Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host's ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dose-dependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis.
Animals ; Apoptosis ; Apoptosis Regulatory Proteins ; Atrophy* ; Blotting, Western ; Caspase 3 ; Cell Count ; Dexamethasone ; Ghrelin* ; Mice* ; Mitogen-Activated Protein Kinases ; Phosphorylation ; Signal Transduction ; Thymocytes ; Thymus Gland*

Coronary artery involvement leading to acute coronary syndrome is a rare complication of essential thrombocythemia. A 43-year-old woman with essential thrombocythemia complained of severe acute chest pain. She had undergone percutaneous coronary intervention (PCI) with a drug-eluting stent (DES), due to unstable angina, 3 and 2 years earlier. Emergency coronary angiography revealed total occlusion of the DES with thrombus. Twenty minutes after successful primary PCI with a DES, an acute stent thrombosis developed. She was subsequently treated with coronary artery bypass graft surgery.
Acute Coronary Syndrome ; Adult ; Angina, Unstable ; Chest Pain ; Coronary Angiography ; Coronary Artery Bypass ; Coronary Vessels ; Drug-Eluting Stents ; Emergencies ; Female ; Humans ; Percutaneous Coronary Intervention ; Stents ; Thrombocythemia, Essential ; Thrombosis ; Transplants

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1beta is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL-1beta production may be a way to prevent gastric cancer. Withaferin A (WA), a withanolide purified from Withania somnifera, is known to exert anti-inflammatory and anti-tumor effects. In the present study, we explored the inhibitory activity of WA on H. pylori-induced production of IL-1beta in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1beta production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1beta and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, IkappaB-alpha phosphorylation by H. pylori infection was suppressed by WA in BMDCs. Western blot analysis revealed that H. pylori induced cleavage of caspase-1 and IL-1beta, as well as increased procaspase-1 and pro IL-1beta protein levels, and that both were suppressed by co-treatment with WA. Finally, we determined whether WA can directly inhibit ac tivation of the NLRP3 inflammasome. NLRP3 activators induced IL-1beta secretion in LPS-primed macrophages, which was inhibited by WA in a dose-dependent manner, whereas IL-6 production was not affected by WA. Moreover, cleavage of IL-1beta and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1beta production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer.
Blotting, Western ; Caspase 1 ; Dendritic Cells* ; Down-Regulation ; Gastritis ; Gene Expression ; Helicobacter pylori ; Helicobacter* ; Humans ; Interleukin-1beta ; Interleukin-6 ; Macrophages ; NF-kappa B* ; Peptic Ulcer ; Phosphorylation ; Stomach Neoplasms ; Withania

The gradual loss of telomeric DNA can contribute to replicative senescence and thus, having longer telomeric DNA is generally considered to provide a longer lifespan. Maintenance and stabilization of telomeric DNA is assisted by binding of multiple DNA-binding proteins, including those involved in double strand break (DSB) repair. We reasoned that declining DSB repair capacity and increased telomere shortening in aged individuals may be associated with decreased expression of DSB repair proteins capable of telomere binding. Our data presented here show that among the DSB repair proteins tested, only the expression of Ku70 and Mre11 showed statistically significant age-dependent changes in human lymphocytes. Furthermore, we found that expressions of Ku70 and Mre11 are statistically correlated, which indicate that the function of Ku70 and Mre11 may be related. All the other DSB repair proteins tested, Sir2, TRF1 and Ku80, did not show any significant differences upon aging. In line with these data, people who live in the regional community (longevity group), which was found to have statistically longer average life span than the rest area, shows higher level of Ku70 expression than those living in the neighboring control community. Taken together, our data show, for the first time, that Ku70 and Mre11 may represent new biomarkers for aging and further suggest that maintenance of higher expression of Ku70 and Mre11 may be responsible for keeping longer life span observed in the longevity group.
Telomere/genetics ; Middle Aged ; Longevity ; Humans ; DNA-Binding Proteins/*metabolism ; DNA Repair/*genetics ; DNA/genetics ; Cell Aging/*physiology ; CD4-Positive T-Lymphocytes/metabolism ; Antigens, Nuclear/*metabolism ; Aging/*physiology ; Aged, 80 and over ; Aged ; Adult