88 research outputs found
GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease
BackgroundAgonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among the most promising drugs in clinical development for the treatment of obesity and type 2 diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia and thus to reduce the cardiovascular disease risk independently of body weight loss has not been explored yet.MethodsAfter 8 weeks on western diet, LDL receptor knockout (LDLR-/-) male mice were treated with daily subcutaneous injections of long-acting acylated GIP analog (acyl-GIP;10nmol/kg body weight) for 28 days. Body weight, food intake, whole-body composition were monitored throughout the study. Fasting blood glucose and intraperitoneal glucose tolerance test (ipGTT) were determined on day 21 of the study. Circulating lipid levels, lipoprotein profiles and atherosclerotic lesion size was assessed at the end of the study. Acyl-GIP effects on fat depots were determined by histology and transcriptomics.ResultsHerein we found that treatment with acyl-GIP reduced dyslipidemia and atherogenesis in male LDLR-/- mice. Acyl-GIP administration resulted in smaller adipocytes within the inguinal fat depot and RNAseq analysis of the latter revealed that acyl-GIP may improve dyslipidemia by directly modulating lipid metabolism in this fat depot.ConclusionsThis study identified an unanticipated efficacy of chronic GIPR agonism to improve dyslipidemia and cardiovascular disease independently of body weight loss, indicating that treatment with acyl-GIP may be a novel approach to alleviate cardiometabolic disease
Resource Windfall and Corruption: Evidence from a Natural Experiment in Peru *
Abstract The relationship between economic conditions and corruption has been subject of an intense discussion in the empirical literature due to the lack of good quality data on objective measures of corruption and the presence of omitted variables, measurement error and reverse causality problems. Using a rich and novel dataset that includes a complete set of bribery-related questions for the period 2002-2006, I exploit an exogenous variation in the economic conditions of a set of mineral-rich local governments in Peru which is due to an interaction between a fiscal rule that forces the central government to allocate 50% of the income taxes paid by mining companies to these governments and the extraordinary rise of the international prices of mineral resources observed since 2003. Using different empirical strategies, I find that, after the increase of prices of mineral resources, the predicted probability of being asked to pay a bribe by a local public official reduces by 1.5-1.8 percentage points in districts with access to this type of transfers, being the effect larger in mineral producer districts (2.7 percentage points). This represents a 52-62% reduction on the average probability. However, when focusing in areas most benefited from the positive shock of mineral prices, I find a positive effect on corruption with an increase in the former predicted probability of 4.3 percentage points. Taken together, these results suggest that the increase of transfers due to positive shocks in mineral prices have differential effects on corruption depending on the magnitude of the shock in local government revenues. JEL: Q3, H3, C
GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice
Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance
GLP-1–oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice
What It Takes: A Statistical Analysis of Arkansas Supreme Court’s Petition for Review Process
What It Takes: A Statistical Analysis of Arkansas Supreme Court’s Petition for Review Process
The LysR-type PcaQ protein regulates expression of a protocatechuate-inducible ABC-type transport system in Sinorhizobium meliloti
The LysR protein PcaQ regulates the expression of genes encoding products relevant to the degradation of the aromatic acid protocatechuate (3,4-dihydroxybenzoate), and we have previously defined a PcaQ DNA-binding site located upstream of the target pcaDCHGB operon in Sinorhizobium meliloti. In this work, we show that PcaQ also regulates the expression of the S. meliloti smb20568-smb20787-smb20786-smb20785-smb20784 gene cluster, which is predicted to encode an ABC transport system. ABC transport systems have not been shown before to transport protocatechuate, and we have designated this gene cluster pcaMNVWX. The transcriptional start site of pcaM was mapped, and the predicted PcaQ DNA-binding site was located at "73 to "58 relative to this site. Results from electrophoretic mobility shift assays with purified PcaQ and from expression assays indicated that PcaQ activates expression of the transport system in the presence of protocatechuate. To investigate this transport system further, we generated a pcaM deletion mutant (predicted to encode the substrate-binding protein) and introduced a polar insertion mutation into pcaN, a gene that is predicted to encode a permease. These mutants grew poorly on protocatechuate, presumably because they fail to transport protocatechuate. Genome analyses revealed PcaQ-like DNA-binding sites encoded upstream of ABC transport systems in other members of the a-proteobacteria, and thus it appears likely that these systems are involved in the uptake of protocatechuate. © 2011 SGM
Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety
Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field
Inter-replicon Gene Flow Contributes to Transcriptional Integration in the Sinorhizobium meliloti Multipartite Genome
Integration of newly acquired genes into existing regulatory networks is necessary for successful horizontal gene transfer (HGT). Ten percent of bacterial species contain at least two DNA replicons over 300 kilobases in size, with the secondary replicons derived predominately through HGT. The Sinorhizobium meliloti genome is split between a 3.7 Mb chromosome, a 1.7 Mb chromid consisting largely of genes acquired through ancient HGT, and a 1.4 Mb megaplasmid consisting primarily of recently acquired genes. Here, RNA-sequencing is used to examine the transcriptional consequences of massive, synthetic genome reduction produced through the removal of the megaplasmid and/or the chromid. Removal of the pSymA megaplasmid influenced the transcription of only six genes. In contrast, removal of the chromid influenced expression of ∼8% of chromosomal genes and ∼4% of megaplasmid genes. This was mediated in part by the loss of the ETR DNA region whose presence on pSymB is due to a translocation from the chromosome. No obvious functional bias among the up-regulated genes was detected, although genes with putative homologs on the chromid were enriched. Down-regulated genes were enriched in motility and sensory transduction pathways. Four transcripts were examined further, and in each case the transcriptional change could be traced to loss of specific pSymB regions. In particularly, a chromosomal transporter was induced due to deletion of bdhA likely mediated through 3-hydroxybutyrate accumulation. These data provide new insights into the evolution of the multipartite bacterial genome, and more generally into the integration of horizontally acquired genes into the transcriptome
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