Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme ... more Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme α-galactosidase A. The incidence, ranging from one over 40 000 to one over 11 7000 worldwide is probably underestimated due to its unspecific pattern of presentation. The symptoms, including neurological, gastrointestinal, renal, ophthalmological and dermatologic manifestations, start in childhood and adolescence, cause a significant morbidity and are likely to affect the patient's quality of life. Furthermore, Anderson-Fabry disease always progress leading to a multiorgan dysfunction and life-threatening complications with end-stage renal disease, cardiomyopathy and high incidence of stroke. The estimated life in untreated patients is reduced by 15-20 years respectively in men and women. The enzyme replacement therapy, available in Europe from 2001, results in a reduction of major organs failure, morbidity and mortality. We present the case of an 8-year-old male admitted to our Divi...
ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological fun... more ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increased beta-cell cAMP and activated extracellular signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its antiapoptotic effect was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on beta-cell survival. In human islets, obestatin, whose immunoreactivity colocalized with that of ghrelin, promoted cell survival and blocked cytokine-induced apoptosis through cAMP increase and involvement of adenylyl cyclase/cAMP/PKA signaling. Moreover, obestatin 1) induced PI 3-kinase/Akt, ERK1/2, and also cAMP response element-binding protein phosphorylation; 2) stimulated insulin secretion and gene expression; and 3) upregulated GLP-1R, IRS-2, pancreatic and duodenal homeobox-1, and glucokinase mRNA. These results indicate that obestatin promotes beta-cell and human islet cell survival and stimulates the expression of main regulatory beta-cell genes, identifying a new role for this peptide within the endocrine pancreas.
ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological fun... more ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increased beta-cell cAMP and activated extracellular signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its antiapoptotic effect was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on beta-cell survival. In human islets, obestatin, whose immunoreactivity colocalized with that of ghrelin, promoted cell survival and blocked cytokine-induced apoptosis through cAMP increase and involvement of adenylyl cyclase/cAMP/PKA signaling. Moreover, obestatin 1) induced PI 3-kinase/Akt, ERK1/2, and also cAMP response element-binding protein phosphorylation; 2) stimulated insulin secretion and gene expression; and 3) upregulated GLP-1R, IRS-2, pancreatic and duodenal homeobox-1, and glucokinase mRNA. These results indicate that obestatin promotes beta-cell and human islet cell survival and stimulates the expression of main regulatory beta-cell genes, identifying a new role for this peptide within the endocrine pancreas.
The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and... more The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms. Reverse transcriptase-polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the beta-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia-reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36. Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.
In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activ... more In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activation (PA) and impaired antioxidant status (AS), all predisposing factors for cardiovascular disease leading to increased morbidity and mortality. Furthermore, the metabolic syndrome (MetS) is an important cardiovascular risk factor, which progressively develops and may already be present during late childhood or adolescence. However, scarce data exist on oxidative-antioxidant balance and PA in childhood and adolescence in the presence of partial (PMetS) or full MetS. The aim of the study was to evaluate OS, PA, and AS in prepubertal and adolescent obese girls with partial or full MetS. 96 girls with a clinical and metabolic evaluation for obesity and 44 healthy normal-weight sex- and age-matched girls were studied. IDF-adopted criteria were used to define full and partial MetS and the patient population was divided into 4 groups: the first comprised 31 pre-pubertal girls with PMetS (PR-PMetS), the second 37 adolescents with PMetS (AD-PMetS), the third 10 prepubertal girls with full MetS (PR-MetS), and the fourth 18 adolescents with full MetS (AD-MetS). The OS was evaluated by measuring plasma 15-F(2t)-Isoprostane levels (15-F(2t)-IsoP) and protein carbonyls, PA by thromboxane B(2) levels (TXB(2)), and AS by serum vitamin E and plasma total antioxidant capacity (TAC) levels. 15-F(2t)-IsoP, protein carbonyls, and TXB(2) levels were significantly gradually amplified, and vitamin E and TAC reduced, and significantly correlated with obesity from childhood to adolescence and from partial to full MetS. This study demonstrates the loss of the normal homeostatic balance between oxidant-antioxidant state in obese children and adolescents with manifestations of partial and full MetS.
