New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a neurodegenerative and vascular pathology that is considered one of the leading causes of blindness worldwide, resulting from complications of advanced diabetes mellitus (DM). Current therapies consist of protocols aiming to alleviate the existing clinical signs associated with microvascular alterations limited to the advanced disease stages. In response to the low resolution and limitations of the DR treatment, there is an urgent need to develop more effective alternative therapies to optimize glycemic, vascular, and neuronal parameters, including the reduction in the cellular damage promoted by inflammation and oxidative stress. Recent evidence has shown that dietary polyphenols reduce oxidative and inflammatory parameters of various diseases by modulating multiple cell signaling pathways and gene expression, contributing to the improvement of several chronic diseases, including metabolic and neurodegenerative diseases. However, despite the growing evidence for the bioactivities of phenolic compounds, there is still a lack of data, especially from human studies, on the therapeutic potential of these substances. This review aims to comprehensively describe and clarify the effects of dietary phenolic compounds on the pathophysiological mechanisms involved in DR, especially those of oxidative and inflammatory nature, through evidence from experimental studies. Finally, the review highlights the potential of dietary phenolic compounds as a prophylactic and therapeutic strategy and the need for further clinical studies approaching the efficacy of these substances in DR management.

Evidence for Quercetin as a Dietary Supplement for the Treatment of Cardio-Metabolic Diseases in Pregnancy: A Review in Rodent Models.

Quercetin supplementation during pregnancy and lactation has been linked to a lower risk of maternal cardio-metabolic disorders such as gestational diabetes mellitus (GDM), dyslipidemia, preeclampsia, attenuation of malnutrition-related conditions, and gestational obesity in animal studies. Pre-clinical studies have shown that maternal supplementation with quercetin reduces cardio-metabolic diseases in dams and rodents' offspring, emphasizing its role in modifying phenotypic plasticity. In this sense, it could be inferred that quercetin administration during pregnancy and lactation is a viable strategy for changing cardio-metabolic parameters throughout life. Epigenetic mechanisms affecting the AMP-activated protein kinase (AMPK), nuclear factor-kappa B (NF-κB), and phosphoinositide 3-kinase (PI3 K) pathways could be associated with these changes. To highlight these discoveries, this review outlines the understanding from animal studies investigations about quercetin supplementation and its capacity to prevent or decrease maternal and offspring cardio-metabolic illnesses and associated comorbidities.

Gut microbiota: A potential therapeutic target for management of diabetic retinopathy?

Diabetic Retinopathy (DR) is one of the main complications of Diabetes Mellitus (DM), drastically impacting individuals of working age over the years, being one of the main causes of blindness in the world. The existing therapies for its treatment consist of measures that aim only to alleviate the existing clinical signs, associated with the microvasculature. These treatments are limited only to the advanced stages and not to the preclinical ones. In response to a treatment with little resolution and limited for many patients with DM, investigations of alternative therapies that make possible the improvement of the glycemic parameters and the quality of life of subjects with DR, become extremely necessary. Recent evidence has shown that deregulation of the microbiota (dysbiosis) can lead to low-grade, local and systemic inflammation, directly impacting the development of DM and its microvascular complications, including DR, in an axis called the intestine-retina. In this regard, the present review seeks to comprehensively describe the biochemical pathways involved in DR as well as the association of the modulation of these mechanisms by the intestinal microbiota, since direct changes in the microbiota can have a drastic impact on various physiological processes. Finally, emphasize the strong potential for modulation of the gut-retina axis, as therapeutic and prophylactic target for the treatment of DR.

The influence of dehydroepiandrosterone on effector functions of neutrophils

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands, gonads and brain. It is a precursor to sex hormones and also is known to have immune modulatory activity. However, little is known about the relationship between DHEA and neutrophils and thus our study evaluates the influence of DHEA in the effector functions of neutrophils. Human neutrophils were treated in vitro with DHEA and further infected with Salmonella enterica serovar Typhimurium. The treatment of neutrophils with 0.01 µM of DHEA increased the phagocytosis of Salmonella independent of TLR4 as the treatment did not modulate the TLR4 expression. Additionally, DHEA caused a decrease in ROS (reactive oxygen species) production and did not influence the formation of the neutrophil extracellular trap (NET). Steroid treated neutrophils, infected or stimulated with LPS (lipopolysaccharide), showed reduced production of IL-8, compared to untreated cells. Also, the protein levels of p-NFκB were decreased in neutrophils treated with DHEA, and this reduction could explain the reduced levels of IL-8. These results led us to conclude that the steroid hormone DHEA has important modulatory functions in neutrophils

Oral administration of Lactobacillus fermentum post-weaning improves the lipid profile and autonomic dysfunction in rat offspring exposed to maternal dyslipidemia.

