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  1. Rapamycin

    OpenAIRE

    Srivastava, Rupesh K.; Utley, Adam; Shrikant, Protul A.

    2012-01-01

    Vaccines that generate Ag-specific CD8+ T-cell responses of appropriate quality, magnitude and duration are highly desirable. The ability of mTOR to regulate CD8+ T-cell functional differentiation must be exploited for clinical benefit. In a recent paper, we report that varying the regimen of rapamycin administration regulates viral vaccine-induced CD8+ T-cell responses for tumor immunity. These observations validate the use of rapamycin in vaccination strategies and demonstrate the efficacy ...

  2. Chronic rapamycin treatment causes diabetes in male mice

    National Research Council Canada - National Science Library

    Schindler, Christine E; Partap, Uttara; Patchen, Bonnie K; Swoap, Steven J

    2014-01-01

    .... We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance...

  3. Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment.

    Science.gov (United States)

    Liu, Yang; Pandeswara, Srilakshmi; Dao, Vinh; Padrón, Álvaro; Drerup, Justin M; Lao, Shunhua; Liu, Aijie; Hurez, Vincent; Curiel, Tyler J

    2017-01-15

    mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1-8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell-dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L(+) CD8(+) central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520-31. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

    OpenAIRE

    Arriola Apelo, Sebastian I.; Neuman, Joshua C.; Baar, Emma L.; Syed, Faizan A.; Cummings, Nicole E.; Brar, Harpreet K.; Pumper, Cassidy P.; Kimple, Michelle E.; Lamming, Dudley W.

    2015-01-01

    Summary Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA?approved drug rapamycin has been shown to promote lifespan and delay age?related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long?term prophylactic use of rapamycin as a therapy for age?related diseases. While the beneficial effects of rapamycin are larg...

  5. Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer

    Directory of Open Access Journals (Sweden)

    Weiqian Chen

    2016-12-01

    Full Text Available Mechanistic/mammalian target of rapamycin (mTOR has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment.

  6. Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats.

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    Drion, Cato M; Borm, Lars E; Kooijman, Lieneke; Aronica, Eleonora; Wadman, Wytse J; Hartog, Aloysius F; van Vliet, Erwin A; Gorter, Jan A

    2016-05-01

    Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/or antiseizure effects using different treatment strategies in the electrogenic post-status epilepticus (SE) rat model. Effects of mTOR inhibitor rapamycin were tested using the following three treatment protocols: (1) "stop-treatment"-post-SE treatment (6 mg/kg/day) was discontinued after 3 weeks; rats were monitored for 5 more weeks thereafter, (2) "pretreatment"-rapamycin (3 mg/kg/day) was applied during 3 days preceding SE; and (3) "chronic phase-treatment"-5 days rapamycin treatment (3 mg/kg/day) in the chronic phase. We also tested curcumin, an alternative mTOR inhibitor with antiinflammatory and antioxidant effects, using chronic phase treatment. Seizures were continuously monitored using video-electroencephalography (EEG) recordings; mossy fiber sprouting, cell death, and inflammation were studied using immunohistochemistry. Blood was withdrawn regularly to assess rapamycin and curcumin levels with high performance liquid chromatography (HPLC). Stop-treatment led to a strong reduction of seizures during the 3-week treatment and a gradual reappearance of seizures during the following 5 weeks. Three days pretreatment did not prevent seizure development, whereas 5-day rapamycin treatment in the chronic phase reduced seizure frequency. Washout of rapamycin was slow and associated with a gradual reappearance of seizures. Rapamycin treatment (both 3 and 6 mg/kg) led to body growth reduction. Curcumin treatment did not reduce seizure frequency or lead to a decrease in body weight. The present study indicates that rapamycin cannot prevent epilepsy in the electrical stimulation post-SE rat model but has seizure-suppressing properties as long as rapamycin blood levels are sufficiently high. Oral curcumin treatment had no effect on chronic

  7. Rapamycin treatment causes developmental delay, pigmentation defects, and gastrointestinal malformation on Xenopus embryogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Moriyama, Yuki [Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan); Ohata, Yoshihisa [Department of Education (Sciences), Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan); Mori, Shoko [Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan); Matsukawa, Shinya [Department of Education (Sciences), Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan); Michiue, Tatsuo [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 (Japan); Asashima, Makoto [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 (Japan); Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Baien, Tsukuba, Ibaraki 305-8562 (Japan); Kuroda, Hiroki, E-mail: ehkurod@ipc.shizuoka.ac.jp [Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan); Department of Education (Sciences), Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)

    2011-01-28

    Research highlights: {yields} Does famous anti-aging drug rapamycin work from the beginning of life? The answer is yes. {yields} This study shows that developmental speed of frog embryo was dose-dependently decreased by rapamycin treatment. {yields} In additions, morphogenetic effects such as less pigmentations and gut malformation are occurred by rapamycin. -- Abstract: Rapamycin is a drug working as an inhibitor of the TOR (target of rapamycin) signaling pathway and influences various life phenomena such as cell growth, proliferation, and life span extension in eukaryote. However, the extent to which rapamycin controls early developmental events of amphibians remains to be understood. Here we report an examination of rapamycin effects during Xenopus early development, followed by a confirmation of suppression of TOR downstream kinase S6K by rapamycin treatment. First, we found that developmental speed was declined in dose-dependent manner of rapamycin. Second, black pigment spots located at dorsal and lateral skin in tadpoles were reduced by rapamycin treatment. Moreover, in tadpole stages severe gastrointestinal malformations were observed in rapamycin-treated embryos. Taken together with these results, we conclude that treatment of the drug rapamycin causes enormous influences on early developmental period.

  8. Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors.

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    Thomas, Diana L; Doty, Rosalinda; Tosic, Vesna; Liu, Jia; Kranz, David M; McFadden, Grant; Macneill, Amy L; Roy, Edward J

    2011-10-01

    Adoptive transfer of tumor-specific T cells has shown some success for treating metastatic melanoma. We evaluated a novel strategy to improve adoptive therapy by administering both T cells and oncolytic myxoma virus to mice with syngeneic B16.SIY melanoma brain tumors. Adoptive transfer of activated CD8(+) 2C T cells that recognize SIY peptide doubled survival time, but SIY-negative tumors recurred. Myxoma virus killed B16.SIY cells in vitro, and intratumoral injection of virus led to selective and transient infection of the tumor. Virus treatment recruited innate immune cells to the tumor and induced IFNβ production in the brain, resulting in limited oncolytic effects in vivo. To counter this, we evaluated the safety and efficacy of co-administering 2C T cells, myxoma virus, and either rapamycin or neutralizing antibodies against IFNβ. Mice that received either triple combination therapy survived significantly longer with no apparent side effects, but eventually relapsed. Importantly, rapamycin treatment did not impair T cell-mediated tumor destruction, supporting the feasibility of combining adoptive immunotherapy and rapamycin-enhanced virotherapy. Myxoma virus may be a useful vector for transient delivery of therapeutic genes to a tumor to enhance T cell responses.

  9. Health Effects of Long-Term Rapamycin Treatment: The Impact on Mouse Health of Enteric Rapamycin Treatment from Four Months of Age throughout Life.

    Directory of Open Access Journals (Sweden)

    Kathleen E Fischer

    Full Text Available Rapamycin, an mTOR inhibitor, has been shown to extend lifespan in a range of model organisms. It has been reported to extend lifespan in multiple strains of mice, administered chronically or acutely early or late in life. The ability of rapamycin to extend health (healthspan as opposed to life is less well documented. To assess the effects chronic rapamycin treatment on healthspan, enteric rapamycin was given to male and female C57BL/6J mice starting at 4 months of age and continued throughout life. Repeated, longitudinal assessments of health in individual animals were made starting at 16 months of age (=12 months of treatment until death. A number of health parameters were improved (female grip strength, female body mass and reduced sleep fragmentation in both sexes, others showed no significant difference, while at least one (male rotarod performance was negatively affected. Rapamycin treatment affected many measures of health in a highly sex-specific manner. While sex-specific phenotypic effects of rapamycin treatment have been widely reported, in this study we document sex differences in the direction of phenotypic change. Rapamycin-fed males and females were both significantly different from controls; however the differences were in the opposite direction in measures of body mass, percent fat and resting metabolic rate, a pattern not previously reported.

  10. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Won Seop Kim

    2013-06-01

    Full Text Available Korean J Pediatr 2011;54:241-5. <a href='http://dx.doi.org/10.3345/kjp.2011.54.6.241'>http://dx.doi.org/10.3345/kjp.2011.54.6.241</a>. PMID: 21949518 [PubMed] <div style="border-top:1px solid #0092C8"></div> The following article<sup>1</sup> is being retracted as a part of the manuscript was plagiarized. Yeong-Ho Rha, MD, PhD Editor-in-Chief, Korean J Pediatr 1.Kim WS. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis. Korean J Pediatr 2011;54:241-5.

  11. Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Pei-Jie Shi

    2016-02-01

    Full Text Available Abstract Background Acute lymphoblastic leukemia (ALL is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK down-regulation in the treatment of ALL. Methods The effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID mouse model. Results When combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1 cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2 gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis. Conclusions FAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel

  12. Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Rachel M. Saré

    2018-01-01

    Full Text Available Fragile X syndrome (FXS, the most common form of inherited intellectual disability, is also highly associated with autism spectrum disorders (ASD. It is caused by expansion of a CGG repeat sequence on the X chromosome resulting in silencing of the FMR1 gene. This is modeled in the mouse by deletion of Fmr1 (Fmr1 KO. Fmr1 KO mice recapitulate many of the behavioral features of the disorder including seizure susceptibility, hyperactivity, impaired social behavior, sleep problems, and learning and memory deficits. The mammalian target of rapamycin pathway (mTORC1 is upregulated in Fmr1 KO mice and is thought to be important for the pathogenesis of this disorder. We treated Fmr1 KO mice chronically with an mTORC1 inhibitor, rapamycin, to determine if rapamycin treatment could reverse behavioral phenotypes. We performed open field, zero maze, social behavior, sleep, passive avoidance, and audiogenic seizure testing. We found that pS6 was upregulated in Fmr1 KO mice and normalized by rapamycin treatment, but, except for an anxiogenic effect, it did not reverse any of the behavioral phenotypes examined. In fact, rapamycin treatment had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice. These results suggest that targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.

  13. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Won Seop Kim

    2011-06-01

    Full Text Available Tuberous sclerosis complex (TSC is a genetic multisystem disorder that results from mutations in the TSC1 or TSC2 genes, and is associated with hamartomas in several organs, including subependymal giant cell tumors. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. The TSC1- and TSC2-encoded proteins modulate cell function via the mammalian target of rapamycin (mTOR signaling cascade, and are key factors in the regulation of cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. The mTOR pathway represents a logical candidate for drug targeting, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

  14. Effects of rapamycin treatment after controlled cortical impact injury on neurogenesis and synaptic reorganization in the mouse dentate gyrus

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    Corwin R Butler

    2015-11-01

    Full Text Available Post-traumatic epilepsy (PTE is one consequence of traumatic brain injury (TBI. A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR. Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact was investigated. Rapamycin (3 or 10 mg/kg, an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8-13 weeks, evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle-treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis.

  15. Low-Dose Rapamycin Treatment Increases the Ability of Human Regulatory T Cells to Inhibit Transplant Arteriosclerosis In Vivo

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    Hester, J; Schiopu, A; Nadig, S N; Wood, K J

    2012-01-01

    Regulatory T cells (Treg) are currently being tested in clinical trials as a potential therapy in cell and solid organ transplantation. The immunosuppressive drug rapamycin has been shown to preferentially promote Treg expansion. Here, we hypothesized that adjunctive rapamycin therapy might potentiate the ability of ex vivo expanded human Treg to inhibit vascular allograft rejection in a humanized mouse model of arterial transplantation. We studied the influence of combined treatment with low-dose rapamycin and subtherapeutic Treg numbers on the development of transplant arteriosclerosis (TA) in human arterial grafts transplanted into immunodeficient BALB/cRag2−/−Il2rg−/− mice reconstituted with allogeneic human peripheral blood mononuclear cell. In addition, we assessed the effects of the treatment on the proliferation and apoptosis of naïve/effector T cells. The combined therapy efficiently suppressed T-cell proliferation in vivo and in vitro. Neointima formation in the human arterial allografts was potently inhibited compared with each treatment alone. Interestingly, CD4+ but not CD8+ T lymphocytes were sensitive to Treg and rapamycin-induced apoptosis in vitro. Our data support the concept that rapamycin can be used as an adjunctive therapy to improve efficacy of Treg-based immunosuppressive protocols in clinical practice. By inhibiting TA, Treg and rapamycin may prevent chronic transplant dysfunction and improve long-term allograft survival PMID:22500984

  16. Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats.

    NARCIS (Netherlands)

    Drion, C.M.; Borm, L.E.; Kooijman, L.; Aronica, E.; Wadman, W.J.; Hartog, A.F.; van Vliet, E.A.; Gorter, J.A.

    2016-01-01

    OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/or antiseizure effects using different treatment

  17. Prospective pilot study on combined use of pulsed dye laser and 1% topical rapamycin for treatment of nonfacial cutaneous capillary malformation.

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    Doh, Eun Jin; Ohn, Jungyoon; Kim, Min Ji; Kim, Young Gull; Cho, Soyun

    2017-11-01

    The regeneration or revascularization of blood vessels after pulsed dye laser (PDL) treatment is one of the causes of treatment failures of cutaneous capillary malformations (CM). Recently, topical administration of rapamycin was introduced as a possible adjunctive therapeutic option to minimize postlaser revascularization in facial CM. We evaluated the effect of combined use of 1% topical rapamycin with PDL compared to PDL alone in cutaneous CM of trunk or extremities and tried to identify the optimal duration of topical rapamycin application. Three adjacent areas of cutaneous CM that had never been treated before were selected in each patient and underwent the following regimens: (A) PDL + vehicle for 8 weeks post-PDL; (B) PDL + topical rapamycin for 1-week post-PDL and (C) PDL + topical rapamycin for 8 weeks post-PDL. Each test site was treated by PDL for two sessions with 8 weeks interval. Only one of six patients showed clinical improvement with combined rapamycin treatment. Overall, there was no statistically significant difference in erythema and blanching rate among PDL alone and combined rapamycin regimens. One percent topical rapamycin does not seem to be effective as a treatment modality for cutaneous CM of trunk or extremities.

  18. Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis.

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    Martin, D F; DeBarge, L R; Nussenblatt, R B; Chan, C C; Roberge, F G

    1995-01-15

    Immunosuppressive drugs currently available for the treatment of autoimmune diseases display a narrow therapeutic window between efficacy and toxic side effects. The use of combinations of drugs that have a synergistic effect may expand this window and reduce the risk of toxicity. We evaluated the combination effect of rapamycin (Rapa) and cyclosporin A (CsA) in an autoimmune disease model of the eye. The dose-effect relationship of Rapa with CsA was measured in vitro on the inhibition of proliferation of retinal S-Ag-primed lymphocytes. A median effect analysis was performed and a combination index (CI) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic over a wide dose range (lowest CI = 0.31). Calculated dose reduction factors indicated that Rapa could be reduced nine-fold and CsA reduced five-fold when these drugs were used in combination. These reduced doses were tested in vivo for the treatment of experimental autoimmune uveoretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, developed EAU with a median severity of 2.5. Fourteen of 15 rats treated with Rapa, 0.01 mg/kg/day, developed EAU with a median severity of 3.25. Complete inhibition of EAU was achieved in all 15 animals treated with the combination of Rapa and CsA (combined vs CsA alone, p toxicity of these drugs for the treatment of autoimmune uveitis.

  19. Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer

    Science.gov (United States)

    Navarrete, Alicia; Armitage, Emily G; Musteanu, Monica; García, Antonia; Mastrangelo, Annalaura; Bujak, Renata; López-Casas, Pedro P; Hidalgo, Manuel; Barbas, Coral

    2014-01-01

    In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism. PMID:25505613

  20. Rapamycin: one drug, many effects

    Science.gov (United States)

    Li, Jing; Kim, Sang Gyun; Blenis, John

    2014-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapamycin monotherapy and the potential utility of combination therapy with rapamycin. PMID:24508508

  1. Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial.

    Directory of Open Access Journals (Sweden)

    Lieke M C Gijezen

    Full Text Available Birt-Hogg-Dubé syndrome (BHD is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR. Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects.No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients as well as the placebo treated facial sides (both 74%. No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion. No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients than after placebo (58% of patients; p = 0.625. A burning sensation, erythema, itching and dryness were most frequently reported.This study provides no evidence that treatment of fibrofolliculomas with topical

  2. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence

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    Thuy Nguyen, Hanh; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-01

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (-14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  3. Rapamycin carbonate esters

    OpenAIRE

    Rhodes, A; Sandhu, S S; Onis, J. E; McKendrick, John

    2009-01-01

    Certain embodiments include carbonate esters of rapamycin at position 42 that are synthesized by a lipase catalyzed regio-specific process. These compounds or a pharmaceutically acceptable salt thereof are useful in the treatment of organ and tissue transplant rejection, autoimmune disease, proliferative disorder, restenosis, cancer, or microbial infection.

  4. A novel amblyopia treatment system based on LED light source

    Science.gov (United States)

    Zhang, Xiaoqing; Chen, Qingshan; Wang, Xiaoling

    2011-05-01

    A novel LED (light emitting diode) light source of five different colors (white, red, green, blue and yellow) is adopted instead of conventional incandescent lamps for an amblyopia treatment system and seven training methods for rectifying amblyopia are incorporated so as for achieving an integrated therapy. The LED light source is designed to provide uniform illumination, adjustable light intensity and alterable colors. Experimental tests indicate that the LED light source operates steadily and fulfills the technical demand of amblyopia treatment.

  5. Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, protects diabetic heart against ischaemia/reperfusion injury.

    Science.gov (United States)

    Samidurai, Arun; Salloum, Fadi N; Durrant, David; Chernova, Olga B; Kukreja, Rakesh C; Das, Anindita

    2017-10-01

    Enhanced mammalian target of rapamycin (mTOR) signalling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischaemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR that has been rationally designed to increase water solubility of rapamycin to facilitate p.o. administration and enhance bioavailability. We examined the effect of Rapatar on the metabolic status and protection against myocardial I/R injury in type 2 diabetic mice. Adult male db/db mice were treated daily for 10 weeks with Rapatar (0.75 mg·kg-1 ·day-1 , p.o.) or vehicle. Isolated hearts were connected to a Langendorff perfusion system and subjected to global ischaemia (30 min) and reperfusion (1 h). Rapatar reduced fasting plasma glucose and triglyceride levels, prevented the gain in body weight and also improved glucose tolerance and insulin sensitivity in db/db mice compared with control. Cardiac function was improved following Rapatar treatment in db/db mice. Myocardial infarct size was reduced in Rapatar-treated mice with improved post-ischaemic rate-force product. Western blot analyses demonstrated a significant inhibition of phosphorylation of ribosomal protein S6 (downstream target of mTORC1), but not Akt (Ser473 , target of mTORC2) following chronic treatment with Rapatar. Rapatar also induced phosphorylation of AMPK, STAT3, ERK1/2 and glycogen synthase kinase 3β, without interfering with phosphorylation of p38. Our studies indicate that chronic treatment with Rapatar improves metabolic status and cardiac function with a reduction of infarct size following myocardial I/R injury in diabetic mice. © 2017 The British Pharmacological Society.

  6. Rapamycin: One Drug, Many Effects

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    Li, Jing; Kim, Sang Gyun; Blenis, John

    2014-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapa...

  7. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment.

    Science.gov (United States)

    Wang, Tina; Tsui, Brian; Kreisberg, Jason F; Robertson, Neil A; Gross, Andrew M; Yu, Michael Ku; Carter, Hannah; Brown-Borg, Holly M; Adams, Peter D; Ideker, Trey

    2017-03-28

    Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

  8. TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast

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    Rallis, Charalampos; Codlin, Sandra; Bähler, Jürg

    2013-01-01

    Target of rapamycin complex 1 (TORC1) is implicated in growth control and aging from yeast to humans. Fission yeast is emerging as a popular model organism to study TOR signaling, although rapamycin has been thought to not affect cell growth in this organism. Here, we analyzed the effects of rapamycin and caffeine, singly and combined, on multiple cellular processes in fission yeast. The two drugs led to diverse and specific phenotypes that depended on TORC1 inhibition, including prolonged chronological lifespan, inhibition of global translation, inhibition of cell growth and division, and reprograming of global gene expression mimicking nitrogen starvation. Rapamycin and caffeine differentially affected these various TORC1-dependent processes. Combined drug treatment augmented most phenotypes and effectively blocked cell growth. Rapamycin showed a much more subtle effect on global translation than did caffeine, while both drugs were effective in prolonging chronological lifespan. Rapamycin and caffeine did not affect the lifespan via the pH of the growth media. Rapamycin prolonged the lifespan of nongrowing cells only when applied during the growth phase but not when applied after cells had stopped proliferation. The doses of rapamycin and caffeine strongly correlated with growth inhibition and with lifespan extension. This comprehensive analysis will inform future studies into TORC1 function and cellular aging in fission yeast and beyond. PMID:23551936

  9. FK506 Binding Protein Mediates Glioma Cell Growth and Sensitivity to Rapamycin Treatment by Regulating NF-κB Signaling Pathway

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    Wei Jiang

    2008-03-01

    Full Text Available FK506 binding protein 5 (FKBP5 belongs to a family of immunophilins named for their ability to bind immunosuppressive drugs, also known as peptidyl-prolyl cis-trans isomerases, and also with chaperones to help protein folding. Using glioma cDNA microarray analysis, we found that FKBP5 was overexpressed in glioma tumors. This finding was further validated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The roles of FKBP5 in glioma cells were then examined. We found that cell growth was suppressed after FKBP5 expression was inhibited by short interfering RNA transfection and enhanced by FKBP5 overexpression. Electrophoretic mobility shift assay showed that nuclear factor-kappa B (NF-κB and DNA binding was enhanced by FKBP5 overexpression. The expression level of I-kappa B alpha and phosphorylated NF-κB was regulated by the expression of FKBP5. These data suggest that FKBP5 is involved in NF-κB pathway activation in glioma cells. In addition, FKBP5 overexpression in rapamycin-sensitive U87 cells blocked the cells' response to rapamycin treatment, whereas rapamycin-resistant glioma cells, both PTEN-positive and -negative, were synergistically sensitive to rapamycin after FKBP5 was knocked down, suggesting that the FKBP5 regulates glioma cell response to rapamycin treatment. In conclusion, our study demonstrates that FKBP5 plays an important role in glioma growth and chemoresistance through regulating signal transduction of the NF-κB pathway.

  10. Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin

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    Slingluff Craig L

    2005-10-01

    Full Text Available Abstract Background Targeted inhibition of protein kinases is now acknowledged as an effective approach for cancer therapy. However, targeted therapies probably have limited success because cancer cells have alternate pathways for survival and proliferation thereby avoiding inhibition. We tested the hypothesis that combination of targeted agents would be more effective than single agents in arresting melanoma cell proliferation. Methods We evaluated whether BAY43-9006, an inhibitor of the B-Raf kinase, and rapamycin, an inhibitor of the mTOR kinase, would inhibit serum-stimulated proliferation of human melanoma cell lines, either alone or in combination. Proliferation was measured by quantitating melanoma cell numbers with a luciferase for ATP. Phosphorylation of proteins downstream of targeted kinase(s was assayed by immunoblots. Statistical significance was determined with the Student-T test. Isobologram analysis was performed to distinguish additive versus synergistic effects of combinations of drugs. Results Serum-stimulated proliferation of multiple human melanoma cell lines was inhibited by BAY43-9006 and by rapamycin. Melanoma cells containing the B-Raf mutation V599E were more sensitive than cells with wild-type B-raf to 10 nM doses of both BAY43-9006 and rapamycin. Regardless of B-Raf mutational status, the combination of low dose rapamycin and BAY43-9006 synergistically inhibited melanoma cell proliferation. As expected, rapamycin inhibited the phosphorylation of mTOR substrates, p70S6K and 4EBP1, and BAY43-9006 inhibited phosphorylation of ERK, which is dependent on B-Raf activity. We also observed unexpected rapamycin inhibition of the phosphorylation of ERK, as well as BAY43-9006 inhibition of the phosphorylation of mTOR substrates, p70S6K and 4EBP1. Conclusion There was synergistic inhibition of melanoma cell proliferation by the combination of rapamycin and BAY 43-9006, and unexpected inhibition of two signaling pathways by agents

  11. Yeast m6A Methylated mRNAs Are Enriched on Translating Ribosomes during Meiosis, and under Rapamycin Treatment.

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    Bodi, Zsuzsanna; Bottley, Andrew; Archer, Nathan; May, Sean T; Fray, Rupert G

    2015-01-01

    Interest in mRNA methylation has exploded in recent years. The sudden interest in a 40 year old discovery was due in part to the finding of FTO's (Fat Mass Obesity) N6-methyl-adenosine (m6A) deaminase activity, thus suggesting a link between obesity-associated diseases and the presence of m6A in mRNA. Another catalyst of the sudden rise in mRNA methylation research was the release of mRNA methylomes for human, mouse and Saccharomyces cerevisiae. However, the molecular function, or functions of this mRNA 'epimark' remain to be discovered. There is supportive evidence that m6A could be a mark for mRNA degradation due to its binding to YTH domain proteins, and consequently being chaperoned to P bodies. Nonetheless, only a subpopulation of the methylome was found binding to YTHDF2 in HeLa cells.The model organism Saccharomyces cerevisiae, has only one YTH domain protein (Pho92, Mrb1), which targets PHO4 transcripts for degradation under phosphate starvation. However, mRNA methylation is only found under meiosis inducing conditions, and PHO4 transcripts are apparently non-methylated. In this paper we set out to investigate if m6A could function alternatively to being a degradation mark in S. cerevisiae; we also sought to test whether it can be induced under non-standard sporulation conditions. We find a positive association between the presence of m6A and message translatability. We also find m6A induction following prolonged rapamycin treatment.

  12. Yeast m6A Methylated mRNAs Are Enriched on Translating Ribosomes during Meiosis, and under Rapamycin Treatment.

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    Zsuzsanna Bodi

    Full Text Available Interest in mRNA methylation has exploded in recent years. The sudden interest in a 40 year old discovery was due in part to the finding of FTO's (Fat Mass Obesity N6-methyl-adenosine (m6A deaminase activity, thus suggesting a link between obesity-associated diseases and the presence of m6A in mRNA. Another catalyst of the sudden rise in mRNA methylation research was the release of mRNA methylomes for human, mouse and Saccharomyces cerevisiae. However, the molecular function, or functions of this mRNA 'epimark' remain to be discovered. There is supportive evidence that m6A could be a mark for mRNA degradation due to its binding to YTH domain proteins, and consequently being chaperoned to P bodies. Nonetheless, only a subpopulation of the methylome was found binding to YTHDF2 in HeLa cells.The model organism Saccharomyces cerevisiae, has only one YTH domain protein (Pho92, Mrb1, which targets PHO4 transcripts for degradation under phosphate starvation. However, mRNA methylation is only found under meiosis inducing conditions, and PHO4 transcripts are apparently non-methylated. In this paper we set out to investigate if m6A could function alternatively to being a degradation mark in S. cerevisiae; we also sought to test whether it can be induced under non-standard sporulation conditions. We find a positive association between the presence of m6A and message translatability. We also find m6A induction following prolonged rapamycin treatment.

  13. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

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    Tim F Cloughesy

    2008-01-01

    Full Text Available There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR, we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation varied substantially. Tumor cell proliferation (measured by Ki-67 staining was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test.Rapamycin

  14. Longevity, aging and rapamycin

    OpenAIRE

    Ehninger, Dan; Neff, Frauke; Xie, Kan

    2014-01-01

    The federal drug administration (FDA)-approved compound rapamycin was the first pharmacological agent shown to extend maximal lifespan in both genders in a mammalian species. A major question then is whether the drug slows mammalian aging or if it has isolated effects on longevity by suppressing cancers, the main cause of death in many mouse strains. Here, we review what is currently known about the effects that pharmacological or genetic mammalian target of rapamycin (mTOR) inhibition have o...

