Non-competitive inhibition of myo-inositol transport in cultured bovine retinal capillary pericytes by glucose and reversal by Sorbinil

Inflammation, Aging and Cancer: Friend or Foe?

“…The influence of these hormones and growth factors on multiple organs and sub-cellular systems (e.g., CNS and brain cognition, stem cells, mitochondrial function, neurogenesis and myelination, traumatic injury, wound healing responses) in reproductive and non-reproductive, immune and non-immune systems and their association in the development of chronic diseases or cancer have been the topic of extensive studies (Davis et al, 2011, Deng et al, 2008, Khatami 2009, Mikkola and Clakson 2002, Pisani 2008, Piatkliewicz and Czech 2011, Poulsen and Kruger 2006, Rauvala and Rouhianen 2001, Ren et al, 2009, Schwarts and Pashko 2004. For example, steroids or insulin play important roles not only in the function of reproductive organs and regulation of fluid homeostasis and/or metabolic pathways and immune responses to stress, but they are also involved in physiology, function and remodeling of bone, neuronal function, myelination and neurogeneration of brain and CNS and/or membrane-associated fatty acid metabolism (Bosch et al, 2002, Brunello et al, 2011, Campisi 2011, Chung et al, 2011, Goronzy and Wavand 2005, Hotamisisligil 2006, Khatami 1990, Li et al, 1986, Mikkola and Clarkson 2002, Sansoni et al, 2008, Simon and Balkau 2010, van Kruijsdijk et al, 2009). Insulin deficiency, insulin-resistance or hyper-insulinimia, or glucose toxicity and hyperglycemia of diabetes-induced increased glycosylation of proteins (advanced glycation end-products-AGE and their receptors RAGE) are associated with disturbances in transport and metabolism of important nutrients (e.g., ascorbic acid, pyridoxal phosphate, myo-inositol, etc), increased oxidative stress, accumulation of ROS, and co-expression of pro-and anti-inflammatory mediators such as NF-kB, VEGF, TNF-, IL1a, IL-6, IL-8, IL-12, and Ikappa B kinase (IKK-), platelets' CD40L, VCAM-1, in endothelial, hepatocytes or myeloid cells and/or tissues that are insulin-dependent (e.g., muscle, liver, adipocytes) or insulin-independent (e.g., vasculature, kidney, nerves, retina, RPE, lens) for glucose transport or metabolism , 1990, Li et al, 1986, Park et al, 2005…”

“…For example, steroids or insulin play important roles not only in the function of reproductive organs and regulation of fluid homeostasis and/or metabolic pathways and immune responses to stress, but they are also involved in physiology, function and remodeling of bone, neuronal function, myelination and neurogeneration of brain and CNS and/or membrane-associated fatty acid metabolism (Bosch et al, 2002, Brunello et al, 2011, Campisi 2011, Chung et al, 2011, Goronzy and Wavand 2005, Hotamisisligil 2006, Khatami 1990, Li et al, 1986, Mikkola and Clarkson 2002, Sansoni et al, 2008, Simon and Balkau 2010, van Kruijsdijk et al, 2009). Insulin deficiency, insulin-resistance or hyper-insulinimia, or glucose toxicity and hyperglycemia of diabetes-induced increased glycosylation of proteins (advanced glycation end-products-AGE and their receptors RAGE) are associated with disturbances in transport and metabolism of important nutrients (e.g., ascorbic acid, pyridoxal phosphate, myo-inositol, etc), increased oxidative stress, accumulation of ROS, and co-expression of pro-and anti-inflammatory mediators such as NF-kB, VEGF, TNF-, IL1a, IL-6, IL-8, IL-12, and Ikappa B kinase (IKK-), platelets' CD40L, VCAM-1, in endothelial, hepatocytes or myeloid cells and/or tissues that are insulin-dependent (e.g., muscle, liver, adipocytes) or insulin-independent (e.g., vasculature, kidney, nerves, retina, RPE, lens) for glucose transport or metabolism , 1990, Li et al, 1986, Park et al, 2005, Pisan 2008, Piatkiewicz and Czech 2011, Simon and Balkau 2010, Stern et al, 2002. The relationship between diabetes, inflammation and production of AGE/RAGE and the increased risk of certain cancers has been the topic of many recent studies (Piatkiewicz and Czech 2011, Simon and Balkau 2010, Simon et al, 2010, Zhang and Hu 2010.…”

Altered endothelin-1 induced contraction and second messenger generation in bovine retinal microvascular pericytes cultured in high glucose medium

“…Previous work has shown that sodium-dependent, ouabain-sensitive myoinositol uptake in BRP is inhibited by elevated glucose concentrations [27]. This results in a decrease in their myoinositol content and is associated with a reduction of both their basal PIP2 levels and phospholipase C activity [28].…”

Comparison of the Effects of Zopolrestat and Sorbinil on Lens Myo lnositol Influx

“…MI is actively transported into the cells of many tissues. The effects of glucose on Ml transport are described both as competitive and noncompetitive [19][20][21], In the ocular lens, acute exposure to high glucose concentrations lowers the maximal transport rale and increases the concentration at which MI influx is half maximally activated, which represents a mixed competitive and noncom petitive inhibition [19][20][21]. Our previous work showed that the competitive component re sults from direct competition of ¿¿glucose with the MI transporter, whereas the noncom petitive component is the result of a high intra cellular sorbitol concentration [8].…”