4-Methlycatechol prevents NGF/p75(NTR)-mediated apoptosis via NGF/TrkA system in pancreatic beta cells

In this study, it was aimed to investigate whether 4-methylcatechol (4-MC) could serve as an autocrine antiapoptotic agent by increasing nerve growth factor (NGF) in beta cells of hyperglycemic rats. Rats were divided into four groups: the first group was given citrate buffer and saline, the second group was administered 4-MC, the third group received streptozotocin (STZ), and the fourth group was given both 4-MC and STZ. 4-MC (10 mu g/kg) was administered by daily intraperitoneal injection for 10 days before the animals were rendered hyperglycemic by administration of STZ (75 mg/kg). With 4-MC pretreatment on hyperglycemic rats the following results were noted: (i) Increase in plasma glucose, beta cell apoptosis and caspase-8 activation was prevented. (ii) Reduction of NGF(+) and tyrosine receptor kinase A (TrkA)(+) beta cell number was blocked. (iii) p75 neurotrophin receptor (p75(NTR))(+) beta cell number was increased. These data suggest that 4-MC might exert its antiapoptotic actions through NGF/TrkA system which may block NGF/p75(NTR) activation in pancreatic beta cells of hyperglycemic rats. (C) 2011 Elsevier Ltd. All rights reserved

Ras signaling in NGF reduction and TNF-alpha-related pancreatic beta cell apoptosis in hyperglycemic rats

Recent evidence suggested that tumor necrosis factor-alpha (TNF-alpha) and nerve growth factor (NGF) withdrawal activated a common apoptotic pathway. Here, we aimed to investigate the possible role of apoptotic Ras effectors RASSF1 and NORE1 in NGF reduction and TNF-alpha-related beta cell apoptosis in streptozotocin (STZ)-induced hyperglycemic rats. Rats were divided into four groups: the first group was given saline and citrate buffer, the second group was injected 4-methylcatechol (4-MC), an inducer of NGF synthesis, the third group received STZ, and the fourth group was given both 4-MC and STZ. 4-MC (10 mu g/kg) was administered by daily intraperitoneal injection for 10 days before the animals were rendered hyperglycemic by administration of single dose STZ (75 mg/kg). With 4-MC pretreatment to hyperglycemic rats the following results were noted: (i) Decrease in pancreatic NGF level was blocked, (ii) Increase in pancreatic TNF-alpha level and the number of TNF-alpha(+) beta cell in the islets were prevented, (iii) Increase in the number of beta cell synthhesized apoptotic Ras effectors that RASSF1 and NORE1 was blocked, (iv) While pancreatic lipid peroxidation level decreased, antioxidant molecule glutathione and antioxidant enzymes glutathione peroxidase, catalase and superoxide dismutase activities increased, (v) Pancreatic caspase-3 activity and the number of cleaved caspase-3(+) beta cells were decreased. These results strengthen the idea that TNF-alpha and reduction in NGF can activate a common apoptotic pathway. Moreover, these data display that new apoptotic Ras effector molecules RASSF1 and NORE1 play important role with oxidative stress in NGF reduction and TNF-alpha-related pancreatic beta cell apoptosis in hyperglycemic rats. Furthermore, these findings suggest that 4-MC can prevent beta cell apoptosis possibly through increasing NGF synthesis in hyperglycemic rats

Exendin-4 exerts its effects through the NGF/p75(NTR) system in diabetic mouse pancreas

Glucagon-like peptide-1 (GLP-1) ameliorates the symptoms of diabetes through stimulation of insulin secretion. We have investigated the possible components of cellular mechanism triggered by exendin-4, a potent GLP-1 receptor agonist, in streptozotocin (STZ) induced diabetic mice pancreas. BALB/c male mice were divided into four groups for this investigation. The first group was given citrate buffer only, the second group was administered exendin-4 alone, the third group received STZ, and the fourth group was given both STZ and exendin-4. Exendin-4 (3 mu g/kg) was administered by daily subcutaneous injection for 30 days after the animals were rendered diabetic by administration of STZ (200 mg/kg). With exendin-4 treatment on diabetic mice, the following results were noted: (i) exendin-4 suppressed the increase in plasma glucose and inhibited somatostatin expression induced by STZ, (ii) reduction of insulin prevalence was inhibited, while expression of p75 neurotrophin receptor (p75(NTR)), pancreatic nerve growth factor (NGF), and NGF-positive islet cell prevalence increased, (iii) there were no alterations in the severity of proliferated cell nuclear antigen positive or apoptotic beta cells in pancreatic islets, and (iv) pancreatic catalase, glutathione peroxidase, and superoxide dismutase activities significantly increased. In conclusion, these data suggest that exendin-4 might exert its actions through the NGF/p75(NTR) system and decrease somatostatin expression

