The forest therapy program did not induce prolonged systolic blood pressure (SBP) reduction. However, considering the significant decrease in cortisol level and improvement in QoL measures, this may be a useful model of community hypertension management program.
Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive cerebellar ataxia, recurrent sinopulmonary infections, oculocutaneous telangiectasia, selective immunoglobulin deficiency, and defective cellular immunity. We report a 4-year-old girl with ataxia telangiectasia whose initial magnetic resonance imaging (MRI) scan at 17 months of age showed leukoencephalopathy compatible with a leukodystrophy, a neuroimaging feature of ataxia telangiectasia that has not been described. Ataxia telangiectasia was not suspected until the child developed more typical clinical features. Diffuse white-matter high signal intensity on T2-weighted MRI scans may occur in the early stages of ataxia telangiectasia. This disease should be considered in the differential diagnosis of any child with a history and MRI findings suggestive of one of the leukodystrophies. The nonneurologic manifestations of ataxia telangiectasia may be of help diagnostically in this clinical setting.
Background: Fibrosis can develop as a late side effect of radiation exposure in a variety of tissues, including lung and skin. Late radiation injury and fibrosis are characterized by parenchymal cell depletion, inflammation, senescence, fibroblast proliferation, and excessive deposition of collagen. Plasminogen activator inhibitor 1 (PAI-1) is a critical mediator of cellular senescence and fibrin stabilization, and its expression is increased in experimental fibrosis models. We sought to determine if inhibition of PAI-1 signaling with a recombinant truncated protein (rPAI-123) would protect from the development of radiation-induced lung injury. Methods: C57Bl/6 mice received intraperitoneal injections of rPAI-123 (5.4 μg/kg/day) or vehicle (PBS) for 18 weeks beginning two days prior to radiation exposure. Cohorts of mice treated with rPAI-123 or vehicle were exposed to thoracic irradiation in 5 daily fractions of 6 Gy (RT), and followed for survival (n = 8 per group) and tissue collection (n = 3 per each time point). Histologic changes in irradiated lungs were evaluated by Masson-Trichrome staining at 19 weeks after RT. Senescence was assessed with staining for beta-galactosidase activity in lung tissue and primary pneumocytes. To define the roles of rPAI-123 in the fibroproliferative response, cell proliferation (MTT assay) and collagen deposition (Hydroxyproline assay) were examined in a mouse fibroblast cell line in vitro. Results: Administration of rPAI-123 increased C57Bl/6 mice survival from 37.5% to 62.5% at 19 weeks after radiation exposure. At 19 weeks after irradiation, hydroxyproline content was markedly decreased in mice received rPAI-123 compared to mice received vehicle (RT+rPAI-123: 56.2±10.79, RT+vehicle: 84.97±2.98, μg/lung respectively, p = 0.001 between RT+vehicle and RT+rPAI-123). C57Bl/6 mice exposed to RT+vehicle had dense foci of subplueral fibrosis at 19 weeks, whereas the lungs of mice exposed to RT+rPAI-123 were largely devoid of fibrotic foci. Cellular senescence in response to radiation was significantly decreased by rPAI-123 treatment in primary type2 pneumocyte culture (2-fold reduction at 5 days after RT, p = 0.036), and in lung tissues (>2-fold reduction at 4, 8, and 16 weeks after RT, p<0.001 at each time point). Treatment of NIH-3T3 fibroblasts with rPAI-123 resulted in decreased collagen production, but had no effect on proliferation.Conclusions: These studies identify that rPAI-123 has a novel protection mechanism against radiation-induced fibrosis in murine lungs due to its ability to reduce senescence in type2 pneumocytes, and the potential to be an effective therapy option for radiation induced fibrosis. Citation Format: Eunjoo Chung, Ayla White, Bradley T. Scroggins, Grace B. McKay-Corkum, Mary Jo Mulligan-Kehoe, Deborah E. Citrin. A truncated Plasminogen Activator Inhibitor-1 protein protects from pulmonary fibrosis mediated by irradiation in a murine model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1803. doi:10.1158/1538-7445.AM2015-1803