  15. Rapamycin Synergizes with Cisplatin in Antiendometrial Cancer Activation by Improving IL-27–Stimulated Cytotoxicity of NK Cells

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    Wen-Jie Zhou

    2018-01-01

    Full Text Available Natural killer (NK cell function is critical for controlling initial tumor growth and determining chemosensitivity of the tumor. A synergistic relationship between rapamycin and cisplatin in uterine endometrial cancer (UEC in vitro has been reported, but the mechanism and the combined therapeutic strategy for endometrial cancer (EC are still unknown. We found a positive correlation between the level of IL-27 and the differentiated stage of UEC. The increase of IL-27 in uterine endometrial cancer cell (UECC lines (Ishikawa, RL95-2 and KLE led to a high cytotoxic activity of NK cells to UECC in the co-culture system. Exposure with rapamycin enhanced the cytotoxicity of NK cells by upregulating the expression of IL-27 in UECC and IL-27 receptors (IL-27Rs: WSX-1 and gp130 on NK cells and further restricted the growth of UEC in Ishikawa-xenografted nude mice. In addition, treatment with rapamycin resulted in an increased autophagy level of UECC, and IL-27 enhanced this ability of rapamycin. Cisplatin-mediated NK cells' cytotoxic activity and anti-UEC activation were independent of IL-27; however, the combination of rapamycin and cisplatin led to a higher cytotoxic activity of NK cells, smaller UEC volume and longer survival rate in vivo. These results suggest that rapamycin and cisplatin synergistically activate the cytotoxicity of NK cells and inhibit the progression of UEC in both an IL-27–dependent and –independent manner. This provides a scientific basis for potential rapamycin-cisplatin combined therapeutic strategies targeted to UEC, especially for the patients with low differentiated stage or abnormally low level of IL-27.

  16. Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors

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    Dabora Sandra L

    2010-02-01

    Full Text Available Abstract Background Tuberous Sclerosis Complex (TSC is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC. Methods In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase. Results TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2+/- mice compared with C57BL/6 Tsc2+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%. Conclusions Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC

  17. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice.

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    Adam L Hartman

    Full Text Available The mammalian target of rapamycin (mTOR pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.Following intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤ 6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.The only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.The efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.

  18. Stable Isotope Labeling Reveals Novel Insights Into Ubiquitin-Mediated Protein Aggregation With Age, Calorie Restriction, and Rapamycin Treatment.

    Science.gov (United States)

    Basisty, Nathan B; Liu, Yuxin; Reynolds, Jason; Karunadharma, Pabalu P; Dai, Dao-Fu; Fredrickson, Jeanne; Beyer, Richard P; MacCoss, Michael J; Rabinovitch, Peter S

    2017-08-18

    Accumulation of protein aggregates with age was first described in aged human tissue over 150 years ago and has since been described in virtually every human tissue. Ubiquitin modifications are a canonical marker of insoluble protein aggregates; however, the composition of most age-related inclusions remains relatively unknown. To examine the landscape of age-related protein aggregation in vivo, we performed an antibody-based pulldown of ubiquitinated proteins coupled with metabolic labeling and mass spectrometry on young and old mice on calorie restriction (CR), rapamycin (RP)-supplemented, and control diets. We show increased abundance of many ubiquitinated proteins in old mice and greater retention of preexisting (unlabeled) ubiquitinated proteins relative to their unmodified counterparts-fitting the expected profile of age-increased accumulation of long-lived aggregating proteins. Both CR and RP profoundly affected ubiquitinome composition, half-live, and the insolubility of proteins, consistent with their ability to mobilize these age-associated accumulations. Finally, confocal microscopy confirmed the aggregation of two of the top predicted aggregating proteins, keratins 8/18 and catalase, as well as their attenuation by CR and RP. Stable-isotope labeling is a powerful tool to gain novel insights into proteostasis mechanisms, including protein aggregation, and could be used to identify novel therapeutic targets in aging and protein aggregation diseases. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model

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    Chung, Eun Joo [Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); Sowers, Anastasia; Thetford, Angela [Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); McKay-Corkum, Grace; Chung, Su I. [Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); Mitchell, James B. [Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); Citrin, Deborah E., E-mail: citrind@mail.nih.gov [Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States)

    2016-11-15

    Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF. Methods and Materials: C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for β-galactosidase activity. Results: Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days (P=.006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 ± 11.8 μg per lung; irradiation plus rapamycin, 21.4 ± 6.0 μg per lung; P=.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1β and transforming growth factor β induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P<.001). Conclusions: Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes.

  20. Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells

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    Li Hui

    2011-03-01

    Full Text Available Abstract Background To elucidate whether rapamycin, the inhibitor of mTOR (mammalian target of rapamycin, can potentiate the cytotoxic effect of docetaxel in lung cancer cells and to probe the mechanism underlying such enhancement. Methods Lung cancer cells were treated with docetaxel and rapamycin. The effect on the proliferation of lung cancer cells was evaluated using the MTT method, and cell apoptosis was measured by flow cytometry. Protein expression and level of phosphorylation were assayed using Western Blot method. Results Co-treatment of rapamycin and docetaxel was found to favorably enhance the cytotoxic effect of docetaxel in four lung cancer cell lines. This tumoricidal boost is associated with a reduction in the expression and phosphorylation levels of Survivin and ERK1/2, respectively. Conclusion The combined application of mTOR inhibitor and docetaxel led to a greater degree of cancer cell killing than that by either compound used alone. Therefore, this combination warrants further investigation in its suitability of serving as a novel therapeutic scheme for treating advanced and recurrent lung cancer patients.

  1. Inhibition of MDM2 Re-Sensitizes Rapamycin Resistant Renal Cancer Cells via the Activation of p53.

    Science.gov (United States)

    Tian, Xin; Dai, Shundong; Sun, Jing; Jiang, Shenyi; Sui, Chengguang; Meng, Fandong; Li, Yan; Fu, Liye; Jiang, Tao; Wang, Yang; Su, Jia; Jiang, Youhong

    2016-01-01

    Rapamycin is a potential anti-cancer agent, which modulates the activity of mTOR, a key regulator of cell growth and proliferation. However, several types of cancer cells are resistant to the anti-proliferative effects of rapamycin. In this study, we report a MDM2/p53-mediated rapamycin resistance in human renal cancer cells. Trypan blue exclusion tests were used to determine the cell viability. Changes in mRNA and protein expression were measured using real-time PCR and western blot, respectively. Xenograft models were established to evaluate the in vivo effects of rapamycin combined with a MDM2 inhibitor. Rapamycin treatment suppresses the expression of MDM2 and exogenous overexpression of MDM2 in A498 cells contributes to rapamycin resistance. By establishing a rapamycin resistant cell line, we observed that MDM2 was significantly upregulated in rapamycin resistant cells than that in rapamycin sensitive cells. Importantly, the rapamycin resistant cells demonstrated attenuated accumulation of p53 in the nucleus in response to rapamycin treatment. Moreover, the inhibition of MDM2 by siMDM2 sensitizes A498 cells to rapamycin through the activation of p53. In both in vitro and in vivo models, the combination of rapamycin with the MDM2 inhibitor, MI-319, demonstrated a synergistic inhibitory effect on rapamycin resistant cells. Our study reports a novel mechanism for rapamycin resistance in human renal cancer and provides a new perspective for the development of anti-cancer drugs. © 2016 S. Karger AG, Basel.

  2. Rapamycin extends murine lifespan but has limited effects on aging.

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    Neff, Frauke; Flores-Dominguez, Diana; Ryan, Devon P; Horsch, Marion; Schröder, Susanne; Adler, Thure; Afonso, Luciana Caminha; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Garrett, Lillian; Hans, Wolfgang; Hettich, Moritz M; Holtmeier, Richard; Hölter, Sabine M; Moreth, Kristin; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Rathkolb, Birgit; Rozman, Jan; Naton, Beatrix; Ordemann, Rainer; Adamski, Jerzy; Beckers, Johannes; Bekeredjian, Raffi; Busch, Dirk H; Ehninger, Gerhard; Graw, Jochen; Höfler, Heinz; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Stypmann, Jörg; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Fuchs, Helmut; Gailus-Durner, Valérie; Hrabe de Angelis, Martin; Ehninger, Dan

    2013-08-01

    Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

  3. Development of a method for the characterization and operation of UV-LED for water treatment.

    Science.gov (United States)

    Kheyrandish, Ataollah; Mohseni, Madjid; Taghipour, Fariborz

    2017-10-01

    Tremendous improvements in semiconductor technology have made ultraviolet light-emitting diodes (UV-LEDs) a viable alternative to conventional UV sources for water treatment. A robust and validated experimental protocol for studying the kinetics of microorganism inactivation is key to the further development of UV-LEDs for water treatment. This study proposes a protocol to operate UV-LEDs and control their output as a polychromatic radiation source. In order to systematically develop this protocol, the results of spectral power distribution, radiation profile, and radiant power measurements of a variety of UV-LEDs are presented. A wide range of UV-LEDs was selected for this study, covering various UVA, UVB, and UVC wavelengths, viewing angles from 3.5° to 135°, and a variety of output powers. The effects of operational conditions and measurement techniques were investigated on these UV-LEDs using a specially designed and fabricated setup. Operating conditions, such as the UV-LED electrical current and solder temperature, were found to significantly affect the power and peak wavelength output. The measurement techniques and equipment, including the detector size, detector distance from the UV-LED, and potential reflection from the environment, were shown to influence the results for many of the UV-LEDs. The results obtained from these studies were analyzed and applied to the development of a protocol for UV-LED characterization. This protocol is presented as a guideline that allows the operation and control of UV-LEDs in any structure, as well as accurately measuring the UV-LED output. Such information is essential for performing a reliable UV-LED assessment for the inactivation of microorganisms and for obtaining precise kinetic data. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin.

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    Li, Haitao; Teng, Yunfei; Sun, Jin; Liu, Jianyong

    2017-11-01

    Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Rapamycin regulates biochemical metabolites

    OpenAIRE

    Tucci, Paola; Porta, Giovanni; Agostini, Massimiliano; Antonov, Alexey; Garabadgiu, Alexander Vasilievich; Melino, Gerry; Willis, Anne E

    2013-01-01

    The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis. p53, and its less investigated family member p73, have been shown to interact closely with mTOR pathways through the transcriptional regulation of different target genes. To investigate the metabolic changes that occur upon inhibition of the mTOR pathway and the role of p73 in this response p...

  6. Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model.

    Directory of Open Access Journals (Sweden)

    Wenru Su

    Full Text Available Glaucoma is a leading cause of irreversible blindness. Injury of retinal ganglion cells (RGCs accounts for visual impairment of glaucoma. Here, we report rapamycin protects RGCs from death in experimental glaucoma model and the underlying mechanisms. Our results showed that treatment with rapamycin dramatically promote RGCs survival in a rat chronic ocular hypertension model. This protective action appears to be attributable to inhibition of neurotoxic mediators release and/or direct suppression of RGC apoptosis. In support of this mechanism, in vitro, rapamycin significantly inhibits the production of NO, TNF-α in BV2 microglials by modulating NF-κB signaling. In experimental animals, treatment with rapamycin also dramatically inhibited the activation of microglials. In primary RGCs, rapamycin was capable of direct suppression the apoptosis of primary RGCs induced by glutamate. Mechanistically, rapamycin-mediated suppression of RGCs apoptosis is by sparing phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity in cell and animal model. These results demonstrate that rapamycin is neuroprotective in experimental glaucoma, possibly via decreasing neurotoxic releasing and suppressing directly apoptosis of RGCs.

  7. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

    Science.gov (United States)

    Kolosova, Nataliya G; Vitovtov, Anton O; Muraleva, Natalia A; Akulov, Andrey E; Stefanova, Natalia A; Blagosklonny, Mikhail V

    2013-06-01

    Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

  8. Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats.

    Science.gov (United States)

    Liu, Shangjing; Huang, Longxian; Geng, Yanqing; He, Junlin; Chen, Xuemei; Xu, Hao; Li, Rong; Wang, Yingxiong; Ding, Yubin; Liu, Xueqing

    2017-10-01

    Rapamycin (sirolimus) is an antiproliferative drug that has been widely used in the clinic as an immunosuppressant and a potential anticancer agent. Certain reports have indicated that rapamycin may induce male infertility through impairing sperm quality. The present study investigated the mechanism of male infertility caused by rapamycin and examined whether withdrawal of rapamycin could recover the number of sperm in rats. Male Sprague‑Dawley rats (n=100) were divided randomly into 5 groups: 3 rapamycin‑treated groups (2, 4 and 6 mg/kg) and 2 control groups [Blank and dimethyl sulfoxide (DMSO)]. Organ coefficients of the testes, number of sperm and hematoxylin‑eosin staining analyses demonstrated that rapamycin treatment markedly damaged the structure of the seminiferous tubule and reduced the number of sperm. Immunohistochemistry of mechanistic target of rapamycin (mTOR) and Ki67 in testes tissue, and western blotting of phosphorylated‑p70S6K and p70S6K, supported the hypothesis that rapamycin causes sperm reduction through inhibiting proliferation of spermatogonia. Unfortunately, 24 weeks after cessation of rapamycin treatment, only the number of sperm in 2 mg/kg group was restored back to the normal level. In addition, to the best of our knowledge, the present study was the first to demonstrate that low doses rapamycin leads to activation of autophagy in rat testes. This may be a self‑protective mechanism of the cell in response to external stress. Thus, spermatogenesis can be recovered in the testes from rats in the low dose group. High doses of rapamycin resulted in excessive consumption of autophagy proteins, and the damage could not be compensated. In addition, it was revealed that cell apoptosis increased after treatment with rapamycin. In conclusion, the present study demonstrated that rapamycin inhibits spermatogenesis through suppressing phosphorylation of p70S6K and changing the autophagy status, ultimately reducing the number of sperm

  9. Effect of rapamycin treatment during post-activation and/or in vitro culture on embryonic development after parthenogenesis and in vitro fertilization in pigs.

    Science.gov (United States)

    Elahi, F; Lee, H; Lee, J; Lee, S T; Park, C K; Hyun, S-H; Lee, E

    2017-10-01

    This study investigated the effects of early induction of autophagy on embryonic development in pigs. For this, oocytes or embryos were treated with an autophagy inducer, rapamycin (RP), during post-activation (Pa), in vitro fertilization (IVF) and/or in vitro culture (IVC). When parthenogenesis (PA) embryos were untreated (control) or treated with various concentrations of RP for 4 hr during Pa, 100 nm RP showed a higher blastocyst formation (48.8 ± 2.7%) than the control (34.6 ± 3.0%). When PA embryos were treated during the first 24 hr of IVC, blastocyst formation was increased (p < .05) by 1 and 10 nm RP (61.9 ± 3.0 and 59.6 ± 3.0%, respectively) compared to the control (43.2 ± 1.8%) and 100 nm RP (47.8 ± 3.2%), with a higher embryo cleavage in response to 10 nm RP (87.3 ± 2.4%) than the control (74.1 ± 3.2%). RP treatment during IVC and Pa + IVC showed increased blastocyst formation (44.7 ± 2.5 and 44.1 ± 2.0%, respectively) compared to the control (33.2 ± 2.0%). In addition, RP treatment during Pa and/or IVC increased glutathione content and inversely reduced reactive oxygen species. In IVF, RP treatment for 6 hr during IVF significantly increased embryonic development (34.0 ± 2.6%) compared to the control (24.8 ± 1.6%), but treatment during IVC for 24 hr with RP did not (23.0 ± 3.8%). Autophagy was significantly increased in PA oocytes by the RP treatment during Pa but not altered by the treatment during the first 24 hr of IVC. Overall, RP treatment positively regulated the pre-implantation development of pig embryos, probably by regulating cellular redox state and stimulating autophagy. © 2017 Blackwell Verlag GmbH.

  10. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I : Magnetic resonance imaging

    NARCIS (Netherlands)

    van Vliet, Erwin A; Otte, Wim M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

    OBJECTIVE: The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this

  11. Rapamycin prolongs graft survival and induces CD4+IFN-γ+IL-10+ regulatory type 1 cells in old recipient mice.

    Science.gov (United States)

    Quante, Markus; Heinbokel, Timm; Edtinger, Karoline; Minami, Koichiro; Uehara, Hirofumi; Nian, Yeqi; Azuma, Haruhito; Abdi, Reza; Elkhal, Abdallah; Tullius, Stefan G

    2017-08-02

    Although the elderly represents a rapidly growing population among transplant recipients, age-specific aspects have not been considered sufficiently in clinical trials. Moreover, age-specific effects of immunosuppressive therapies remain poorly understood. Here, we assessed the impact of Rapamycin on alloimmune responses in old recipients using a fully MHC-mismatched murine transplantation model. Old untreated recipients displayed a prolonged skin graft survival compared to their young counterparts, an observation that confirmed data of our previous experiments. Rapamycin led to a significant prolongation of graft survival in both, young and old recipients. However, graft survival was age-dependent and extended in old vs. young recipients (19 days vs. 12 days, p=0.004). This age-specific effect was not linked to changes in frequencies or subset composition of either CD8 or CD4 T cells. Moreover, antiproliferative effects of Rapamycin on CD8 and CD4 T cells as assessed by in vivo BrdU-incorporation were comparable and age-independent. In contrast, the systemic production of IL-10 was markedly elevated in old recipients treated with Rapamycin. In parallel to this shift in cytokine balance, IFN-γ/IL-10 double-positive regulatory type 1 cells emerged during Th1-differentiation of old T helper cells in presence of Rapamycin. Similarly, CD4IFN-γIL-10 cells expanded among Foxp3-negative cells after in vivo treatment of old recipients with Rapamycin. Our results highlight novel aspects of age-dependent immunosuppressive effects of Rapamycin, with relevance for age-specific immunosuppressive regimens.

  12. Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin.

    Directory of Open Access Journals (Sweden)

    Keita Saito

    Full Text Available Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII by electron paramagnetic resonance imaging (EPRI and magnetic resonance imaging (MRI to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3 and measurements of tumor pO(2 and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2 levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2<10 mm Hg in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.

  13. Tumor growth effects of rapamycin on human biliary tract cancer cells

    Directory of Open Access Journals (Sweden)

    Heuer Matthias

    2012-06-01

    Full Text Available Abstract Background Liver transplantation is an important treatment option for patients with liver-originated tumors including biliary tract carcinomas (BTCs. Post-transplant tumor recurrence remains a limiting factor for long-term survival. The mammalian target of rapamycin-targeting immunosuppressive drug rapamycin could be helpful in lowering BTC recurrence rates. Therein, we investigated the antiproliferative effect of rapamycin on BTC cells and compared it with standard immunosuppressants. Methods We investigated two human BTC cell lines. We performed cell cycle and proliferation analyses after treatment with different doses of rapamycin and the standard immunosuppressants, cyclosporine A and tacrolimus. Results Rapamycin inhibited the growth of two BTC cell lines in vitro. By contrast, an increase in cell growth was observed among the cells treated with the standard immunosuppressants. Conclusions These results support the hypothesis that rapamycin inhibits BTC cell proliferation and thus might be the preferred immunosuppressant for patients after a liver transplantation because of BTC.

  14. Rapamycin causes growth arrest and inhibition of invasion in human chondrosarcoma cells.

    Science.gov (United States)

    Song, Jian; Wang, Xiaobo; Zhu, Jiaxue; Liu, Jun

    2016-01-01

    Chondrosarcoma is a highly malignant tumor that is characterized by a potent capacity to invade locally and cause distant metastasis and notable for its lack of response to conventional chemotherapy or radiotherapy. Rapamycin, the inhibitor of mammalian target of rapamycin (mTOR), is a valuable drug with diverse clinical applications and regulates many cellular processes. However, the effects of rapamycin on cell growth and invasion of human chondrosarcoma cells are not well known. We determined the effect of rapamycin on cell proliferation, cell cycle arrest and invasion by using MTS, flow cytometry and invasion assays in two human chondrosarcoma cell lines, SW1353 and JJ012. Cell cycle regulatory and invasion-related genes' expression analysis was performed by quantitative RT-PCR (qRT-PCR). We also evaluated the effect of rapamycin on tumor growth by using mice xenograph models. Rapamycin significantly inhibited the cell proliferation, induced cell cycle arrest and decreased the invasion ability of human chondrosarcoma cells. Meanwhile, rapamycin modulated the cell cycle regulatory and invasion-related genes' expression. Furthermore, the tumor growth of mice xenograph models with human chondrosarcoma cells was significantly inhibited by rapamycin. These results provided further insight into the role of rapamycin in chondrosarcoma. Therefore, rapamycin targeted therapy may be a potential treatment strategy for chondrosarcoma.

  15. Rapamycin extends murine lifespan but has limited effects on aging

    Science.gov (United States)

    Neff, Frauke; Flores-Dominguez, Diana; Ryan, Devon P.; Horsch, Marion; Schröder, Susanne; Adler, Thure; Afonso, Luciana Caminha; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Garrett, Lillian; Hans, Wolfgang; Hettich, Moritz M.; Holtmeier, Richard; Hölter, Sabine M.; Moreth, Kristin; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Rathkolb, Birgit; Rozman, Jan; Naton, Beatrix; Ordemann, Rainer; Adamski, Jerzy; Beckers, Johannes; Bekeredjian, Raffi; Busch, Dirk H.; Ehninger, Gerhard; Graw, Jochen; Höfler, Heinz; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Stypmann, Jörg; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Fuchs, Helmut; Gailus-Durner, Valérie; Hrabe de Angelis, Martin; Ehninger, Dan

    2013-01-01

    Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin’s effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin’s longevity effects from effects on aging itself. PMID:23863708

  16. Improving insomnia in primary care patients: A randomized controlled trial of nurse-led group treatment.

    Science.gov (United States)

    Sandlund, Christina; Hetta, Jerker; Nilsson, Gunnar H; Ekstedt, Mirjam; Westman, Jeanette

    2017-07-01

    Insomnia is a common health problem, and most people who seek help for insomnia consult primary care. In primary care, insomnia treatment typically consists of hypnotic drugs, although cognitive behavioral therapy for insomnia is the recommended treatment. However, such treatment is currently available to few primary care patients. To evaluate the effects of a group treatment program for insomnia led by nurses in primary care. were the Insomnia Severity Index, a 2-week sleep diary, and a questionnaire on frequency of hypnotic drug use. A randomized controlled trial with pre- and post-treatment assessment and a 1-year post-treatment follow-up of the intervention group. Routine primary health care; 7 primary care centers in Stockholm, Sweden. Patients consulting primary care for insomnia were assessed for eligibility. To be included, patients had to have insomnia disorder and be 18 years or older. Patients were excluded if they if they worked night shifts or had severe untreated somatic and/or mental illness, bipolar disorder, or untreated sleep disorder other than insomnia. One-hundred and sixty-five patients 20 to 90 years were included. Most were women, and many had co-existing somatic and/or mental health problems. The post-treatment dropout rate was 20%. The intervention was a nurse-led group treatment for insomnia based on the techniques of cognitive behavioral therapy for insomnia. The nurses had 2days of training in how to deliver the program. Ninety patients were randomized to the intervention and 75 to the control group (treatment as usual). Data from 82 in the intervention and 71 in the control group were analyzed in accordance with intention-to-treat principles. Fifty-four of the 72 in the intervention group who participated in the group treatment program were followed up after 1year. Mean Insomnia Severity Index score decreased significantly from 18.4 to 10.7 after group treatment but remained unchanged after treatment as usual (17.0 to 16.6). The effect

  17. Sensitivity to Ethephon Degreening Treatment Is Altered by Blue LED Light Irradiation in Mandarin Fruit.

    Science.gov (United States)

    Deng, Lili; Yuan, Ziyi; Xie, Jiao; Yao, Shixiang; Zeng, Kaifang

    2017-08-02

    Although citrus fruits are not climacteric, exogenous ethylene is widely used in the degreening treatment of citrus fruits. Irradiation with blue light-emitting diode (LED) light (450 nm) for 10 h can promote the formation of good coloration of ethephon-degreened fruit. This study evaluated the effect of blue LED light irradiation on the pigments contents of ethephon-degreened fruit and evaluated whether the blue LED light irradiation could influence the sensitivity of mandarin fruit to ethylene. The results indicated that blue light can accelerate the color change of ethephon-degreened fruit, accompanied by changes in plastid ultrastructure and chlorophyll and carotenoid contents. Ethephon-induced expressions of CitACS1, CitACO, CitETR1, CitEIN2, CitEIL1, and CitERF2 were enhanced by blue LED light irradiation, which increased the sensitivity to ethylene in ethephon-degreened fruits. These results indicate that blue LED light-induced changes in sensitivity to ethylene in mandarin fruit may be responsible for the improved coloration of ethephon-degreened mandarin fruits.

  18. Tomato FK506 Binding Protein 12KD (FKBP12 mediates the interaction between rapamycin and Target of Rapamycin (TOR

    Directory of Open Access Journals (Sweden)

    Fangjie Xiong

    2016-11-01

    Full Text Available Target of Rapamycin (TOR signaling is an important regulator in multiple organisms including yeast, plants and animals. However, the TOR signaling in plants is much less understood as compared to that in yeast and animals. TOR kinase can be efficiently suppressed by rapamycin in the presence of functional FK506 Binding Protein 12KD (FKBP12 in yeast and animals. In most examined higher plants rapamycin fails to inhibit TOR kinase due to the non-functional FKBP12. Here we find that tomato plants showed obvious growth inhibition when treated with rapamycin and the inhibitory phenotype is similar to suppression of TOR causing by active-site TOR inhibitors (asTORis such as KU63794, AZD8055 and Torin1. The chemical genetic assays using TOR inhibitors and heterologous expressing SlFKBP12 in Arabidopsis indicated that the TOR signaling is functional in tomato. The protein gel shifting and TOR inhibitors combination assays showed that SlFKBP12 can mediate the interaction between rapamycin and TOR. Furthermore, comparative expression profiling analysis between treatments with rapamycin and KU63794 identified highly overlapped Differentially Expressed Genes (DEGs which are involved in many anabolic and catabolic processes, such as photosynthesis, cell wall restructuring, and senescence in tomato. These observations suggest that SlFFBP12 is functional in tomato. The results provided basic information of TOR signaling in tomato, and also some new insights into how TOR controls plant growth and development through reprogramming the transcription profiles

  19. Beneficial role of rapamycin in experimental autoimmune myositis.

    Directory of Open Access Journals (Sweden)

    Nicolas Prevel

    Full Text Available We developed an experimental autoimmune myositis (EAM mouse model of polymyositis where we outlined the role of regulatory T (Treg cells. Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation, is known to spare Treg. Our aim was to test the efficacy of rapamycin in vivo in this EAM model and to investigate the effects of the drug on different immune cell sub-populations.EAM is induced by 3 injections of myosin emulsified in CFA. Mice received rapamycin during 25 days starting one day before myosin immunization (preventive treatment, or during 10 days following the last myosin immunization (curative treatment.Under preventive or curative treatment, an increase of muscle strength was observed with a parallel decrease of muscle inflammation, both being well correlated (R(2 = -0.645, p<0.0001. Rapamycin induced a general decrease in muscle of CD4 and CD8 T cells in lymphoid tissues, but spared B cells. Among T cells, the frequency of Treg was increased in rapamycin treated mice in draining lymph nodes (16.9 ± 2.2% vs. 9.3 ± 1.4%, p<0.001, which were mostly activated regulatory T cells (CD62L(lowCD44(high: 58.1 ± 5.78% vs. 33.1 ± 7%, treated vs. untreated, p<0.001. In rapamycin treated mice, inhibition of proliferation (Ki-67(+ is more important in effector T cells compared to Tregs cells (p<0.05. Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44(low CD62L(high naive T cell and in CD62L(low CD44(high activated T cell.Rapamycin showed efficacy both as curative and preventive treatment in our murine model of experimental myositis, in which it induced an increase of muscle strength with a parallel decrease in muscle inflammation. Rapamycin administration was also associated with a decrease in the frequency of effector T cells, an increase in Tregs, and, when administered as preventive treatment, an upregulation of KFL2 in naive and activated T cells.

  20. Rapamycin Rescues the Poor Developmental Capacity of Aged Porcine Oocytes

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    Seung Eun Lee

    2014-05-01

    Full Text Available Unfertilized oocytes age inevitably after ovulation, which limits their fertilizable life span and embryonic development. Rapamycin affects mammalian target of rapamycin (mTOR expression and cytoskeleton reorganization during oocyte meiotic maturation. The goal of this study was to examine the effects of rapamycin treatment on aged porcine oocytes and their in vitro development. Rapamycin treatment of aged oocytes for 24 h (68 h in vitro maturation [IVM]; 44 h+10 μM rapamycin/24 h, 47.52±5.68 or control oocytes (44 h IVM; 42.14±4.40 significantly increased the development rate and total cell number compared with untreated aged oocytes (68 h IVM, 22.04±5.68 (p<0.05. Rapamycin treatment of aged IVM oocytes for 24 h also rescued aberrant spindle organization and chromosomal misalignment, blocked the decrease in the level of phosphorylated-p44/42 mitogen-activated protein kinase (MAPK, and increased the mRNA expression of cytoplasmic maturation factor genes (MOS, BMP15, GDF9, and CCNB1 compared with untreated, 24 h-aged IVM oocytes (p<0.05. Furthermore, rapamycin treatment of aged oocytes decreased reactive oxygen species (ROS activity and DNA fragmentation (p<0.05, and downregulated the mRNA expression of mTOR compared with control or untreated aged oocytes. By contrast, rapamycin treatment of aged oocytes increased mitochondrial localization (p<0.05 and upregulated the mRNA expression of autophagy (BECN1, ATG7, MAP1LC3B, ATG12, GABARAP, and GABARAPL1, anti-apoptosis (BCL2L1 and BIRC5; p<0.05, and development (NANOG and SOX2; p<0.05 genes, but it did not affect the mRNA expression of pro-apoptosis genes (FAS and CASP3 compared with the control. This study demonstrates that rapamycin treatment can rescue the poor developmental capacity of aged porcine oocytes.