Prostaglandin-E1 has a protective effect on renal ischemia/reperfusion-induced oxidative stress and inflammation mediated gastric damage in rats.

Gastrointestinal complications are frequent in renal transplant recipients. In this regard, renal ischemia/reperfusion injury (IRI)-induced gastric damage seems to be important and there is no data available on the mechanism of this pathology. Because of its anti-inflammatory and anti-oxidant properties, it can be suggested that prostaglandin-E-1 (PGE(1)) protects cells from renal IRI-induced gastric damage. The aim of this study was to investigate the molecular mechanisms of gastric damage induced by renal IRI and the effect of PGE(1) on these mechanisms. We set an experiment with four different animal groups: physiological saline-injected and sham-operated rats, PGE(1) (20 mu g/kg)-administered and sham operated rats, renal IRI subjected rats, and PGE(1)-radministered and renal IRI subjected rats. The protective effect of PGE(1) on renal IRI-induced gastric damage was determined based on reduced histological damage and lactate dehydrogenase activity. Moreover, we demonstrated that PGE(1) shows its protective effect through reducing the production of reactive oxygen species and malondialdehyde levels. During histological examination, we observed the presence of common mononuclear cell infiltration. Therefore, pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta levels were measured and it has been shown that PGE(1) suppressed both cytokines. Furthermore, it was found that PGE(1) reduced the number of NF-kappa B+ and caspase-3(+) inflammatory cells, and also NF-kappa B DNA-binding activity, while increasing proliferating cell nuclear antigen epithelial cells in the stomach tissue of rats subjected to renal IR. Our data showed that PGE(1), has a protective effect on renal IRI-induced oxidative stress and inflammation mediated gastric damage in rats. (C) 2016 Elsevier B.V. All rights reserved

The relation among NGF, EGF and insulin is important for triggering pancreatic beta cell apoptosis

Background Nerve growth factor (NGF) is a well-known mediator for maintaining the survival of neurons, while recent studies report that its absence induces apoptosis in cultured beta cells of humans and rats. However, its relationship with other growth factors that have important roles in the survival and function of beta cells such as epidermal growth factor (EGF) has not yet been elucidated. The aim of this study was to investigate the effects of NGF withdrawal on the synthesis and secretion of EGF, insulin with respect to beta cell apoptosis in hyperglycemic rats

Exendin-4 attenuates renal tubular injury by decreasing oxidative stress and inflammation in streptozotocin-induced diabetic mice.

In this study, we aimed to research the restorative effects of exendin-4, a GLP-1 analog, on renal tubular injury in streptozotocin-induced diabetes model. BALB/c male mice were divided into four groups: non-diabetic, non-diabetic+exendin-4 (3g/kg), diabetic and diabetic+exendin-4. In our diabetic model, we observed renal injury mainly in tubular area rather than glomeruli and exendin-4 decreased tubular injury with its glucose lowering effect. Besides, PCNA positive tubular cells, activities of LDH and Na+-K+-ATPase were also significantly declined by the administration of exendin-4. Furthermore, exendin-4 attenuated the levels of ROS, MDA, 8-OHdG, proinflammatory cytokines (TNF-, IL-1), chemokine MCP-1, ICAM-1, and fibrosis-related molecules (transforming growth factor 1 and fibronectin). In consistent with reducing tubular injury, macrophage infiltration and both MCP-1 and ICAM-1 production in tubular cells were decreased. These results indicate that exendin-4 may decrease renal tubular injury seen in the beginning of diabetic nephropathy by decreasing ROS production and inflammation