Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α, γ, and σ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators

Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

SummaryMice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53−/− mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1–A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses

dSETDB1 and SU(VAR)3–9 Sequentially Function during Germline-Stem Cell Differentiation in Drosophila melanogaster

Germline-stem cells (GSCs) produce gametes and are thus true “immortal stem cells”. In Drosophila ovaries, GSCs divide asymmetrically to produce daughter GSCs and cystoblasts, and the latter differentiate into germline cysts. Here we show that the histone-lysine methyltransferase dSETDB1, located in pericentric heterochromatin, catalyzes H3-K9 trimethylation in GSCs and their immediate descendants. As germline cysts differentiate into egg chambers, the dSETDB1 function is gradually taken over by another H3-K9-specific methyltransferase, SU(VAR)3–9. Loss-of-function mutations in dsetdb1 or Su(var)3–9 abolish both H3K9me3 and heterochromatin protein-1 (HP1) signals from the anterior germarium and the developing egg chambers, respectively, and cause localization of H3K9me3 away from DNA-dense regions in most posterior germarium cells. These results indicate that dSETDB1 and SU(VAR)3–9 act together with distinct roles during oogenesis, with dsetdb1 being of particular importance due to its GSC-specific function and more severe mutant phenotype

High-resolution sonography of the rib: can fracture and metastasis be differentiated?

OBJECTIVE: Our aim was to evaluate whether high-resolution sonography can provide additional information concerning rib lesions compared with radiography or bone scintigraphy. MATERIALS AND METHODS: Fifty-eight patients with high-uptake rib lesions seen on bone scintigraphy were selected. Radiography and rib high-resolution sonography were performed on these patients. High-resolution sonography was performed using a linear 5-12 MHz transducer. By means of clinical history, histopathologic examination, and follow-up observation, these patients were classified into rib fracture (n = 37), rib metastasis (n = 18), or unknown (n = 3) groups. High-resolution sonography images of the 55 proven cases were reviewed for the presence of five representative findings: cortical disruption, callus formation, cortical deformity, mass, or bone destruction. The frequencies of these findings were compared between the groups with fracture and metastasis. RESULTS: Rib lesions were matched by bone scintigraphy and high-resolution sonography in 53 (96%) of 55 patients and by bone scintigraphy and plain radiography in 23 (42%) of 55 patients. High-resolution sonography revealed 17 (94%) of 18 patients with metastasis and 36 (97%) of 37 patients with rib fractures. Metastatic lesions were seen as mass formation (n = 13) and irregular bone destruction (n = 7) on high-resolution sonography. Fracture was seen as cortical disruption with or without hematoma (n = 17), callus formation (n = 9), or cortical deformity, such as angling or stepping (n = 12). CONCLUSION: High-resolution sonography of the ribs is a useful method of characterizing rib lesions in patients who have hot-uptake lesions on bone scintigraphy