Lower serum osteocalcin concentrations in patients with type 2 diabetes and relationships with vascular risk factors among patients with coronary artery disease.

BACKGROUND: Lower serum concentrations of the osteoblast-derived protein, osteocalcin, have been associated with poorer glycemic control, insulin resistance and atherosclerosis, and with the development of type 2 diabetes (T2DM). METHODS: This study compares concentrations of two physiological forms of osteocalcin, carboxylated (cOCN) and uncarboxylated (unOCN), between participants with T2DM (n = 20) and age-, gender- and body mass index (BMI)-matched participants without T2DM (n = 40) among patients with coronary artery disease (CAD), and it explores relationships between osteocalcin concentrations and cardiovascular risk factors. RESULTS: Concentrations of unOCN (2.71 ±â€¯1.86 vs. 4.70 ±â€¯2.03 ng/mL; t = -3.635, p = 0.001) and cOCN (8.70 ±â€¯2.27 vs. 10.77 ±â€¯3.69 ng/mL; t = -2.30, p = 0.025) were lower in participants with T2DM. In participants without T2DM, concentrations of cOCN were associated with fitness (VO2Peak rho = 0.317, p = 0.047) and lower body fat (rho = -0.324, p = 0.041). In participants with T2DM, lower unOCN was associated with HbA1c (rho = -0.516, p = 0.020). Higher body mass was associated with higher unOCN (rho = 0.423, p = 0.009) in participants without T2DM, but with lower concentrations of both unOCN (rho = -0.590, p = 0.006) and cOCN (rho = -0.632, p = 0.003) in participants with T2DM. CONCLUSION: In patients with CAD, lower osteocalcin concentrations were related to type 2 diabetes, and to adverse fitness, metabolic and obesity profiles.

DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.

Androgen receptor (AR) activation is critical for prostate cancer (PCa) development and progression, including castration resistance. The nuclear export signal of AR (NESAR) has an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin-ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in PCa specimens and its expression was correlated with Gleason scores and prostate-specific antigen recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to PCa progression through Siah2.

Manipulation of androgens and alterations in the androgen receptor axis in prostate cancer.

Androgens play a key role in prostate cancer (PCa) development and progression. For decades, androgen deprivation therapy (ADT) has been the primary treatment for men with metastatic prostate cancer. ADT initially results in the regression of prostate cancers, however, this effect is limited and patients inevitably develop an androgen refractory form of the disease. Many studies have implicated the androgen receptor (AR), the key mediator of androgen action, as an important player in PCa recurrence. Changes such as AR gene amplification, AR mutations, and in AR subcellular localization, and AR coregulator status that result in the upregulation of AR activity are often associated with androgen refractory prostate cancers. This review seeks to highlight some of the changes in the AR axis in androgen refractory tumors and the recent advances in ADT. A greater understanding of the AR axis will provide a basis for improving existing methods and developing new methods for the treatment of prostate cancer.

Urothelial progenitor cells: regional differences in the rat bladder.

OBJECTIVES: Because the trigone is a unique region in the caudal bladder with a higher risk of neoplasia, we hypothesized that this area would have a high proportion of progenitor cells. As yet there is no marker nor methodology to specifically isolate urothelial stem cells, and thus demonstrate multi-potential differentiation and self-renewal. Here, our goal was to evaluate the distribution of progenitor cells that carry two general major attributes of stem cells: clonogenicity and proliferative capacity. MATERIALS AND METHODS: The bladders of Fisher rats were divided into caudal and cephalic segments and primary cultures were established from the harvested urothelial cells. RESULTS: We found that colony-forming efficiency was almost 2-fold higher for cells from the caudal bladder compared to the cephalic bladder. Doubling time was significantly faster for cells harvested from the caudal bladder at initial plating. This suggested that the caudal bladder harbours a higher density of urothelial progenitor cells. With passage to p4, the differences between the upper and lower bladder were lost, suggesting selection of proliferative cells with serial passage. Based on Ki-67 staining, there was no geographical difference in cell proliferation under normal homeostatic in vivo conditions. CONCLUSIONS: These results demonstrate geographical sequestration of urothelial progenitor cells to the area of the bladder that encompasses the bladder neck and trigone, which may be a factor in pathological disparities between the trigone and remaining bladder.

The effect of a suppressed rad52 mutation on the suppression of rad6 by srs2.

We have cloned a suppressor of a temperature-sensitive rad52 allele and found it to be a mutation in PUP1, a gene encoding a protease subunit of the 20s proteasome. This identity prompted us to examine the interrelationship among PUP1, RAD52, SRS2 and RAD6 because srs2 mutations not only suppress some rad52 mutations but also suppress deletions of rad6, a gene encoding a protein in the ubiquination-dependent proteolysis pathway. We have found that while srs2 suppresses the UV sensitivity of rad6 in the presence of RAD52, srs2 cannot suppress rad6 when the temperature-sensitive allele of rad52 is present. This inability of srs2 to suppress rad6 is irrespective of the incubation temperature or whether pup1 is suppressing the temperature-sensitive rad52 mutation.

Cold-sensitive rad52 alleles of yeast.

We have characterized two rad52 mutations that are cold-sensitive for growth on MMS agar. The mutations change residues 61 and 69, respectively, in the 504 amino-acid open reading frame. Neither mutation has a profound effect on mitotic crossing-over or on gene conversion. One has a severe deficiency in sporulation at all temperatures, while the other has a partial deficiency and reduced spore viability. Both mutants are retarded in growth on MMS agar by a high-copy plasmid expressing RAD51.

Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect.

Neuropeptide Y (NPY) elicits eating when injected directly into the paraventricular nucleus (PVN) or perifornical hypothalamus (PFH). To identify the essential regions of the NPY molecule and the relative contributions of Y1 and Y2 receptors, the eating stimulatory potency of NPY was compared to that of its fragments, analogues, and agonists when injected into the PVN or PFH of satiated rats. Additionally, antisera to NPY was injected into the cerebral ventricles (ICV) to determine whether passive immunization suppresses the eating produced by mild food deprivation. Tests with NPY fragments revealed that NPY(2-36) was surprisingly potent, nearly three times more so than intact NPY. In contrast, fragments with further N-terminal deletions were progressively less effective or ineffective, as was the free acid form of NPY. Collectively, this suggests that both N- and C-terminal regions of NPY participate in the stimulation of eating. Tests with agonists revealed that the putative Y1 agonist [Pro34]NPY elicited a strong dose-dependent feeding response, while the putative Y2 agonist, C2-NPY, had only a small effect at the highest doses. Although this suggests mediation by Y1 receptors, the uncharacteristically high potency of NPY(2-36) may additionally suggest that the receptor subtype underlying feeding is distinct from that mediating other responses. Additional results revealed that ICV injection of antisera to NPY, which should inactivate endogenous NPY, produced a concentration-dependent suppression of eating induced by mild food deprivation. This finding, along with published work demonstrating enhanced levels of hypothalamic NPY in food-deprived rats, suggests that endogenous NPY mediates the eating produced by deprivation.