The hypothalamic hormone growth hormone-releasing hormone (GHRH), has been shown to function via ... more The hypothalamic hormone growth hormone-releasing hormone (GHRH), has been shown to function via its receptor splice variants as an autocrine/paracrine growth factor in normal and malignant cell lines and tissues, besides positively regulating growth hormone (GH) ...
Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiov... more Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation. A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months. The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed. NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.
The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a ye... more The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a yet undefined receptor; however, its potential neuroprotective activities are still unknown. Here, obestatin effects were investigated on proliferation and survival of adult rat hippocampal progenitor cells (AHPs). Obestatin immunoreactivity was found in AHPs; moreover, obestatin binding to AHPs was displaced by the GLP-1R agonist Ex-4 and antagonist Ex-9. Furthermore, obestatin increased cell proliferation and survival in growth factor deprived medium and inhibited apoptosis; these effects were blocked by Ex-9. The underlying mechanisms involved Gαs/cAMP/PKA/CREB signaling, phosphorylation of ERK1/2 and PI3K/Akt, and the PI3K targets GSK-3β/β-catenin and mTOR. Obestatin also counteracted Aβ1-42-induced detrimental effects through inhibition of GSK-3β activity and Tau hyperphosphorylation, main hallmarks of neuronal death in Alzheimer's disease. These findings indicate a novel protective role for obestatin in AHPs and candidate this peptide as potential therapeutic target for increasing neurogenesis and for approaching neurodegenerative disorders.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012
The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investi... more The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion....
Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions ar... more Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestat...
The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulati... more The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects; hence, it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. Human des-acyl ghrelin [1.2 nmol/kg per hour] was infused intravenously for 15 minutes, followed by washout (rebaseline) and infusion of acyl ghrelin at the same dose. (3)H-oleate and (14)C-glucose were coinfused and arterial and coronary sinus blood sampled to measure cardiac free fatty acid and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF because baseline oxidation levels of free fatty acids and glucose were, respectively, >70% lower and >160% higher compared with control. Neither des-acyl ghr...
Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme ... more Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme α-galactosidase A. The incidence, ranging from one over 40 000 to one over 11 7000 worldwide is probably underestimated due to its unspecific pattern of presentation. The symptoms, including neurological, gastrointestinal, renal, ophthalmological and dermatologic manifestations, start in childhood and adolescence, cause a significant morbidity and are likely to affect the patient's quality of life. Furthermore, Anderson-Fabry disease always progress leading to a multiorgan dysfunction and life-threatening complications with end-stage renal disease, cardiomyopathy and high incidence of stroke. The estimated life in untreated patients is reduced by 15-20 years respectively in men and women. The enzyme replacement therapy, available in Europe from 2001, results in a reduction of major organs failure, morbidity and mortality. We present the case of an 8-year-old male admitted to our Divi...
ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological fun... more ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increased beta-cell cAMP and activated extracellular signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its antiapoptotic effect was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on beta-cell survival. In human islets, obestatin, whose immunoreactivity colocalized with that of ghrelin, promoted cell survival and blocked cytokine-induced apoptosis through cAMP increase and involvement of adenylyl cyclase/cAMP/PKA signaling. Moreover, obestatin 1) induced PI 3-kinase/Akt, ERK1/2, and also cAMP response element-binding protein phosphorylation; 2) stimulated insulin secretion and gene expression; and 3) upregulated GLP-1R, IRS-2, pancreatic and duodenal homeobox-1, and glucokinase mRNA. These results indicate that obestatin promotes beta-cell and human islet cell survival and stimulates the expression of main regulatory beta-cell genes, identifying a new role for this peptide within the endocrine pancreas.
ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological fun... more ABSTRACT Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increased beta-cell cAMP and activated extracellular signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its antiapoptotic effect was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on beta-cell survival. In human islets, obestatin, whose immunoreactivity colocalized with that of ghrelin, promoted cell survival and blocked cytokine-induced apoptosis through cAMP increase and involvement of adenylyl cyclase/cAMP/PKA signaling. Moreover, obestatin 1) induced PI 3-kinase/Akt, ERK1/2, and also cAMP response element-binding protein phosphorylation; 2) stimulated insulin secretion and gene expression; and 3) upregulated GLP-1R, IRS-2, pancreatic and duodenal homeobox-1, and glucokinase mRNA. These results indicate that obestatin promotes beta-cell and human islet cell survival and stimulates the expression of main regulatory beta-cell genes, identifying a new role for this peptide within the endocrine pancreas.