Informed consent is a legal principle implemented during the 1974 Nuremberg Code and developed during subsequent medical lawsuits, and currently established as a code of conduct for subject safety and protection during medical/research experiments. Informed consent is also widely used in Korea but controversies exist on its nature and applicability. This paper determines the origin of such controversy in the absence of “comprehension” of informed consent under the Korea societal context. It starts by addressing the problem of interpreting “informed” as only the transferal of just the information itself. This paper thus (1) searches the dictionary meaning and common usage of “informed consent”; (2) evaluates international methods used to promote research participants understanding in consent processes such as Teach Back, iMedConsent, and Emmi Program; and (3) considers literature evaluating the effectiveness of the above methods. Ultimately, for the current research atmosphere in Korea that emphasizes the researcher’s “sufficient explanation” to change into that emphasizing “sufficient comprehension”, the researcher must not only inform the subject, but also check whether the subject has been sufficiently informed. Achieving this requires breaking away from conventional theory to practical research and attempts on the realistic usage of informed consent. Finally, the researcher must perceive communication with the subject as primarily important during the consent process and confirm that the subject has understood the explained information. The subject’s comprehension may differ due to demographic and social factors, and consideration of the information quantity and time spent on consent is necessary.
Ionizing radiation is commonly used in the treatment of broad range of malignancies. However radiation induces DNA damage and oxidative stress in malignant and normal cells and stimulates inflammation in irradiated tissues. These vents may lead to tumor cell death, but also to a range of side effects including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Recently, we reported that accelerated senescence of type II pneumocytes, the alveolar stem cell, results in depletion of type II pneumocytes and precedes pulmonary fibrosis. Targeted isolated depletion of type II pneumocytes is known to result in fibrosis. To understand the underlying mechanisms between RIPF and senescence, we investigated the role of several molecules which were markedly changed in irradiated lungs with fibrogenic exposures. Secretory Clusterin/Apolipoprotein J (sCLU) is a heterodimeric disulfide-linked glycoprotein encoded by a single gene. sCLU expression is implicated in physiological processes including development, lipid transportation, differentiation, cellular senescence, and in many age-related diseases including neurodegeneration, vascular damage, diabetes and tumorigenesis. It was recently proposed that sCLU is a sensitive cellular biosensor of oxidative stress that functions to protect cells from the deleterious effects of free radicals and their derivatives. We investigated sCLU expression in primary murine pneumocytes after exposure to irradiation. Increased sCLU expression following irradiation was confirmed by immunocytochemical assays and quantitative real-time PCR in primary pneumocyte cultures. At 5 days after irradiation, sCLU expression colocalized with senescence-associated beta-galactosidase (SA-beta-gal) activity. To determine the temporal relationship between sCLU expression and SA-beta-gal activity, sCLU expression and SA-beta-galactosidase activity was measured in murine lung tissues at 2 and 4 weeks after radiation exposures. As observed in pneumocyte cultures, the expression of sCLU mRNA was significantly increased in murine lungs after fibrogenic irradiation, with staining colocalizing to cells staining positive for SA-beta-gal activity. IGF-1, known to induce sCLU expression, was positively correlated with the levels of sCLU in irradiated lungs. Inhibition of IGF-1 signaling reduced sCLU expression in primary pneumocytes exposed to fibrogenic irradiation. Collectively, these data suggest that sCLU may provide a marker or target of type II pneumocyte senescence after irradiation. Citation Format: Eunjoo Chung, Jason Horton, Ayla White, Bradly Scroggins, Kathryn Hudak, Deborah Citrin. Enhanced expression of secretory clusterin/apolipoprotein J (sCLU) in pulmonary alveolar stem cells after ionizing radiation exposure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2014-852
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