325 research outputs found
Acute promyelocytic leukemia following mitoxantrone as single agent for the treatment of multiple sclerosis
No full textConformational Analysis f Organic Carbonyl Compounds. Part 3. A 1H and 13C Nuclear Magnetic Resonance Study of Formyl and Acetyl Derivatives of Benzo[b]furan
No full textA conformational study of formyl and acetyl derivatives of benzo[b]furan provides evidences that in the case of 2- and 7-derivatives, the E,Z-conformational mixture is solvent dependent: the Z prevailing in solvent with higher polarity
Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin
No full textSeveral proteins, including transthyretin (TTR), can generate in tissues extracellular insoluble aggregates, in the form of fibrils, that are associated with pathological states known as amyloidoses. To date, more than 80 different TTR point mutations have been associated with hereditary amyloidosis in humans. In vitro, the formation of amyloid fibrils by human TTR is known to be triggered by acidic pH. We show here that, in vitro, the natural amyloidogenic I84S and the non-natural I84A TTR mutant forms exhibit a propensity to produce fibrils in an acidic medium significantly higher than that of wild-type TTR. The two mutant forms have been crystallized at both neutral and acidic pH. Their neutral pH crystal structures are very similar to that of wild-type TTR, consistent with previous evidence indicating that only minor structural changes are induced by amyloidogenic mutations. On the contrary, their crystal structures at moderately low pH (4.6) show significant conformational differences as compared to their neutral pH structures. Remarkably, such changes are not induced in wild-type TTR crystallized at low pH. The most relevant consist of the unwinding of the TTR short α-helix and of the change in conformation of the loop connecting the α-helix to β-strand F. Only one monomer of the crystallographic dimer is affected, causing a disruption of the tetrameric symmetry. This asymmetry and a possible destabilization of the tetrameric quaternary structure of TTR may be responsible for the amyloidogenic potential of the two TTR mutant forms at low pH
Conformational Analysis f Organic Carbonyl Compounds. Part 3. A 1H AND 13C Nuclear Magnetic Resonance Study of Formyl and Acetyl Derivatives of Benzo[b]thiophene
No full textThe conformational analysis of formyl and acetyl derivatives of benzo[b]thiophen was carried out by employing nmr chemical shifts (1-H and 13-C) and coupling constants. By measuring the lanthanide-induced shifts (LIS) and simulating experimental chemical shifts the relative conformer stability was determined. The results show that all the molecules examined are present almost completely in the Z conformation and that the stabilization of one conformer in this heterocyclic system seems due almost exclusively to the mesomeric interaction originating in the trans-arrangement of the C=O bond and the C=C bond having the higher double-bond character
The potential role of glutamate in the current diabetes epidemic
No full textIn the present article, we propose the perspective that abnormal glutamate homeostasis might contribute to diabetes pathogenesis. Previous reports and our recent data indicate that chronically high extracellular glutamate levels exert direct and indirect effects that might participate in the progressive loss of β-cells occurring in both T1D and T2D. In addition, abnormal glutamate homeostasis may impact all the three accelerators of the "accelerator hypothesis" and could partially explain the rising frequency of T1D and T2D
Bariatric surgery and bone disease: From clinical perspective to molecular insights
No full textThe use of bariatric surgery for the treatment of morbid obesity has increased annually for the last decade. Although many studies have demonstrated the efficacy and durability of bariatric surgery for weight loss, there are limited data regarding long-term side effects of these procedures. Recently, there has been an increased focus on the impact of bariatric surgery on bone metabolism. Bariatric surgery utilizes one or more of three mechanisms of action resulting in sustained weight loss. These include restriction (gastric banding, vertical banded gastroplasty and sleeve gastrectomy), malabsorption surgery with or without associated restriction (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion and jejunoileal bypass) and changes in gut-derived hormones that control energy metabolism also referred to as neuro-hormonal control of energy metabolism (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion, jejunoileal bypass, surgical procedures as above and gastric sleeve). Weight reduction has been associated with increased bone resorption but the mechanisms behind this have not yet been fully elucidated. Each of the mechanisms of action of bariatric surgery (restriction, malabsorption, neuro-hormonal control of energy metabolism) may uniquely affect bone resorption. In this paper we will review the current state of knowledge regarding the relationship between bariatric surgery and bone metabolism with emphasis on possible mechanisms of action such as malnutrition, hormonal interactions and mechanical unloading of the skeleton. Further, we suggest a future research agenda. © 2012 Macmillan Publishers Limited
Regulation of Phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus
No full textInsulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). In the present study, we have examined these processes in animal models of insulin-resistant and insulin-deficient diabetes mellitus. After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob / ob mouse. There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. Insulin-stimulated total PI 3-kinase activity was also absent in both tissues of the ob / ob mouse. By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resis tant diabetic states, such as that seen in the ob / ob mouse
Plasticity in islets of Langerhans in type 2 diabetes
No full textBackground and aims:
Studies in the last years indicate that the adult pancreas has an inherent regenerative capacity to produce new β-cells in response to increased metabolic demand or after injury. Different mechanisms of beta cell regeneration have been proposed to occur in the adult pancreas: i) replication from endogenous β-cell, ii) neogenesis from non-β-cells precursors and iii) β-cell formation by a transdifferentiation program. This last mechanism consists in the conversion of one endocrine cell type into another (non-beta cells into beta) by lineage reprogramming. It has been clearly identified in animal models; its existence and relevance in humans has never been demonstrated.