  1. New treatment of cellulite with infrared-LED illumination applied during high-intensity treadmill training.

    Science.gov (United States)

    Paolillo, Fernanda Rossi; Borghi-Silva, Audrey; Parizotto, Nivaldo Antonio; Kurachi, Cristina; Bagnato, Vanderlei Salvador

    2011-08-01

    Phototherapy improves cellular activation which is an important factor for the treatment of cellulite. The objective of this research was to develop and evaluate the effects of a new (noninvasive and nonpharmacological) clinical procedure to improve body aesthetics: infrared-LED (850 nm) plus treadmill training. Twenty women (25-55 years old) participated in this study. They were separated in two groups: the control group, which carried out only the treadmill training (n = 10), and the LED group, with phototherapy during the treadmill training (n = 10). The training was performed for 45 minutes twice a week over 3 months at intensities between 85% and 90% maximal heart rate (HR(max)). The irradiation parameters were 39 mW/cm(2) and a fluence of 106 J/cm(2). The treatment was evaluated by interpreting body composition parameters, photographs and thermography. This was primarily a treatment for cellulite with a reduction of saddlebag and thigh circumference. At the same time, the treadmill training prevented an increase of body fat, as well as the loss of lean mass. Moreover, thermal images of the temperature modification of the thighs are presented. These positive effects can result in a further improvement of body aesthetics using infrared-LED together with treadmill training.

  2. Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation.

    Science.gov (United States)

    Dai, Ying; Zheng, Kangni; Clark, Joanne; Swerdlow, Russell H; Pulst, Stefan M; Sutton, James P; Shinobu, Leslie A; Simon, David K

    2014-02-01

    Mitochondrial DNA (mtDNA) mutations cause a variety of mitochondrial disorders for which effective treatments are lacking. Emerging data indicate that selective mitochondrial degradation through autophagy (mitophagy) plays a critical role in mitochondrial quality control. Inhibition of mammalian target of rapamycin (mTOR) kinase activity can activate mitophagy. To test the hypothesis that enhancing mitophagy would drive selection against dysfunctional mitochondria harboring higher levels of mutations, thereby decreasing mutation levels over time, we examined the impact of rapamycin on mutation levels in a human cytoplasmic hybrid (cybrid) cell line expressing a heteroplasmic mtDNA G11778A mutation, the most common cause of Leber's hereditary optic neuropathy. Inhibition of mTORC1/S6 kinase signaling by rapamycin induced colocalization of mitochondria with autophagosomes, and resulted in a striking progressive decrease in levels of the G11778A mutation and partial restoration of ATP levels. Rapamycin-induced upregulation of mitophagy was confirmed by electron microscopic evidence of increased autophagic vacuoles containing mitochondria-like organelles. The decreased mutational burden was not due to rapamycin-induced cell death or mtDNA depletion, as there was no significant difference in cytotoxicity/apoptosis or mtDNA copy number between rapamycin and vehicle-treated cells. These data demonstrate the potential for pharmacological inhibition of mTOR kinase activity to activate mitophagy as a strategy to drive selection against a heteroplasmic mtDNA G11778A mutation and raise the exciting possibility that rapamycin may have therapeutic potential for the treatment of mitochondrial disorders associated with heteroplasmic mtDNA mutations, although further studies are needed to determine if a similar strategy will be effective for other mutations and other cell types.

  3. Treatment with beta-blockers in nurse-led heart failure clinics

    DEFF Research Database (Denmark)

    Gustafsson, Finn; Schou, Morten; Videbaek, Lars

    2007-01-01

    BACKGROUND: Beta-blockers (BBs) are a cornerstone in the treatment of chronic heart failure (HF), but several surveys have documented that many patients are not offered treatment or are not titrated to target doses. In part to address this problem, specialized, nurse-led HF clinics have been...... initiated in many countries. However, little information is available to describe if such programs are successful in initiating and up-titrating BBs in daily clinical practice. AIMS: To assess the proportion of patients with HF due to left ventricular systolic dysfunction on BB treatment three months after...... months (Ptitration continues to be a challenge even in specialized clinics dedicated to this task. Elderly patients appear to be less likely to receive treatment....

  4. A new LED device used for photodynamic therapy in treatment of moderate to severe acne vulgaris.

    Science.gov (United States)

    Dong, Yiyun; Zhou, Guoyu; Chen, Jinan; Shen, Lingyue; Jianxin, Zhao; Xu, Qing; Zhu, Yulan

    2016-03-01

    This study investigated the efficacy and safety of a newly designed LED device used in photodiagnosis and photodynamic therapy of moderate to severe acne vulgaris in Chinese patients. Forty-six patients with moderate to severe facial acne showing high degrees of fluorescence by ultraviolet light examination were illuminated during ALA-PDT with two wavelengths of light (543-548 nm, and 630±6 nm, respectively) after 2 h of incubation with ALA. Each patient received treatment once every 30 days for two or three sessions. Two independent investigators assigned an acne severity score at baseline, one week after each treatment, as well as 4, 8, and 12 weeks after the completion of treatment. Adverse effects were recorded during and after each treatment. All patients rated their satisfaction with the results of treatment at a 12-week follow up visit. The ALA-PDL treatment regimen showed an overall effectiveness rate of 89.13% (41/46 patients). Some degree of clinical efficacy was seen in 71.42%, 86.67%, and 95.83% of patients with grades IV, V, and VI acne, respectively, and the rate of clinical effectiveness increased with increasing acne severity. When compared with baseline scores, significant reductions in acne scores were obtained at 8, and 12 weeks after completion of treatment. Maximum efficacy was shown at the 12 week follow up. No severe adverse events were observed. ALA-PDT administered with the newly designed LED device was an effective treatment for moderate to severe acne vulgaris, and side effects were mild and reversible. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. mTORC1 inhibitors rapamycin and metformin affect cardiovascular markers differentially in ZDF rats.

    Science.gov (United States)

    Nistala, Ravi; Raja, Ahmad; Pulakat, Lakshmi

    2017-03-01

    Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.

  6. Phototherapeutic treatment of patients with peripheral nervous system diseases by means of LED arrays

    Science.gov (United States)

    Zharov, Vladimir P.; Kalinin, Konstantin L.; Menyaev, Yulian A.; Zmievskoy, Gregory N.; Savin, Alexei A.; Stulin, Igor D.; Shihkerimov, Raphiz K.; Shapkina, Alla V.; Velsher, Leonid Z.; Stakhanov, Mikhail L.

    2001-05-01

    The further development of new method of phototherapy based on use of light-emitting diodes (LED) arrays has been presented. LEDs array distribution is side of cylindrical surface, covering pathology region, was used for treatment group of patients with an affected peripheral nervous system. The main group consisted of patients with humeral plexopathy - one of possible neurological manifestation of postmastectomic syndrome as result of breast cancer radical treatment. This disease was accompanied also by some other peripheral nervous system diseases: diabetic polyneuropathy, compression ischemic mononeuropathy, festering wounds and others. The phototherapeutic method is just directed on improvement of patient's conditions in combination with other traditional methods of treatment. The main parameters of photomatrix therapeutic system: wavelength - 660 nm, line width - no more than 20 nm, intensity of radiation on the surface of edema - 0.5-3 mW/cm2 (in dependence of apparatuses type). To control and study efficiency of phototreatment ultrasonic dopplerography, thermography, electromyography and viscosimetry have been used.

  7. Application of Photocatalysts and LED Light Sources in Drinking Water Treatment

    Directory of Open Access Journals (Sweden)

    Gopal Achari

    2013-09-01

    Full Text Available This study investigates a cross-section of TiO2 compositions for which existing evidence suggests the prospect of improved performance compared to standard Degussa P25. In the context of a program aimed toward a 365 nm LED based photo-reactor, the question is whether a distinctly superior photocatalyst composition for drinking water treatment is now available that would shape design choices. An answer was sought by synthesizing several photocatalysts with reported high reactivity in some context in the literature, and by performing photocatalysts reactivity tests using common pollutants of water system including Natural Organic Matter (NOM and Emerging Contaminants (ECs from the pesticide and pharmaceutical classes. 365 nm Light Emitting Diodes (LEDs were used as the irradiation source. Since LEDs are now available in the UV, we did not examine the TiO2 modifications that bring band gap excitation into the region beyond 400 nm. The results suggest that the choice of the photocatalyst should be best made to fit the reactor design and photocatalyst mounting constraints such as mass transport, reactive surface, and light field. No photocatalyst composition overall, superior for all classes emerged.

  8. Implementation of a Resident-Led Osteopathic Manipulative Treatment Clinic in an Allopathic Residency.

    Science.gov (United States)

    Busey, Blake; Newsome, Jelaun; Raymond, Tyler; O'Mara, Heather

    2015-12-01

    With the growing number of osteopathic physicians practicing in the United States and the creation of a single graduate medical education system, a continued need exists for focused education in osteopathic principles, philosophy, and treatment modalities in primarily allopathic residency programs. To create and integrate a resident-led osteopathic manipulative treatment (OMT) clinic in an allopathic residency program. After an informal needs assessment on the basis of resident survey data, a resident-led OMT clinic was created within a military allopathic family medicine residency program. A standard operating procedure, resident survey, and scheduling system were created by the residents for approval by the departmental and hospital leadership. Resident survey data pertaining to the time available to perform OMT, education, and faculty supervision of OMT were obtained before the clinic implementation and 1 year after implementation. Nine osteopathic residents were surveyed before the OMT clinic implementation to illustrate a need for continued osteopathic medical education, faculty support, and skill maintenance. Sixteen osteopathic residents were surveyed after the OMT clinic implementation. More residents indicated that the establishment of an osteopathic curriculum was important (3 of 9 in the preclinic survey vs 9 of 16 in the postclinic survey) and that the program promoted the use of OMT (0 of 9 in the preclinic survey vs 13 of 16 in the postclinic survey). A resident-led OMT clinic can be successfully implemented, maintained, and expanded in an allopathic residency program by implementing an OMT curriculum, offering elective rotations, and encouraging regular use of OMT. The current project can be used as a framework for implementing an OMT clinic.

  9. A Systematic Review of Light Emitting Diode (LED) Phototherapy for Treatment of Psoriasis: An Emerging Therapeutic Modality.

    Science.gov (United States)

    Ho, Derek; Koo, Eugene; Mamalis, Andrew; Jagdeo, Jared

    2017-05-01

    Background: Psoriasis is a chronic, inflammatory skin condition. The economic burden of psoriasis is approximately $35.2 billion in the United States per year, and treatment costs are increasing at a higher rate than general inflation. Light emitting diode (LED) phototherapy may represent a cost-effective, efficacious, safe, and portable treatment modality for psoriasis. Objective: The goal of our manuscript is to review the published literature and provide evidence-based recommendations on LED phototherapy for the treatment of psoriasis. Methods & Materials: A search of the databases Pubmed, EMBASE, Web of Science, and CINAHL was performed on April 5, 2016. Key search terms were related to psoriasis and LED-based therapies. Results: A total of 7,793 articles were generated from the initial search and 5 original articles met inclusion criteria for our review. Grade of recommendation: B for LED-blue light. Grade of recommendation: C for LED-ultraviolet B, LED-red light, and combination LED-near-infrared and LED-red light. Conclusion: We envision further characterizing the effects of LED phototherapy to treat psoriasis in patients may increase adoption of LED-based modalities and provide clinicians and patients with new therapeutic options that balance safety, efficacy, and cost. J Drugs Dermatol. 2017;16(5):482-488..

  10. Therapeutic effects of rapamycin on alcoholic cardiomyopathy.

    Science.gov (United States)

    Tu, Xilin; Wang, Chao; Ru, Xiaoxue; Jing, Lili; Zhou, Lijun; Jing, Ling

    2017-10-01

    The present study aimed to investigate whether rapamycin has therapeutic potential as a treatment for alcoholic cardiomyopathy. Rats were divided into eight groups (n=7 in each group): The control group; the alcohol group; abstinence in the first week; abstinence in the third week; abstinence in the fourth week; abstinent+rapamycin (AB-RAP) until the first week (AB-RAP 1); AB-RAP until the third week (AB-RAP 3); and AB-RAP until the fourth week (AB-RAP 4). Subsequently, echocardiography, and hematoxylin-eosin and Masson's staining were performed, followed by electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Finally, expression levels of B cell lymphoma-2, Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 were detected by immunohistochemistry and western blot analysis. The levels of left ventricular end-diastolic dimension in AB-RAP 3 (7.00±0.41) and AB-RAP 4 (6.33±0.68) groups were significantly lower when compared with the alcohol group (8.01±0.30; P<0.05). Compared with the alcohol group, the apoptosis rate of left ventricular myocardial tissue in the AB+RAP 3 (37.68±2.15) and AB+RAP 4 (26.97±2.11) groups was significantly reduced (P<0.05). To conclude, rapamycin may be considered as a therapeutic tool to attenuate alcoholic cardiomyopathy and improve cardiac function through increasing autophagy and reducing apoptosis.

  11. Microcystic Lymphatic Malformation Successfully Treated With Topical Rapamycin.

    Science.gov (United States)

    García-Montero, Pablo; Del Boz, Javier; Sanchez-Martínez, Miguel; Escudero Santos, Isabel María; Baselga, Eulalia

    2017-05-01

    Microcystic lymphatic malformations (MLM) are low-flow vascular malformations composed of multiple small cysts. MLM usually affect deep-lying structures, which makes their treatment even more difficult and complex. A novel and interesting treatment is rapamycin, a mammalian target of rapamycin inhibitor that when orally administrated has offered favorable results. However, until recently, topical rapamycin had not been used in the treatment of MLM. Case 1 is a girl aged 13 years with extensive MLM affecting the muscles in the right buttock. The patient had received frequent cycles of cryotherapy, but they had failed to control the associated symptoms. In the previous 12 months, the patient had reported greater discomfort, swelling, exudate, and superinfection of the affected region. Because no specific treatment has yet been approved for MLM, and as a step before the use of aggressive systemic or intralesional treatments, it was decided to initiate treatment with 1% rapamycin ointment. After 4 months of treatment, the patient presented a marked improvement, with a significant reduction of associated complications and no major side effects. Case 2 is a boy aged 5 years who underwent surgery for an intergluteal lipoblastoma at 3 weeks of life and developed a MLM on the scar 6 months afterward. The lesion showed slow growth and continuous exudation with frequent episodes of superinfection. Treatments with laser multiplex and intralesional bleomycin were performed unsuccessfully. In the previous 4 months, the patient had been treated with 1% rapamycin ointment with significant improvement and no side effects. Copyright © 2017 by the American Academy of Pediatrics.

  12. Divergent tissue and sex effects of rapamycin on the proteasome-chaperone network of old mice

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    Karl Andrew Rodriguez

    2014-11-01

    Full Text Available Rapamycin, an allosteric inhibitor of the mTOR kinase, increases longevity in mice in a sex-specific manner. In contrast to the widely accepted theory that a loss of proteasome activity is detrimental to both life- and healthspan, biochemical studies in vitro reveal that rapamycin inhibits 20S proteasome peptidase activity. We tested if this unexpected finding is also evident after chronic rapamycin treatment in vivo by measuring peptidase activities for both the 26S and 20S proteasome in liver, fat, and brain tissues of old, male and female mice fed encapsulated chow containing 2.24mg/kg (14 ppm rapamycin for 6 months. Further we assessed if rapamycin altered expression of the chaperone proteins known to interact with the proteasome-mediated degradation system (PMDS, heat shock factor 1 (HSF1, and the levels of key mTOR pathway proteins. Rapamycin had little effect on liver proteasome activity in either gender, but increased proteasome activity in female brain lysates and lowered its activity in female fat tissue. Rapamycin-induced changes in molecular chaperone levels were also more substantial in tissues from female animals. Furthermore, mTOR pathway proteins showed more significant changes in female tissues compared to those from males. These data show collectively that there are divergent tissue and sex effects of rapamycin on the proteasome-chaperone network and that these may be linked to the disparate effects of rapamycin on males and females. Further our findings suggest that rapamycin induces indirect regulation of the PMDS/heat-shock response through its modulation of the mTOR pathway rather than via direct interactions between rapamycin and the proteasome.

  13. Rapamycin promotes osteogenesis under inflammatory conditions.

    Science.gov (United States)

    Li, Xing; Chang, Bei; Wang, Banchao; Bu, Wenhuan; Zhao, Liang; Liu, Jie; Meng, Lin; Wang, Lu; Xin, Ying; Wang, Dandan; Tang, Qi; Zheng, Changyu; Sun, Hongchen

    2017-12-01

    Chronic periodontitis, a common oral disease, usually results in irreversible bone resorption. Bone regeneration is a complex process between bone‑forming activity of osteoblasts and bone‑resorbing activity of osteoclasts, and still remains a challenge for physicians clinically. A previous study demonstrated that the mechanistic target of rapamycin signaling pathway is involved in osteogenic differentiation of mesenchymal stromal cells. Herein, whether rapamycin could be used to induce osteogenic differentiation of primary bone marrow‑derived mesenchymal stem cells (BMSCs) in vitro and promote new bone formation in vivo were evaluated. The results demonstrated that rapamycin alone was not enough to fully induce osteoblast differentiation in vitro and enhanced bone regeneration in vivo. Interestingly, rapamycin in rapamycin plus lipopolysaccharide (LPS)‑treated BMSCs significantly increased the gene expression levels of Sp7 transcription factor, runt related transcription factor 2, alkaline phosphatase (ALP) and collagen I (Col I), ALP activity, and calcium nodule at different time points in vitro, indicating that osteoblast differentiation occurs by rapamycin when BMSCs are exposed to LPS simultaneously. It was also demonstrated that rapamycin in rapamycin plus LPS‑treated rats promoted bone regeneration in vivo. These results suggest that rapamycin may influence osteoblast differentiation and new bone formation after LPS induces an inflammatory environment. Rapamycin may be used to treat periodontitis associated with bone loss in future clinical practice.

  14. Assessment of Response of Kidney Tumors to Rapamycin and Atorvastatin in Tsc1+/- Mice.

    Science.gov (United States)

    Shen, Ming Hong; Samsel, Paulina; Shen, Louise L; Narov, Kalin; Yang, Jian; Sampson, Julian R

    2017-10-01

    Atorvastatin is widely used to lower blood cholesterol and to reduce risk of cardiovascular disease-associated complications. Epidemiological investigations and preclinical studies suggest that statins such as atorvastatin have antitumor activity for various types of cancer. Tuberous sclerosis (TSC) is a tumor syndrome caused by TSC1 or TSC2 mutations that lead to aberrant activation of mTOR and tumor formation in multiple organs. Previous studies have demonstrated that atorvastatin selectively suppressed growth and proliferation of mouse Tsc2 null embryonic fibroblasts through inhibition of mTOR. However, atorvastatin alone did not reduce tumor burden in the liver and kidneys of Tsc2+/- mice as assessed by histological analysis, and no combination therapy of rapamycin and atorvastatin has been tried. In this study, we used T2-weighted magnetic resonance imaging to track changes in tumor number and size in the kidneys of a Tsc1+/- mouse model and to assess the efficacy of rapamycin and atorvastatin alone and as a combination therapy. We found that rapamycin alone or rapamycin combined with atorvastatin significantly reduced tumor burden, while atorvastatin alone did not. Combined therapy with rapamycin and atorvastatin appeared to be more effective for treating renal tumors than rapamycin alone, but the difference was not statistically significant. We conclude that combined therapy with rapamycin and atorvastatin is unlikely to provide additional benefit over rapamycin as a single agent in the treatment of Tsc-associated renal tumors. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qiang [Department of Neurology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233 (China); Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China); Zhang, Ting [Department of Neurology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233 (China); Wang, Jixian [Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China); Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030 (China); Zhang, Zhijun [Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030 (China); Zhai, Yu [Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China); Yang, Guo-Yuan, E-mail: gyyang0626@gmail.com [Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China); Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030 (China); Sun, Xiaojiang, E-mail: sunxj19@gmail.com [Department of Neurology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233 (China)

    2014-02-07

    Highlights: • Rapamycin enhances mitophagy via increasing p62 translocation to the mitochondria. • Rapamycin attenuates brain ischemic damage and improves mitochondrial function. • The protection of rapamycin to mitochondrial is linked to enhanced mitophagy. - Abstract: Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague–Dawley rats underwent transient middle cerebral artery occlusion (tMCAO). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Δψm) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarct volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p < 0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy.

  16. Suppression of Th17-polarized airway inflammation by rapamycin.

    Science.gov (United States)

    Joean, Oana; Hueber, Anja; Feller, Felix; Jirmo, Adan Chari; Lochner, Matthias; Dittrich, Anna-Maria; Albrecht, Melanie

    2017-11-10

    Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.

  17. Potential use of rapamycin in HIV infection

    DEFF Research Database (Denmark)

    Donia, Marco; McCubrey, James A; Bendtzen, Klaus

    2010-01-01

    The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies...... indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1...... replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood...

  18. Rapamycin regulates autophagy and cell adhesion in induced pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Areechun Sotthibundhu

    2016-11-01

    Full Text Available Abstract Background Cellular reprogramming is a stressful process, which requires cells to engulf somatic features and produce and maintain stemness machineries. Autophagy is a process to degrade unwanted proteins and is required for the derivation of induced pluripotent stem cells (iPSCs. However, the role of autophagy during iPSC maintenance remains undefined. Methods Human iPSCs were investigated by microscopy, immunofluorescence, and immunoblotting to detect autophagy machinery. Cells were treated with rapamycin to activate autophagy and with bafilomycin to block autophagy during iPSC maintenance. High concentrations of rapamycin treatment unexpectedly resulted in spontaneous formation of round floating spheres of uniform size, which were analyzed for differentiation into three germ layers. Mass spectrometry was deployed to reveal altered protein expression and pathways associated with rapamycin treatment. Results We demonstrate that human iPSCs express high basal levels of autophagy, including key components of APMKα, ULK1/2, BECLIN-1, ATG13, ATG101, ATG12, ATG3, ATG5, and LC3B. Block of autophagy by bafilomycin induces iPSC death and rapamycin attenuates the bafilomycin effect. Rapamycin treatment upregulates autophagy in iPSCs in a dose/time-dependent manner. High concentration of rapamycin reduces NANOG expression and induces spontaneous formation of round and uniformly sized embryoid bodies (EBs with accelerated differentiation into three germ layers. Mass spectrometry analysis identifies actin cytoskeleton and adherens junctions as the major targets of rapamycin in mediating iPSC detachment and differentiation. Conclusions High levels of basal autophagy activity are present during iPSC derivation and maintenance. Rapamycin alters expression of actin cytoskeleton and adherens junctions, induces uniform EB formation, and accelerates differentiation. IPSCs are sensitive to enzyme dissociation and require a lengthy differentiation time

  19. Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

    Science.gov (United States)

    Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

    2017-01-01

    Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

  20. Regression of Subependymal Giant Cell Astrocytoma With Rapamycin in Tuberous Sclerosis Complex

    Science.gov (United States)

    Koenig, Mary Kay; Butler, Ian J.; Northrup, Hope

    2011-01-01

    The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas. The patient was started at a dose of 0.2 mg/kg/day. Levels were maintained between 11 and 13 ng/mL. Magnetic resonance imaging of the brain 2½ months after initiating rapamycin demonstrated a decrease in size of both astrocytomas (11 to 7.5 mm on the right and 8 to 5 mm on the left). Further studies are needed with prolonged observation to confirm these findings, determine the length of necessary treatment, and evaluate recurrence risk after discontinuation of rapamycin. PMID:18952591

  1. Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin

    Science.gov (United States)

    Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R.; Liu, Zhonglin; Barber, Christie; Rusche, Jadrian J.; Petricoin, Emmanuel; Calvert, Valerie; Einspahr, Janine G.; Dickinson, Jesse; Stratton, Steven P.; Curiel-Lewandrowski, Clara; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M.; Dong, Zigang; Alberts, David S.; Bowden, G. Timothy

    2016-01-01

    The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

  2. Magneto-LED therapy in the treatment of inflammatory lesions and erosions of the glans penis – case report

    Directory of Open Access Journals (Sweden)

    Jarosław Pasek

    2016-10-01

    Full Text Available Introduction . Inflammatory lesions and erosions of the glans penis defined as balanitis or balanoposthitis constitute a disease in which the effectiveness of conservative treatment is not sufficient. Objective. To present the therapeutic efficacy of magneto-LED therapy in the treatment, and to present a patient with inflammatory lesions and erosions of the glans penis. Case report. The patient, 68 years old with inflammatory lesions and erosions of the glans penis of 2–4 years duration, was previously treated with various methods of local therapy without effect. As a result of a 32-week long magneto-LED therapy cycle, complete resolution of skin lesions with subsidence of the burning sensation during urination and reduced swelling and inflammatory erythema of the glans, as well as disappearance of the white coating and unpleasant smell, was achieved. Conclusions . Magneto-LED therapy is an efficient method of treatment of inflammatory lesions and erosions of the glans penis.

  3. Rapamycin Ameliorates Proteinuria and Restores Nephrin and Podocin Expression in Experimental Membranous Nephropathy

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    Stavros Stratakis

    2013-01-01

    Full Text Available Objective. Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN. However, the mechanisms underlying this beneficial effect have not been elucidated. Methods. Passive Heymann Nephritis (PHN was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague-Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa. The remaining six rats were used as the proteinuric control group (PHN while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC. All rats were sacrificed at the end of the 7th week. Results. Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression. Conclusions. Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin.

  4. Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin.

    Science.gov (United States)

    Shao, Ping; Ma, Linxiao; Ren, Yile; Liu, Huijie

    2017-10-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is associated with symptoms, including synovial membrane inflammatory pain, joint synovitis and stiffness. However, there are no effective methods available to cure this disease. In the present study, rapamycin was used to modulate immunity in RA. To limit the cytotoxicity of rapamycin, rapamycin was loaded into well‑characterized biocompatible nanoparticles. In vitro, rapamycin particles downregulated the activation of dendritic cell surface markers, including CD80+ and CD40+, upon interacting with macrophages. The rapamycin particles reduced the secretion of inflammatory cytokines, including interleukin (IL)‑6, tumor necrosis factor (TNF) and IL‑1β, which are characteristic of RA. In vivo, the rapamycin particles decreased the symptoms of RA in mice, and the production of inflammatory cytokines was associated with the occurrence of RA. The present study partially revealed the interactions between rapamycin and two types of immune cell in RA disease, and may potentially offer a solution to improve the treatment of RA.

  5. NASA sponsored Light Emitting Diode (LED) development helps in cancer treatment

    Science.gov (United States)

    1997-01-01

    What started out as an attempt to develop a light which would allow for the growth of plants in space led to a remarkable discovery: The Light Emitting Diode (LED). This device through extensive study and experimentation has developed into a tool used by surgeons in the fight against brain cancer in children. Pictured is a mock-up of brain surgery being performed. By encapsulating the end of the LED with a balloon, light is diffused over a larger area of the brain allowing the surgeon a better view. This is one of many programs that begin as research for the space program, and through extensive study end up benefitting all of mankind.

  6. High efficiency GaN-based LEDs using plasma selective treatment of p-GaN surface

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young-Bae; Naoi, Yoshiki; Sakai, Shiro [Department of Electrical and Electronic Engineering, University of Tokushima, 2-1 Minami-josanjima, Tokushima 770-8506 (Japan); Takaki, Ryohei; Sato, Hisao [Nitride Semiconductor Co., Ltd., 115-7 Itayajima, Akinokami, Seto-cho, Naruto, Tokushima 771-0360 (Japan)

    2003-11-01

    We have studied a new method of increasing the extraction efficiency of a GaN-based light-emitting diode (LED) using a plasma surface treatment. In this method, prior to the evaporation of a semitransparent p-metal, the surface of a p-GaN located beneath a p-pad is selectively exposed to a nitrogen plasma in a reactive ion etching (RIE) chamber. The electrical characteristics of the plasma treated p-GaN remarkably changes its resistivity into semi-insulator without any parasitic damage. Since the LEDs with a new method have no light absorption in a p-pad region, a higher optical power can be extracted compared to a conventional LEDs without plasma selective treatment on the p-GaN surface. (copyright 2003 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  7. Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice.

    Science.gov (United States)

    Bürger, Claudia; Shirsath, Nitesh; Lang, Victoria; Diehl, Sandra; Kaufmann, Roland; Weigert, Andreas; Han, Ying-Ying; Ringel, Christian; Wolf, Peter

    2017-10-02

    The mTOR (mechanistic target of rapamycin) inhibitor rapamycin has long been known for its immune suppressive properties, but it has shown limited therapeutic success when given systemically to patients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by interfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapamycin treatment. Immunohistological analysis revealed that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibition as a novel anti-psoriatic strategy.

  8. Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Satish K. Madala

    2011-01-01

    Full Text Available Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD and interstitial pulmonary fibrosis (IPF. Gene-targeted mice that lack SP-C (−/− develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of −/− mice. +/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated +/+ and −/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated −/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF.

