Significance: Nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2) is a transcription factor predominantly affecting the expression of antioxidant genes. NRF2 plays a significant role in the control of redox balance, which is crucial in cancer cells. NRF2 activation regulates numerous cancer hallmarks, including metabolism, cancer stem cell characteristics, tumor aggressiveness, invasion, and metastasis formation. We review the molecular characteristics of the NRF2 pathway and discuss its interactions with the cancer hallmarks previously listed. Recent Advances: The noncanonical activation of NRF2 was recently discovered, and members of this pathway are involved in carcinogenesis. Further, cancer-related changes (e.g., metabolic flexibility) that support cancer progression were found to be redox-and NRF2 dependent. Critical Issues: NRF2 undergoes Janus-faced behavior in cancers. The pro-or antineoplastic effects of NRF2 are context dependent and essentially based on the specific molecular characteristics of the cancer in question. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. The biggest challenge in the NRF2 field is to determine which cancers can be targeted for better clinical outcomes. Further, large-scale genomic and transcriptomic studies are missing to correlate the clinical outcome with the activity of the NRF2 system. Future Directions: To exploit NRF2 in a clinical setting in the future, the druggable members of the NRF2 pathway should be identified. In addition, it will be important to study how the modulation of the NRF2 system interferes with cytostatic drugs and their combinations. Antioxid. Redox Signal. 00, 000-000.

Transcript levels for selected ATP synthase membrane FO-subunits—including DAPIT—in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F1α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency.

There are strong data showing that malnutrition is highly prevalent in intensive care unit patients (20–50% in the worldwide), presenting a negative accumulated body energy balance. This results in an increased mortality, infections, and hospital length stay with high costs associated with the total treatment. Parenteral nutrition is the first option when the patient's physical condition is not suitable for oral nutrient intake. It is composed essentially by lipids as an energy source, metabolic, and structural function. However, these patients also require a mixture of essential and nonessential fatty acids (SMOF emulsions) to supply not only energy needs but also restore immunological, anti-inflammatory, and proregenerative functions. A revision of the safety and efficacy of Smoflipid® in patients requiring long-term parenteral nutrition was discussed here. Although controversial data are available indicating the contraindications or effectiveness of its use, most of studies presented indicate favorable benefits associated with improved clinical outcomes. The reported roles of this supplementation include positive immunomodulatory and anti-inflammatory effects, positive impact in liver function, reduction of hospital stay, and nosocomial infections as additional contributions to its energetic role, which in many cases results in reduced total costs per patient. Finally, many authors propose that the use of Smoflipid® should become a gold standard of parenteral nutrition in intensive unit care patients and that the costs associated with this supplement should not be limiting for its use, not only to improve the clinical outcome but also to reduce the treatment costs.

Type 2 diabetes (T2D) can go undiagnosed for years, leading to a stage where chronic high blood sugar produces complications such as delayed wound healing. Reports have shown that BLT2 activation improves keratinocyte migration and wound healing, as well as protecting the epidermal barrier through the promotion of actin polymerization.The goal of this study was to elucidate the role of BLT2 expression in skin epithelial integrity in T2D.For this purpose, we used both wild type (WT) and BLT2 knockout mice in a model, in which a T2D-like phenotype was induced by keeping the animals on a high fat (HF) diet over 5 weeks. In a parallel in vitro approach, we cultured BLT2-transfected HaCaT cells at both low and high glucose concentrations for 48 h. Structure, transepithelial resistance (TEER), IL-1ß, IL-8 or CXCL2, MMP9, Filaggrin, Loricrin and Keratin 10 (K10) were evaluated ex vivo and in vitro. Additionally, wound healing (WH) was studied in vitro.The skin from T2D and BLT2 knockout mice showed a reduction in TEER and the expression of IL-1ß, and in increase in CXCL2, MMP9, Filaggrin, Loricrin and K10 expression. The structure suggested an atrophic epidermis; however, the skin was dramatically affected in the BLT2 knockout mice kept on a HF diet.HaCaT-BLT2 cells presented as an organized monolayer and showed higher TEER and wound healing compared with vector only-transfected HaCaT-Mock cells. Likewise, alterations in the expression of skin inflammatory, matrix degradation and differentiation markers under low and high glucose conditions were less severe than in HaCaT-Mock cells.Our results suggest that BLT2 improves epithelial integrity and function by regulating differentiation markers, cytokines and MMP9. Furthermore, BLT2 attenuates the damaging effects of high glucose levels, thereby accelerating wound healing.

Increased markers of cardiovascular risk are already present in young adults with metabolic syndrome but without type 2 diabetes or hypertension.

BackgroundType 2 diabetes (T2D) can go undiagnosed for years, leading to a stage where produces complications such as delayed skin wound healing. Animal models have been developed in the last decades to study the pathological progression in this disease. Streptozotocin (STZ), that has a selective pharmacological toxicity toward pancreatic β cells, in addition to high fat diet has been widely used to induce diabetes however no evidence has shown its effects on the skin integrity.MethodsEighteen C57BL/6J male mice, were divided in 3 groups; the first was fed with chow diet and the second was kept on a high fat diet and the third injected with STZ intraperitoneal for 5 days consecutively before starting the diet protocol with high fat. Mice were maintained 5 weeks in total.ResultsWe show that animals treated with STZ-high fat diet exhibit skin injuries without significant alterations on basal insulin and triglycerides, compared to the control. The skin from these animals presents higher levels of oxidative stress, lower levels of adhesion proteins and alterations in lipid mediators, effects that are not produced by the high fat diet itself.ConclusionOur results suggest that this in vivo model represents a relevant approach for studying skin damage induced by diabetes.

Glutamine is one of the conditionally essential free amino acids with multiple biological functions. Its supplementation to parenteral nutrition has been widely used for the management of complications in intensive care. However, controversial clinical reports have generated reluctance in the use of this pharmaco-nutrient. In this commentary, we address the impact of four studies that influenced the recommendations on glutamine supplementation by the Canadian Clinical Practice Guide 2015. Because of the importance of this guideline in clinical practice, we strongly believe that a more rigorous and critical evaluation is required to support recommendations in future guidelines.

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