IGF-1 Signaling Modulates Oxidative Metabolism and Stress Resistance in ARPE-19 Cells Through PKM2 Function.

The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it.

Special Issue: "Anti-inflammatory Effects of Glucagon-like Peptide-1".

From the failure of gut extracts in diabetic patients' therapy to the effective action in cardiovascular outcomes [...

Crosstalk between the Rod Outer Segments and Retinal Pigmented Epithelium in the Generation of Oxidative Stress in an In Vitro Model.

Dysfunction of the retinal pigment epithelium (RPE) is associated with several diseases characterized by retinal degeneration, such as diabetic retinopathy (DR). However, it has recently been proposed that outer retinal neurons also participate in the damage triggering. Therefore, we have evaluated the possible crosstalk between RPE and photoreceptors in priming and maintaining oxidative damage of the RPE.

Klotho: A new therapeutic target in diabetic retinopathy?

Klotho (Kl) is considered an antiaging gene, mainly for the inhibition of the insulin-like growth factor-1 signaling. Kl exists as full-length transmembrane, which acts as co-receptor for fibroblast growth factor receptor, and in soluble forms (sKl). The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state.

Caveolin-1 and Atherosclerosis: Regulation of LDLs Fate in Endothelial Cells.

Caveolae are 50-100 nm cell surface plasma membrane invaginations observed in terminally differentiated cells. They are characterized by the presence of the protein marker caveolin-1. Caveolae and caveolin-1 are involved in regulating several signal transduction pathways and processes.

Anti-Inflammatory Effects of GLP-1R Activation in the Retina.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, mainly produced by enteroendocrine L cells, which participates in the regulation of glucose homeostasis, and in reduction in body weight by promoting satiety. Actions of GLP-1 are mediated by activation of its receptor GLP-1R, which is widely expressed in several tissues including the retina. The effects of GLP-1R activation are useful in the management of type 2 diabetes mellitus (T2DM).

High Glucose Impairs Expression and Activation of MerTK in ARPE-19 Cells.

MerTK (Mer Tyrosine Kinase) is a cell surface receptor that regulates phagocytosis of photoreceptor outer segments (POS) in retinal pigment epithelial (RPE) cells. POS phagocytosis is impaired in several pathologies, including diabetes. In this study, we investigate whether hyperglycemic conditions may affect MerTK expression and activation in ARPE-19 cells, a retinal pigment epithelial cellular model.

Caveolin-1 Down-Regulation Reduces VEGF-A Secretion Induced by IGF-1 in ARPE-19 Cells.

The insulin-like growth factor 1 (IGF-1) stimulates expression and secretion of vascular endothelial growth factor-A (VEGF-A), the main actor in ocular neovascularization, by RPE cells. Activity of IGF-1 is regulated by interaction between its receptor and Caveolin-1 (Cav-1), the main component of caveolae. The aim of this study was to investigate whether modulation of Cav-1 expression affects synthesis and secretion of VEGF-A.

The Hormetic Effect of Metformin: "Less Is More"?

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5'-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations.

Emerging Role of Caveolin-1 in GLP-1 Action.

Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues.

miR-126 Mimic Counteracts the Increased Secretion of VEGF-A Induced by High Glucose in ARPE-19 Cells.

Vascular endothelial growth factor-A (VEGF-A) has a pathologic role in microvascular diabetic complication, such as diabetic retinopathy (DR). miR-126 plays an important role in vascular development and angiogenesis by regulating the expression of VEGF-A. Since levels of miR-126 have been found downregulated in diabetes, this study is aimed at investigating whether hyperglycemia affects expression of miR-126 in a retinal pigment epithelium cell line.

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism.

Rod outer segments (OS) express the FF-ATP synthase and the respiratory chain, conducting an ectopic aerobic metabolism that produces free radicals in vitro. Diabetic retinopathy, a leading cause of vision loss, is associated with oxidative stress in the outer retina. Since metformin and glibenclamide, two anti-type 2 diabetes drugs, target the respiratory complexes, we studied the effect of these two drugs, individually or in association, on the free radical production in purified bovine rod OS.

Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System.

The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1.

Response to anti-VEGF-A treatment of retinal pigment epithelial cells in vitro.

Purpose: The neovascular or wet form of age-related macular degeneration is characterized by the growth of abnormal blood vessels in the retina stimulated by vascular endothelial growth factors (VEGF). In the last decade, several anti-VEGF drugs have been developed for treating neovascular diseases of the eyes. This study was conducted to compare the effects of 2 anti-VEGF-A drugs, ranibizumab and aflibercept, on the expression and secretion of VEGF family members in retinal pigment epithelial cells (RPE) in vitro.

Response to anti-VEGF-A treatment of endothelial cells in vitro.

This study was conducted to compare the effects of two anti-VEGF-A drugs, Ranibizumab and Aflibercept, on the expression and secretion of VEGFs family members, and on their influence in proliferation and migration of endothelial cells (HECV) in vitro. HECV cells were exposed 24 h (T1), 4 days (T2) and 6 days (T3) to Ranibizumab or Aflibercept at pharmacodynamically relevant concentrations (Ranibizumab: 12.5 μg/ml and 125 μg/ml; Aflibercept: 50 μg/ml and 500 μg/ml).

Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics.

The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6.

Effects of High Glucose Levels and Glycated Serum on GIP Responsiveness in the Pancreatic Beta Cell Line HIT-T15.

Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone produced in the gastrointestinal tract that stimulates glucose dependent insulin secretion. Impaired incretin response has been documented in diabetic patients and was mainly related to the inability of the pancreatic beta cells to secrete insulin in response to GIP. Advanced Glycation End Products (AGEs) have been shown to play an important role in pancreatic beta cell dysfunction.

Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes.

In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion.

Advanced glycation end products play adverse proinflammatory activities in osteoporosis.

Osteoporosis is a major public health burden that is expected to further increase as the global population ages. In the last twenty years, advanced glycation end products (AGEs) have been shown to be critical mediators both in the pathogenesis and development of osteoporosis and other chronic degenerative diseases related to aging. The accumulation of AGEs within the bone induces the formation of covalent cross-links with collagen and other bone proteins which affects the mechanical properties of tissue and disturbs bone remodelling and deterioration, underlying osteoporosis.

Glucagon-like peptide-1 secreting cell function as well as production of inflammatory reactive oxygen species is differently regulated by glycated serum and high levels of glucose.

Glucagon-like peptide-1 (GLP-1), an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS) or high levels of glucose (HG)) may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag.

Retinal pigment epithelial cells express a functional receptor for glucagon-like peptide-1 (GLP-1).

Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that has been shown to improve glucose homeostasis in type 2 diabetes. The biological effects of GLP-1 are mediated by its specific receptor GLP-1R that is expressed in a wide range of tissues, where it is responsible of the extra-pancreatic effects of GLP-1. Since the retinal pigment epithelium (RPE), that forms the outer retinal barrier, has a key role in protecting from diabetic retinopathy (DR), we investigated the potential expression and function of GLP-1R in a RPE cell line.

Update on the protective molecular pathways improving pancreatic beta-cell dysfunction.

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes.

Glucagon-like peptide-1 triggers protective pathways in pancreatic beta-cells exposed to glycated serum.

Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture.

An emerging role of glucagon-like peptide-1 in preventing advanced-glycation-end-product-mediated damages in diabetes.

Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake.

Vascular endothelial growth factor-C secretion is increased by advanced glycation end-products: possible implication in ocular neovascularization.

Purpose: Neovascularization is a common complication of many degenerative and vascular diseases of the retina. Advanced glycation end-products (AGEs) have a pathologic role in the development of retinal neovascularization, mainly for their ability in upregulating vascular endothelial growth factor-A (VEGF-A) secretion. The aim of this study was to investigate whether AGEs are able to modulate the secretion of VEGF-C, another angiogenic factor that increases the effect of VEGF-A.