  9. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    Directory of Open Access Journals (Sweden)

    Teresa Krakauer

    2012-09-01

    Full Text Available Staphylococcal enterotoxin B (SEB and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

  10. Rapamycin Influences the Efficiency of Fertilization and Development in the Mouse: A Role for Autophagic Activation

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    Geun-Kyung Lee

    2016-08-01

    Full Text Available The mammalian target of rapamycin (mTOR regulates cellular processes such as cell growth, metabolism, transcription, translation, and autophagy. Rapamycin is a selective inhibitor of mTOR, and induces autophagy in various systems. Autophagy contributes to clearance and recycling of macromolecules and organelles in response to stress. We previously reported that vitrified-warmed mouse oocytes show acute increases in autophagy during warming, and suggested that it is a natural response to cold stress. In this follow-up study, we examined whether the modulation of autophagy influences survival, fertilization, and developmental rates of vitrified-warmed mouse oocytes. We used rapamycin to enhance autophagy in metaphase II (MII oocytes before and after vitrification. The oocytes were then subjected to in vitro fertilization (IVF. The fertilization and developmental rates of vitrified-warmed oocytes after rapamycin treatment were significantly lower than those for control groups. Modulation of autophagy with rapamycin treatment shows that rapamycin-induced autophagy exerts a negative influence on fertilization and development of vitrified-warmed oocytes.

  11. Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases.

    Science.gov (United States)

    Kaplan, Frederick S; Zeitlin, Leonid; Dunn, Stephen P; Benor, Shira; Hagin, David; Al Mukaddam, Mona; Pignolo, Robert J

    2017-12-11

    Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Compressive strength measurements of hybrid dental composites treated with dry heat and light emitting diodes (LED post cure treatment

    Directory of Open Access Journals (Sweden)

    Jenny Krisnawaty

    2014-11-01

    Full Text Available Hybrid composites are mostly used on large cavities as restorative dental materials, whether it is used directly or indirectly. The mechanical properties of composite resin shall increase if it is treated with post cure treatment. The aim of this study is to evaluate compressive strength differences between dry heat and Light Emitting Diodes (LED treatment on the hybrid dental composite. A quasi-experimental was applied on this research with a total of 30 samples that were divided into two groups. Each sample was tested using LLOYD Universal Testing Machine with 1 mm/min speed to evaluate the compressive strength. The compressive strength results were marked when the sample was broken. The results of two groups were then analyzed using t-test statistical calculation. The results of this study show that post cure treatment on hybrid composite using LED light box (194.138 MPa was lower than dry heat treatment (227.339 MPa, which was also significantly different from statistical analysis. It can be concluded that compressive strength of LED light box was lower than dry heat post-cure treatment on the hybrid composite resin.

  13. Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.

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    Siegmund, Stephanie E; Yang, Hua; Sharma, Rohit; Javors, Martin; Skinner, Owen; Mootha, Vamsi; Hirano, Michio; Schon, Eric A

    2017-12-01

    Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential 'rapamycin metabolic signature.' These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases. © The Author 2017. Published by Oxford University Press.

  14. Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice.

    Science.gov (United States)

    Khaibullina, Alfia; Almeida, Luis E F; Wang, Li; Kamimura, Sayuri; Wong, Edward C C; Nouraie, Mehdi; Maric, Irina; Albani, Sarah; Finkel, Julia; Quezado, Zenaide M N

    2015-12-01

    Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000Hz (Aβ-fiber) and 250Hz (Aδ-fiber)] and unmyelinated (5Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p=0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000Hz and 250Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000Hz [21Units (7, 35), mean difference (95% CI), p=0.009 for sex∗treatment interaction] and 250Hz [9Units (1, 16), p=0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000Hz(Aβ-fiber, r=0.58, p=0.01) and 250Hz(Aδ-fiber, r=0.6, p=0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis

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    Mu Dezhi

    2010-11-01

    Full Text Available Abstract Background Glucocorticoid (GC resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL. In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex treatment. Methods Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl- 2,5-diphenyltetrazolium bromide (MTT assay. Fluorescence-activated cell sorting (FACS analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR, the cell cycle regulatory proteins, and apoptosis associated proteins. Results 10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G1-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1. Conclusion Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G0/G1 phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting

  16. Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs.

    Directory of Open Access Journals (Sweden)

    Melissa C Paoloni

    2010-06-01

    Full Text Available Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients.This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog. Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy.Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of

  17. Towards natural mimetics of metformin and rapamycin.

    Science.gov (United States)

    Aliper, Alexander; Jellen, Leslie; Cortese, Franco; Artemov, Artem; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G; Zhavoronkov, Alex

    2017-11-15

    Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

  18. The exploration of monochromatic near-infrared LED improved anoxygenic photosynthetic bacteria Rhodopseudomonas sp. for wastewater treatment.

    Science.gov (United States)

    Qi, Xiang; Ren, Yiwei; Tian, Enling; Wang, Xingzu

    2017-10-01

    The future wastewater treatment requires high-efficiency and energy-saving technology. Anoxygenic photosynthetic bacteria (APB) is deemed as an eco-friendly microorganism, which could be employed in wastewater treatment. Here, monochromatic near-infrared (MNIR) light emitting diode (LED) was used, and three key factors (light quality, light intensity and photoperiod) of it were analyzed by a response surface methodology (RSM) in APB wastewater treatment. The results showed that light quality was the biggest impact factor in APB wastewater treatment, and nearly 58.07% of NH4+-N and 70.62% of chemical oxygen demand (COD) could be removed based on 46.4% of that theoretically possible. The light quality's study revealed that APB had the highest NH4+-N and COD removal, biomass production, and bacteriochlorophyll a production with 850nm IR LED. Moreover, the application of optimal MNIR LED could not only save energy, but also avoid algae bloom of photo-bioreactors (PBR). Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)

    DEFF Research Database (Denmark)

    Bramow, S; Ott, P; Thomsen Nielsen, F

    2001-01-01

    , CYP1A2, CYP2E1 and CYP2BI/II). Cyclosporine A caused moderate cholestatic changes in liver enzymes, which was synergistically exacerbated by sirolimus. The data suggest that the underlying mechanisms behind cholestasis were not totally identical in the different treatment regimens. Cholestasis...

  20. Differential Effects of Rapamycin and Dexamethasone in Mouse Models of Established Allergic Asthma

    Science.gov (United States)

    Mushaben, Elizabeth M.; Brandt, Eric B.; Hershey, Gurjit K. Khurana; Le Cras, Timothy D.

    2013-01-01

    The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4–6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4+ T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4+ T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established. PMID:23349887

  1. [Effects of mTOR Inhibitor Rapamycin on Burkitt's Lymphoma Cells].

    Science.gov (United States)

    Zhou, Lun-Huan; Zhu, Xiong-Peng; Xiao, Hui-Fang; Xin, Peng-Liang; Li, Chun-Tuan

    2017-10-01

    To explore the effects of mTOR inhibitor rapamycin on proliferation, cell cycle and apoptosis of Burkitt's lymphoma cell line Raji and CA46 cells and its mechanism, so as to provide the experimental evidence for a therapeutic target of Burkitt's lymphoma. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide(MTT) assay was performed to assess the inhibitory effect of rapamycin on proliferation of Burkitt's lymphoma cell line Raji and CA46 cells. The cell cycle distribution of Raji and CA46 cells was analyzed by flow cytometry with propidium iodide(PI) single staining. The cell apoptosis of Raji and CA46 cells was analyzed by flow cytometry with FITC Annexin V+PI double staining. The expressions of RPS6, p-RPS6, survivin and caspase-3 proteins were detected by Western blot after treating with rapamycin. Rapamycin markedly inhibited the proliferation of both Raji and CA46 cells in a time- and concentration-dependent manners, showing good biological activity, the cell proliferation inhibition rate reached about 20% after treatment with 1 nmol/L rapamycin. After treatment with different concentrations of rapamycin for 24 and 48 hours, the proportion of both cells in G1/G0 phase in the treated groups was significantly increased in a time- and concentration-dependent manners in comparison with the solvent control group. With regard to the cells in S and G2/M phase, the decreased population was accompanied by the increase of G1/G0 phase cells. After treatment with 100 nmol/L rapamycin for 48 hours, both Raji and CA46 cells demonstrated an apparent apoptosis,especially late apoptosis by flow cytometry with Annexin V+PI staining. After treatment with rapamycin, the expression of p-RPS6 and survivin of Raji and CA46 cells was obviously down-regulated, the expression of caspase-3 was obviously up-regulated in a time- and dose-dependent manners. However, rapamycin did not obviously affect the expression of RPS6. The rapamycin can effectively inhibit cell proliferation

  2. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)

    DEFF Research Database (Denmark)

    Bramow, S; Ott, P; Thomsen Nielsen, F

    2001-01-01

    then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9...... secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most...... CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA....

  3. Characterization of an Optical Device with an Array of Blue Light Emitting Diodes LEDS for Treatment of Neonatal Jaundice.

    Science.gov (United States)

    Sebbe, Priscilla Fróes; Villaverde, Antonio G. J. Balbin; Nicolau, Renata Amadei; Barbosa, Ana Maria; Veissid, Nelson

    2008-04-01

    Phototherapy is a treatment that consists in irradiating a patient with light of high intensity, which promotes beneficial photochemical transformations in the irradiated area. The phototherapy for neonates is applied to break down the bilirubin, an organic pigment that is a sub product of the erythrocytes degradation, and to increase its excretion by the organism. Neonates should be irradiated with light of wavelength that the bilirubin can absorb, and with spectral irradiances between 4 and 16 μW/cm2/nm. The efficiency of the treatment depends on the irradiance and the area of the body that is irradiated. A convenient source of light for treatment of neonatal jaundice is the blue Light Emitter Diode (LED), emitting in the range of 400 to 500 nm, with power of the order of 10-150 mW. Some of the advantages for using LEDS are: low cost, operating long lifetime (over 100,000 hours), narrow emission linewith, low voltage power supply requirement and low heating. The aim of this work was to build and characterize a device for phototherapy treatment of neonatal jaundice. This consists of a blanket with 88 blue LEDs (emission peak at 472 nm), arranged in an 8×11 matrix, all connected in parallel and powered by a 5V-2A power supply. The device was characterized by using a spectroradiometer USB2000 (Ocean Optics Inc, USA), with a sensitivity range of 339-1019 nm. For determination of light spatial uniformity was used a calibrated photovoltaic sensor for measuring light intensity and mapping of the light intensity spatial distribution. Results indicate that our device shows a uniform spatial distribution for distances from the blanket larger than 10 cm, with a maximum of irradiance at such a distance. This device presenting a large and uniform area of irradiation, efficient wavelength emission and high irradiance seems to be promising for neonates' phototherapy treatment.

  4. Clinical comparison of salicylic acid peel and LED-Laser phototherapy for the treatment of Acne vulgaris in teenagers.

    Science.gov (United States)

    Alba, Monique Narciso; Gerenutti, Marli; Yoshida, Valquíria Miwa Hanai; Grotto, Denise

    2017-02-01

    Acne vulgaris treatments usually cause sensitivity, teratogenicity and bacterial resistance. Investigations of other therapeutic techniques, such as phototherapy, are highly relevant. Thus, we compared the effectiveness of two Acne vulgaris treatments in adolescents: peeling with salicylic acid (SA) and phototherapy. Teens were randomly divided into: group I, treatment with SA peels (10%) and group II, treatment with phototherapy (blue LED and red laser lights). Photographs were taken before and after ten sessions of each treatment, carried out weekly, and compared. To compare the differences between the treatments, the Student t-test was used. P values treatment of acne in teenagers since the number of comedones, papules and pustules decreased significantly at the end of the session. However, when the two treatments were compared, phototherapy showed a significant difference in reducing the number of pustules. The combined use of red and blue lights due to their anti-inflammatory and wound-healing properties is a more efficient alternative for treating Acne vulgaris in relation to SA and proves more reliable and without side effects, improving the adolescents' skin health.

  5. Delayed and short course of rapamycin prevents organ rejection after allogeneic liver transplantation in rats.

    Science.gov (United States)

    Hamdani, Salim; Thiolat, Allan; Naserian, Sina; Grondin, Cynthia; Moutereau, Stéphane; Hulin, Anne; Calderaro, Julien; Grimbert, Philippe; Cohen, José Laurent; Azoulay, Daniel; Pilon, Caroline

    2017-10-14

    To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats. Allogeneic OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with rapamycin. An 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8+CD45RClow T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not rejected. Our results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8+CD45RClow T cells as associated with the state of tolerance.

  6. Rapamycin is highly effective in murine models of immune-mediated bone marrow failure.

    Science.gov (United States)

    Feng, Xingmin; Lin, Zenghua; Sun, Wanling; Hollinger, Maile K; Desierto, Marie J; Keyvanfar, Keyvan; Malide, Daniela; Muranski, Pawel; Chen, Jichun; Young, Neal S

    2017-10-01

    Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8+ T cells (notably T cells specific to target cells bearing minor histocompatibility antigen H60), and preserved hematopoietic stem and progenitor cells. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naïve T cells. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T-cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting through different mechanisms to cyclosporine. Its specific expansion of regulatory T cells and elimination of clonogenic CD8+ effectors support its potential clinical utility in the treatment of aplastic anemia. Copyright© 2017 Ferrata Storti Foundation.

  7. The Prevalence and Impact of Hyperglycemia and Hyperlipidemia in Patients With Advanced Cancer Receiving Combination Treatment With the Mammalian Target of Rapamycin Inhibitor Temsirolimus and Insulin Growth Factor-Receptor Antibody Cixutumumab.

    Science.gov (United States)

    Busaidy, Naifa L; LoRusso, Patricia; Lawhorn, Kristie; Hess, Kenneth R; Habra, Mohammed Amir; Fu, Siqing; Hong, David S; Chen, Helen X; Doyle, Lawrence A; Kurzrock, Razelle; Naing, Aung

    2015-07-01

    Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome. The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS). Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS. The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS. Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects

  8. Rapamycin enhances docetaxel-induced cytotoxicity in a androgen-independent prostate cancer xenograft model by survivin downregulation

    Energy Technology Data Exchange (ETDEWEB)

    Morikawa, Yasuyuki, E-mail: yasu-m@med.gunma-u.ac.jp [Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maeabshi, Gunma 3718511 (Japan); Koike, Hidekazu; Sekine, Yoshitaka; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Suzuki, Kazuhiro [Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maeabshi, Gunma 3718511 (Japan)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer Rapamycin (RPM) enhances the susceptibility of PC3 cells to docetaxel. Black-Right-Pointing-Pointer Low-dosage of docetaxel (DTX) did not reduce survivin expression levels in PC3 cells. Black-Right-Pointing-Pointer Combination treatment of RPM with DTX suppressed the expression of surviving. Black-Right-Pointing-Pointer SiRNA against survivin enhanced the susceptibility of PC3 cells to DTX. Black-Right-Pointing-Pointer RPM and DTX cotreatment inhibited PC3 cell growth and decreased surviving in vivo. -- Abstract: Background: Docetaxel is a first-line treatment choice in castration-resistant prostate cancer (CRPC). However, the management of CRPC remains an important challenge in oncology. There have been many reports on the effects of rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR), in the treatment of carcinogenesis. We assessed the cytotoxic effects of the combination treatment of docetaxel and rapamycin in prostate cancer cells. Furthermore, we examined the relationship between these treatments and survivin, which is a member of the inhibitory apoptosis family. Methods: Prostate cancer cells were cultured and treated with docetaxel and rapamycin. The effects on proliferation were evaluated with the MTS assay. In addition, we evaluated the effect on proliferation of the combination treatment induced knockdown of survivin expression by small interfering RNA transfection and docetaxel. Protein expression levels were assayed using western blotting. PC3 cells and xenograft growth in nude mice were used to evaluate the in vivo efficacy of docetaxel and its combination with rapamycin. Results: In vitro and in vivo, the combination of rapamycin with docetaxel resulted in a greater inhibition of proliferation than treatment with rapamycin or docetaxel alone. In addition, in vitro and in vivo, rapamycin decreased basal surviving levels, and cotreatment with docetaxel further decreased these levels

  9. A system for treatment of diabetic foot ulcers using led irradiation and natural latex

    Directory of Open Access Journals (Sweden)

    Gustavo Adolfo Marcelino de Almeida Nunes

    Full Text Available Abstract Introduction: We developed and tested a new system for inducing the healing of diabetic foot ulcers. The system relies on the regenerative properties of its two components: an insole with a sheet of natural latex and a device that contains a matrix of light emitting diodes with wavelength of 635 nm. Methods The electronic and latex based devices were developed, and a four weeks test was performed in one control group (CG of five ulcers and one experimental group (EG of eight ulcers. The CG was treated with a standard approach, based on a silver-releasing foam dressing, and the EG was treated with the system under test. For each ulcer, an index for quantifying the percentage ulcer recovery, named CRU(%, has been calculated; a CRU(% = 0% means no healing, and a CRU(% = 100% means total healing. Results There were statistically significant increases of CRU(% of 51.8% (p = 0.022, for the CG, and of 78.4% (p < 0.001, for the EG. The increase in the EG was higher than the increase in the CG, and the difference was statistically significant (p < 0.001. The results showed that the proposed method had, for these particular sets of ulcers, faster healing rates, than for the standard method. Conclusion The results hint that the proposed method seems promising as a future treatment method. However, the technique must undergo further testing before it can be considered for extensive clinical applications.

  10. Rapamycin-induced autophagy restricts porcine epidemic diarrhea virus infectivity in porcine intestinal epithelial cells.

    Science.gov (United States)

    Ko, Seongyeol; Gu, Min Jeong; Kim, Cheol Gyun; Kye, Yoon Chul; Lim, Younggap; Lee, Ji Eun; Park, Byung-Chul; Chu, Hyuk; Han, Seung Hyun; Yun, Cheol-Heui

    2017-10-01

    Porcine epidemic diarrhea virus (PEDV) invades porcine intestinal epithelial cells (IECs) and causes diarrhea and dehydration in pigs. In the present study, we showed a suppression of PEDV infection in porcine jejunum intestinal epithelial cells (IPEC-J2) by an increase in autophagy. Autophagy was activated by rapamycin at a dose that does not affect cell viability and tight junction permeability. The induction of autophagy was examined by LC3I/LC3II conversion. To confirm the autophagic-flux (entire autophagy pathway), autophagolysosomes were examined by an immunofluorescence assay. Pre-treatment with rapamycin significantly restricted not only a 1 h infection but also a longer infection (24 h) with PEDV, while this effect disappeared when autophagy was blocked. Co-localization of PEDV and autophagosomes suggests that PEDV could be a target of autophagy. Moreover, alleviation of PEDV-induced cell death in IPEC-J2 cells pretreated with rapamycin demonstrates a protective effect of rapamycin against PEDV-induced epithelial cell death. Collectively, the present study suggests an early prevention against PEDV infection in IPEC-J2 cells via autophagy that might be an effective strategy for the restriction of PEDV, and opens up the possibility of the use of rapamycin in vivo as an effective prophylactic and prevention treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Convergence of Ubiquitylation and Phosphorylation Signaling in Rapamycin-Treated Yeast Cells

    DEFF Research Database (Denmark)

    Iesmantavicius, Vytautas; Weinert, Brian Tate; Choudhary, Chuna Ram

    2014-01-01

    for reduced ubiquitylation and reduced protein abundance. The convergence of multiple proteome-level changes on the Rsp5 system indicates a key role of this pathway in the response to rapamycin treatment. Collectively, these data reveal new insights into the global proteome dynamics in response to rapamycin...... treatment and provide a first detailed view of the co-regulation of phosphorylation and ubiquitylation-dependent signaling networks by this compound......., and vesicle trafficking. TOR regulates cellular physiology by modulating phosphorylation and ubiquitylation signaling networks, however, the global scope of such regulation is not fully known. Here, we used mass spectrometry (MS)-based proteomics approach for the parallel quantification of ubiquitylation...

  12. The rapamycin-regulated gene expression signature determines prognosis for breast cancer

    Directory of Open Access Journals (Sweden)

    Tsavachidis Spiridon

    2009-09-01

    Full Text Available Abstract Background Mammalian target of rapamycin (mTOR is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Results Colony formation and sulforhodamine B (IC50 in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI, of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%. In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile RMI was significantly associated with longer survival (P = 0.015. On multivariate analysis, RMI (P = 0.029, tumor size (P = 0.015 and lymph node status (P = 0.001 were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41. In the Wang dataset, RMI predicted time to disease relapse (P = 0.009. Conclusion Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment.

  13. A Signal-On Fluorosensor Based on Quench-Release Principle for Sensitive Detection of Antibiotic Rapamycin

    Directory of Open Access Journals (Sweden)

    Hee-Jin Jeong

    2015-03-01

    Full Text Available An antibiotic rapamycin is one of the most commonly used immunosuppressive drugs, and also implicated for its anti-cancer activity. Hence, the determination of its blood level after organ transplantation or tumor treatment is of great concern in medicine. Although there are several rapamycin detection methods, many of them have limited sensitivity, and/or need complicated procedures and long assay time. As a novel fluorescent biosensor for rapamycin, here we propose “Q’-body”, which works on the fluorescence quench-release principle inspired by the antibody-based quenchbody (Q-body technology. We constructed rapamycin Q’-bodies by linking the two interacting domains FKBP12 and FRB, whose association is triggered by rapamycin. The fusion proteins were each incorporated position-specifically with one of fluorescence dyes ATTO520, tetramethylrhodamine, or ATTO590 using a cell-free translation system. As a result, rapid rapamycin dose-dependent fluorescence increase derived of Q’-bodies was observed, especially for those with ATTO520 with a lowest detection limit of 0.65 nM, which indicates its utility as a novel fluorescent biosensor for rapamycin.

  14. Rapamycin increases oxidative stress response gene expression in adult stem cells

    Science.gov (United States)

    Kofman, Amber E.; McGraw, Margeaux R.; Payne, Christopher J.

    2012-01-01

    Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescence in vitro and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment, including superoxide dismutase 1, glutathione reductase, and delta-aminolevulinate dehydratase. When we examined the expression of these genes in 55-week-old wild type SSCs, their levels were significantly reduced compared to 3-week-old SSCs, suggesting that their downregulation is coincident with the aging process in adult stem cells. We conclude that rapamycin-induced stimulation of oxidative stress response genes may promote cellular longevity in SSCs, while a decline in gene expression in aged stem cells could reflect the SSCs' diminished potential to alleviate oxidative stress, a hallmark of aging. PMID:22529334

  15. LED colorimetry

    Science.gov (United States)

    Schanda, J.; Muray, K.; Kranicz, Balazs

    2002-06-01

    LEDs (Light Emitting Diodes) become the most important light sources in traffic signal applications, but their use increases in other areas, e.g. indoor and outdoor signals and information boards, now also in general lighting. They become popular also as instrumental radiation sources. LEDs emit in narrow emission bands, and as every semiconductor, their optical characteristics are temperature dependent. In outdoor applications they are exposed to extreme temperatures, influencing both their absolute intensity and their chromaticity. In the present paper we investigate the spectral power distribution of different types of real LEDs, as well as the change of their spectrum with temperature. The question of measuring these spectra will be re-visited. Instruments tested fall into three categories: high-end double spectrometer, single grating instrument and array type instruments of different quality. These instruments show very different stray light rejection, band-pass, and wavelength accuracy characteristics, leading to non- negligible errors of LED chromaticity if calibration is made with incandescent lamps. Results on the influence of these factors and of spectral bandwidth and sampling rate for measuring modern LEDs will be provided. Chromaticity will be calculated based on above spectral measurements and color differences will be evaluated. This becomes a hot topic with present LED cluster construction, as LEDs mounted in a panel side by side have to agree both in chromaticity and luminous intensity to an extent that is below visual acceptability levels.

  16. Mood-stabilizing effects of rapamycin and its analog temsirolimus: relevance to autophagy.

    Science.gov (United States)

    Kara, Nirit Z; Flaisher-Grinberg, Shlomit; Anderson, Grant W; Agam, Galila; Einat, Haim

    2017-08-02

    Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.

  17. How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story.

    Science.gov (United States)

    Richardson, Arlan; Galvan, Veronica; Lin, Ai-Ling; Oddo, Salvatore

    2015-08-01

    The discovery that rapamycin increases lifespan in mice and restores/delays many aging phenotypes has led to the speculation that rapamycin has 'anti-aging' properties. The major question discussed in this review is whether a manipulation that has anti-aging properties can alter the onset and/or progression of Alzheimer's disease, a disease in which age is the major risk factor. Rapamycin has been shown to prevent (and possibly restore in some cases) the deficit in memory observed in the mouse model of Alzheimer's disease (AD-Tg) as well as reduce Aβ and tau aggregation, restore cerebral blood flow and vascularization, and reduce microglia activation. All of these parameters are widely recognized as symptoms central to the development of AD. Furthermore, rapamycin has also been shown to improve memory and reduce anxiety and depression in several other mouse models that show cognitive deficits as well as in 'normal' mice. The current research shows the feasibility of using pharmacological agents that increase lifespan, such as those identified by the National Institute on Aging Intervention Testing Program, to treat Alzheimer's disease. Published by Elsevier Inc.

  18. Systematic Review on Role of Mammalian Target of Rapamycin Inhibitors as an Alternative to Calcineurin Inhibitors in Renal Transplant: Challenges and Window to Excel.

    Science.gov (United States)

    Kumar, Jayant; Bridson, Julie M; Sharma, Ajay; Halawa, Ahmed

    2017-06-01

    This review focuses on the current limited evidence of graft function and graft survival in various immunosuppressive regimens involving mammalian target of rapamycin inhibitors with or without calcineurin inhibitors. We evaluated the current literature for describing the role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus databases using medical subject heading terms. Our detailed analyses of all relevant literature showed use of mammalian target of rapamycin inhibitor-based de novo regimens, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimens, and late conversion from a calcineurin inhibitor-based regimen to mammalian target of rapamycin inhibitor-based regimens. Notably, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimen seemed to be a more practical and realistic approach toward immunosuppressive treatment of renal transplant recipients. However, in view of the high rejection rate observed in these studies, it is advisable not to offer these regimens to patients with moderate to high immunologic risk. The present evidences suggest that treatment with mammalian target of rapamycin inhibitors allows early and substantial calcineurin inhibitor minimization. The mammalian target of rapamycin inhibitors everolimus and sirolimus are preferred due to their complementary mechanisms of action and favorable nephrotoxicity profile, which have opened the way for calcineurin inhibitor reduction/withdrawal in the early posttransplant period.

  19. Rapamycin enhances lytic replication of Epstein-Barr virus in gastric carcinoma cells by increasing the transcriptional activities of immediate-early lytic promoters.

    Science.gov (United States)

    Wang, Man; Wu, Wei; Zhang, Yinfeng; Yao, Guoliang; Gu, Bianli

    2017-11-21

    Epstein-Barr virus (EBV), a human herpesvirus, is linked to both epithelial and lymphoid malignancies. Induction of EBV reactivation is a potential therapeutic strategy for EBV-associated tumors. In this study, we assessed the effects of rapamycin on EBV reactivation in gastric carcinoma cells. We found that rapamycin upregulated expression of EBV lytic proteins and increased the viral proliferation triggered by the EBV lytic inducer sodium butyrate. Reverse transcription-qPCR, luciferase activity assays, chromatin immunoprecipitation and western blotting were employed to explore the mechanism by which rapamycin promotes EBV reactivation. Our results showed that rapamycin treatment resulted in increased mRNA levels of EBV immediate-early genes. Rapamycin also enhanced the transcriptional activities of the EBV immediate-early lytic promoters Zp and Rp by strengthening Sp1 binding. Repression of the cellular ataxia telangiectasia-mutated/p53 pathway by siRNA-mediated knockdown of the ataxia telangiectasia-mutated gene significantly abrogated virus reactivation by rapamycin/sodium butyrate treatment, indicating that the ataxia telangiectasia-mutated/p53 pathway is involved in rapamycin-promoted EBV reactivation. Taken together, these findings demonstrate that rapamycin might have the potential to enhance the effectiveness of oncolytic viral therapies developed for EBV-associated malignancies. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. A controlled trial of the Litebook light-emitting diode (LED) light therapy device for treatment of Seasonal Affective Disorder (SAD)

    National Research Council Canada - National Science Library

    Desan, Paul H; Weinstein, Anea J; Michalak, Erin E; Tam, Edwin M; Meesters, Ybe; Ruiter, Martine J; Horn, Edward; Telner, John; Iskandar, Hani; Boivin, Diane B; Lam, Raymond W

    2007-01-01

    .... Light treatment devices using efficient light-emitting diodes (LEDs) whose output is relatively concentrated in short wavelengths may enable a more convenient effective therapy for Seasonal Affective Disorder (SAD). Methods...

  1. Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

    Science.gov (United States)

    Shah, Mihir; Edman, Maria C.; Reddy Janga, Srikanth; Yarber, Frances; Meng, Zhen; Klinngam, Wannita; Bushman, Jonathan; Ma, Tao; Liu, Siyu; Louie, Stan; Mehta, Arjun; Ding, Chuanqing; MacKay, J. Andrew; Hamm-Alvarez, Sarah F.