BACKGROUND: Maternal dyslipidemia alters the gut microbiota composition and contributes to the development of arterial hypertension (AH) in offspring. Here, we evaluated the effects of a new Lactobacillus fermentum probiotic formulation given post-weaning on cardiometabolic parameters and gut microbiota in male and female rat offspring from dams exposed to maternal dyslipidemia during pregnancy and lactation. METHODS: Wistar rats (n = 14) were fed with a control diet (CTL = 7) or a dyslipidemic diet (DLP = 7) during pregnancy and lactation. After weaning, male and female offspring received a standard diet up to 90 days of life. Rats were allocated into three groups: CTL group + saline solution (n = 14); DLP group + saline solution (n = 14) and DLP group receiving a probiotic cocktail (n = 14). A vehicle or probiotic formulation containing L. fermentum 139, L. fermentum 263 and L. fermentum 296 (ratio 1 : 1 : 1, 1 × 109 CFU mL-1) was administered daily by oral gavage for 8 weeks. RESULTS: The intervention with the probiotic formulation of L. fermentum in male and female offspring reduced total cholesterol (TC) and increased HDL-c, but did not affect the insulin resistance induced by maternal dyslipidemia. Additionally, the male and female rats that received the probiotic formulation of L. fermentum demonstrated improvement in fecal Lactobacillus sp. counts, blood pressure and sympathetic tone, without affecting baroreflex modulation. CONCLUSION: The probiotic formulation containing L. fermentum improved the lipid profile and autonomic dysfunction in male and female offspring exposed to maternal dyslipidemia.

SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy.

Molecular alterations in cell death pathways and imbalances in regulators of up- or downstream signaling pathways can lead to resistance to cell death, which is one of the hallmarks of cancer. These signaling modifications are strategies that tumor cells use to resist chemotherapy and that contribute to the high recurrence rate of head and neck squamous cell carcinoma (HNSCC). The SET oncoprotein is a PP2A inhibitor that accumulates in HNSCC and represents a promising therapeutic target. Here we report the role that SET protein plays in resistance to death of two HNSCC cell lines: Cal 27 and HN13. SET protein regulated intracellular redox balance by controlling cellular localization of APE 1 - an endonuclease that is part of the SET complex and regulates antioxidant gene transcription. SET protein knockdown (siSET) associated with tert-butyl hydroperoxide-induced oxidative stress sensitized Cal 27 and HN13 cells to apoptosis via the extrinsic and intrinsic pathways, respectively. SET protein upregulated autophagy in HNSCC cells in a PP2A-dependent manner and apparently regulated ULK1 expression. The fact that siSET lowered Bcl-2 phosphorylation levels indicated that SET protein interfered with an alternative pathway that modulated autophagy in HNSCC cells. Overall, SET protein regulated intracellular redox state and sustained autophagy in HNSCC cells, which may explain resistance to death of HNSCC cells. Altogether, the findings reported herein support SET protein as therapeutic target for HNSCC.

Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease?

The gut microbiota plays an important role in host metabolism and its dysregulation have been related to cardiometabolic disorders (CMD), such as type 2 diabetes mellitus (T2D), dyslipidemia and arterial hypertension, as well as to chronic kidney diseases (CKD). The implication of the gut microbiota on systemic disorders has been associated with changes in its composition (dysbiosis) as a result of the oxidative unbalance in the body. This alteration may be the result of the adoption of unhealthy lifestyle behavior, including lack of physical activity and fat- or sugar-rich diets, which are largely associated with increased incidence of CMD and CKD. In last years, a number of clinical trials and experimental studies have demonstrated that probiotics can modulate the host metabolism, resulting in amelioration of systemic disease phenotypes by the improvement of dyslipidemia, glycemic profile and blood pressure or CKD parameters. The beneficial effects of probiotics consumption have been associated with their anti-inflammatory, antioxidant and gut-modulating properties. Despite of some mechanistic evidence, these effects are not totally elucidated. The present review summarizes and clarifies the effects of probiotics administration on CMD and CKD using combined evidence from clinical and experimental studies. Considering that the microbiota dysregulation has been associated with inflammation and oxidative stress and consequently with CMD and CKD, supplementation with probiotics is discussed as a strategy for management of CMD and CKD.