (MDA) levels (p <0.001), increasing reduced glutathione (p <0.001) and disminishing GPx (p <0.05) activity. NO-HTy, NO-HTy-A and NO-HTy-E decreased glutathione reductase activity (p <0.05). Conclusion: the nitroderivatives do not present cytotoxic effects in the liver and in addition may protect against the oxidative stress involved in degenerative diseases. [Copyright &y& Elsevier]

Abstract: Methylmercury (MeHg) has been suggested to exert cytotoxicity through multiple mechanisms, but the precise biochemical machinery has not been fully defined. This study was aimed at investigating the time-course (0–24h) effect of 2mg/L MeHg on cell death in human HepG2 cells. MeHg decreased cell viability in a time-dependent manner, which was concomitant with increased LDH leakage, reduced GSH levels, CAT activity and altered activity of the antioxidant enzymes GPx and GR at the longest times of incubation (16 and 24h). Activity of the detoxifying enzyme GST was also early enhanced (2h). Caspase-3 activity reached a maximum value at 8h and continued increased up to 24h. This feature was preceded by an enhancement in the caspase-9 activity (2h), whereas caspase-8 activity remained unchanged. MeHg early diminished Bcl-xL/Bcl-xS ratio and increased levels of the pro-apoptotic Bax and Bad. Moreover, MeHg-induced cytotoxicity was completely inhibited by the antioxidants (GSH and NAC) and notably by the mitochondrial complex I inhibitor rotenone, but not by the NADH oxidase inhibitor DPI. In summary, MeHg induced an oxidative stress responsible for apoptosis in HepG2 cells through direct activation of the caspase cascade and altered the cellular antioxidant and detoxificant enzymatic system to later provoke necrosis at later stages. [Copyright &y& Elsevier]

The effects of cocoa feeding against N-nitrosodiethylamine (DEN)-induced liver injury were studied in rats. Animals were divided into five groups. Groups 1 and 2 were fed with standard and cocoa-diet, respectively. Groups 3 and 4 were injected with DEN at 2 and 4weeks, and fed with standard and cocoa-diet, respectively. Group 5 was treated with DEN, received the standard diet for 4weeks and then it was replaced by the cocoa-diet. DEN-induced hepatic damage caused a significant increase in damage markers, as well as a decrease in the hepatic glutathione, diminished levels of p-ERK and enhanced protein carbonyl content, caspase-3 activity and values of p-AKT and p-JNK. The cocoa-rich diet prevented the reduction of hepatic glutathione concentration and catalase and GPx activities in DEN-injected rats, as well as diminished protein carbonyl content, caspase-3 activity, p-AKT and p-JNK levels, and increased GST activity. However, cocoa administration did not abrogate the DEN-induced body weight loss and the increased levels of hepatic-specific enzymes and LDH. These results suggested that cocoa-rich diet attenuates the DEN-induced liver injury. [Copyright &y& Elsevier]