Tapping the nucleotide pool of the host: novel nucleotide carrier proteins of Protochlamydia amoebophila

Protochlamydia amoebophila UWE25 is related to the Chlamydiaceae comprising major pathogens of humans, but thrives as obligate intracellular symbiont in the protozoan host Acanthamoeba sp. The genome of P. amoebophila encodes five paralogous carrier proteins belonging to the nucleotide transporter (NTT) family. Here we report on three P. amoebophila NTT isoforms, PamNTT2, PamNTT3 and PamNTT5, which possess several conserved amino acid residues known to be critical for nucleotide transport. We demonstrated that these carrier proteins are able to transport nucleotides, although substrate specificities and mode of transport differ in an unexpected manner and are unique among known NTTs. PamNTT2 is a counter exchange transporter exhibiting submillimolar apparent affinities for all four RNA nucleotides, PamNTT3 catalyses an unidirectional proton-coupled transport confined to UTP, whereas PamNTT5 mediates a proton-energized GTP and ATP import. All NTT genes of P. amoebophila are transcribed during intracellular multiplication in acanthamoebae. The biochemical characterization of all five NTT proteins from P. amoebophila in this and previous studies uncovered that these metabolically impaired bacteria are intimately connected with their host cell’s metabolism in a surprisingly complex manner

Central depletion of brain-derived neurotrophic factor in mice results in high bone mass and metabolic phenotype.

Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal differentiation/survival, in the regulation of food intake, and in the pathobiology of obesity and type 2 diabetes mellitus. BDNF and its receptor are expressed in osteoblasts and chondrocyte. BDNF in vitro has a positive effect on bone; whether central BDNF affects bone mass in vivo is not known. We therefore examined bone mass and energy utilization in brain-targeted BDNF conditional knock-out mice (Bdnf2lox/2lox/93). The deletion of BDNF in the brain led to a metabolic phenotype characterized by hyperphagia, obesity and increased abdominal white adipose tissue (WAT). Central BDNF deletion produces a marked skeletal phenotype characterized by increased femur length, elevated whole bone mineral density and bone mineral content. The skeletal changes are developmentally regulated and appear concurrently with the metabolic phenotype, suggesting that the metabolic and skeletal actions of BDNF are linked. The increased bone development is evident in both the cortical and trabecular regions. Compared to control, Bdnf2lox/2lox/93 mice show greater trabecular bone volume (BV/TV +50% for distal femur, p<0.001; +35% for vertebral body, p<0.001) and mid-femoral cortical thickness (+11 to 17%, p<0.05), measured at 3 and 6 months of age. The skeletal and metabolic phenotypes were gender-dependent with female being more affected than male mice. However, uncoupling Protein-1 expression in brown fat, a marker of sympathetic tone, was not different between genotypes. We show that deletion of central BDNF expression in mice results in increased bone mass and WAT, with no significant changes in sympathetic signaling or peripheral serotonin, associated with hyperphagia, obesity and leptin resistance

Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion

Introduction: Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer