Validating potential targets is an important step in the drug discovery process. In this study, we tested the feasibility of using inducible RNA interference (RNAi) in vivo to obtain an unbiased evaluation on the efficacy of inhibiting hypoxia-inducible factor-1alpha (HIF-1alpha) in established tumors. We showed that HIF-1alpha inhibition resulted in transient tumor stasis or tumor regression, ...

The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key factors that suppress bile acid biosynthesis in the liver. PGC-1alpha [PPARgamma (peroxisome-proliferator-activated receptor gamma) co-activator-1alpha] is known to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We performed cell-based reporter assays using the expression system of a GAL4-FXR ...

The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a vital role in calcium metabolism, tissue differentiation, and normal bone growth. Biosynthesis of 1,25(OH)2D3 is catalyzed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase). Although activity of this enzyme has been described in several tissues, the kidneys are recognize...

Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism ...

When oxygen supply is restricted, protein synthesis is rapidly abrogated owing to inhibition of global translation. However, HIF-1alpha protein expression can persist during hypoxia, owing to an internal ribosome entry site (IRES) in the 5'-untranslated region of its mRNA. Here, we report on the molecular mechanism of HIF-1alpha IRES-mediated translation during oxygen deprivation. Using RNA aff...

Heterogeneous metabolic microenvironments in tumors affect local cell growth, survival, and overall therapeutic efficacy. Hypoxia-inducible-factor-1alpha (HIF-1alpha) is a transcription factor that responds to low-oxygen environments by upregulating genes for cell survival and metabolism. To date, the metabolic effects of HIF-1alpha in three-dimensional tissue have not been investigated. Prelim...

The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. Th...

AbstractLet W be a non-empty subset of a free group. The automorphism of a group G is said to be a marginal automorphism, if for all x in G,x^−1alpha(x) in W^*(G), where W^*(G) is the marginal subgroup of G.In this paper, we give necessary and sufficient condition for a purelynon-abelian p-group G, such that the set of all marginal automorphismsof G forms an elementary abelian p-group.

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is capable of coactivating several nuclear receptors and transcription factors that participate in the regulation of multiple metabolic processes, including gluconeogenesis, mitochondrial biogenesis, and adaptive thermogenesis. Uridine phosphorylase (UPase) catalyzes the reversible conversion of uridine into uracil...

Chronic inflammation is a critical component of carcinogenesis and tumor progression. Reactive nitrogen and oxygen species generated by inflammatory cells form mutagenic DNA lesions, such as 8-nitroguanine, which may play an integral role in inflammation-related carcinogenesis. Hypoxia-inducible factor (HIF)-1alpha has been established as a prognostic biomarker in various tumors, including mali...