    2017-01-01

    Purpose To evaluate the efficacy of topical rapamycin in treating autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome. Methods We developed rapamycin in a poly(ethylene glycol)-distearoyl phosphatidylethanolamine (PEG-DSPE) micelle formulation to maintain solubility. Rapamycin or PEG-DSPE eye drops (vehicle) were administered in a well-established Sjögren's syndrome disease model, the male nonobese diabetic (NOD) mice, twice daily for 12 weeks starting at 8 weeks of age. Mouse tear fluid was collected and tear Cathepsin S, a putative tear biomarker for Sjögren's syndrome, was measured. Lacrimal glands were retrieved for histological evaluation, and quantitative real-time PCR of genes associated with Sjögren's syndrome pathogenesis. Tear secretion was measured using phenol red threads, and corneal fluorescein staining was used to assess corneal integrity. Results Lymphocytic infiltration of lacrimal glands from rapamycin-treated mice was significantly (P = 0.0001) reduced by 3.8-fold relative to vehicle-treated mice after 12 weeks of treatment. Rapamycin, but not vehicle, treatment increased tear secretion and decreased corneal fluorescein staining after 12 weeks. In rapamycin-treated mice, Cathepsin S activity was significantly reduced by 3.75-fold in tears (P eye. PMID:28122086

  2. PTEN and rapamycin inhibiting the growth of K562 cells through regulating mTOR signaling pathway

    Directory of Open Access Journals (Sweden)

    Chen Hao

    2008-12-01

    Full Text Available Abstract Objective To investigate, in vitro, the regulatory effects of tumor-suppressing gene PTEN on mTOR (mammalian target of rapamycin signaling pathway, the effects of transfected PTEN and rapamycin on the growth inhibition, and apoptosis induction for human leukemia cell line K562 cells. Methods K562 cells were transfected with recombined adenovirus-PTEN vector containing green fluorescent protein (Ad-PTEN-GFP, followed by the treatment of the cells with or without rapamycin. The proliferation inhibition rate and apoptotic rate of these transfected and/or rapamycin treated K562 cells were measured by MTT assay and flow cytometry (FCM, the expression levels of PTEN-, mTOR-, cyclinD1- and P27kip1- mRNA were measured by real-time fluorescent relative-quantification reverse transcriptional PCR (FQ-PCR, the protein expression levels of PTEN, Akt, p-Akt were detected by western blotting. Results The proliferation of K562 cells was inhibited by PTEN gene transfection with/without the treatment of rapamycin. The expression levels of PTEN- and P27kip1- mRNA were up-regulated, and the mTOR- and cyclinD1- mRNA were down-regulated in K562 cells after the cells transfected with wild type PTEN gene and treated with rapamycin. Conclusion PTEN and rapamycin inhibited mTOR expression by acting as an upstream regulator of mTOR. Low dose rapamycin in combination with over-expressed PTEN might have synergistic effects on inhibiting the proliferation and promoting apoptosis of K562 cells.

  3. Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres

    NARCIS (Netherlands)

    Falke, Lucas L.; van Vuuren, Stefan H.; Kazazi-Hyseni, Filis; Ramazani, Farshad; Nguyan, Tri Q.; Veldhuis, Gert J.; Maarseveen, Erik M.; Zandstra, Jurjen; Zuidema, Johan; Duque, Luisa F.; Steendam, Rob; Popa, Eliane R.; Kok, Robbert Jan; Goldschmeding, Roe

    Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic

  4. LED lamp

    Science.gov (United States)

    Galvez, Miguel; Grossman, Kenneth; Betts, David

    2013-11-12

    There is herein described a lamp for providing white light comprising a plurality of light sources positioned on a substrate. Each of said light sources comprises a blue light emitting diode (LED) and a dome that substantially covers said LED. A first portion of said blue light from said LEDs is transmitted through said domes and a second portion of said blue light is converted into a red light by a first phosphor contained in said domes. A cover is disposed over all of said light sources that transmits at least a portion of said red and blue light emitted by said light sources. The cover contains a second phosphor that emits a yellow light in response to said blue light. The red, blue and yellow light combining to form the white light and the white light having a color rendering index (CRI) of at least about 80.

  5. Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Cuesta-López, Emilio; Azorín, Sebastián; Selgas, Rafael

    2009-01-01

    This is the first report of a case of a reduction in kidney volume and preservation of renal function in a patient with autosomal-dominant polycystic kidney disease (ADPKD) receiving rapamycin. A 42-year-old man with ADPKD and a severe persistent bleeding from his solitary left kidney was successfully treated with tranexamic acid (TXA). He also received low-dose rapamycin for 8 months, and this was associated with a 23.5% reduction in kidney volume, improvement and stabilization of renal function, and normalization of haemoglobin levels. When treatment with rapamycin was interrupted, renal function deteriorated within an 8-month period and haemodialysis (HD) became necessary. Kidney volume increased at once, and life-threatening bleeding prompted a nephrectomy 4 months after the onset of HD. These data suggest that the reduction in kidney volume and preservation of renal function with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin. PMID:25949309

  6. Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Cuesta-López, Emilio; Azorín, Sebastián; Selgas, Rafael

    2009-04-01

    This is the first report of a case of a reduction in kidney volume and preservation of renal function in a patient with autosomal-dominant polycystic kidney disease (ADPKD) receiving rapamycin. A 42-year-old man with ADPKD and a severe persistent bleeding from his solitary left kidney was successfully treated with tranexamic acid (TXA). He also received low-dose rapamycin for 8 months, and this was associated with a 23.5% reduction in kidney volume, improvement and stabilization of renal function, and normalization of haemoglobin levels. When treatment with rapamycin was interrupted, renal function deteriorated within an 8-month period and haemodialysis (HD) became necessary. Kidney volume increased at once, and life-threatening bleeding prompted a nephrectomy 4 months after the onset of HD. These data suggest that the reduction in kidney volume and preservation of renal function with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin.

  7. Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway.

    Directory of Open Access Journals (Sweden)

    Lei Liu

    2010-05-01

    Full Text Available Serine/threonine (Ser/Thr protein phosphatase 2A (PP2A has been implicated as a novel component of the mammalian target of rapamycin (mTOR signaling pathway. Recently we have demonstrated that mTOR regulates cell motility in part through p70 S6 kinase 1 (S6K1 and eukaryotic initiation factor 4E (eIF4E binding protein 1 (4E-BP1 pathways. Little is known about the role of PP2A in the mTOR-mediated cell motility. Here we show that rapamycin inhibited the basal or insulin-like growth factor 1 (IGF-1-induced motility of human Ewing sarcoma (Rh1 and rhabdomyosarcoma (Rh30 cells. Treatment of the cells with rapamycin activated PP2A activity, and concurrently inhibited IGF-1 stimulated phosphorylation of Erk1/2. Inhibition of Erk1/2 with PD98059 did not significantly affect the basal mobility of the cells, but dramatically inhibited IGF-1-induced cell motility. Furthermore, inhibition of PP2A with okadaic acid significantly attenuated the inhibitory effect of rapamycin on IGF-1-stimulated phosphorylation of Erk1/2 as well as cell motility. Consistently, expression of dominant negative PP2A conferred resistance to IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. Expression of constitutively active MKK1 also attenuated rapamycin inhibition of IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. The results suggest that rapamycin inhibits cell motility, in part by targeting PP2A-Erk1/2 pathway.

  8. Rapamycin-Induced Apoptosis in HGF-Stimulated Lens Epithelial Cells by AKT/mTOR, ERK and JAK2/STAT3 Pathways

    Directory of Open Access Journals (Sweden)

    Fang Tian

    2014-08-01

    Full Text Available Hepatocyte growth factor (HGF induced the proliferation of lens epithelial cells (LECs and may be a major cause of posterior capsule opacification (PCO, which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation have been studied, but none have been used in clinic. Recently, accumulating evidence has suggested rapamycin, the inhibitor of mTOR (mammalian target of Rapamycin, was associated with the induction of apoptosis in LECs. The purpose of our study was to investigate the potential effects of rapamycin on HGF-induced LECs and the underlying mechanisms by which rapamycin exerted its actions. Using cell proliferation, cell viability and flow cytometric apoptosis assays, we found that rapamycin potently not only suppressed proliferation but also induced the apoptosis of LECs in a dose-dependent manner under HGF administration. Further investigation of the underlying mechanism using siRNA transfection revealed that rapamycin could promote apoptosis of LECs via inhibiting HGF-induced phosphorylation of AKT/mTOR, ERK and JAK2/STAT3 signaling molecules. Moreover, the forced expression of AKT, ERK and STAT3 could induce a significant suppression of apoptosis in these cells after treatment of rapamycin. Together, these findings suggested that rapamycin-induced apoptosis in HGF-stimulated LECs is accompanied by inhibition of AKT/mTOR, ERK and JAK2/STAT3 pathways, which supports its use to inhibit PCO in preclinical studies and provides theoretical foundation for future possible practice.

  9. Topical application of rapamycin ointment ameliorates Dermatophagoides farina body extract-induced atopic dermatitis in NC/Nga mice.

    Science.gov (United States)

    Yang, Fei; Tanaka, Mari; Wataya-Kaneda, Mari; Yang, Lingli; Nakamura, Ayumi; Matsumoto, Shoji; Attia, Mostafa; Murota, Hiroyuki; Katayama, Ichiro

    2014-08-01

    Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by relapsing eczema and intense prurigo, requires effective and safe pharmacological therapy. Recently, rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been reported to play a critical role in immune responses and has emerged as an effective immunosuppressive drug. In this study, we assessed whether inhibition of mTOR signalling could suppress dermatitis in mice. Rapamycin was topically applied to inflamed skin in a murine AD model that was developed by repeated topical application of Dermatophagoides farina body (Dfb) extract antigen twice weekly for 7 weeks in NC/Nga mice. The efficacy of topical rapamycin treatment was evaluated immunologically and serologically. Topical application of rapamycin reduced inflammatory cell infiltration in the dermis, alleviated the increase of serum IgE levels and resulted in a significant reduction in clinical skin condition score and marked improvement of histological findings. In addition, increased mTOR phosphorylation in the lesional skin was observed in our murine AD model. Topical application of rapamycin ointment inhibited Dfb antigen-induced dermatitis in NC/Nga mice, promising a new therapy for atopic dermatitis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification.

    Science.gov (United States)

    Qureshi, Ammar T; Dey, Devaveena; Sanders, Erin M; Seavey, Jonathan G; Tomasino, Allison M; Moss, Kaitlyn; Wheatley, Benjamin; Cholok, David; Loder, Shawn; Li, John; Levi, Benjamin; Davis, Thomas A

    2017-11-01

    A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α-positive cells, and α-smooth muscle actin-positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α-positive cells, 4) α-smooth muscle actin-positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin.

    Science.gov (United States)

    Zemp, Franz J; Lun, Xueqing; McKenzie, Brienne A; Zhou, Hongyuan; Maxwell, Lori; Sun, Beichen; Kelly, John J P; Stechishin, Owen; Luchman, Artee; Weiss, Samuel; Cairncross, J Gregory; Hamilton, Mark G; Rabinovich, Brian A; Rahman, Masmudur M; Mohamed, Mohamed R; Smallwood, Sherin; Senger, Donna L; Bell, John; McFadden, Grant; Forsyth, Peter A

    2013-07-01

    Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor-initiating cells (BTICs). We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts. The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing "advanced" BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo. Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.

  12. Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells.

    Science.gov (United States)

    Stanford, Marianne M; Barrett, John W; Nazarian, Steven H; Werden, Steven; McFadden, Grant

    2007-02-01

    Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global effects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

  13. Multi-scale optical imaging of the delayed type hypersensitivity reaction attenuated by rapamycin.

    Science.gov (United States)

    Luo, Meijie; Zhang, Zhihong; Li, Hui; Qiao, Sha; Liu, Zheng; Fu, Ling; Shen, Guanxin; Luo, Qingming

    2014-01-01

    Neutrophils and monocytes/macrophages (MMs) play important roles in the development of cell-mediated delayed type hypersensitivity (DTH). However, the dynamics of neutrophils and MMs during the DTH reaction and how the immunosuppressant rapamycin modulates their behavior in vivo are rarely reported. Here, we take advantage of multi-scale optical imaging techniques and a footpad DTH reaction model to non-invasively investigate the dynamic behavior and properties of immune cells from the whole field of the footpad to the cellular level. During the classic elicitation phase of the DTH reaction, both neutrophils and MMs obviously accumulated at inflammatory foci at 24 h post-challenge. Rapamycin treatment resulted in advanced neutrophil recruitment and vascular hyperpermeability at an early stage (4 h), the reduced accumulation of neutrophils (> 50% inhibition ratio) at 48 h, and the delayed involvement of MMs in inflammatory foci. The motility parameters of immune cells in the rapamycin-treated reaction at 4 h post-challenge displayed similar mean velocities, arrest durations, mean displacements, and confinements as the classic DTH reaction at 24 h. These results indicate that rapamycin treatment shortened the initial preparation stage of the DTH reaction and attenuated its intensity, which may be due to the involvement of T helper type 2 cells or regulatory T cells.

  14. Synthesis of I-125 labeled photoaffinity rapamycin analogs

    Energy Technology Data Exchange (ETDEWEB)

    Shu, A.Y.L.; Yamashita, D.S.; Holt, D.A.; Heys, J.R. [SmithKline Beecham Pharmaceuticals, King of Prussia, PA (United States)

    1996-03-01

    Two no-carrier-added {sup 125}I-labelled photoaffinity rapamycin analogs were prepared: 7-demethoxy-7-(4-azido-3-{sup 125}I-benzyloxy) rapamycin and its C{sub 28}-C{sub 29} seco analog. The key reactions of the synthesis were substitution of the C{sub 7} methoxyl of rapamycin with 4-azido-3-tributylstannylbenzyloxy group, exchange of tributyltin with {sup 125}I using Na{sup 125}I and Chloramine-T, and a ZnCl{sub 2} mediated retro-Aldol cleavage of the C{sub 28}-C{sub 29} bond of rapamycin. (author).

  15. Metabolic effects of acute thiamine depletion are reversed by rapamycin in breast and leukemia cells.

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    Shuqian Liu

    Full Text Available Thiamine-dependent enzymes (TDEs control metabolic pathways that are frequently altered in cancer and therefore present cancer-relevant targets. We have previously shown that the recombinant enzyme thiaminase cleaves and depletes intracellular thiamine, has growth inhibitory activity against leukemia and breast cancer cell lines, and that its growth inhibitory effects were reversed in leukemia cell lines by rapamycin. Now, we first show further evidence of thiaminase therapeutic potential by demonstrating its activity against breast and leukemia xenografts, and against a primary leukemia xenograft. We therefore further explored the metabolic effects of thiaminase in combination with rapamycin in leukemia and breast cell lines. Thiaminase decreased oxygen consumption rate and increased extracellular acidification rate, consistent with the inhibitory effect of acute thiamine depletion on the activity of the TDEs pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes; these effects were reversed by rapamycin. Metabolomic studies demonstrated intracellular thiamine depletion and the presence of the thiazole cleavage product in thiaminase-treated cells, providing validation of the experimental procedures. Accumulation of ribose and ribulose in both cell lines support the thiaminase-mediated suppression of the TDE transketolase. Interestingly, thiaminase suppression of another TDE, branched chain amino ketoacid dehydrogenase (BCKDH, showed very different patterns in the two cell lines: in RS4 leukemia cells it led to an increase in BCKDH substrates, and in MCF-7 breast cancer cells it led to a decrease in BCKDH products. Immunoblot analyses showed corresponding differences in expression of BCKDH pathway enzymes, and partial protection of thiaminase growth inhibition by gabapentin indicated that BCKDH inhibition may be a mechanism of thiaminase-mediated toxicity. Surprisingly, most of thiaminase-mediated metabolomic effects were also

  16. Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes.

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    Singh, Abhishek Kumar; Garg, Geetika; Singh, Sandeep; Rizvi, Syed Ibrahim

    2017-10-01

    Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

  17. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder.

    Science.gov (United States)

    Parker, Whitney E; Orlova, Ksenia A; Parker, William H; Birnbaum, Jacqueline F; Krymskaya, Vera P; Goncharov, Dmitry A; Baybis, Marianna; Helfferich, Jelte; Okochi, Kei; Strauss, Kevin A; Crino, Peter B

    2013-04-24

    A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

  18. Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

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    Kathryn M. Silk

    2012-01-01

    Full Text Available While human embryonic stem cells (hESCs may one day facilitate the treatment of degenerative diseases requiring cell replacement therapy, the success of regenerative medicine is predicated on overcoming the rejection of replacement tissues. Given the role played by dendritic cells (DCs in the establishment of immunological tolerance, we have proposed that DC, rendered tolerogenic during their differentiation from hESC, might predispose recipients to accept replacement tissues. As a first step towards this goal, we demonstrate that DC differentiated from H1 hESCs (H1-DCs are particularly responsive to the immunosuppressive agent rapamycin compared to monocyte-derived DC (moDC. While rapamycin had only modest impact on the phenotype and function of moDC, H1-DC failed to upregulate CD40 upon maturation and displayed reduced immunostimulatory capacity. Furthermore, coculture of naïve allogeneic T cells with rapamycin-treated H1-DC promoted an increased appearance of CD25hi Foxp3+ regulatory T cells, compared to moDC. Our findings suggest that conditioning of hESC-derived DC with rapamycin favours a tolerogenic phenotype.

  19. Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy

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    Xiang Bai

    2015-08-01

    Full Text Available Background: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy. Methods: We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day improves motor function in neuronal A53T α-synuclein transgenic mice (TG and explored underlying mechanisms using a variety of behavioral and biochemical approaches. Results: After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal. Conclusion: Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.

  20. Improving the scalability of psychological treatments in developing countries: an evaluation of peer-led therapy quality assessment in Goa, India.

    Science.gov (United States)

    Singla, Daisy R; Weobong, Benedict; Nadkarni, Abhijit; Chowdhary, Neerja; Shinde, Sachin; Anand, Arpita; Fairburn, Christopher G; Dimijdan, Sona; Velleman, Richard; Weiss, Helen; Patel, Vikram

    2014-09-01

    Psychological treatments delivered by lay therapists, with little or no previous mental health training, have been shown to be effective in treating a range of mental health problems. In low resource settings, the dearth of available experts to assess therapy quality potentially leads to a bottleneck in scaling up lay therapist delivered psychological treatments. Peer-led supervision and the assessment of therapy quality may be one solution to address this barrier. The purpose of this study was two-fold: 1) to assess lay therapist quality ratings compared to expert supervisors in a multisite study where lay therapists delivered two locally developed, psychological treatments for harmful and dependent drinking and severe depression; 2) assess the acceptability and feasibility of peer-led supervision compared to expert-led supervision. We developed two scales, one for each treatment, to compare lay therapist and expert ratings on audio-taped treatment sessions (n = 189). Our findings confirmed our primary hypothesis of increased levels of agreement between peer and expert ratings over three consecutive time periods as demonstrated by a decrease in the differences in mean therapy quality rating scores. This study highlights that lay therapists can be trained to effectively assess each other's therapy sessions as well as experts, and that peer-led supervision is acceptable for lay therapists, thus, enhancing the scalability of psychological treatments in low-resource settings. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Rapamycin inhibits poly(ADP-ribosyl)ation in intact cells

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    Fahrer, Joerg, E-mail: joerg.fahrer@uni-ulm.de [Molecular Toxicology Group, Department of Biology, University of Konstanz (Germany); Wagner, Silvia [Clinic of General, Visceral- and Transplantation Surgery, ZMF, University Hospital Tuebingen (Germany); Buerkle, Alexander [Molecular Toxicology Group, Department of Biology, University of Konstanz (Germany); Koenigsrainer, Alfred [Clinic of General, Visceral- and Transplantation Surgery, ZMF, University Hospital Tuebingen (Germany)

    2009-08-14

    Rapamycin is an immunosuppressive drug, which inhibits the mammalian target of rapamycin (mTOR) kinase activity inducing changes in cell proliferation. Synthesis of poly(ADP-ribose) (PAR) is an immediate cellular response to genotoxic stress catalyzed mostly by poly(ADP-ribose) polymerase 1 (PARP-1), which is also controlled by signaling pathways. Therefore, we investigated whether rapamycin affects PAR production. Strikingly, rapamycin inhibited PAR synthesis in living fibroblasts in a dose-dependent manner as monitored by immunofluorescence. PARP-1 activity was then assayed in vitro, revealing that down-regulation of cellular PAR production by rapamycin was apparently not due to competitive PARP-1 inhibition. Further studies showed that rapamycin did not influence the cellular NAD pool and the activation of PARP-1 in extracts of pretreated fibroblasts. Collectively, our data suggest that inhibition of cellular PAR synthesis by rapamycin is mediated by formation of a detergent-sensitive complex in living cells, and that rapamycin may have a potential as therapeutic PARP inhibitor.

  2. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2

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    Lan eYe

    2012-09-01

    Full Text Available Rapamycin, an inhibitor of mTOR complex 1 (mTORC1, improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 hours. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Chronic rapamycin treatment may also impair insulin action via the inhibition of mTORC1-dependent mitochondrial biogenesis and activity, which could result in a buildup of lipid intermediates that are known to trigger insulin resistance. We confirmed that rapamycin inhibits expression of PGC-1α, a key mitochondrial transcription factor, and acutely reduces respiration rate in myotubes. However, rapamycin did not stimulate phosphorylation of PKCθ, a central mediator of lipid-induced insulin resistance. Instead, we found dramatic disruption of mTORC2, which coincided with the onset of insulin resistance. Selective inhibition of mTORC1 or mTORC2 by shRNA-mediated knockdown of specific components (Raptor and Rictor, respectively confirmed that mitochondrial effects of rapamycin are mTORC1-dependent, whereas insulin resistance was recapitulated only by knockdown of mTORC2. Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo.

  3. Rapamycin-loaded Immunoliposomes Functionalized with Trastuzumab: A Strategy to Enhance Cytotoxicity to HER2-positive Breast Cancer Cells.

    Science.gov (United States)

    Eloy, Josimar O; Petrilli, Raquel; Brueggemeier, Robert W; Marchetti, Juliana Maldonado; Lee, Robert J

    2017-01-01

    Liposomes have been employed to improve pharmacokinetics and reduce side effects of drugs. They can be functionalized with antibodies for targeted delivery. While the monoclonal antibody trastuzumab has been employed in the therapy of HER2-positive breast cancer, the resistance developed during treatment has been reported. Rapamycin could be used in combination with trastuzumab for improved therapeutic response. In this study, we aimed to develop rapamycin-loaded liposomes and immunoliposomes with trastuzumab, characterize them and evaluate their in vitro cytotoxicity. Formulations were prepared by the thin film hydration method and immunoliposome was conjugated to antibody by covalent bond. Characterization involved particle size, polydispersity, zeta potential, encapsulation efficiency, functionalization efficiency, DSC and FTIR assays. Cell studies were conducted through the MTT assay. SPC:Chol:DSPE-PEG formulation prepared at 1:10 drug to lipid ratio presented high encapsulation efficiency, appropriate particle size, low polydispersity, negative zeta potential and colloidal stability. Rapamycin exhibited intermolecular interactions with lipids and underwent crystallinity reduction. Rapamycin-loaded immunoliposomes were prepared with high trastuzumab functionalization efficiency and antibody stability. Cytotoxicity studies showed that the HER2-positive SK-BR-3 cell line was sensitive to trastuzumab, either as free drug or in the context of immunoliposomes, and is more sensitive to rapamycin than the triple negative MDA-MB-231 cells. For MDA-MB-231, the liposomal rapamycin was more cytotoxic than the free drug. Furthermore, the immunoliposomes showed potent cytotoxicity against SK-BR-3 cells. Finally, rapamycin and trastuzumab exhibited in vitro synergistic effect, particularly through immunoliposomes. The formulation developed herein has potential for in vivo evaluation.

  4. Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.

    Directory of Open Access Journals (Sweden)

    Amy L Brewster

    Full Text Available Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1 pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.

  5. A controlled trial of the Litebook light-emitting diode (LED) light therapy device for treatment of Seasonal Affective Disorder (SAD)

    NARCIS (Netherlands)

    Desan, Paul H.; Weinstein, Andrea J.; Michalak, Erin E.; Tam, Edwin M.; Meesters, Ybe; Ruiter, Martine J.; Horn, Edward; Telner, John; Iskandar, Hani; Boivin, Diane B.; Lam, Raymond W.

    2007-01-01

    Background: Recent research has emphasized that the human circadian rhythm system is differentially sensitive to short wavelength light. Light treatment devices using efficient light-emitting diodes (LEDs) whose output is relatively concentrated in short wavelengths may enable a more convenient

  6. OP16, a novel ent-kaurene diterpenoid, potentiates the antitumor effect of rapamycin by inhibiting rapamycin-induced feedback activation of Akt signaling in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Peng, Ke-Zheng; Ke, Yu; Zhao, Qi; Tian, Fei; Liu, Hong-Min; Hou, Guiqin; Lu, Zhaoming

    2017-09-15

    Hyperactivation of mTOR signaling pathway has been viewed as a significant molecular pathogenesis of cancer. However, inhibition of mTOR by rapamycin and its analogs could induce numerous negative feedback loops to attenuate their therapeutic efficacy. As a traditional Chinese herbal medicine, Rabdosia rubescens has been used to treat esophageal squamous cell carcinoma (ESCC) for hundreds of years, and its major effective component is oridonin. Here we reported that OP16, a novel analog of oridonin, showed potent inhibition of cell proliferation and Akt phosphorylation in ESCC cells. The combination of OP16 and rapamycin possesses synergistic anti-proliferative and pro-apoptotic effects both in ESCC cells and ESCC xenografts, and no obvious adverse effect was observed in vivo. Mechanistic analysis revealed that OP16 could inhibit rapamycin-induced Akt activation through the p70S6K-mediated negative feedback loops, and the combination of OP16 and rapamycin was more effective in activating caspase-dependent apoptotic signaling cascade. This study supports the combined use of OP16 with rapamycin as a feasible and effective therapeutic approach for future treatment of ESCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Short-term effects of a peer co-led educational programme delivered before mental health treatment: A randomised controlled trial.

    Science.gov (United States)

    Lara-Cabrera, M L; Gjerden, M; Gråwe, R W; Linaker, O M; Steinsbekk, A

    2016-07-01

    To investigate the 1-month effects of an educational programme co-led by peers delivered before treatment on treatment preferences, self-management knowledge and motivation in comparison to usual care. Adults referred to a community mental health centre were randomised to either a control group (n=48) or a peer co-led educational programme (intervention group, n=45). The programme consisted of an 8-hour group education session followed by an individual pretreatment planning session. The main topics of the educational programme were treatment options, patients' rights, self-management, the importance of patient activation and participation. At 1-month follow-up, a significantly larger proportion of the patients in the intervention group knew which type of treatment they preferred (76.7% vs. 32.5%, pgroup had significantly higher self-management knowledge (pmotivation (p=0.543). At 1-month following the delivery of a pretreatment educational programme, we found that participants' knowledge of treatment preferences and self-management had improved. Educational interventions co-led by peers can optimise the process of informing and educating outpatients, thereby helping patients to clarify their treatment preferences. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  8. A brain proteomic investigation of rapamycin effects in the Tsc1+/- mouse model.

    Science.gov (United States)

    Wesseling, Hendrik; Elgersma, Ype; Bahn, Sabine

    2017-01-01

    Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1+/- mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. Molecular alterations in the frontal cortex and hippocampus of Tsc1+/- and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MSE) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. LC-MSE analysis of Tsc1+/- mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MSE analysis was also employed on Tsc1+/- and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1+/- mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found

  9. Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria.

    Science.gov (United States)

    Gordon, Emile B; Hart, Geoffrey T; Tran, Tuan M; Waisberg, Michael; Akkaya, Munir; Skinner, Jeff; Zinöcker, Severin; Pena, Mirna; Yazew, Takele; Qi, Chen-Feng; Miller, Louis H; Pierce, Susan K

    2015-06-02

    Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection

  10. Rapamycin Reduces Seizure Frequency in Tuberous Sclerosis Complex

    Science.gov (United States)

    Muncy, Jennifer; Butler, Ian J.; Koenig, Mary Kay

    2011-01-01

    The authors present a 10-year-old girl with tuberous sclerosis complex who has been receiving rapamycin for 10 months for seizure control. She was started at 0.05 mg/kg/d and titrated to an effective dose of 0.15 mg/kg/d. There was a dramatic reduction in seizure frequency with rapamycin therapy. Further studies are needed to objectively investigate the benefits of rapamycin in tuberous sclerosis complex and to clarify its mechanism of seizure control. PMID:19151365

  11. Rapamycin extends life- and health span because it slows aging.

    Science.gov (United States)

    Blagosklonny, Mikhail V

    2013-08-01

    Making headlines, a thought-provocative paper by Neff, Ehninger and coworkers claims that rapamycin extends life span but has limited effects on aging. How is that possibly possible? And what is aging if not an increase of the probability of death with age. I discuss that the JCI paper actually shows that rapamycin slows aging and also extends lifespan regardless of its direct anti-cancer activities. Aging is, in part, MTOR-driven: a purposeless continuation of developmental growth. Rapamycin affects the same processes in young and old animals: young animals' traits and phenotypes, which continuations become hyperfunctional, harmful and lethal later in life.

  12. Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells

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    Xiaodong Mu

    2013-01-01

    Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone. Mortality is determined by the presence of metastatic disease, but little is known regarding the biochemical events that drive metastases. Two murine OS cell lines, K7M2 and K12, are related but differ significantly in their metastatic potentials: K7M2 is highly metastatic whereas K12 displays much less metastatic potential. Using this experimental system, the mammalian target of rapamycin (mTOR pathway has been implicated in OS metastasis. We also discovered that aldehyde dehydrogenase (ALDH, a stem cell marker activity is higher in K7M2 cells than K12 cells. Rapamycin treatment reduces the expression and enzymatic activity of ALDH in K7M2 cells. ALDH inhibition renders these cells more susceptible to apoptotic death when exposed to oxidative stress. Furthermore, rapamycin treatment reduces bone morphogenetic protein-2 (BMP2 and vascular endothelial growth factor (VEGF gene expression and inhibits K7M2 proliferation, migration, and invasion in vitro. Inhibition of ALDH with disulfiram correlated with decreased mTOR expression and activity. In conclusion, we provide evidence for interaction between mTOR activity, ALDH activity, and metastatic potential in murine OS cells. Our work suggests that mTOR and ALDH are therapeutic targets for the treatment and prevention of OS metastasis.

  13. Effects of Rapamycin Combined with Low Dose Prednisone in Patients with Chronic Immune Thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Jiaming Li

    2013-01-01

    Full Text Available We conducted this randomized trial to investigate the efficacy and safety of rapamycin treatment in adults with chronic immune thrombocytopenia (ITP. Eighty-eight patients were separated into the control (cyclosporine A plus prednisone and experimental (rapamycin plus prednisone groups. The CD4+CD25+CD127low regulatory T (Treg cells level, Foxp3 mRNA expression, and the relevant cytokines levels were measured before and after treatment. The overall response (OR was similar in both groups (experimental group versus control group: 58% versus 62%, P=0.70. However, sustained response (SR was more pronounced in the experimental group than in the control group (68% versus 39%, P<0.05. Both groups showed similar incidence of adverse events (7% versus 11%, P=0.51. As expected, the low pretreatment baseline level of Treg cells was seen in all patients (P<0.001; however, the experimental group experienced a significant rise in Treg cell level, and there was a strong correlation between the levels of Treg cells and TGF-beta after the treatment. In addition, the upregulation maintained a stable level during the follow-up phase. Thus, rapamycin plus low dose prednisone could provide a new promising option for therapy of ITP.

  14. Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus.

    Science.gov (United States)

    Briggs, Joseph W; Ren, Ling; Chakrabarti, Kristi R; Tsai, Yien Che; Weissman, Allan M; Hansen, Ryan J; Gustafson, Daniel L; Khan, Yousuf A; Dinman, Jonathan D; Khanna, Chand

    2017-01-01

    Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.

  15. Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus.

    Directory of Open Access Journals (Sweden)

    Joseph W Briggs

    Full Text Available Activation of the unfolded protein response (UPR in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.

  16. Rapamycin Prolongs the Survival of Corneal Epithelial Cells in Culture

    OpenAIRE

    Sanaz Gidfar; Farnoud Y. Milani; Milani, Behrad Y.; Xiang Shen; Medi Eslani; Ilham Putra; Michael J. Huvard; Hossein Sagha; Djalilian, Ali R.

    2017-01-01

    Rapamycin has previously been shown to have anti-aging effects in cells and organisms. These studies were undertaken to investigate the effects of rapamycin on primary human corneal epithelial cells in vitro. Cell growth and viability were evaluated by bright field microscopy. Cell proliferation and cycle were evaluated by flow cytometry. The expression of differentiation markers was evaluated by quantitative PCR and Western blot. Senescence was evaluated by senescence-associated ?-Galactosid...

  17. Rapamycin promotes β-amyloid production via ADAM-10 inhibition

    Science.gov (United States)

    Zhang, Sheqing; Salemi, Jon; Hou, Huayan; Zhu, Yuyan; Mori, Takashi; Giunta, Brian; Obregon, Demian; Tan, Jun

    2010-01-01

    Rapamycin is a well known immunosuppressant drug for rejection prevention in organ transplantation. Numerous clinical trials using rapamycin analogs, involving both children and adults with various disorders are currently ongoing worldwide. Most recently, rapamycin gained much attention for what appears to be life-span extending properties when administered to mice. The risk for Alzheimer disease (AD) is strongly and positively correlated with advancing age and is characterized by deposition of β-amyloid peptides (Aβ) as senile plaques in the brain. We report that rapamycin (2.5 μM), significantly increases Aβ generation in murine neuron-like cells (N2a) transfected with the human “Swedish” mutant amyloid precursor protein (APP). In concert with these observations, we found rapamycin significantly decreases the neuroprotective amino-terminal APP (amyloid precursor protein) cleavage product, soluble APP-α (sAPP-α) while increasing production of the β-carboxyl-terminal fragment of APP (β-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate α-secretase which opposes Aβ generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Aβ-overproducing transgenic mice with rapamycin (3 mg/kg/day) for 2 weeks. We found increased Aβ levels associated with decreased sAPP-α at an average rapamycin plasma concentration of 169.7 ± 23.5 ng/mL by high performance liquid chromatography (HPLC). These data suggest that although rapamycin may increase the lifespan in some mouse models, it may not decrease the risk for age-associated neurodegenerative disorders such as AD. PMID:20542014

  18. Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol.

    Science.gov (United States)

    Kline, William O; Panaro, Frank J; Yang, Hayung; Bodine, Sue C

    2007-02-01

    Clenbuterol and other beta2-adrenergic agonists are effective at inducing muscle growth and attenuating muscle atrophy through unknown mechanisms. This study tested the hypothesis that clenbuterol-induced growth and muscle sparing is mediated through the activation of Akt and mammalian target of rapamycin (mTOR) signaling pathways. Clenbuterol was administered to normal weight-bearing adult rats to examine the growth-inducing effects and to adult rats undergoing muscle atrophy as the result of hindlimb suspension or denervation to examine the muscle-sparing effects. The pharmacological inhibitor rapamycin was administered in combination with clenbuterol in vivo to determine whether activation of mTOR was involved in mediating the effects of clenbuterol. Clenbuterol administration increased the phosphorylation status of PKB/Akt, S6 kinase 1/p70(s6k), and eukaryotic initiation factor 4E binding protein 1/PHAS-1. Clenbuterol treatment induced growth by 27-41% in normal rats and attenuated muscle loss during hindlimb suspension by 10-20%. Rapamycin treatment resulted in a 37-97% suppression of clenbuterol-induced growth and a 100% reduction of the muscle-sparing effect. In contrast, rapamycin was unable to block the muscle-sparing effects of clenbuterol after denervation. Clenbuterol was also shown to suppress the expression of the MuRF1 and MAFbx transcripts in muscles from normal, denervated, and hindlimb-suspended rats. These results demonstrate that the effects of clenbuterol are mediated, in part, through the activation of Akt and mTOR signaling pathways.

  19. Effects of blue diode laser (445 nm) and LED (430-480 nm) radiant heat treatments on dental glass ionomer restoratives

    Science.gov (United States)

    Dionysopoulos, Dimitrios; Tolidis, Kosmas; Strakas, Dimitrios; Gerasimou, Paris; Sfeikos, Thrasyvoulos; Gutknecht, Norbert

    2018-02-01

    The purpose of this in vitro study was to evaluate the effect of two radiant heat treatments on water sorption, solubility and surface roughness of three conventional glass ionomer cements by using a blue diode laser (445 nm) and a light emitting diode (LED) unit (430-480 nm). Thirty disk-shaped specimens were prepared for each tested GIC (Equia Fil, Ketac Universal Aplicap and Riva Self Cure). The experimental groups (n = 10) of the study were as follows: Group 1 was the control group, in Group 2 the specimens were irradiated for 60 s at the top surface using a LED light-curing unit and in Group 3 the specimens were irradiated for 60 s at the top surface using a blue light diode laser. Statistical analysis was performed using one-way ANOVA and Tukey post hoc tests at a level of significance of a = 0.05. Radiant heat treatments with both laser and LED devices significantly decreased water sorption and solubility (p 0.05). Among the tested materials there were differences in water sorption and solubility (p 0.05). The use of the blue diode laser for this radiant heat treatment was harmless for the surface of the tested GICs and may be advantageous for the longevity of their restorations.

  20. Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway.

    Science.gov (United States)

    Broekaart, Diede W M; van Scheppingen, Jackelien; Geijtenbeek, Karlijne W; Zuidberg, Mark R J; Anink, Jasper J; Baayen, Johannes C; Mühlebner, Angelika; Aronica, Eleonora; Gorter, Jan A; van Vliet, Erwin A

    2017-08-01

    Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. The expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post-SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug-resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures. In post-SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin-treated post-SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle-treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug-resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)-1β-induced (immuno)proteasome gene expression could be attenuated by rapamycin. Because dysregulation of the (immuno)proteasome system is observed before the occurrence of spontaneous seizures in rats, is associated with progression of epilepsy, and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy. Wiley Periodicals, Inc. © 2017

  1. Outcome of treatment seeking rural gamblers attending a nurse-led cognitive-behaviour therapy service: A pilot study

    Directory of Open Access Journals (Sweden)

    Barry Tolchard

    2016-03-01

    Conclusion: This study suggests that rural problem gamblers experience different levels of co-morbid anxiety and depression from their urban counterparts, but once in treatment appear to respond quicker. ACBT approach was found to be effective in treating rural gamblers and outcomes were maintained. Ensuring better availability and access to such treatment in rural areas is important. Nurses are in a position as the majority health professional in rural areas to provide such help.

  2. Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer.

    Science.gov (United States)

    Guilbert, Cynthia; Annis, Matthew G; Dong, Zhifeng; Siegel, Peter M; Miller, Wilson H; Mann, Koren K

    2013-01-01

    Inhibitors of the mammalian target of rapamycin (mTORi) have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs) may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways.

  3. Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer.

    Directory of Open Access Journals (Sweden)

    Cynthia Guilbert

    Full Text Available Inhibitors of the mammalian target of rapamycin (mTORi have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways.

  4. New dental applications with LEDs

    DEFF Research Database (Denmark)

    Argyraki, A.; Ou, Yiyu; Petersen, Paul Michael

    Visible and ultraviolet LEDs will in the future give rise to new dental applications. Fluorescence imaging, photodynamic therapy and photoactivated disinfection are important future candidates for diagnostics and treatment in dentistry.......Visible and ultraviolet LEDs will in the future give rise to new dental applications. Fluorescence imaging, photodynamic therapy and photoactivated disinfection are important future candidates for diagnostics and treatment in dentistry....

  5. Light Emitting Diode (LED)

    Science.gov (United States)

    1997-01-01

    A special lighting technology was developed for space-based commercial plant growth research on NASA's Space Shuttle. Surgeons have used this technology to treat brain cancer on Earth, in two successful operations. The treatment technique called photodynamic therapy, requires the surgeon to use tiny pinhead-size Light Emitting Diodes (LEDs) (a source releasing long wavelengths of light) to activate light-sensitive, tumor-treating drugs. Laser light has been used for this type of surgery in the past, but the LED light illuminates through all nearby tissues, reaching parts of a tumor that shorter wavelengths of laser light carnot. The new probe is safer because the longer wavelengths of light are cooler than the shorter wavelengths of laser light, making the LED less likely to injure normal brain tissue near the tumor. It can also be used for hours at a time while still remaining cool to the touch. The LED probe consists of 144 tiny pinhead-size diodes, is 9-inches long, and about one-half-inch in diameter. The small balloon aids in even distribution of the light source. The LED light source is compact, about the size of a briefcase, and can be purchased for a fraction of the cost of a laser. The probe was developed for photodynamic cancer therapy by the Marshall Space Flight Center under a NASA Small Business Innovative Research program grant.

  6. Light Emitting Diodes (LEDs)

    Science.gov (United States)

    1997-01-01

    A special lighting technology was developed for space-based commercial plant growth research on NASA's Space Shuttle. Surgeons have used this technology to treat brain cancer on Earth, in two successful operations. The treatment technique, called Photodynamic Therapy, requires the surgeon to use tiny, pinhead-size Light Emitting Diodes (LEDs) (a source that releases long wavelengths of light ) to activate light-sensitive, tumor-treating drugs. 'A young woman operated on in May 1999 has fully recovered with no complications and no evidence of the tumor coming back,' said Dr. Harry Whelan, a pediatric neurologist at the Medical Hospital of Wisconsin in Milwaukee. Laser light has been used for this type of surgery in the past, but the LED light illuminates through all nearby tissues, reaching parts of a tumor that shorter wavelengths of laser light carnot. The new probe is safer because the longer wavelengths of light are cooler than the shorter wavelengths of laser light, making the LED less likely to injure normal brain tissue near the tumor. It can be used for hours at a time while still remaining cool to the touch. The LED light source is compact, about the size of a briefcase, and can be purchased for a fraction of the cost of a laser. The LEDs, developed and managed by NASA's Marshall Space Flight Center, have been used on seven Space Shuttle flights inside the Microgravity Astroculture Facility. This technology has also been successfully used to further commercial research in crop growth.

  7. Whey Protein Concentrate Renders MDA-MB-231 Cells Sensitive to Rapamycin by Altering Cellular Redox State and Activating GSK3β/mTOR Signaling.

    Science.gov (United States)

    Cheng, Shih-Hsuan; Tseng, Yang-Ming; Wu, Szu-Hsien; Tsai, Shih-Meng; Tsai, Li-Yu

    2017-11-21

    Whey protein concentrate (WPC) is an amino acid-rich supplement that has been shown to increase cellular antioxidant capacity. Mammalian target of rapamycin (mTOR) is a crucial regulator of signaling in mammalian cells, and serves as a therapeutic target for triple-negative breast cancer (TNBC). This study was designed to investigate the effect of combining WPC with rapamycin on MDA-MB-231 human breast cancer cells. These cells were found to be insensitive to rapamycin and exhibited higher glutathione (GSH) and reactive oxygen species levels than non-tumorigenic MCF-10A cells. However, for MDA-MB-231 cells, the half maximal inhibitory concentration of rapamycin was lower when this drug was administered in combination with WPC than when used alone. Furthermore, combining WPC with rapamycin depleted GSH levels and reduced Nrf2 nuclear accumulation. In addition, WPC activated GSK3β/mTOR signaling, and GSK3β appeared to be involved in the WPC-mediated Nrf2 reduction and mTOR activation. In conclusion, WPC induced rapamycin sensitivity in MDA-MB-231 cells by altering their redox state and activating GSK3β/mTOR signaling. These results not only suggest a novel therapeutic approach for breast cancer treatment, but also provide insight into the critical pathways affecting the resistance to mTOR inhibition observed in a subgroup of TNBC patients.

  8. Integrated aerobic biological-chemical treatment of winery wastewater diluted with urban wastewater. LED-based photocatalysis in the presence of monoperoxysulfate.

    Science.gov (United States)

    Solís, Rafael R; Rivas, Francisco Javier; Ferreira, Leonor C; Pirra, Antonio; Peres, José A

    2018-01-28

    The oxidation of Winery Wastewater (WW) by conventional aerobic biological treatment usually leads to inefficient results due to the presence of organic substances, which are recalcitrant or toxic in conventional procedures. This study explores the combination of biological and chemical processes in order to complete the oxidation of biodegradable and non-biodegradable compounds in two sequential steps. Thus, a biological oxidation of a diluted WW is carried out by using the activated sludge process. Activated sludge was gradually acclimated to the Diluted Winery Wastewater (DWW). Some aspects concerning the biological process were evaluated (kinetics of the oxidation and sedimentation of the sludge produced). The biological treatment of the DWW led to a 40-50% of Chemical Oxygen Demand (COD) removal in 8 h, being necessary the application of an additional process. Different chemical processes combining UVA-LEDs radiation, monoperoxysulfate (MPS) and photocatalysts were applied in order to complete the COD depletion and efficient removal of polyphenols content, poorly oxidized in the previous biological step. From the options tested, the combination of UVA, MPS and a novel LaCoO 3 -TiO 2 composite, with double route of MPS decomposition through heterogeneous catalysis and photocatalysis, led to the best results (95% of polyphenol degradation, and additional 60% of COD removal). Initial MPS concentration and pH effect in this process were assessed.

  9. Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide

    Science.gov (United States)

    Akinci, Baris; Sankella, Shireesha; Gilpin, Christopher; Ozono, Keiichi; Garg, Abhimanyu; Agarwal, Anil K.

    2017-01-01

    Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with a homozygous null mutation in ZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near-normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed a lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from a single RD patient's fibroblasts also suggest that prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype. PMID:28050601

  10. Balloon Coating with Rapamycin Using an On-site Coating Device

    Energy Technology Data Exchange (ETDEWEB)

    Schmehl, Joerg, E-mail: joerg.schmehl@med.uni-tuebingen.de [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Ruhr, Juergen von der [Institute of Anatomy, University of Tuebingen (Germany); Dobratz, Markus; Kehlbach, Rainer [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Braun, Isabelle [Translumina GmbH (Germany); Greiner, Tim-Oliver [Clinic of Thoracic and Cardiovascular Surgery, University Hospital of Tuebingen (Germany); Claussen, Claus D. [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Behnisch, Boris [Translumina GmbH (Germany)

    2013-06-15

    Purpose. The efficacy of drug-eluting balloons has been demonstrated in clinical trials. The drug predominantly used is paclitaxel because of its lipophilic properties and the rapid onset of action. The aim of the investigation was to evaluate the feasibility and efficacy of an alternative balloon coating with rapamycin that can be applied on site.MethodsThe balloon coating (3.0/18 and 3.0/12 mm, Cathy No. 4, Translumina GmbH) with rapamycin was conducted with a coating machine (Translumina GmbH). Concentrations were 2, 2 Multiplication-Sign 2, 3, and 4 %. Measurements regarding the amount of substance released to the vessel wall were carried out on explanted porcine coronaries by means of ultraviolet and visible-light spectroscopy. Inflation time varied between 30 and 120 s. The biological effect of the coating was evaluated in a porcine peripheral overstretch and stent implantation model. Results. The amount of rapamycin on the balloon surface ranged from 558 {+-} 108 {mu}g for the 2 % solution to 1,441 {+-} 228 {mu}g in the 4 % solution. An amount of 95 {+-} 63-193 {+-} 113 {mu}g was released into the vessel wall. The quantitative measurements of the angiographic examinations 4 weeks after treatment revealed a reduction of diameter stenosis from 20.6 {+-} 17.4 % in the control group to 11.6 {+-} 5.5 % in the drug-eluting balloon group. Conclusion. A balloon coating with rapamycin omitting an excipient is possible with a dose-adjustable coating machine. However, the biological effects are moderate, which make further optimization of the coating process and evaluation of appropriate excipients necessary.

  11. Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin.

    Science.gov (United States)

    Biswas, Moanaro; Rogers, Geoffrey L; Sherman, Alexandra; Byrne, Barry J; Markusic, David M; Jiang, Haiyan; Herzog, Roland W

    2017-01-05

    Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses. Additionally, it extensively characterises the role of the IgG backbone in B cell depletion by anti-CD20 antibodies. For this, inhibitors were generated in BALB/c-HA mice by weekly IV injection of FVIII. Subsequently, anti-mCD20 (18B12) with IgG2a or IgG1 backbone was injected IV in two doses three weeks apart and B cell depletion and recovery was characterised. Rapamycin was administered orally 3x/week (for 1 month) while continuing FVIII injections. Altering the IgG backbone of anti-mCD20 from IgG2a to IgG1 reduced overall depletion of B cells (including memory B cells), and marginal zone, B-10, and B-1b cells were specifically unaffected. While neither antibody was effective alone, in combination with rapamycin, anti-mCD20 IgG2a but not IgG1 was able to reverse inhibitors in HA mice. This regimen was particularly effective for starting titres of ~10 BU. Although IgG1 anti-mCD20 spared potentially tolerogenic B cell subsets, IgG2a directed sustained hyporesponsiveness when administered in conjunction with rapamycin. This regimen represents a promising treatment for inhibitor reversal in HA, as both of these compounds have been extensively used in human patients.

  12. The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation.

    Directory of Open Access Journals (Sweden)

    Tomohiro Okamoto

    Full Text Available The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and induction of inflammatory cytokines, such as interleukin-6 (IL-6 and monocyte chemoattractant protein-1 (MCP-1, and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3, which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-κB activation, mTOR inhibition suppressed NF-κB activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF-κB in the retina. In addition, the inhibition of NF-κB suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-κB during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin

  13. Online, social media and mobile technologies for psychosis treatment: a systematic review on novel user-led interventions.

    Science.gov (United States)

    Alvarez-Jimenez, M; Alcazar-Corcoles, M A; González-Blanch, C; Bendall, S; McGorry, P D; Gleeson, J F

    2014-06-01

    Internet and mobile-based interventions provide a unique opportunity to deliver cost-effective, accessible, time-unlimited support to people with psychosis. The aims of this study were to systematically compile and analyze the evidence on the acceptability, feasibility, safety and benefits of online and mobile-based interventions for psychosis. Systematic review of peer-reviewed studies examining the usability, acceptability, feasibility, safety or efficacy of user-led, Internet or mobile-based interventions, with at least 80% of participants diagnosed with schizophrenia-spectrum disorders. Of 38 potentially relevant articles, 12 were eligible for inclusion. Interventions included web-based psycho-education; web-based psycho-education plus moderated forums for patients and supporters; integrated web-based therapy, social networking and peer and expert moderation; web-based CBT; personalized advice based on clinical monitoring; and text messaging interventions. Results showed that 74-86% of patients used the web-based interventions efficiently, 75-92% perceived them as positive and useful, and 70-86% completed or were engaged with the interventions over the follow-up. Preliminary evidence indicated that online and mobile-based interventions show promise in improving positive psychotic symptoms, hospital admissions, socialization, social connectedness, depression and medication adherence. Internet and mobile-based interventions for psychosis seem to be acceptable and feasible and have the potential to improve clinical and social outcomes. The heterogeneity, poor quality and early state of current research precludes any definite conclusions. Future research should investigate the efficacy of online and mobile interventions through controlled, well-powered studies, which investigate intervention and patient factors associated with take-up and intervention effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Effect of a Cooling Step Treatment on a High-Voltage GaN LED During ICP Dry Etching

    Science.gov (United States)

    Lin, Yen-Sheng; Hsiao, Sheng-Yu; Tseng, Chun-Lung; Shen, Ching-Hsing; Chiang, Jung-Sheng

    2017-02-01

    In this study, a lower dislocation density for a GaN surface and a reduced current path are observed at the interface of a SiO2 isolation sidewall, using high-resolution transmission electron microscopy. This is grown using a 3-min cooling step treatment during inductivity coupled plasma dry etching. The lower forward voltage is measured, the leakage current decreases from 53nA to 32nA, and the maximum output power increases from 354.8 W to 357.2 W for an input current of 30 mA. The microstructure and the optoelectronic properties of high-voltage light-emitting-diodes is proven to be affected by the cooling step treatment, which allows enough time to release the thermal energy of the SiO2 isolation well.

  15. Fracture resistance of endodontically-treated teeth submitted to bleaching treatment with hydrogen peroxide and titanium dioxide nanoparticles photoactivated by LED-laser

    Directory of Open Access Journals (Sweden)

    Keren Cristina JORDÃO-BASSO

    Full Text Available Objective: The aim of this study was evaluate the fracture resistance of endodontically-treated teeth after bleaching treatment using 15% hydrogen peroxide plus titanium dioxide nanoparticles (15HPTiO2 photoactivated by LED-laser, in comparison with protocols using 35% hydrogen peroxide (35HP, 37% carbamide peroxide (37CP or sodium perborate (SP. Material and method: After endodontic treatment, fifty bovine extracted incisors were divided into five groups (n = 10: G1- without bleaching; G2- 35HP; G3- 37CP; G4- 15HPTiO2 photoactivated by LED-laser and G5- SP. In G2 and G4, the bleaching protocol was applied in 4 sessions, with a 7 day interval between each session. In G3 and G5, the materials were kept in the pulp chamber for 21 days, but replaced every 7 days. After 21 days, the crowns were subjected to compressive load at a cross head speed of 0.5 mm/min, applied at 135° to the long axis of the root using an eletromechanical testing machine, until fracture. The data were submitted to ANOVA and Tukey tests (p = 0.05. Result: The bleaching treatment in endodontically-treated teeth with 15HP plus TiO2 nanoparticles and photoactivated by LED-laser caused reduction of the fracture resistance similarly provided by 35HP, 37CP or SP (p>0.05. All bleaching treatments reduced the fracture resistance compared to unbleached teeth (p<0.05. Conclusion: All bleaching protocols reduced the fracture resistance of endodontically-treated teeth, but there were no differences between each other.

  16. Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT

    Directory of Open Access Journals (Sweden)

    Guadalupe Tirma González-Mateo

    2015-01-01

    Full Text Available Preservation of peritoneal membrane (PM is essential for long-term survival in peritoneal dialysis (PD. Continuous presence of PD fluids (PDF in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT and endothelial-to-mesenchymal transition (Endo-MT seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group. Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-β, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT.

  17. Target of rapamycin activation predicts lifespan in fruit flies.

    Science.gov (United States)

    Scialò, Filippo; Sriram, Ashwin; Naudí, Alba; Ayala, Victoria; Jové, Mariona; Pamplona, Reinald; Sanz, Alberto

    2015-01-01

    Aging and age-related diseases are one of the most important health issues that the world will confront during the 21(st) century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory.

  18. A controlled trial of the Litebook light-emitting diode (LED light therapy device for treatment of Seasonal Affective Disorder (SAD

    Directory of Open Access Journals (Sweden)

    Telner John

    2007-08-01

    Full Text Available Abstract Background Recent research has emphasized that the human circadian rhythm system is differentially sensitive to short wavelength light. Light treatment devices using efficient light-emitting diodes (LEDs whose output is relatively concentrated in short wavelengths may enable a more convenient effective therapy for Seasonal Affective Disorder (SAD. Methods The efficacy of a LED light therapy device in the treatment of SAD was tested in a randomized, double-blind, placebo-controlled, multi-center trial. Participants aged 18 to 65 with SAD (DSM-IV major depression with seasonal pattern were seen at Baseline and Randomization visits separated by 1 week, and after 1, 2, 3 and 4 weeks of treatment. Hamilton Depression Rating Scale scores (SIGH-SAD were obtained at each visit. Participants with SIGH-SAD of 20 or greater at Baseline and Randomization visits were randomized to active or control treatment: exposure to the Litebook LED treatment device (The Litebook Company Ltd., Alberta, Canada which delivers 1,350 lux white light (with spectral emission peaks at 464 nm and 564 nm at a distance of 20 inches or to an inactivated negative ion generator at a distance of 20 inches, for 30 minutes a day upon awakening and prior to 8 A.M. Results Of the 26 participants randomized, 23 completed the trial. Mean group SIGH-SAD scores did not differ significantly at randomization. At trial end, the proportions of participants in remission (SIGH-SAD less than 9 were significantly greater (Fisher's exact test, and SIGH-SAD scores, as percent individual score at randomization, were significantly lower (t-test, with active treatment than with control, both in an intent-to-treat analysis and an observed cases analysis. A longitudinal repeated measures ANOVA analysis of SIGH-SAD scores also indicated a significant interaction of time and treatment, showing superiority of the Litebook over the placebo condition. Conclusion The results of this pilot study support

  19. A controlled trial of the Litebook light-emitting diode (LED) light therapy device for treatment of Seasonal Affective Disorder (SAD).

