ABSTRACT
MicroRNAs (miRNAs) are promising drug targets for obesity and metabolic disorders. Recently, miRNA mimics are providing a unique mechanism of action that guides the process for drug development and sets out the context of their therapeutic application. miRNA (miR)-21 expression in white adipose tissue (WAT) has been associated with obesity. We aimed to analyze miR-21 expression levels in relation to diabetes and obesity to determine the effect that miR-21 mimic has on processes involved in WAT functionality, to dissect the underlying molecular mechanisms, and to study the potential therapeutic application of the miR-21 mimic against obesity. We found higher miR-21 levels in WAT from non-diabetic obese compared to normoweight humans and mice. Moreover, in 3T3-L1 adipocytes, miR-21 mimic affect genes involved in WAT functionality regulation and significantly increase the expression of genes involved in browning and thermogenesis. Interestingly, in vivo treatment with the miR-21 mimic blocked weight gain induced by a high-fat diet in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancement, WAT browning, and brown adipose tissue (AT) thermogenic programming through vascular endothelial growth factor A (VEGF-A), p53, and transforming growth factor ß1 (TGF-ß1) signaling pathways. Our findings suggest that miR-21 mimic-based therapy may provide a new opportunity to therapeutically manage obesity and consequently, its associated alterations.
ABSTRACT
BACKGROUND AND OBJECTIVES: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate. METHODS: Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls. RESULTS: Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353). CONCLUSIONS: Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p(M-H)=0.001; OR(M-H) (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: p(M-H)=0.03; OR(M-H) (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: p(M-H)=0.01; OR(M-H) (95% CI)= 0.89 (0.81-0.97)].
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Genetic Predisposition to Disease/genetics , Interleukin-12 Subunit p40/genetics , Membrane Proteins/genetics , Multiple Sclerosis/genetics , Proto-Oncogene Proteins c-cbl/genetics , Adult , Female , Genome-Wide Association Study , Genotype , Humans , Male , Polymorphism, Single NucleotideABSTRACT
OBJECTIVE: To evaluate the results of a plan for improving pharmacy indicators in a Primary Care (PC) Health Area. DESIGN: Quasi-experimental study with a control group. The differences between the pre-intervention (Jan-Dec 2007) and post-intervention (Jan-Dec 2008) periods were evaluated. SETTING AND PARTICIPANTS: Intervention group: Primary Care doctors from PC Area 7 of the Community of Madrid (n=397). CONTROL GROUP: the rest of PC doctors of the Community of Madrid (n=4428). METHOD: A multi-focus plan in which the main activities were: sessions in the health centres with the worst results, involvement of those responsible for the Rational Use of Drugs, interviews with the doctors with the most improvable indicators, recognition of those with good indicators, and preparing short notes on drugs. MAIN MEASUREMENTS: Prescription and notification indicators associated with the safety of drugs. RESULTS: In relation to Madrid, the absolute improvements of Area 7 in the accumulated indicators, %Generic drugs, %Statins, %ARAII y %Omeprazole were 0.29; 1.17; 0.61 and 0.37 percentage points, respectively. DHD Osteoporosis equalled the improvement of Madrid. In Area 7, the increase in notifications of suspected serious ADRs was 180% and number of ADR notifications of ADRs was 233%, better than the Madrid data (48% and 21%). The notification of medication errors showed similar increases in both groups (PC Area 7 1567% vs. Madrid PC 1633%). CONCLUSIONS: Implementing a multi-focus improvement plan with feasible and specific actions can be a useful tool for improving pharmacy indicators.