Aim of this study was to examine the islet composition and architecture in control and diabetic subjects and to verify the existence of the transdifferentiation process in diabetic islets.
Materials and methods: we collected human pancreatic sections from 12 normal (7M/5F, mean age 69±7 years) and 14 diabetic donors (8M/ 6F; mean age 66.4±10.34 years; diabetes)(paraffin embedded and cryopreserved). Sections were double/triple stained with antibodies directed against hormones (insulin, glucagon and somatostatin) and samples were analysed by confocal microscopy. The total islet area, β/α/δ-cell area, % of endocrine cells co-expressing insulin and glucagon (Indicative of cell transdifferentiation), frequency of heterologous and homologous contacts among different categories of endocrine cells were calculated by means of the image-Pro 3D analyser software.
Results: In pancreatic sections derived from diabetic subjects there is a significant decrease of the total islet area (27±5% reduction compared to healthy controls; p=0.01) and cell density (15±7.9% reduction compared to healthy controls) due to b-cell death and b-amyloid accumulation. In particular, we detected a 49±7% (p<0.0001) reduction in the b-cell area of T2D subjects if compared to healthy controls (the reduction was particularly evident in the islet core). No significant modification of a-cell area was measured. The overlap coefficient between the insulin and glucagone staining (co-localization index between the two stainings in the same cell) was significantly increased in diabetic subjects compared to controls (T2D 0.36±0.03; CTR 0.20±0.04; p<0.05), thus suggesting the presence of a transdifferentiation process. No correlation was found between the overlap coefficient and subjects age, sex, diabetes duration, islet area. Interestingly, subjects with higher overlap coefficient were under insulin treatment, thus suggesting a correlation with a significant islet dysfunction.
Conclusions:
The validation of transdifferentiation as an alternative and important mechanism occurring in adult diabetic pancreases and the understanding of how this event can be manipulated may lead to the design of new biological and pharmacological treatments aimed at promoting the survival of residual β-cell and preventing diabetes progression and/or development
Evidence for the involvement of phosphatidylinositol 3-kinase in fMLP-stimulated neutrophil adhesion to ICAM-1-transfected cells
No full textPhosphatidylinositol 3-kinase (PI-3K) controls important intracellular steps involved in inflammation, immunity, and cell growth. PI-3K also modulates leukocyte integrin adhesiveness. In this study we evaluated the role of PI-3K on neutrophil adhesion to intercellular adhesion molecule-1 (ICAM-1)-transfected cells. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophil adhesion was inhibited by wortmannin and LY294002, two unrelated PI-3K inhibitors, whereas phorbol myristate acetate (PMA)-induced neutrophil adhesion was not inhibited by them. After fMLP stimulation, a rapid activation of AKT and ERK was observed. However, only activation of AKT was reversed by the PI-3K inhibitors. Neutrophil expression of the β2-integrins Mac-1, lymphocyte function -associated antigen-1(LFA-1.), and gp150.95 was not affected by wortmannin, nor was expression of the activation epitope recognized by MAB24. We conclude that (a) PI-3K is involved in fMLP-activated neutrophil adhesion to ICAM- 1-transfected cells, (b) the mechanism involved is not mediated by the modulation of β2-integrin expression or activation, and (c) another mechanism seems to involve the adhesion to ICAM-1 when a cellular system of adhesion is used
In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus
No full textIn vivo vanadate and vanadyl have been shown to mimic the action of insulin and to be effective treatment for animal models of both Type I and Type II diabetes. The molecular mechanism of action of the vanadium salts on insulin sensitivity remains uncertain, and several potential sites proposed for the insulin-like effects are reviewed. In human trials, insulin sensitivity improved in patients with NIDDM, as well as in some patients with IDDM after two weeks of treatment with sodium metavanadate. This increase in insulin sensitivity was primarily due to an increase in non-oxidative glucose disposal, whereas oxidative glucose disposal and both basal and insulin stimulated suppression of hepatic glucose output (HGP) were unchanged. Clinically, oral vanadate was associated with a small decrease in insulin requirements in IDDM subjects. Of additional benefit, there was a decrease in total cholesterol levels in both IDDM and NIDDM subjects. Furthermore, there was an increase in the basal activities of MAP and S6 kinases to levels similar to the insulin-stimulated levels in controls, but there was little or no further stimulation with insulin was seen. Further understanding of the mechanism of vanadium action may ultimately be useful in the design of drugs that improve glucose tolerance
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