    Science.gov (United States)

    Desan, Paul H; Weinstein, Andrea J; Michalak, Erin E; Tam, Edwin M; Meesters, Ybe; Ruiter, Martine J; Horn, Edward; Telner, John; Iskandar, Hani; Boivin, Diane B; Lam, Raymond W

    2007-08-07

    Recent research has emphasized that the human circadian rhythm system is differentially sensitive to short wavelength light. Light treatment devices using efficient light-emitting diodes (LEDs) whose output is relatively concentrated in short wavelengths may enable a more convenient effective therapy for Seasonal Affective Disorder (SAD). The efficacy of a LED light therapy device in the treatment of SAD was tested in a randomized, double-blind, placebo-controlled, multi-center trial. Participants aged 18 to 65 with SAD (DSM-IV major depression with seasonal pattern) were seen at Baseline and Randomization visits separated by 1 week, and after 1, 2, 3 and 4 weeks of treatment. Hamilton Depression Rating Scale scores (SIGH-SAD) were obtained at each visit. Participants with SIGH-SAD of 20 or greater at Baseline and Randomization visits were randomized to active or control treatment: exposure to the Litebook LED treatment device (The Litebook Company Ltd., Alberta, Canada) which delivers 1,350 lux white light (with spectral emission peaks at 464 nm and 564 nm) at a distance of 20 inches or to an inactivated negative ion generator at a distance of 20 inches, for 30 minutes a day upon awakening and prior to 8 A.M. Of the 26 participants randomized, 23 completed the trial. Mean group SIGH-SAD scores did not differ significantly at randomization. At trial end, the proportions of participants in remission (SIGH-SAD less than 9) were significantly greater (Fisher's exact test), and SIGH-SAD scores, as percent individual score at randomization, were significantly lower (t-test), with active treatment than with control, both in an intent-to-treat analysis and an observed cases analysis. A longitudinal repeated measures ANOVA analysis of SIGH-SAD scores also indicated a significant interaction of time and treatment, showing superiority of the Litebook over the placebo condition. The results of this pilot study support the hypothesis that light therapy with the Litebook is an

  20. Efficacy of Polyphenon E, Red Ginseng, and Rapamycin on Benzo(apyrene-Induced Lung Tumorigenesis in A/J Mice

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    Ying Yan

    2006-01-01

    Full Text Available The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(apyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity × tumor volume in a dose-dependent fashion. Polyphenon E (2% wt/wt in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.

  1. Investigation of Ni/Ag contact to p-GaN with an O{sub 2} plasma treatment and its application to GaN-based LEDs

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Nan-Ming [Department of Materials Science and Engineering, Institute of Nanotechnology and Microsystems Engineering, National Cheng Kung University, Tainan 701 (China); Shei, Shih-Chang [Department of Electrical Engineering, National University of Tainan, Tainan 700 (China); Chang, Shoou-Jinn [Department of Materials Science and Engineering, Institute of Nanotechnology and Microsystems Engineering, National Cheng Kung University, Tainan 701 (China); Department of Electrical Engineering, Institute of Microelectronics, Advanced Optoelectronic Technology Center, Center for Micro/Nano Science and Technology, National Cheng Kung University, Tainan 701 (China)

    2012-08-15

    In this paper, the contact structure of Ni-Ag/p-GaN with different O{sub 2} plasma treatment times for 1 and 5 min was utilized for investigation. From experimental results, the Ni-Ag contact to p-GaN with different O{sub 2} plasma treatment for 1 and 5 min reveals Schottky behaviors. Based on the variation of the specific contact resistance with respect to temperature, the dominant transport mechanism of Ni-Ag/p-GaN structure presented form thermionic emission to field emission as increasing time from 1 to 5 min. From the X-ray photoelectron spectroscopy (XPS) results, the increase of the N vacancies and antisite defects (O{sub N}) would enhance the resistance of the treated p-GaN underneath the contact, which would make the Ni-Ag/p-GaN contact reveal Schottky behavior. With a 20 mA current injection, the operation voltage of light-emitting diodes (LEDs) with Ni/Ag contact to p-GaN through O{sub 2} plasma treatment 400 W-5 min was 3.13 V larger than the LEDs with Ni/Ag contact to p-GaN through O{sub 2} plasma treatment 400 W-1 min. This is due to the larger specific contact resistance. The 3.13 V operation voltage is still good and acceptable. Furthermore, the largest output power among all devices can be achieved. Besides, the reliability is still good. (Copyright copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  2. Bone growth during rapamycin therapy in young rats

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    He Yu-Zhu

    2009-01-01

    Full Text Available Abstract Background Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties. Methods Weanling three week old rats were given rapamycin at 2.5 mg/kg daily by gavage for 2 or 4 weeks and compared to a Control group given equivalent amount of saline. Morphometric measurements and biochemical determinations for serum calcium, phosphate, iPTH, urea nitrogen, creatinine and insulin-growth factor I (IGF-I were obtained. Histomorphometric analysis of the growth plate cartilage, in-situ hybridization experiments and immunohistochemical studies for various proteins were performed to evaluate for chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption. Results At the end of the 2 weeks, body and tibia length measurements were shorter after rapamycin therapy associated with an enlargement of the hypertrophic zone in the growth plate cartilage. There was a decrease in chondrocyte proliferation assessed by histone-4 and mammalian target of rapamycin (mTOR expression. A reduction in parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP and an increase in Indian hedgehog (Ihh expression may explain in part, the increase number of hypertrophic chondrocytes. The number of TRAP positive multinucleated chondro/osteoclasts declined in the chondro-osseous junction with a decrease in the receptor activator of nuclear factor kappa β ligand (RANKL and vascular endothelial growth factor (VEGF expression. Although body and tibial length remained short after 4 weeks of rapamycin, changes in the expression of chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption which were significant after 2 weeks of rapamycin improved at the end of 4 weeks. Conclusion When given to young rats, 2 weeks of rapamycin

  3. Mammalian target of rapamycin activity is required for expansion of CD34(+) hematopoietic progenitor cells

    NARCIS (Netherlands)

    Geest, Christian R.; Zwartkruis, Fried J.; Vellenga, Edo; Coffer, Paul J.; Buitenhuis, Miranda

    Background The mammalian target of rapamycin is a conserved protein kinase known to regulate protein synthesis, cell size and proliferation. Aberrant regulation of mammalian target of rapamycin activity has been observed in hematopoietic malignancies, including acute leukemias and myelodysplastic

  4. Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

    NARCIS (Netherlands)

    Geest, C.R.; Zwartkruis, G.J.T.; Vellenga, E.; Coffer, P.J.; Buitenhuis, M.

    2009-01-01

    Background The mammalian target of rapamycin is a conserved protein kinase known to regulate protein synthesis, cell size and proliferation. Aberrant regulation of mammalian target of rapamycin activity has been observed in hematopoietic malignancies, including acute leukemias and

  5. The effect of rapamycin on biodiesel-producing protist Euglena gracilis.

    Science.gov (United States)

    Mukaida, Shiho; Ogawa, Takumi; Ohishi, Kazuko; Tanizawa, Yasuhiro; Ohta, Daisaku; Arita, Masanori

    2016-06-01

    Rapamycin induces autophagy with lipid remodeling in yeast and mammalian cells. To investigate the lipid biosynthesis of Euglena gracilis, rapamycin was supplemented in comparison with two model algae, Chlamydomonas reinhardtii and Cyanidioschyzon merolae. In Euglena, rapamycin induced the reduction of chlorophylls and the accumulation of neutral lipids without deterring its cell proliferation. Its lipidomic profile revealed that the fatty acid composition did not alter by supplementing rapamycin. In Chlamydomonas, however, rapamycin induced serious growth inhibition as reported elsewhere. With a lower concentration of rapamycin, the alga accumulated neutral lipids without reducing chlorophylls. In Cyanidioschyzon, rapamycin did not increase neutral lipids but reduced its chlorophyll content. We also tested fatty acid elongase inhibitors such as pyroxasulfone or flufenacet in Euglena with no significant change in its neutral lipid contents. In summary, controlled supplementation of rapamycin can increase the yield of neutral lipids while the scheme is not always applicable for other algal species.

  6. Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis

    NARCIS (Netherlands)

    Ai, Ding; Jiang, Hongfeng; Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Ganda, Anjali; Abramowicz, Sandra; Welch, Carrie; Almazan, Felicidad; Zhu, Yi; Miller, Yury I.; Tall, Alan R.

    2014-01-01

    The mammalian target of rapamycin complex 1 inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma low-density lipoprotein levels. This suggests an antiatherogenic effect possibly mediated by the modulation of inflammatory responses in atherosclerotic plaques.

  7. Giant bilateral renal angiomyolipomas and lymphangioleiomyomatosis presenting after two successive pregnancies successfully treated with surgery and rapamycin.

    Science.gov (United States)

    Peces, Ramón; Cuesta-López, Emilio; Peces, Carlos; Selgas, Rafael

    2011-01-01

    We report the case of a 25-year-old woman who presented with abdominal and flank pain with two successive pregnancies and was diagnosed of giant bilateral renal AMLs and pulmonary LAM associated with TSC in the post-partum of her second pregnancy. This case illustrates that in women with TSC rapid growth from renal AMLs and development of LAM may occur with successive pregnancies. It also stresses the potential for preservation of renal function despite successive bilateral renal surgery of giant AMLs. Moreover, the treatment with a low-dose rapamycin may be an option for LAM treatment. Finally, a low-dose rapamycin may be considered as an adjuvant treatment together to kidney-sparing conservative surgery for renal AMLs.

  8. Giant Bilateral Renal Angiomyolipomas and Lymphangioleiomyomatosis Presenting after Two Successive Pregnancies Successfully Treated with Surgery and Rapamycin

    Directory of Open Access Journals (Sweden)

    Ramón Peces

    2011-01-01

    Full Text Available We report the case of a 25-year-old woman who presented with abdominal and flank pain with two successive pregnancies and was diagnosed of giant bilateral renal AMLs and pulmonary LAM associated with TSC in the post-partum of her second pregnancy. This case illustrates that in women with TSC rapid growth from renal AMLs and development of LAM may occur with successive pregnancies. It also stresses the potential for preservation of renal function despite successive bilateral renal surgery of giant AMLs. Moreover, the treatment with a low-dose rapamycin may be an option for LAM treatment. Finally, a low-dose rapamycin may be considered as an adjuvant treatment together to kidney-sparing conservative surgery for renal AMLs.

  9. Sex-specific Tradeoffs With Growth and Fitness Following Life-span Extension by Rapamycin in an Outcrossing Nematode, Caenorhabditis remanei.

    Science.gov (United States)

    Lind, Martin I; Zwoinska, Martyna K; Meurling, Sara; Carlsson, Hanne; Maklakov, Alexei A

    2016-07-01

    Rapamycin inhibits the nutrient-sensing TOR pathway and extends life span in a wide range of organisms. Although life-span extension usually differs between the sexes, the reason for this is poorly understood. Because TOR influences growth, rapamycin likely affects life-history traits such as growth and reproduction. Sexes have different life-history strategies, and theory predicts that they will resolve the tradeoffs between growth, reproduction, and life span differently. Specifically, in taxa with female-biased sexual size dimorphism, reduced growth may have smaller effects on male fitness. We investigated the effects of juvenile, adult, or life-long rapamycin treatment on growth, reproduction, life span, and individual fitness in the outcrossing nematode Caenorhabditis remanei Life-long exposure to rapamycin always resulted in the strongest response, whereas postreproductive exposure did not affect life span. Although rapamycin resulted in longer life span and smaller size in males, male individual fitness was not affected. In contrast, size and fitness were negatively affected in females, whereas life span was only extended under high rapamycin concentrations. Our results support the hypothesis that rapamycin affects key life-history traits in a sex-specific manner. We argue that the fitness cost of life-span extension will be sex specific and propose that the smaller sex generally pay less while enjoying stronger life-span increase. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin signaling pathway mediates contractility of human endometriotic stromal cells: A promising new target for the treatment of endometriosis-associated fibrosis

    Directory of Open Access Journals (Sweden)

    Wakana Abe

    2014-11-01

    Conclusion: The current findings suggest that the PI3K-Akt-mTOR signaling pathway is involved in the development of endometriosis-associated fibrosis. The PI3K-Akt-mTOR signaling pathway is a promising target for the treatment of endometriosis.

  11. Inhibition of mammalian target of rapamycin by rapamycin increases the radiosensitivity of esophageal carcinoma Eca109 cells

    OpenAIRE

    ZHANG, DEJUN; XIANG, JIE; GU, YUMING; XU, WEI; XU, HAO; ZU, MAOHENG; PEI, DONGSHENG; ZHENG, JUNNIAN

    2014-01-01

    The aim of the present study was to investigate whether radiation induces the mammalian target of rapamycin (Rap) (mTOR) signaling pathway in esophageal carcinoma Eca109 cells, and whether mTOR inhibition by rapamycin increases Eca109 cell radiosensitivity. Changes in the levels of mTOR signaling pathway and DNA damage-repair proteins in Eca109 cells prior to and following radiation were determined. The Eca109 cells were treated with Rap (0, 100, 200 and 400 nmol/l) in combination with radiat...

  12. Differing Effects of Systemically Administered Rapamycin on Consolidation and Reconsolidation of Context vs. Cued Fear Memories

    Science.gov (United States)

    Glover, Ebony M.; Ressler, Kerry J.; Davis, Michael

    2010-01-01

    Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) kinase, has attracted interest as a possible prophylactic for post-traumatic stress disorder (PTSD)-associated fear memories. We report here that although rapamycin (40 mg/kg, i.p.) disrupted the consolidation and reconsolidation of fear-potentiated startle paradigm to a…

  13. Fototerapia (LEDs 660/890nm no tratamento de úlceras de perna em pacientes diabéticos: estudo de caso Phototherapy (LEDs 660/890nm in the treatment of leg ulcers in diabetic patients: case study

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    Débora Garbin Minatel

    2009-07-01

    Full Text Available Avaliou-se a fototerapia na cicatrização de úlceras de perna (UP mistas em dois pacientes diabéticos (tipo 2, hipertensos. O aparelho apresentava sonda 1 (S1 (1 LED de 660nm, 5mW aplicado em 3 UP e sonda 2 (S2 (32 LEDs de 890nm e 4 LEDs de 660nm, 500mW em 6 UP. Após antissepsia,úlceras foram tratadas com sondas a 3J/cm2, 30seg, 2x/semana seguido pelo curativo diário com sulfadiazina de prata a 1% por 12 semanas. Pela análise com software Image J®, as UP com S2 tiveram índices de cicatrização médios de 0,6; 0,7 e 0,9 enquanto S1 foi de 0,2; 0,4 e 0,6 no 30º, 60º e 90º dias, respectivamente. A fototerapia acelerou a cicatrização das úlceras de perna em pacientes diabéticos.This study evaluated the use of phototherapy in the healing of mixed leg ulcers in two diabetic patients (type 2 with arterial hypertension. The device had probe 1 (one 660nm LED, 5mW applied in 3 ulcers and probe 2 (32 890nm LEDs associated with 4 660nm LEDs, 500mW in 6 ulcers. After asepsis, ulcers were treated with probes to 3 J/cm2, 30sec per point, twice a week, followed by topical daily dressing with 1% silver sulphadiazine during 12 weeks. The following analyses of ulcers with software Image J showed that probe 2 presented mean healing rates of 0.6; 0.7 and 0.9, whereas probe 1 had 0.2;0.4 and 0.6 at 30, 60 and 90 days, espectively. Phototherapy accelerated wound healing of leg ulcers in diabetic patients.

  14. Effects of Cyclosporine, Tacrolimus, and Rapamycin on Osteoblasts.

    Science.gov (United States)

    Martín-Fernández, M; Rubert, M; Montero, M; de la Piedra, C

    2017-11-01

    One factor that can contribute to severe bone loss after transplantation is the direct action of immunosuppressants on bone cells. The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on the release of three local factors directly implicated in bone-remodeling regulation and apoptosis of human osteoblasts: interleukin (IL)-6, osteoprotegerin, and receptor activator of nuclear factor κβ (RANKL). Human osteoblasts were obtained from five different patients who underwent orthopedic surgery. These cells were treated with what are considered to be a clinically high dose and an acceptable dose of each immunosuppressant-RAPA 50 ng/mL and 12 ng/mL, FK-506 20 ng/mL and 5 ng/mL, CsA 1000 ng/mL and 250 ng/mL-or vehicle. Apoptotic cell death was quantified using flow cytometry of DNA content in permeabilized, propidium iodide-stained cells. IL-6 was measured using enzyme-linked immunosorbent assay (ELISA; Quantikine Human IL6, R&D Systems, Minneapolis, Minn, United States). Messenger RNA (mRNA) expression of osteoprotegerin, RANKL, and IL-6 was measured using quantitative RT-PCR. A significant increase in IL-6 (mRNA and released protein) was observed in the presence of FK-506 and RAPA. Addition of RAPA to the cultures of osteoblasts produced a significant increase in the OPG/RANKL ratio. A significant increase in osteoblast apoptosis was observed in the cells treated with FK-506 and RAPA 24 hours after the addition of immunosuppressants. CsA did not produce any significant changes in osteoblasts. These results suggest that an increase in osteoblast apoptosis by osteoblasts may be one of the mechanisms by which bone loss occurs after RAPA and FK-506 treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Mammalian target of rapamycin inhibitor-associated stomatitis

    NARCIS (Netherlands)

    Boers-Doets, Christine B.; Raber-Durlacher, Judith E.; Treister, Nathaniel S.; Epstein, Joel B.; Arends, Anniek B. P.; Wiersma, Diede R.; Lalla, Rajesh V.; Logan, Richard M.; van Erp, Nielka P.; Gelderblom, Hans

    2013-01-01

    With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR

  16. Rapamycin alleviates oxidative stress-induced damage in rat erythrocytes.

    Science.gov (United States)

    Singh, Abhishek Kumar; Singh, Sandeep; Garg, Geetika; Rizvi, Syed Ibrahim

    2016-10-01

    An imbalanced cellular redox system promotes the production of reactive oxygen species (ROS) that may lead to oxidative stress-mediated cell death. Erythrocytes are the best-studied model of antioxidant defense mechanism. The present study was undertaken to investigate the effect of the immunosuppressant drug rapamycin, an inducer of autophagy, on redox balance of erythrocytes and blood plasma of oxidatively challenged rats. Male Wistar rats were oxidatively challenged with HgCl2 (5 mg/kg body mass (b.m.)). A significant (p membrane redox system (PMRS), intracellular Ca2+ influx, lipid peroxidation (LPO), osmotic fragility, plasma protein carbonyl (PCO) content, and plasma advanced oxidation protein products (AOPP) and simultaneously significant reduction in glutathione (GSH) level and ferric reducing ability of plasma (FRAP) were observed in rats exposed to HgCl2. Furthermore, rapamycin (0.5 mg/kg b.m.) provided significant protection against HgCl2-induced alterations in rat erythrocytes and plasma by reducing ROS production, PMRS activity, intracellular Ca2+ influx, LPO, osmotic fragility, PCO content, and AOPP and also restored the level of antioxidant GSH and FRAP. Our observations provide evidence that rapamycin improves redox status and attenuates oxidative stress in oxidatively challenged rats. Our data also demonstrate that rapamycin is a comparatively safe immunosuppressant drug.

  17. Photobiomodulation versus light-emitting diode (LED) therapy in the treatment of temporomandibular disorder: study protocol for a randomized, controlled clinical trial.

    Science.gov (United States)

    Langella, Luciana G; Silva, Paula F C; Costa-Santos, Larissa; Gonçalves, Marcela L L; Motta, Lara J; Deana, Alessandro M; Fernandes, Kristianne P S; Mesquita-Ferrari, Raquel A; Bussadori, Sandra Kalil

    2018-01-26

    Temporomandibular disorder (TMD) is described as a subgroup of orofacial pain with a set of signs and symptoms that involve the temporomandibular joint, masticatory muscles, ears, and neck. TMD can occur unilaterally or bilaterally and approximately 70% of the population is affected with at least one sign. The disorder progresses with orofacial pain, muscle pain involving the masticatory and cervical muscles, joint noises (clicks and pops), joint block, mandibular dysfunction, and headache. The etiology can be abnormal occlusion and/or posture, trauma involving local tissues, repetitive microtrauma, parafunctional habits, and an increase in emotional stress. Studies have demonstrated that phototherapy is an efficient option for the treatment of TMD, leading to improvements in pain and orofacial function. The aim of the proposed study is to compare the effects of two sources of photobiomodulation in individuals with TMD. A randomized, controlled, double-blind, clinical trial is proposed, which will involve 80 individuals aged 18-65 years allocated to either a laser group or light-emitting diode (LED) group submitted to 12 sessions of phototherapy. The Research Diagnostic Criteria for TMDs will be used to evaluate all participants. Pain will be measured using the visual analog scale and maximum vertical mandibular movement will be determined with the aid of digital calipers. This study compares the effects of two modalities of laser therapy on the pain and orofacial function of patients with TMD dysfunction. Photobiomodulation and LED therapy are treatment options for reducing the inflammatory process and pain as well as inducing the regeneration of the target tissue. ClinicalTrials.gov, NCT03257748 . Registered on 8 August 2017.

  18. Truth Telling and Treatment Strategies in End-of-Life Care in Physician-Led Accountable Care Organizations: Discrepancies Between Patients' Preferences and Physicians' Perceptions.

    Science.gov (United States)

    Huang, Hsien-Liang; Cheng, Shao-Yi; Yao, Chien-An; Hu, Wen-Yu; Chen, Ching-Yu; Chiu, Tai-Yuan

    2015-04-01

    Providing patient-centered care from preventive medicine to end-of-life care in order to improve care quality and reduce medical cost is important for accountable care. Physicians in the accountable care organizations (ACOs) are suitable for participating in supportive end-of-life care especially when facing issues in truth telling and treatment strategy. This study aimed to investigate patients' attitudes toward truth telling and treatment preferences in end-of-life care and compare patients' attitudes with their ACOs physicians' perceptions.This nationwide study applied snowball sampling to survey physicians in physician-led ACOs and their contracted patients by questionnaire from August 2010 to July 2011 in Taiwan. The main outcome measures were beliefs about palliative care, attitudes toward truth telling, and treatment preferences.The data of 314 patients (effective response rate = 88.7%) and 177 physicians (88.5%) were analyzed. Regarding truth telling about disease prognosis, 94.3% of patients preferred to be fully informed, whereas only 80% of their physicians had that perception (P truth telling even when encountering terminal disease status (98.1% vs 85.3%). Regarding treatment preferences in terminal illness, nearly 90% of patients preferred supportive care, but only 15.8% of physicians reported that their patients had this preference (P truth telling and treatment strategies in end-of-life care. It is important to enhance physician-patient communication about end-of-life care preferences in order to achieve the goal of ACOs. Continuing education on communication about end-of-life care during physicians' professional development would be helpful in the reform strategies of establishing accountable care around the world.

  19. Rapamycin attenuates BAFF-extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B-lymphoid cells.

    Science.gov (United States)

    Zeng, Qingyu; Qin, Shanshan; Zhang, Hai; Liu, Beibei; Qin, Jiamin; Wang, Xiaoxue; Zhang, Ruijie; Liu, Chunxiao; Dong, Xiaoqing; Zhang, Shuangquan; Huang, Shile; Chen, Long

    2018-01-01

    B cell activating factor from the TNF family (BAFF) stimulates B-cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)-stimulated B-cell proliferation/survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF-promoted B cell proliferation/survival is also related to blocking hsBAFF-stimulated phosphorylation of Akt, S6K1, and 4E-BP1, as well as expression of survivin in normal and B-lymphoid (Raji and Daudi) cells. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor or rictor enhanced rapamycin's suppression of hsBAFF-induced survivin expression and proliferation/viability in B cells. Also, PP242, an mTORC1/2 kinase inhibitor, repressed survivin expression, and cell proliferation/viability more potently than rapamycin (mTORC1 inhibitor) in B cells in response to hsBAFF. Of interest, ectopic expression of constitutively active Akt (myr-Akt) or constitutively active S6K1 (S6K1-ca), or downregulation of 4E-BP1 conferred resistance to rapamycin's attenuation of hsBAFF-induced survivin expression and B-cell proliferation/viability, whereas overexpression of dominant negative Akt (dn-Akt) or constitutively hypophosphorylated 4E-BP1 (4EBP1-5A), or downregulation of S6K1, or co-treatment with Akt inhibitor potentiated the inhibitory effects of rapamycin. The findings indicate that rapamycin attenuates excessive hsBAFF-induced cell proliferation/survival via blocking mTORC1/2 signaling in normal and neoplastic B-lymphoid cells. Our data underscore that rapamycin may be a potential agent for preventing excessive BAFF-evoked aggressive B-cell malignancies and autoimmune diseases. © 2017 Wiley Periodicals, Inc.

  20. THE EFFECT OF RAPAMYCIN ON SECRETORY ACTIVITY OF THE RABBIT OVARIAN FRAGMENTS

    Directory of Open Access Journals (Sweden)

    Sushmita Nath

    2012-02-01

    Full Text Available The aim of our study was to examine the effect of rapamycin on secretory activity of the rabbit ovarian fragments. The secretion of steroid (progesterone, testosterone, estradiol and peptide (prolactine hormones by ovarian fragments after rapamycin addition at the doses 0, 1, 10, 100 μg.ml-1 was determined. Fragments were incubated with rapamycin for 48 hours. Hormones were determinated by RIA. The experimental data showed that, addition of rapamycin did not affect progesterone and prolactine release (at all doses. Estradiol secretion was inhibited by rapamycin at the doses of 1, 10 and 100 μg.ml-1. Testosterone was inhibited by the rapamycin at the doses of 1 and 10 μg.ml-1 but not at 100 μg.ml-1. In conclusion, our results suggest a direct effect of rapamycin on ovarian functionsand a possible involvement in the regulation of steroidogenesis.

  1. Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications.

    Science.gov (United States)

    Lieberthal, Wilfred; Levine, Jerrold S

    2012-07-15

    The mTOR pathway plays an important role in a number of common renal diseases, including acute kidney injury (AKI), diabetic nephropathy (DN), and polycystic kidney diseases (PKD). The activity of mTOR complex 1 (mTORC1) is necessary for renal regeneration and repair after AKI, and inhibition of mTORC1 by rapamycin has been shown to delay recovery from ischemic AKI in animal studies, and to prolong delayed graft function in humans who have received a kidney transplant. For this reason, administration of rapamycin should be delayed or discontinued in patients with AKI until full recovery of renal function has occurred. On the other hand, inappropriately high mTORC1 activity contributes to the progression of the metabolic syndrome, the development of type 2 diabetes, and the pathogenesis of DN. In addition, chronic hyperactivity of mTORC1, and possibly also mTORC2, contributes to cyst formation and enlargement in a number of forms of PKD. Inhibition of mTOR, using either rapamycin (which inhibits predominantly mTORC1) or "catalytic" inhibitors (which effectively inhibit both mTORC1 and mTORC2), provide exciting possibilities for novel forms of treatment of DN and PKD. In this second part of the review, we will examine the role of mTOR in the pathophysiology of DN and PKD, as well as the potential utility of currently available and newly developed inhibitors of mTOR to slow the progression of DN and/or PKD.

  2. The Effect of Different Dosing Schedules of Intravitreal Sirolimus, a Mammalian Target of Rapamycin (mTOR) Inhibitor, in the Treatment of Non-Infectious Uveitis (An American Ophthalmological Society Thesis).

    Science.gov (United States)

    Nguyen, Quan Dong; Sadiq, Mohammad Ali; Soliman, Mohamed Kamel; Agarwal, Aniruddha; Do, Diana V; Sepah, Yasir J

    2016-08-01

    To determine if two different doses of intravitreal sirolimus, an mTOR inhibitor, can decrease inflammation and is safe in eyes with non-infectious posterior, intermediate, or panuveitis in the Sirolimus as a Therapeutic Approach UVEitis: Protocol-2 (SAVE-2) Study. SAVE-2 is a prospective randomized, phase II, open-label interventional clinical trial conducted at 4 clinical centers in the United States. Eligible subjects were randomized into one of two treatments. Group 1 received 440µg of intravitreal sirolimus in study eyes on days 0, 30, 60, 90, 120, and 150; group 2 received 880µg of intravitreal sirolimus on days 0, 60, and 120. Fellow eyes were also eligible to receive sirolimus (of opposite dose to that of study eye). Primary endpoint of the study was at month 6 (M6). 24 subjects have been randomized in SAVE-2 and are included in the analysis. Vitreous haze decreased by ≥2 steps in 63.6% and 50% of patients in groups 1 and 2, respectively at M6 (p=0.695). Mean change in best-corrected visual acuity for subjects was +3.66 and -2.91 ETDRS letters in group 1 and 2, respectively. Among subjects with macular edema at baseline (n=13), the mean change in foveal thickness was -89.42µm in group 1 and +81.5µm in group 2 at M6. Both low and high doses of intravitreal sirolimus were found to decrease vitreous haze in eyes with non-infectious uveitis. Low dose (440µg) sirolimus administered monthly may be more efficacious in reducing uveitic macular edema than high dose (880µg) administered every 2 months.

  3. The effect of varying LED light sources and influent carbon/nitrogen ratios on treatment of synthetic sanitary sewage using Chlorella vulgaris.

