Peptides and Pseudopeptides as SIRT6 Deacetylation Inhibitors

相似文献   

Effects of aging and calorie restriction of Fischer 344 rats on hepatocellular response to proliferative signals

It is well established that the proliferative potential of the liver declines with aging. Epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats, and this reduction correlates with diminished activation of the extracellular signal-regulated kinase (ERK) pathway and lower phosphorylation of the EGF receptor on residue Y1173. Calorie restriction (CR) can increase rodent life span and retard many age-associated declines in physiologic function, but its influence on cell proliferation is unknown. Here, we investigated the effects of long-term CR on proliferation of hepatocytes derived from young and aged rats following in vitro stimulation with either low-dose hydrogen peroxide or EGF. CR reduced the proliferative response of hepatocytes derived from young hosts, but long-term CR was associated with enhanced proliferation in aged cells relative to that of ad libitum (AL)-fed animals. ERK activation mirrored the effects of CR on proliferation, in that young CR cells exhibited lower ERK activation than young AL cells, but old CR cells showed higher ERK activation than old AL cells. Finally, a decline in EGF receptor phosphorylation on Y1173, which normally occurs with aging, was absent in cells of old hosts maintained on long-term CR, supporting the view that alterations in this early signaling event underlie the age-related decline in proliferative potential in rat hepatocytes.     

Novel electrocardiographic features in carriers of hypertrophic cardiomyopathy causing sarcomeric mutations

Objectives

The sensitivity and specificity of the conventional 12-lead ECG to identify carriers of hypertrophic cardiomyopathy (HCM) – causing mutations without left ventricular hypertrophy (LVH) has been limited. We assessed the ability of novel electrocardiographic parameters to improve the detection of HCM mutation carriers.

The effect of dietary cellulose on life span and biochemical variables of male mice

Sixteen month old C57BL/6J male mice were fed either a nutritionally adequate diet or this diet diluted with either 33% or 50% cellulose. The life span of the animals fed the latter two diets was longer than that of the controls, but only statistically significant in the animals fed the diet diluted with 50% cellulose. The rates of cellular protein synthesis were estimated in liver by determining: 1) the half lives of proteins by the rate of disappearance of radioactivity following the intraperitoneal injection of C¹⁴ labeled sodium bicarbonate, and 2) the cellular protein levels estimated by the concentration of proteins and DNA of the tissue. The rates of disappearance of radioactivity from the liver proteins of mice were not statistically significantly affected by these dietary regimens. However, there was a 27% decrease in the cellular protein synthesis of liver in the animals fed the diets containing cellulose.     

Lymphonodular hyperplasia of the terminal ileum associated with colitis shows an increase gammadelta+ t-cell density in children

OBJECTIVE: Recently we reported a close association between lymphonodular hyperplasia (LNH) of the bulb of the duodenum and increased densities of intraepithelial gammadelta+ T-cells in subjects with untreated food allergies. In this study we sought to determine whether children with LNH of the terminal ileum (TI) show a similar correlation. METHODS: The mucosal specimens taken by colonoscopy from the TIs of 22 children with LNH of the TI without colitis, 13 with right-sided colitis or pancolitis, nine with left-sided colitis, eight with Crohn's disease, and three endoscopically healthy subjects were studied for T-cell subsets with monoclonal antibodies using a three-layer peroxidase staining method. RESULTS: LNH of the TI was found in 32 of the 55 subjects (58%). In 22 it was the only endoscopic finding, but in nine of 13 subjects (69%) it was related to right-sided colitis or pancolitis. In patients with left-sided colitis or Crohn's disease it was diagnosed only rarely. In the whole study population, LNH of the of the TI showed a significant association with the increment in the density of gammadelta+ T-cells. The subjects with LNH of the TI and colitis starting from the cecum showed the highest values, discriminating them statistically from any other study group. Accordingly their gammadelta+/CD3+ ratio was high. Even in the subjects with LNH of the TI without colitis, the increment in gammadelta+ T-cells was significant as compared with the subjects with left-sided colitis. Upregulations of D-related expression on the mucosa of the TI were similar regardless of the presence of LNH or colitis or an increment in gammadelta+ T-cells. CONCLUSION: Our preliminary observations showed increased densities of intraepithelial gammadelta+ T-cells and elevated gammadelta+/CD3+ ratios in subjects with LNH on the mucosa of the TI, especially if related to colitis starting at the cecem, but not in subjects with typical left-sided colitis or granulomatous Crohn's disease. The study also provides further evidence suggesting the significance of food-borne antigens in the pathogenetic mechanism of right-sided colitis or pancolitis. The finding also indicates the significance of classifying colitis into gammadelta-positive and -negative diseases, and has implications for the treatment of these entities.     

