: Glucolipotoxicity-induced oxidative stress and mitochondrial dysfunction of pancreatic β-cells are one of the mechanisms that have been related to the low insulin secretion and cell death during diabetes development. In early or non-chronic stages, the pancreatic β-cells respond to hyperglycemia or hyperlipidemia, stimulating insulin secretion. However, the chronic effect of both leads to the establishment of glucolipotoxicity which induces constant overstimulation of pancreatic β-cells, a condition that leads to cell death by apoptosis. The mechanism described, at this moment, is the accelerated mitochondrial dysfunction triggered by the high production of reactive oxygen species (ROS) due to excess nutrients. At first, mitochondria respond to over-nutrition accelerating oxygen consumption and consequently increasing the ATP synthesis. A permanent increase of ATP/ADP ratio leads to a constant inhibition of K+ ATP-channel and therefore a continuous insulin secretion accompanied by an increase in ROS. Finally, ROS accumulation compromises mitochondrial function due to the uncontrolled oxidation of proteins, lipids, and DNA generating functional alterations such as a drop of membrane potential, deregulation of mitochondrial dynamics, low rate of ATP synthesis and consequently the cell death. This review aims to describe the effect of glucolipotoxicity-induced oxidative stress and its relationship with mitochondrial dysfunction in β-cell during type 2 diabetes development.
Western-style diet often leads to food overconsumption, which triggers the development of comorbidities such as obesity, insulin resistance, hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, and heart failure (HF). Several studies suggested that intermittent fasting (IF) protects against the development of those morbidities. This study presents evidence of the beneficial effects of IF on HF. Based on the current evidence, we discuss the potential molecular mechanisms by which IF works and where liver ketone bodies (KBs) play important roles. There is evidence that IF promotes a metabolic switch in highly metabolic organs, such as the heart, which increases the use of KBs during fasting. However, besides their role as energy substrates, KBs participate in the signaling pathways that control the expression of genes involved in oxidative stress protection and metabolism. Several molecular factors, such as adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor, fibroblast growth factor 21 (FGF21), sirtuins, and nuclear factor erythroid 2-related factor 2 (Nrf2) are involved. Furthermore, IF appears to maintain circadian rhythms, essential in highly metabolically active organs. Finally, we highlight the important research topics that need to be pursued to improve current knowledge and strengthen the potential of IF as a preventive and therapeutic approach to HF.
Corneal opacities are a leading cause of visual impairment that affect 4.2 million people annually. The current treatment is corneal transplantation, which is limited by tissue donor shortages. Corneal engineering aims to develop membranes that function as scaffolds in corneal cell transplantation. Here, we describe a method for producing transplantable corneal constructs based on a collagen vitrigel (CVM) membrane and corneal endothelial cells (CECs). The CVMs were produced using increasing volumes of collagen type I: 1X (2.8 μL/mm2), 2X, and 3X. The vitrification process was performed at 40% relative humidity (RH) and 40 °C using a matryoshka-like system consisting of a shaking-oven harboring a desiccator with a saturated K2CO3 solution. The CVMs were characterized via SEM microscopy, cell adherence, FTIR, and manipulation in an ex vivo model. A pilot transplantation of the CECs/CVM construct in rabbits was also carried out. The thickness of the CVMs was 3.65–7.2 µm. The transparency was superior to a human cornea (92.6% = 1X; 94% = 2X; 89.21% = 3X). SEM microscopy showed a homogenous surface and laminar organization. The cell concentration seeded over the CVM increased threefold with no significant difference between 1X, 2X, and 3X (p = 0.323). The 2X-CVM was suitable for surgical manipulation in the ex vivo model. Constructs using the CECs/2X-CVM promoted corneal transparency restoration.
We set a feasible method to produce tailored collagen scaffolds and analyzed its potential for corneal engineering. Collagen-vitrigel membranes (CVM) were produced with a 1:1 ratio of Dulbecco’s Modified Eagle’s medium (DMEM), 1% antibiotics and 8% fetal bovine serum, and 5mg/mL collagen type I. Three volumes of collagen were used: 1X (2.8 L/mm2 of collagen), 2X, and 3X. Vitrification was done at 40% relative humidity (RH), 40° C, and 30 rpm using a matryoshka system set with a shaking-oven and a desiccator with a saturated K2CO3 solution. The CVM was characterized for width, microstructure, transparency, and biocompatibility using NIH3T3 cells. Surgical manipulation was assessed in an ex vivo corneal model. Constructs of corneal endothelial cells (CECs) and 2X-CVM were transplanted into five 18-month-old White New Zealand rabbits. CVM exhibited homogeneous surface and laminar organization. Membrane width increased with gel volume from 3.65µm to 7.2µm. 1X and 2X-CVM exhibited a 99% transmittance. NIH3T3 cells concentration increased 3-fold within 48 h with no significant difference among the 3 CVM (p = 0.323). The 2X-CVM was surgically manipulable. Transplantation of corneal endothelial cells (CECs) seeded over 2X-CVM restored corneal endothelium. The matrioshka system is a feasible method that yields CVM suitable for corneal engineering.
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