Obesity results from numerous, interacting genetic, behavioral, and physiological
factors. Adipogenesis is partially regulated by several adipocyte-selective
microRNAs (miRNAs) and transcription factors that regulate proliferation and
differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this
study, we examined the roles of adipocyte-selective miRNAs in the differentiation of
hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30,
and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a
exhibited significant effects on increasing PPRE luciferase activity (it represents
PPAR-dependent transcription, a major factor in adipogenesis) than others.
Furthermore, miR-148a expression levels increased in adipose tissues from obese
people and mice fed high-fat diet. miR-148a acted by suppressing its target gene,
Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a
accelerated differentiation and partially rescued Wnt1-mediated inhibition of
adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the
upstream region of miR-148a locus identified a 3 kb region containing a functional
cAMP-response element-binding protein (CREB) required for miR-148a expression in
hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human
subjects and mouse model, which represents a CREB-modulated miRNA that acts to
repress Wnt1, thereby promoting adipocyte differentiation.
Elimination of specific surface-exposed single tyrosine (Y) residues substantially improves hepatic gene transfer with adeno-associated virus type 2 (AAV2) vectors. Here, combinations of mutations in the seven potentially relevant Y residues were evaluated for further augmentation of transduction efficiency. These mutant capsids packaged viral genomes to similar titers and retained infectivity. A triple-mutant (Y444+500+730F) vector consistently had the highest level of in vivo gene transfer to murine hepatocytes, approximately threefold more efficient than the best single-mutants, and ~30-80-fold higher compared with the wild-type (WT) AAV2 capsids. Improvement of gene transfer was similar for both single-stranded AAV (ssAAV) and self-complementary AAV (scAAV) vectors, indicating that these effects are independent of viral second-strand DNA synthesis. Furthermore, Y730F and triple-mutant vectors provided a long-term therapeutic and tolerogenic expression of human factor IX (hF.IX) in hemophilia B (HB) mice after administration of a vector dose that only results in subtherapeutic and transient expression with WT AAV2 encapsidated vectors. In summary, introduction of multiple tyrosine-mutations into the AAV2 capsid results in vectors that yield at least 30-fold improvement of transgene expression, thereby lowering the required therapeutic dose and potentially vector-related immunogenicity. Such vectors should be attractive for treatment of hemophilia and other genetic diseases.
In China, ages at menarche and menopause are not associated with diabetes. Later menarche and menopause are associated with decreasing CVD risk and earlier menopause with higher osteoporosis risk. Menarche and menopause history may help identify women with increased risk of developing CVD and osteoporosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.