Hepatotoxicity and Langerhans islets regenerative effects of polar and neutral lipids of Nigella sativa L. in nicotinamide/streptozotocin-induced diabetic rats

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Global upregulation of gene expression associated with renal dysfunction in DOCA-salt-induced hypertensive rats occurs via signaling cascades involving epidermal growth factor receptor: A microarray analysis

Renal dysfunction is a major cause of morbidity and mortality in patients with hypertension. In an attempt to understand the molecular mechanisms leading to renal dysfunction and in particular that of epidermal growth factor receptor (EGFR) and RasGTPase signaling, we analyzed global gene expression changes in the kidneys of deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats with and without treatment with AG1478, a selective inhibitor of EGFR tyrosine kinase, or FPTIII, a farnesyl transferase inhibitor known to inhibit RasGTPase. Microarray-based global gene expression analysis was performed in triplicate for each rat kidney taken from normotensive Wistar rats, DOCA-salt hypertensive (DH) rats, DH rats treated with AG1478, or DH rats treated with FPTIII. From the initial data set of 10,163 gene spots per group, upregulation of 2398 genes and downregulation of only 50 genes by more than 2-fold was observed in hypertensive rat kidneys compared to non-diseased controls. Interestingly, treatment of animals with AG1478 or FPTIII prevented upregulation of more than 97% of genes associated with hypertension in the rat kidney. Analysis of proteinuria, renal artery responsiveness and histopathology studies confirmed that DOCA-salt hypertensive rats had developed kidney damage over the study period and that this kidney dysfunction could be significantly prevented upon AG1478 or FPTIII treatment without normalising blood pressure. Taken together. our data imply that signaling cascades involving EGFR and/or RasGTPase pathways are key contributors to the induction of renal damage in hypertension and these and potentially other downstream effector molecules may serve as novel targets for therapeutic intervention. (C) 2009 Elsevier Inc. All rights reserved.Renal dysfunction is a major cause of morbidity and mortality in patients with hypertension. In an attempt to understand the molecular mechanisms leading to renal dysfunction and in particular that of epidermal growth factor receptor (EGFR) and RasGTPase signaling, we analyzed global gene expression changes in the kidneys of deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats with and without treatment with AG1478, a selective inhibitor of EGFR tyrosine kinase, or FPTIII, a farnesyl transferase inhibitor known to inhibit RasGTPase. Microarray-based global gene expression analysis was performed in triplicate for each rat kidney taken from normotensive Wistar rats, DOCA-salt hypertensive (DH) rats, DH rats treated with AG1478, or DH rats treated with FPTIII. From the initial data set of 10,163 gene spots per group, upregulation of 2398 genes and downregulation of only 50 genes by more than 2-fold was observed in hypertensive rat kidneys compared to non-diseased controls. Interestingly, treatment of animals with AG1478 or FPTIII prevented upregulation of more than 97% of genes associated with hypertension in the rat kidney. Analysis of proteinuria, renal artery responsiveness and histopathology studies confirmed that DOCA-salt hypertensive rats had developed kidney damage over the study period and that this kidney dysfunction could be significantly prevented upon AG1478 or FPTIII treatment without normalising blood pressure. Taken together, our data imply that signaling cascades involving EGFR and/or RasGTPase pathways are key contributors to the induction of renal damage in hypertension and these and potentially other downstream effector molecules may serve as novel targets for therapeutic intervention.</p

Early inhibition of EGFR signaling prevents diabetes-induced up-regulation of multiple gene pathways in the mesenteric vasculature