Osteoclastogenesis is Influenced by Modulation of Gap Junctional Communication with Antiarrhythmic Peptides

Osteoclasts are formed by the fusion of mononuclear precursor cells of the monocyte–macrophage lineage. Among several putative mechanisms, gap-junctional intercellular communication (GJC) has been proposed to have a role in osteoclast fusion and bone resorption. We examined the role of GJC in osteoclastogenesis and in vitro bone resorption with mouse bone marrow hematopoietic stem cells and RAW 264.7 cells. Blocking of gap junctions with 18-α-glycyrrhetinic acid (18GA) led to inhibition of osteoclastogenesis and in vitro bone resorption. Similarly, the GJC inhibitor GAP27 inhibited osteoclast formation. GJC modulation with the antiarrhythmic peptides (AAPs) led to increased amounts of multinuclear RAW 264.7 osteoclasts as well as increased number of nuclei per multinuclear cell. In the culture of bone marrow hematopoietic stem cells in the presence of bone marrow stromal cells AAP reduced the number of osteoclasts, and coculture of MC3T3-E1 preosteoblasts with RAW 264.7 macrophages prevented the action of AAPs to promote osteoclastogenesis. The present data indicate that AAPs modulate the fusion of the pure culture of cells of the monocyte–macrophage lineage. However, the fusion is influenced by GJC in cells of the osteoblast lineage.     

Diffusion of ionic and non-ionic contrast agents in articular cartilage with increased cross-linking—Contribution of steric and electrostatic effects

ObjectiveTo investigate the effect of threose-induced collagen cross-linking on diffusion of ionic and non-ionic contrast agents in articular cartilage.DesignOsteochondral plugs (Ø = 6 mm) were prepared from bovine patellae and divided into two groups according to the contrast agent to be used in contrast enhanced computed tomography (CECT) imaging: (I) anionic ioxaglate and (II) non-ionic iodixanol. The groups I and II contained 7 and 6 sample pairs, respectively. One of the paired samples served as a reference while the other was treated with threose to induce collagen cross-linking. The equilibrium partitioning of the contrast agents was imaged after 24 h of immersion. Fixed charge density (FCD), water content, contents of proteoglycans, total collagen, hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP) and pentosidine (Pent) cross-links were determined as a reference.ResultsThe equilibrium partitioning of ioxaglate (group I) was significantly (p = 0.018) lower (?23.4%) in threose-treated than control samples while the equilibrium partitioning of iodixanol (group II) was unaffected by the threose-treatment. FCD in the middle and deep zones of the cartilage (p < 0.05) and contents of Pent and LP (p = 0.001) increased significantly due to the treatment. However, the proteoglycan concentration was not systematically altered after the treatment. Water content was significantly (?3.5%, p = 0.007) lower after the treatment.ConclusionsSince non-ionic iodixanol showed no changes in partition after cross-linking, in contrast to anionic ioxaglate, we conclude that the cross-linking induced changes in charge distribution have greater effect on diffusion compared to the cross-linking induced changes in steric hindrance.