Dysregulated insulin secretion is associated with pancreatic β-cell hyperplasia and direct acinar-β-cell trans-differentiation in partially eNOS-deficient mice.

eNOS-deficient mice were previously shown to develop hypertension and metabolic alterations associated with insulin resistance either in standard dietary conditions (eNOS-/- homozygotes) or upon high-fat diet (HFD) (eNOS+/- heterozygotes). In the latter heterozygote model, the present study investigated the pancreatic morphological changes underlying the abnormal glycometabolic phenotype. C57BL6 wild type (WT) and eNOS+/- mice were fed with either chow or HFD for 16 weeks.

Anti-Tumor Activity of L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics.

In this paper we review the mechanisms of the antitumor effects of L. (St. John's wort, SJW) and its main active component hyperforin (HPF).

Protective Role of St. John's Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies.

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of L.

Nutrient-Induced Metabolic Stress, Adaptation, Detoxification, and Toxicity in the Pancreatic β-Cell.

Paraphrasing the Swiss physician and father of toxicology Paracelsus (1493-1541) on chemical agents used as therapeutics, "the dose makes the poison," it is now realized that this aptly applies to the calorigenic nutrients. The case here is the pancreatic islet β-cell presented with excessive levels of nutrients such as glucose, lipids, and amino acids. The short-term effects these nutrients exert on the β-cell are enhanced insulin biosynthesis and secretion and changes in glucose sensitivity.

Conformal coating by multilayer nano-encapsulation for the protection of human pancreatic islets: In-vitro and in-vivo studies.

To improve the efficiency of pancreatic islet transplantation, we performed in-vitro and in-vivo experiments with isolated human pancreatic islets coated by multi-layer nano-encapsulation using differently charged polymers [chitosan and poly(sodium styrene sulfonate)] to obtain up to 9 layers. The islet coating (thickness: 104.2 ± 4.

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin.

Objectives: St John's wort extract (SJW) and its component hyperforin (HPF) were shown to potently inhibit cytokine-induced STAT-1 and NF-κB activation in pancreatic β cells and protect them against injury. This study aimed at exploring the time course of STAT-1 inhibition afforded by these natural compounds in the β-cell line INS-1E.

Methods: INS-1E cells were pre-incubated with SJW extract (2-5 μg/ml) or HPF (0.

St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells.

The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT-1 and NF-κB activation and prevent damage in pancreatic β cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in β-cell function, inflammatory response and apoptosis induction.

Labeling and Tracking of Human Pancreatic Islets Using Carbon Nanotubes.

Limited tools are available for the non-invasive monitoring of transplanted islets. In this study, we have compared the widely used superparamagnetic iron oxide nanoparticle ferumoxide (Endorem) and multiwalled carbon nanotubes (MWCNTs) for islet cell labeling and tracking. INS-1 E cells and human pancreatic islets isolated from 12 non-diabetic cadaveric organ donors (age: 62 ±16 yr, BMI: 24.

Partial deletion of eNOS gene causes hyperinsulinemic state, unbalance of cardiac insulin signaling pathways and coronary dysfunction independently of high fat diet.

Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling.

Anti-diabetic properties of a non-conventional radical scavenger, as compared to pioglitazone and exendin-4, in streptozotocin-nicotinamide diabetic mice.

We previously showed that the innovative radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) improves metabolic dysfunctions in a diabetic mouse model. Here, we compared the in vivo effects of IAC with those of the anti-diabetic drugs pioglitazone (PIO) and exendin-4 (EX-4). Diabetes was induced in C57Bl/6J mice by streptozotocin and nicotinamide administration.

Direct interaction of garcinol and related polyisoprenylated benzophenones of Garcinia cambogia fruits with the transcription factor STAT-1 as a likely mechanism of their inhibitory effect on cytokine signaling pathways.

Garcinol (1), a polyisoprenylated benzophenone occurring in Garcinia species, has been reported to exert anti-inflammatory activity in LPS-stimulated macrophages, through inhibition of NF-κB and/or JAK/STAT-1 activation. In order to provide deeper insight into its effects on the cytokine signaling pathway and to clarify the underlying molecular mechanisms, 1 was isolated from the fruits of Garcinia cambogia along with two other polyisoprenylated benzophenones, guttiferones K (2) and guttiferone M (3), differing from each other in their isoprenyl moieties and their positions on the benzophenone core. The affinities of 1-3 for the STAT-1 protein have been evaluated by surface plasmon resonance and molecular docking studies and resulted in KD values in the micromolar range.

Are we overestimating the loss of beta cells in type 2 diabetes?

Aims/hypothesis: Previous work has demonstrated that beta cell amount (whether measured as beta cell mass, beta cell volume or insulin-positive area) is decreased in type 2 diabetes; however, recent findings suggest that mechanisms other than death may contribute to beta cell failure in this disease. To better characterise beta cell mass and function in type 2 diabetes, we performed morphological, ultra-structural and functional studies using histological samples and isolated islets.

Methods: Pancreases from ten non-diabetic (ND) and ten matched type 2 diabetic organ donors were studied by insulin, glucagon and chromogranin A immunocytochemistry and electron microscopy (EM).