Diabetes mellitus is associated with vascular complications including an impairment of vascular function and alterations in the reactivity of blood vessels to vasoactive hormones. However, the signaling mechanisms leading to vascular dysfunction in diabetes are not fully understood. This microarray-based study was designed to identify differential gene expression between the normal and diabetic mesenteric vasculature and to investigate the effect of inhibiting epidermal growth factor receptor (EGFR) signaling on global gene expression in the mesenteric bed of streptozotocin (STZ)-induced diabetic rats Transcriptome analysis was performed in triplicate using oligonucleotide microarrays housing 10,000 rat genes on the mesenteric bed of normal. diabetic. and diabetic rats treated with AG1478, a selective inhibitor of EGFR Four weeks of diabetes led to a profound alteration in gene expression within the mesenteric bed with 1167 of the 3074 annotated genes being up-regulated and 141 genes down-regulated by at least 2-fold. The up-regulated gene ontologies included receptor tyrosine kinases. G-protein coupled receptors and ion channel activity. In particular, significant overexpressions of colipase, phospholipase A2. carboxypeptidases. and receptor tyrosine kinases such as EGFR, erbB2 and fibroblast growth factor receptor were observed in diabetes mesenteric vasculature. A 4 week intraperitoneal treatment of diabetic animals with AG1478 (1.2 mg/kg/alt diem) beginning on the same day as STZ injection prevented up-regulation of the majority (similar to 95%) of the genes associated with STZ diabetes including those apparently "unrelated" to the known EGFR pathway without correction of hyperglycemia These results suggest that activation of EGFR signaling is a key initiating step that leads to induction of multiple signaling pathways in the development of diabetes-induced vascular dysfunction. Thus, therapeutic targeting of EGFR may represent a novel strategy for the prevention and/or treatment of vascular dysfunction in diabetes. (C) 2009 Elsevier Inc All rights reserved.Diabetes mellitus is associated with vascular complications including an impairment of vascular function and alterations in the reactivity of blood vessels to vasoactive hormones. However, the signaling mechanisms leading to vascular dysfunction in diabetes are not fully understood. This microarray-based study was designed to identify differential gene expression between the normal and diabetic mesenteric vasculature and to investigate the effect of inhibiting epidermal growth factor receptor (EGFR) signaling on global gene expression in the mesenteric bed of streptozotocin (STZ)-induced diabetic rats. Transcriptome analysis was performed in triplicate using oligonucleotide microarrays housing 10,000 rat genes on the mesenteric bed of normal, diabetic, and diabetic rats treated with AG1478, a selective inhibitor of EGFR. Four weeks of diabetes led to a profound alteration in gene expression within the mesenteric bed with 1167 of the 3074 annotated genes being up-regulated and 141 genes down-regulated by at least 2-fold. The up-regulated gene ontologies included receptor tyrosine kinases, G-protein coupled receptors and ion channel activity. In particular, significant overexpressions of colipase, phospholipase A2, carboxypeptidases, and receptor tyrosine kinases such as EGFR, erbB2 and fibroblast growth factor receptor were observed in diabetes mesenteric vasculature. A 4-week intraperitoneal treatment of diabetic animals with AG1478 (1.2 mg/kg/alt diem) beginning on the same day as STZ injection prevented up-regulation of the majority (approximately 95%) of the genes associated with STZ diabetes including those apparently &quot;unrelated&quot; to the known EGFR pathway without correction of hyperglycemia. These results suggest that activation of EGFR signaling is a key initiating step that leads to induction of multiple signaling pathways in the development of diabetes-induced vascular dysfunction. Thus, therapeutic targeting of EGFR may represent a novel strategy for the prevention and/or treatment of vascular dysfunction in diabetes.</p

Effect of molecular weight and concentration hyaluronan on the in-vitro release characteristics of ibuprofen and diclofenac sodium across cellulose membrane

BPC Science AbstractsHyaluronan (HA) is a naturally occurring polyanionic glycosaminoglycan. Drugs formulated in HA and applied topically are retained in the skin with little systemic absorption (Brown et al 2000, 2001). However, the precise mechanism of action of HA that facilitates drug delivery and promotes drug localization remain unclear. In this study we investigated the in-vitro release characteristics of two NSAID drugs, ibuprofen (IBF) and diclofenac sodium (DFS), incorporated into vehicles containing four different molecular weight (MW) grades and different concentrations of HA across cellulose membranePeer reviewe

A reappraisal of xanthine dehydrogenase and oxidase in hypoxic reperfusion injury: the role of NADH as an electron donor

Xanthine oxidase (XO) is conventionally known as a generator of reactive oxygen species (ROS) which contribute to hypoxic-reperfusion injury in tissues. However, this role for human XO is disputed due to its distinctive lack of activity towards xanthine, and the failure of allopurinol to suppress reperfusion injury. In this paper, we have employed native gel electrophoresis together with activity staining to investigate the role human xanthine dehydrogenase (XD) and XO in hypoxic reperfusion injury. This approach has provided information which cannot be obtained by conventional spectrophotometric assays. We found that both XD and XO of human umbilical vein endothelial cells (HUVECs) and lymphoblastic leukaemic cells (CEMs) catalysed ROS generation by oxidising NADH, but not hypoxanthine. The conversion of XD to XO was observed in both HUVECs and CEMs in response to hypoxia, although the level of conversion varied. Purified human milk XD generated ROS more efficiently in the presence of NADH than in the presence of hypoxanthine. This NADH oxidising activity was blocked by the FAD site inhibitor, diphenyleneiodonium (DPI), but was not suppressible by the molybdenum site inhibitor, allopurinol. However, in the presence of both DPI and allopwinol the activities of XD/XO were completely blocked with either NADH or hypoxanthine as substrates. We conclude that both human XD and XO can oxidise NADH to generate ROS. Therefore, the conversion of XD to XO is not necessary for post-ischaemic ROS generation. The hypoxic-reperfusion injury hypothesis should be reappraised to take into account the important role played by XD and XO in oxidising NADH to yield ROS