103 research outputs found
Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4
Pancreatic ÎČ-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis
A reduction in functional ÎČ-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1ÎČ) and gamma-interferon (Îł-IFN), activate signaling pathways that direct pancreatic ÎČ-cell death and dysfunction. However, the molecular mechanism of ÎČ-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying ÎČ-cell death in response to IL-1ÎČ+Îł-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1ÎČ+Îł-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-ÎșB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic ÎČ-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines
Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism
Postdoctoral fellowships were from EU Marie Curie (PIEF-GA-2009â252916) and
EMBO (ALTF 753â2010) for SA and EU Marie Curie (PIIF-GA-2009â252846) for C.C. J.
M.H. was a recipient of a doctoral fellowship from Eisai UK Ltd. Work in our laboratories
was supported as follows: BV: MRC [G0700755], BBSRC (BB/I007806/1 and BB/
M013278/1), CRUK (C23338/A15965), the Ludwig Institute for Cancer Research and the
National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research
Centre; J.M.B.: NIH AG039632, GM112524. and the Albert Einstein Diabetes Research
and Training Center Animal Physiology Core DK020541; E.G.: Barry Reed Cancer
Research fund; G.S.: BBSRC (BB/L020874/1) and B.H.F.; S.S.: Anatomical Society of
Great Britain (GT) and a Wellcome Trust Career Development Fellowship 074246/Z04/Z
(S.S.); R.K.S.: Wellcome Trust (WT098498) and M.R.C. (MRC_MC_UU_12012/5); S.A.
T. and L.C.: the Francis Crick Institute, which receives its core funding from CRUK
(FC001187), MRC (FC001187), and the Wellcome Trust (FC001187); Y.-L.C.: the CRUK
Cancer Imaging Centre in association with the MRC and DoH (England) grant C1060/
A10334, C1060/A16464, NHS funding to the NIHR BRC; B.P.: Inserm and the Fondation
pour la recherche médicale
Moderate calorie restriction to achieve normal weight reverses ÎČ-cell dysfunction in diet-induced obese mice: involvement of autophagy
Glucosylceramide transfer from lysosomesâthe missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data
Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTICâHF: baseline characteristics and comparison with contemporary clinical trials
Aims:
The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTICâHF) trial. Here we describe the baseline characteristics of participants in GALACTICâHF and how these compare with other contemporary trials.
Methods and Results:
Adults with established HFrEF, New York Heart Association functional class (NYHA)ââ„âII, EF â€35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokineticâguided dosing: 25, 37.5 or 50âmg bid). 8256 patients [male (79%), nonâwhite (22%), mean age 65âyears] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NTâproBNP 1971âpg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTICâHF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressureâ<â100âmmHg (n = 1127), estimated glomerular filtration rate <â30âmL/min/1.73 m2 (n = 528), and treated with sacubitrilâvalsartan at baseline (n = 1594).
Conclusions:
GALACTICâHF enrolled a wellâtreated, highârisk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation
1100-57 Catheter-based transplantation of autologous bone marrow mononuclear cells safely improves collateral and capillary network in adult swine with myocardial ischemia
- âŠ