St. John's wort extract and hyperforin protect rat and human pancreatic islets against cytokine toxicity.

The extract of Hypericum perforatum (St. John's wort, SJW) and its component hyperforin (HPF) were previously shown to inhibit cytokine-induced activation of signal transducer and activator of transcription-1 and nuclear factor κB and prevent apoptosis in a cultured β-cell line. Objective of this study was to assess the protection exerted by SJW and HPF on isolated rat and human islets exposed to cytokines in vitro.

1,4-Benzothiazine ATP-sensitive potassium channel openers: modifications at the C-2 and C-6 positions.

ATP-sensitive potassium (KATP) channels play a prominent role in controlling cardiovascular function. In this paper, a novel series of 4-(1-oxo-2-cyclopentenyl)-1,4-benzothiazine derivatives modified at the C-2, and C-6 positions were synthesized as openers of vascular KATP channels. Most of the tested compounds evoked vasorelaxing effects on rat aortic rings and membrane hyperpolarization in human vascular smooth muscle cells, with potency similar or superior to that of the reference levcromakalim (LCRK).

PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53.

PRIMA-1 is a chemical compound identified as a growth suppressor of tumor cells expressing mutant p53. We previously found that in the MDA-MB-231 cell line expressing high level of the mutant p53-R280K protein, PRIMA-1 induced p53 ubiquitination and degradation associated to cell death. In this study, we investigated the ability of PRIMA-1 to induce autophagy in cancer cells.

Ultrastructural morphometric analysis of insulin secretory granules in human type 2 diabetes.

We performed an ultrastructural morphometric analysis of insulin secretory granules in pancreatic beta cells from control and type 2 diabetic multiorgan donors. The volume density of insulin granules significantly (p < 0.05) reduced in beta cells from type 2 diabetic patients with respect to non-diabetic subjects, and this reduction was mainly attributable to a decrease in mature granules.

Cobalt-Protoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes.

Myocardial dysfunction and coronary macro/microvascular alterations are the hallmarks of diabetic cardiomyopathy and are ascribed to increased oxidative stress and altered nitric oxide synthase (NOS) activity. We hypothesize that pre-treatment by cobalt-protoporphyrin IX (CoPP) ameliorates both myocardial function and coronary circulation in streptozotocin (STZ)-induced diabetic rats. Isolated hearts from diabetic rats in Langendorff configuration displayed lower left ventricular function and higher coronary resistance (CR) compared to hearts from control animals.

Synthesis and preliminary biological profile of new NO-donor tolbutamide analogues.

We describe a new class of NO-donor hypoglycemic products obtained by joining tolbutamide, a typical hypoglycemic sulfonylurea, with a NO-donor moiety through a hard link. As NO-donors we chose either furoxan (1,2,5-oxadiazole 2-oxide) derivatives or the classical nitrooxy function. A preliminary biological characterization of these compounds, including stimulation of insulin release from cultured rat pancreatic β-cells and in vitro vasodilator and anti-aggregatory activities, is reported.

Palmitate activates autophagy in INS-1E β-cells and in isolated rat and human pancreatic islets.

We have investigated the in vitro effects of increased levels of glucose and free fatty acids on autophagy activation in pancreatic beta cells. INS-1E cells and isolated rat and human pancreatic islets were incubated for various times (from 2 to 24 h) at different concentrations of glucose and/or palmitic acid. Then, cell survival was evaluated and autophagy activation was explored by using various biochemical and morphological techniques.

Histopathology and ex vivo insulin secretion of pancreatic islets in gestational diabetes: A case report.

Gestational diabetes (GD) results from insufficient endogenous insulin supply. No information is available on features of islet cells in human GD. Herein, we describe several properties of islets from a woman with GD.

Altered signal transduction pathways and induction of autophagy in human myotonic dystrophy type 1 myoblasts.

Congenital myotonic dystrophy type 1 (CDM1) affects patients from birth and is associated with mental retardation and impaired muscle development. CDM1 patients carry 1000-3000 CTG repeats in the DMPK gene and display defective skeletal muscles differentiation, resulting in reduced size of myotubes and decreased number of satellite cells. In this study, human myoblasts in culture deriving from control and DM1 embryos (3200 CTG repeats) were analyzed using both a biochemical and electron microscopic approach, in order to provide new insights into the molecular mechanisms underlying such alteration.

A role for autophagy in β-cell life and death.

Autophagy is a vacuolar, self-digesting mechanism responsible for the removal of organelles and defined regions of the cytoplams. This process has, in general, a beneficial role for the cell, since it regulates the turnover of aged proteins and eliminates damaged structures. However, cells that undergo altered autophagy may be triggered to die in a non-apoptotic manner.

The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study.

The use of immunosuppressive drugs in transplanted patients is associated with the development of diabetes, possibly due to β-cell toxicity. To better understand the mechanisms leading to post-transplant diabetes, we investigated the actions of prolonged exposure of isolated human islets to therapeutical levels of tacrolimus (Tac) or cyclosporin A (CsA). Islets were isolated from the pancreas of multiorgan donors by enzymatic digestion and density gradient centrifugation.