The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and... more The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms. Reverse transcriptase-polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the beta-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia-reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36. Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.
In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activ... more In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activation (PA) and impaired antioxidant status (AS), all predisposing factors for cardiovascular disease leading to increased morbidity and mortality. Furthermore, the metabolic syndrome (MetS) is an important cardiovascular risk factor, which progressively develops and may already be present during late childhood or adolescence. However, scarce data exist on oxidative-antioxidant balance and PA in childhood and adolescence in the presence of partial (PMetS) or full MetS. The aim of the study was to evaluate OS, PA, and AS in prepubertal and adolescent obese girls with partial or full MetS. 96 girls with a clinical and metabolic evaluation for obesity and 44 healthy normal-weight sex- and age-matched girls were studied. IDF-adopted criteria were used to define full and partial MetS and the patient population was divided into 4 groups: the first comprised 31 pre-pubertal girls with PMetS (PR-PMetS), the second 37 adolescents with PMetS (AD-PMetS), the third 10 prepubertal girls with full MetS (PR-MetS), and the fourth 18 adolescents with full MetS (AD-MetS). The OS was evaluated by measuring plasma 15-F(2t)-Isoprostane levels (15-F(2t)-IsoP) and protein carbonyls, PA by thromboxane B(2) levels (TXB(2)), and AS by serum vitamin E and plasma total antioxidant capacity (TAC) levels. 15-F(2t)-IsoP, protein carbonyls, and TXB(2) levels were significantly gradually amplified, and vitamin E and TAC reduced, and significantly correlated with obesity from childhood to adolescence and from partial to full MetS. This study demonstrates the loss of the normal homeostatic balance between oxidant-antioxidant state in obese children and adolescents with manifestations of partial and full MetS.
The hypothalamic hormone growth hormone-releasing hormone (GHRH), has been shown to function via ... more The hypothalamic hormone growth hormone-releasing hormone (GHRH), has been shown to function via its receptor splice variants as an autocrine/paracrine growth factor in normal and malignant cell lines and tissues, besides positively regulating growth hormone (GH) ...
Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiov... more Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation. A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months. The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed. NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.
The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a ye... more The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a yet undefined receptor; however, its potential neuroprotective activities are still unknown. Here, obestatin effects were investigated on proliferation and survival of adult rat hippocampal progenitor cells (AHPs). Obestatin immunoreactivity was found in AHPs; moreover, obestatin binding to AHPs was displaced by the GLP-1R agonist Ex-4 and antagonist Ex-9. Furthermore, obestatin increased cell proliferation and survival in growth factor deprived medium and inhibited apoptosis; these effects were blocked by Ex-9. The underlying mechanisms involved Gαs/cAMP/PKA/CREB signaling, phosphorylation of ERK1/2 and PI3K/Akt, and the PI3K targets GSK-3β/β-catenin and mTOR. Obestatin also counteracted Aβ1-42-induced detrimental effects through inhibition of GSK-3β activity and Tau hyperphosphorylation, main hallmarks of neuronal death in Alzheimer's disease. These findings indicate a novel protective role for obestatin in AHPs and candidate this peptide as potential therapeutic target for increasing neurogenesis and for approaching neurodegenerative disorders.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012
The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investi... more The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion....
Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions ar... more Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of beta-cells and human pancreatic islets and the underlying signaling pathways. beta-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. Obestatin showed specific binding on HIT-T15 and INS-1E beta-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-gamma/tumor necrosis factor-alpha/interleukin-1 beta treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys(3)]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in beta-cells and human islets. beta-Cells and islet cells released obestat...
The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulati... more The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects; hence, it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. Human des-acyl ghrelin [1.2 nmol/kg per hour] was infused intravenously for 15 minutes, followed by washout (rebaseline) and infusion of acyl ghrelin at the same dose. (3)H-oleate and (14)C-glucose were coinfused and arterial and coronary sinus blood sampled to measure cardiac free fatty acid and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF because baseline oxidation levels of free fatty acids and glucose were, respectively, >70% lower and >160% higher compared with control. Neither des-acyl ghr...
Uploads
Papers by Fabio Settanni