342 research outputs found
Proglucagon-derived peptides as therapeutics
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development
Antidiabetic actions of GPR55 agonist Abn-CBD and sitagliptin in obese-diabetic high fat fed mice
Effects of artemether on pancreatic islet morphology, islet cell turnover and alpha-cell transdifferentiation in insulin-deficient Glu(CreERT2);ROSA26-eYFP diabetic mice
Mapping Physiological Suitability Limits for Malaria in Africa Under Climate Change
We mapped current and future temperature suitability for malaria
transmission in Africa using a published model that incorporates
nonlinear physiological responses to temperature of the mosquito
vector Anopheles gambiae and the malaria parasite Plasmodium
falciparum. We found that a larger area of Africa currently
experiences the ideal temperature for transmission than
previously supposed. Under future climate projections, we
predicted a modest increase in the overall area suitable for
malaria transmission, but a net decrease in the most suitable
area. Combined with human population density projections, our
maps suggest that areas with temperatures suitable for
year-round, highest-risk transmission will shift from coastal
West Africa to the Albertine Rift between the Democratic
Republic of Congo and Uganda, whereas areas with seasonal
transmission suitability will shift toward sub-Saharan coastal
areas. Mapping temperature suitability places important bounds
on malaria transmissibility and, along with local level
demographic, socioeconomic, and ecological factors, can indicate
where resources may be best spent on malaria control
Understanding uncertainty in temperature effects on vector-borne disease: A Bayesian approach
Extrinsic environmental factors influence the distribution and population
dynamics of many organisms, including insects that are of concern for human
health and agriculture. This is particularly true for vector-borne infectious
diseases, like malaria, which is a major source of morbidity and mortality in
humans. Understanding the mechanistic links between environment and population
processes for these diseases is key to predicting the consequences of climate
change on transmission and for developing effective interventions. An important
measure of the intensity of disease transmission is the reproductive number
. However, understanding the mechanisms linking and temperature, an
environmental factor driving disease risk, can be challenging because the data
available for parameterization are often poor. To address this we show how a
Bayesian approach can help identify critical uncertainties in components of
and how this uncertainty is propagated into the estimate of . Most
notably, we find that different parameters dominate the uncertainty at
different temperature regimes: bite rate from 15-25 C; fecundity across
all temperatures, but especially 25-32 C; mortality from
20-30 C; parasite development rate at 15-16C and again at
33-35C. Focusing empirical studies on these parameters and
corresponding temperature ranges would be the most efficient way to improve
estimates of . While we focus on malaria, our methods apply to improving
process-based models more generally, including epidemiological, physiological
niche, and species distribution models.Comment: 27 pages, including 1 table and 3 figure
Protein hydrolysates from boarfish (Capros aper) and Atlantic salmon (Salmo salar) skin gelatin improve metabolic control in genetically obese diabetic (ob/ob) mice
There is increasing interest in dietary protein for management of Type 2 diabetes mellitus (T2DM) and obesity. The effects of twice-daily oral administration of a salmon skin gelatin hydrolysate (SSGH, 50 mg/kg), boarfish protein hydrolysate (BPH, (50 mg/kg), metformin (200 mg/kg), or saline control, were investigated in ob/ob mice. Non-fasting blood glucose was significantly reduced with SSGH (p < 0.01), BPH (p < 0.001) and metformin (p < 0.001), which were reflected in reductions in glycated haemoglobin (HbA1c) (p < 0.001, p < 0.01 and p < 0.01, respectively). Responses to oral and intraperitoneal glucose tolerance were improved (p < 0.05–0.01), as well as circulating plasma lipid profiles (p < 0.05–0.001). Chronic BPH treatment increased circulating plasma insulin (p < 0.01), whereas SSGH improved insulin sensitivity (p < 0.05), versus respective controls. All treatments significantly reduced energy intake (p < 0.05–0.001) versus (ob/ob) controls, without affecting overall bodyweight. These findings suggest that fish hydrolysates mediate potent anti-diabetic actions similar to metformin and might be suitable for the management and prevention of T2DM
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Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice
Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1 Cre/+; Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2 ; ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells
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Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice
Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1 Cre/+; Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2 ; ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells
Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms
Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability
Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV
Isolated photon production is measured in proton-proton and lead-lead
collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the
pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80
GeV with the CMS detector at the LHC. The measured ET spectra are found to be
in good agreement with next-to-leading-order perturbative QCD predictions. The
ratio of PbPb to pp isolated photon ET-differential yields, scaled by the
number of incoherent nucleon-nucleon collisions, is consistent with unity for
all PbPb reaction centralities.Comment: Submitted to Physics Letters
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