    Science.gov (United States)

    Xu, Bing; Cheng, Pu; Yan, Cheng; Pei, Haiyan; Hu, Wenrong

    2013-07-01

    Sanitary sewage can create serious environmental problems if discharged directly into natural waters without appropriate treatment. This study showed that red light is the optimum light wavelength for growing microalgae Chlorella vulgaris in microalgae biological wastewater treatment systems, given a harvest time of 144 h. Only moderate light intensities (1,000, 1,500, 2,000, and 2,500 μmol m(-2) s(-1)) were able to remove nutrients from synthetic sanitary sewage, but higher light intensity led to better nutrient removal effects. Because of economic considerations, the optimum light intensity range for efficient nutrient removal was determined to be between 1,500 and 2,000 μmol m(-2) s(-1). Furthermore, nutrient removal efficiency was significantly affected by light wavelength, light intensity, the interaction of these two factors, and the interaction among light wavelength, light intensity, and influent carbon/nitrogen (C/N) ratios. Total nitrogen and total phosphorus removal efficiency was also significantly affected by influent C/N ratios. Appropriate control of carbon and nitrogen source concentrations enabled optimal nutrient removal. The optimal influent C/N ratio was determined to be 6:1.

  4. Cargo and Carrier Effects of Rapamycin-Loaded Perfluorocarbon Nanoparticles

    Science.gov (United States)

    Bibee, Kristin Page

    Nanoparticle-based drug delivery has been championed as a means to increase local delivery of therapeutics while decreasing systemic drug exposure. By targeting the particles, and therefore the drugs, to diseased cells of interest, healthy cells will be spared and side effects avoided. This delivery mechanism would be particularly useful for drugs that interfere with cell growth and proliferation pathways, as blocking proliferation in normal cells leads to significant patient morbidity. Rapamycin is a macrolide and a known inhibitor of mTORC1, a protein complex that plays a crucial role in protein translation and cell growth. This work demonstrates the effects of rapamycin complexed with a nanoparticle carrier on two distinct pathologies: a new triple negative breast cancer cell line and a conventional mouse model of muscular dystrophy (mdx). Rapamycin is able to alter mitochondrial function and thus metabolism in both free and nanoparticle-delivered form without killing the cells. Although nanoparticles are considered to be a benign carrier, this work shows that perfluorocarbon nanoparticles are able to induce autophagy in vitro. The benefits of autophagy induction in cancer cells is cell and stage specific, but has been reported to be useful for radiosensitization of triple negative breast cancers. Additionally, the particles are shown to induce autophagy in the mdx model of Duchenne Muscular Dystrophy and, when loaded with rapamycin, dramatically improve strength even in older animals with muscular dystrophy. Overall, this work enhances our understanding of the cellular effects of perfluorocarbon nanoparticles in two different disease models and enhances prospects for clinical translation of nanoparticle-based drug delivery.

  5. Targeting mTOR with rapamycin: One dose does not fit all

    Science.gov (United States)

    Foster, David A.; Toschi, Alfredo

    2009-01-01

    A puzzling aspect of rapamycin-based therapeutic strategies is the wide disparity in the doses needed to suppress mTOR under different circumstances. A recent study revealing mechanistically how rapamycin suppresses mTOR provides two explanations for the differential sensitivities to rapamycin. First, mTOR exists as two functionally distinct complexes (mTORC1 and mTORC2), and while rapamycin suppresses both, it does so at very different concentrations. Whereas mTORC1 is suppressed by concentrations of rapamycin in the low nM range, mTORC2 generally requires low μM concentrations. Second, the efficacy of rapamycin is dependent on the level of phosphatidic acid (PA), which is required for the assembly of both mTORC1 and mTORC2 complexes. Rapamycin interacts with mTOR in a manner that is competitive with PA. Therefore, elevated levels of PA, which is common in cancer cells, increases the level of rapamycin needed to suppress both mTORC1 and mTORC2. A practical outcome of the recent study is that if PA levels are suppressed, mTORC2 becomes sensitive to concentrations of rapamycin that can be achieved clinically. Since mTORC2 is likely more critical for survival signals in cancer cells, the recent findings suggest new strategies for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells. PMID:19270529

  6. LEDs for greenhouse lighting

    OpenAIRE

    Nederhoff, E.M.

    2010-01-01

    Light Emitting Diodes (LED's) are a promising technology for greenhouse lighting with their efficiency to activate plant photosynthesis potentially higher in red LEDs than in HPS lamps. Due to their particular light colour, LEDs can initiate special effects in plants or steer plant processes and plant balance

  7. LEDs for greenhouse lighting

    NARCIS (Netherlands)

    Nederhoff, E.M.

    2010-01-01

    Light Emitting Diodes (LED's) are a promising technology for greenhouse lighting with their efficiency to activate plant photosynthesis potentially higher in red LEDs than in HPS lamps. Due to their particular light colour, LEDs can initiate special effects in plants or steer plant processes and

  8. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue.

    Science.gov (United States)

    Jin, Xiaoguang; Dai, Huaping; Ding, Ke; Xu, Xuefeng; Pang, Baosen; Wang, Chen

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic. There is no effective therapy except for lung transplantation. Rapamycin is an immunosuppressive drug with potent antifibrotic activity. The purpose of this study was to examine the effects of rapamycin on bleomycin-induced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model. Rapamycin was given at a dose of 0.5 mg/kg per gavage, beginning one day before bleomycin instillation and once daily until animal sacrifice. Ten rats in each group were sacrificed at 3, 7, 14, 28 and 56 days after bleomycin administration. Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System. Type I and III collagen fibers were identified by Picro-sirius-polarization. Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay, MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin. Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days. The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P pulmonary fibrosis, which is associated with decreased expression of MMP-9 and TIMP-1.

  9. Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

    Directory of Open Access Journals (Sweden)

    Tillmanns Harald H

    2007-02-01

    Full Text Available Abstract Background Chronic hypoxia induces pulmonary arterial hypertension (PAH. Smooth muscle cell (SMC proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA, a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. Methods Mice were held either at normoxia (N; 21% O2 or at hypobaric hypoxia (H; 0.5 atm; ~10% O2. RAPA-treated animals (3 mg/kg*d, i.p. were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel. The ratio of right ventricle to left ventricle plus septum (RV/[LV+S] was used to determine right ventricular hypertrophy. Results Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38 compared to N (median: 0.28, p = 0.028 which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003. H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N to 139 (H, p Conclusion Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.

  10. Mesangial Cell Mammalian Target of Rapamycin Complex 1 Activation Results in Mesangial Expansion.

    Science.gov (United States)

    Nagai, Kojiro; Tominaga, Tatsuya; Ueda, Sayo; Shibata, Eriko; Tamaki, Masanori; Matsuura, Motokazu; Kishi, Seiji; Murakami, Taichi; Moriya, Tatsumi; Abe, Hideharu; Doi, Toshio

    2017-10-01

    Human glomerular diseases can be caused by several different diseases, many of which include mesangial expansion and/or proliferation followed by glomerulosclerosis. However, molecular mechanisms underlying the pathologic mesangial changes remain poorly understood. Here, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1)-S6 kinase pathway in mesangial expansion and/or proliferation by ablating an upstream negative regulator, tuberous sclerosis complex 1 (TSC1), using tamoxifen-induced Foxd1-Cre mice [Foxd1ER(+) TSC1 mice]. Foxd1ER(+) TSC1 mice showed mesangial expansion with increased production of collagen IV, collagen I, and α-smooth muscle actin in glomeruli, but did not exhibit significant mesangial proliferation or albuminuria. Furthermore, rapamycin treatment of Foxd1ER(+) TSC1 mice suppressed mesangial expansion. Among biopsy specimens from patients with glomerular diseases, analysis of phosphorylated ribosomal protein S6 revealed mesangial cell mTORC1 activation in IgA nephropathy and in lupus mesangial proliferative nephritis but not in the early phase of diabetic nephropathy. In summary, mesangial cell mTORC1 activation can cause mesangial expansion and has clinical relevance for human glomerular diseases. This report also confirms that the tamoxifen-induced mesangium-specific Cre-loxP system is useful for studies designed to clarify the role of the mesangium in glomerular diseases in adults. Copyright © 2017 by the American Society of Nephrology.

  11. A central role for the mammalian target of rapamycin in LPS-induced anorexia in mice.

    Science.gov (United States)

    Yue, Yunshuang; Wang, Yi; Li, Dan; Song, Zhigang; Jiao, Hongchao; Lin, Hai

    2015-01-01

    Bacterial lipopolysaccharide (LPS), also known as endotoxin, induces profound anorexia. However, the LPS-provoked pro-inflammatory signaling cascades and the neural mechanisms underlying the development of anorexia are not clear. Mammalian target of rapamycin (mTOR) is a key regulator of metabolism, cell growth, and protein synthesis. This study aimed to determine whether the mTOR pathway is involved in LPS-induced anorexia. Effects of LPS on hypothalamic gene/protein expression in mice were measured by RT-PCR or western blotting analysis. To determine whether inhibition of mTOR signaling could attenuate LPS-induced anorexia, we administered an i.c.v. injection of rapamycin, an mTOR inhibitor, on LPS-treated male mice. In this study, we showed that LPS stimulates the mTOR signaling pathway through the enhanced phosphorylation of mTOR(Ser2448) and p70S6K(Thr389). We also showed that LPS administration increased the phosphorylation of FOXO1(Ser256), the p65 subunit of nuclear factor kappa B (Panorexia by decreasing the phosphorylation of p70S6K(Thr389), FOXO1(Ser256), and FOXO1/3a(Thr) (24) (/) (32). These results suggest promising approaches for the prevention and treatment of LPS-induced anorexia. © 2015 Society for Endocrinology.

  12. Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF

    Science.gov (United States)

    Medici, Damian; Olsen, Bjorn R.

    2012-01-01

    Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas. PMID:22900063

  13. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF.

    Directory of Open Access Journals (Sweden)

    Damian Medici

    Full Text Available Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF signaling through VEGF receptor 2 (VEGFR2. Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1. VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas.

  14. Potential use of rapamycin in HIV infection

    DEFF Research Database (Denmark)

    Donia, Marco; McCubrey, James A; Bendtzen, Klaus

    2010-01-01

    replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood......, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV-1 infection.......The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies...

  15. LED-roulette : LED's vervangen balletje

    NARCIS (Netherlands)

    Goossens, P.

    2007-01-01

    Iedereen waagt wel eens een gokje, in een loterij of misschien ook in een casino. Wie droomt er immers niet van om op een gemakkelijke manier rijk te worden? Met de hier beschreven LED-roulette valt weliswaar weinig te winnen, maar het is wel een uitstekende manier om het roulettespel thuis te

  16. Have Changes in Treatment of Late-detected Developmental Dysplasia of the Hip During the Last Decades Led to Better Radiographic Outcome?

    Science.gov (United States)

    Terjesen, Terje; Horn, Joachim

    2016-05-01

    Despite considerable changes in the treatment of of late-detected congenital or developmental hip dislocation (DDH) during the last 50 years, it is unclear whether and to what degree these changes have led to better long-term outcome for the patients. The aims of this study were to see whether decreasing use of skin traction and instead a more aggressive approach to open reduction resulted in (1) reduced use of secondary procedures; (2) improved radiographic appearance of the hips at long-term followup; and (3) changes in the proportion of patients developing avascular necrosis. Two groups of patients were compared retrospectively. Inclusion criteria were patient age older than 3 months and younger than 5 years at the initiation of treatment, no associated anomaly, no previous treatment in other hospitals, and available radiographs from the time of diagnosis to skeletal maturity. Group A consisted of 56 patients (51 girls [91%]; 74 hips) primarily treated during the period 1958 to 1962. Group B comprised 38 patients (36 girls [95%]; 40 hips) treated during the period 1996 to 2002. The mean age at the time of hip reduction was 20 months (SD 9.6) in Group A and 17 months (SD 11.9) in Group B. The mean time in skin traction had decreased from 35 days (SD 12.5) to 11 days (SD 5.7) over the years (p skeletal maturity, the proportion of patients with satisfactory radiographic results (Severin Grades I/II) was larger in Group B (33 of 40 hips [82%]) than in Group A (46 of 74 hips [62%]; OR, 0.35; CI, 0.14-0.89; p = 0.025). Femoral head coverage, assessed as the center-edge angle, was greater in Group B than in Group A (mean 26° versus 22°; CI, 0.8-7.9; p = 0.016). There was no difference in the proportion of avascular necrosis of the femoral head (seven of 74 hips [9%] in Group A and five of 40 [13%] in Group B; OR, 1.4; CI, 0.4-4.6; p = 0.614). The move away from prolonged use of skin traction and toward more frequent open reduction for children with a late diagnosis

  17. Mycophenolate Mofetil and Rapamycin Induce Apoptosis in the Human Monocytic U937 Cell Line Through Two Different Pathways.

    Science.gov (United States)

    Nowak, Maxime; Tardivel, Sylviane; Nguyen-Khoa, Thao; Abreu, Sonia; Allaoui, Fatima; Fournier, Natalie; Chaminade, Pierre; Paul, Jean-Louis; Lacour, Bernard

    2017-10-01

    Transplant vasculopathy may be considered as an accelerated form of atherosclerosis resulting in chronic rejection of vascularized allografts. After organ transplantation, a diffuse intimal thickening is observed, leading to the development of an atherosclerosis plaque due to a significant monocyte infiltration. This results from a chronic inflammatory process induced by the immune response. In this study, we investigated the impact of two immunosuppressive drugs used in therapy initiated after organ transplantation, mycophenolate mofetil, and rapamycin, on the apoptotic response of monocytes induced or not by oxidized LDL. Here we show the pro-apoptotic effect of these two drugs through two distinct signaling pathways and we highlight a synergistic effect of rapamycin on apoptosis induced by oxidized LDL. In conclusion, since immunosuppressive therapy using mycophenolate mofetil or rapamycin can increase the cell death in a monocyte cell line, this treatment could exert similar effects on human monocytes in transplant patients, and thus, prevent transplant vasculopathy, atherosclerosis development, and chronic allograft rejection. J. Cell. Biochem. 118: 3480-3487, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Autophagy is required for extension of yeast chronological life span by rapamycin

    Science.gov (United States)

    Alvers, Ashley L.; Wood, Michael S.; Hu, Doreen; Kaywell, Amelia C.; Dunn, William A.; Aris, Jhon P.

    2013-01-01

    Rapamycin is an antibiotic that stimulates autophagy in a wide variety of eukaryotes, including the budding yeast Saccharomyces cerevisiae. Low concentrations of rapamycin extend yeast chronological life span (CLS). We have recently shown that autophagy is required for chronological longevity in yeast, which is attributable in part to a role for autophagy in amino acid homeostasis. We report herein that low concentrations of rapamycin stimulate macroautophagy during chronological aging and extend CLS. PMID:19458476

  19. Broadband Radiometric LED Measurements.

    Science.gov (United States)

    Eppeldauer, G P; Cooksey, C C; Yoon, H W; Hanssen, L M; Podobedov, V B; Vest, R E; Arp, U; Miller, C C

    2016-01-01

    At present, broadband radiometric measurements of LEDs with uniform and low-uncertainty results are not available. Currently, either complicated and expensive spectral radiometric measurements or broadband photometric LED measurements are used. The broadband photometric measurements are based on the CIE standardized V(λ) function, which cannot be used in the UV range and leads to large errors when blue or red LEDs are measured in its wings, where the realization is always poor. Reference irradiance meters with spectrally constant response and high-intensity LED irradiance sources were developed here to implement the previously suggested broadband radiometric LED measurement procedure [1, 2]. Using a detector with spectrally constant response, the broadband radiometric quantities of any LEDs or LED groups can be simply measured with low uncertainty without using any source standard. The spectral flatness of filtered-Si detectors and low-noise pyroelectric radiometers are compared. Examples are given for integrated irradiance measurement of UV and blue LED sources using the here introduced reference (standard) pyroelectric irradiance meters. For validation, the broadband measured integrated irradiance of several LED-365 sources were compared with the spectrally determined integrated irradiance derived from an FEL spectral irradiance lamp-standard. Integrated responsivity transfer from the reference irradiance meter to transfer standard and field UV irradiance meters is discussed.

  20. Broadband Radiometric LED Measurements

    Science.gov (United States)

    Eppeldauer, G. P.; Cooksey, C. C.; Yoon, H. W.; Hanssen, L. M.; Podobedov, V. B.; Vest, R. E.; Arp, U.; Miller, C. C.

    2017-01-01

    At present, broadband radiometric measurements of LEDs with uniform and low-uncertainty results are not available. Currently, either complicated and expensive spectral radiometric measurements or broadband photometric LED measurements are used. The broadband photometric measurements are based on the CIE standardized V(λ) function, which cannot be used in the UV range and leads to large errors when blue or red LEDs are measured in its wings, where the realization is always poor. Reference irradiance meters with spectrally constant response and high-intensity LED irradiance sources were developed here to implement the previously suggested broadband radiometric LED measurement procedure [1, 2]. Using a detector with spectrally constant response, the broadband radiometric quantities of any LEDs or LED groups can be simply measured with low uncertainty without using any source standard. The spectral flatness of filtered-Si detectors and low-noise pyroelectric radiometers are compared. Examples are given for integrated irradiance measurement of UV and blue LED sources using the here introduced reference (standard) pyroelectric irradiance meters. For validation, the broadband measured integrated irradiance of several LED-365 sources were compared with the spectrally determined integrated irradiance derived from an FEL spectral irradiance lamp-standard. Integrated responsivity transfer from the reference irradiance meter to transfer standard and field UV irradiance meters is discussed. PMID:28649167

  1. Dansk LED - Museumsbelysning

    DEFF Research Database (Denmark)

    Poulsen, Peter Behrensdorff; Dam-Hansen, Carsten; Thorseth, Anders

    Projektet har til formål at anvende dansk forskning inden for optik og lys til at realisere innovative energieffektive LED lyssystemer til museumsbranchen.......Projektet har til formål at anvende dansk forskning inden for optik og lys til at realisere innovative energieffektive LED lyssystemer til museumsbranchen....

  2. Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

    Directory of Open Access Journals (Sweden)

    Scott M. Filippone

    2017-01-01

    Full Text Available Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg or DMSO (7.5% was injected intracardially at the onset of reperfusion. Post-I/R survival (87% and cardiac function (fractional shortening, FS: 28.63±3.01% were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4±2.6%. Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2±2.2% and apoptosis (2.87±0.64% as compared to DMSO-treated mice (IS: 47.0±2.3%; apoptosis: 7.39±0.81%. Rapamycin induced phosphorylation of AKT S473 (target of mTORC2 but abolished ribosomal protein S6 phosphorylation (target of mTORC1 after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.

  3. The post-therapeutic effect of rapamycin in mild traumatic brain-injured rats ensuing in the upregulation of autophagy and mitophagy.

    Science.gov (United States)

    Wang, Changxing; Hu, Zhiying; Zou, Yang; Xiang, Mingjun; Jiang, Yuting; Botchway, Benson O A; Huo, Xue; Du, Xiaoxue; Fang, Marong

    2017-09-01

    Mild traumatic brain injury (mTBI), common in juveniles, has been reported to be caused by sports-related concussion. Many young children may suffer from post-concussion syndrome. mTBI, in early stages of life, could play a part in neuron apoptosis and degeneration, cognitive and motor coordination impairment, as well as dementia. Our study was aimed at further investigating the post-therapeutic efficacy of rapamycin in the recuperation of mTBI while at the same time investigating the metamorphosis in both autophagy and mitophagy in mTBI. We created a weight-drop rat mTBI model with the administration of rapamycin at 4 h after every mTBI. Behavioral tests of beam walking and open field task indicated the expected improvement of cognitive and motor coordination functions. Both Western blot and immunofluorescence examinations revealed increased Beclin-1 and PINK1 in the treated rats as well as reduction of caspase-3 and cytochrome C (Cyt C). More so, the TUNEL staining evidenced curtailment of apoptotic cells following treatment with rapamycin. The upregulation of Beclin-1 and PINK1 and the downregulation of caspase-3 and Cyt C extrapolate that rapamycin plays neuroprotective as well as anti-apoptotic role via interposition of both autophagy and mitophagy. © 2017 International Federation for Cell Biology.

  4. Long-Term Alcohol-Induced Activation of Mammalian Target of Rapamycin is a Key Risk Factor of Epilepsy.

    Science.gov (United States)

    Fu, Xiaoling; Guo, Zhe; Gao, Chang; Chu, Qinying; Li, Jianhua; Ma, Hongying; Shu, Gangming

    2016-10-25

    BACKGROUND The aim of this study was to determine whether activation of mammalian target of rapamycin (mTOR) is a key epileptogenic mechanism in the development of alcohol-related seizure. MATERIAL AND METHODS C57BL/6 mice were administered 10% ethanol in drinking water for 9 weeks. Video-electroencephalography (EEG) monitoring was then used to assess seizure frequency after alcohol and rapamycin treatment. In addition, mouse neuroblastoma NG108-15 cells were treated ethanol for 3 days and subsequently treated with AKT inhibitor LY294002 for 2-12 h. The in vitro kinase assay was performed for determining mTOR activity. Western blot analysis was used to determine the expression of P-AKT, P-S6K, and P-S6. RESULTS Long-term ethanol treatment markedly increased the seizure frequency of C57/BL6 mice over time. Moreover, ethanol treatment increased the expression level of P-S6 over time. Ethanol-induced seizure can be reversed by rapamycin. In addition, the in vitro kinase assay showed mTOR activity was activated by ethanol. Compared with NG108-15 cells treated without both ethanol and LY294002, ethanol increased the expression level of P-AKT, P-S6K, and P-S6, whereas LY294002 had opposite effects on expression levels of these proteins. CONCLUSIONS Our findings indicate that long-term alcohol intake increases the risk of epilepsy via activation of mTOR signaling. Moreover, ethanol-induced mTOR activation may be dependent on the AKT-mTOR signaling pathway. The key molecules involved in AKT-mTOR signaling pathway may serve as potential targets in the treatment of epilepsy.

  5. Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex

    Directory of Open Access Journals (Sweden)

    Franz DN

    2013-10-01

    Full Text Available David Neal Franz Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Abstract: Tuberous sclerosis complex (TSC is an autosomal dominant genetic disorder caused by inactivating mutations in either the TSC1 or TSC2 genes. It is characterized by the development of multiple, benign tumors in several organs throughout the body. Lesions occur in the brain, kidneys, heart, liver, lungs, and skin and result in seizures and epilepsy, mental retardation, autism, and renal and pulmonary organ system dysfunction, as well as other complications. Elucidation of the molecular pathways and etiological factors responsible for causing TSC has led to a paradigm shift in the management and treatment of the disease. TSC1 or TSC2 mutations lead to constitutive upregulation of the mammalian target of rapamycin pathway, which affects many cellular processes involved in tumor growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma and renal manifestations (angiomyolipoma associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma. Keywords: everolimus, subependymal giant cell astrocytoma, angiomyolipomas, lymphangioleiomyomatosis, facial angiofibromas, tuberous sclerosis complex

  6. Large area LED package

    Science.gov (United States)

    Goullon, L.; Jordan, R.; Braun, T.; Bauer, J.; Becker, F.; Hutter, M.; Schneider-Ramelow, M.; Lang, K.-D.

    2015-03-01

    Solid state lighting using LED-dies is a rapidly growing market. LED-dies with the needed increasing luminous flux per chip area produce a lot of heat. Therefore an appropriate thermal management is required for general lighting with LEDdies. One way to avoid overheating and shorter lifetime is the use of many small LED-dies on a large area heat sink (down to 70 μm edge length), so that heat can spread into a large area while at the same time light also appears on a larger area. The handling with such small LED-dies is very difficult because they are too small to be picked with common equipment. Therefore a new concept called collective transfer bonding using a temporary carrier chip was developed. A further benefit of this new technology is the high precision assembly as well as the plane parallel assembly of the LED-dies which is necessary for wire bonding. It has been shown that hundred functional LED-dies were transferred and soldered at the same time. After the assembly a cost effective established PCB-technology was applied to produce a large-area light source consisting of many small LED-dies and electrically connected on a PCB-substrate. The top contacts of the LED-dies were realized by laminating an adhesive copper sheet followed by LDI structuring as known from PCB-via-technology. This assembly can be completed by adding converting and light forming optical elements. In summary two technologies based on standard SMD and PCB technology have been developed for panel level LED packaging up to 610x 457 mm2 area size.

  7. Surface Engineering of Porous Silicon Microparticles for Intravitreal Sustained Delivery of Rapamycin

    OpenAIRE

    Nieto, Alejandra; Hou, Huiyuan; Moon, Sang Woong; Sailor, Michael J.; Freeman, William R.; Cheng, Lingyun

    2015-01-01

    Mild oxidation and subsequent silanization of the porous silicon (pSi) rendered the resultant pSi particles optimized for rapamycin loading/release as an intravitreal injectable delivery system. The system slowly released rapamycin and safely resided in rabbit vitreous more than 8 weeks.

  8. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II : Potential mechanisms

    NARCIS (Netherlands)

    van Vliet, Erwin A; Otte, Wim M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure

  9. The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients

    NARCIS (Netherlands)

    Verhave, J.C.; Boucher, A.; Dandavino, R.; Collette, S.; Senecal, L.; Hebert, M.J.; Girardin, C.; Cardinal, H.

    2014-01-01

    Conversion from a calcineurin-inhibitor-based immunosuppression to a rapamycin-based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective

  10. Rapamycin-induced inhibition of HTLV-I LTR activity is rescued by c-Myb

    Directory of Open Access Journals (Sweden)

    Lever Andrew ML

    2007-04-01

    Full Text Available Abstract Background Rapamycin is an immunosuppressive which represses translation of transcripts harbouring a polypyrimidine motif downstream of the mRNA cap site through the mammalian target of rapamycin complex. It inhibits the abnormal autologous proliferation of T-cell clones containing a transcriptionally active human T-lymphotropic virus, type I (HTLV-I provirus, generated from infected subjects. We showed previously that this effect is independent of the polypyrimidine motifs in the viral long terminal repeat (LTR R region suggesting that HTLV-I transcription, and not translation, is being affected. Here we studied whether rapamycin is having an effect on a specific transcription factor pathway. Further, we investigated whether mRNAs encoding transcription factors involved in HTLV-I transcriptional activation, specifically CREB, Ets and c-Myb, are implicated in the rapamycin-sensitivity of the HTLV-I LTR. Results An in vitro analysis of the role of SRE- and NF-κB-mediated transcription highlighted the latter as rapamycin sensitive. Over-expression of c-Myb reversed the rapamycin effect. Conclusion The sensitivity of HTLV-I transcription to rapamycin may be effected through an NF-κB-pathway associated with the rapamycin-sensitive mTORC1 cellular signalling network.

  11. Rapamycin Induces Heme Oxygenase-1 in Liver but Inhibits Bile Flow Recovery after Ischemia

    NARCIS (Netherlands)

    Kist, Alwine; Wakkie, Joris; Madu, Max; Versteeg, Ruth; ten Berge, Judith; Nikolic, Andrej; Nieuwenhuijs, Vincent B.; Porte, Robert J.; Padbury, Robert T. A.; Barritt, Greg J.

    Background/Aims. Rapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of

  12. l-Tryptophan-mediated Enhancement of Susceptibility to Nonalcoholic Fatty Liver Disease Is Dependent on the Mammalian Target of Rapamycin*

    Science.gov (United States)

    Osawa, Yosuke; Kanamori, Hiromitsu; Seki, Ekihiro; Hoshi, Masato; Ohtaki, Hirofumi; Yasuda, Yoichi; Ito, Hiroyasu; Suetsugu, Atsushi; Nagaki, Masahito; Moriwaki, Hisataka; Saito, Kuniaki; Seishima, Mitsuru

    2011-01-01

    Nonalcoholic fatty liver disease is one of the most common liver diseases. l-Tryptophan and its metabolite serotonin are involved in hepatic lipid metabolism and inflammation. However, it is unclear whether l-tryptophan promotes hepatic steatosis. To explore this issue, we examined the role of l-tryptophan in mouse hepatic steatosis by using a high fat and high fructose diet (HFHFD) model. l-Tryptophan treatment in combination with an HFHFD exacerbated hepatic steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum alanine aminotransaminase levels, whereas l-tryptophan alone did not result in these effects. We also found that l-tryptophan treatment increases serum serotonin levels. The introduction of adenoviral aromatic amino acid decarboxylase, which stimulates the serotonin synthesis from l-tryptophan, aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced accumulation of lipid was further increased by serotonin treatment in cultured hepatocytes. These results suggest that l-tryptophan increases the sensitivity to hepatic steatosis through serotonin production. Furthermore, l-tryptophan treatment, adenoviral AADC introduction, and serotonin treatment induced phosphorylation of the mammalian target of rapamycin (mTOR), and a potent mTOR inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty acid with serotonin. These results suggest the importance of mTOR activation for the exacerbation of hepatic steatosis. In conclusion, l-tryptophan exacerbates hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR. PMID:21841000

  13. LED roadway luminaires evaluation.

    Science.gov (United States)

    2012-02-01

    This research explores whether LED roadway luminaire technologies are a viable future solution to providing roadway lighting. Roadway lighting : enhances highway safety and traffic flow during limited lighting conditions. The purpose of this evaluati...

  14. Multicolor LED sensor

    Science.gov (United States)

    Lange, Volker; Ribeiro, Felipe; Tews, Walter; Kühlke, Dietrich

    2008-04-01

    We present a compact and cheap sensor device based on the combination of a standard RGB-LED with a luminescence material. The multicolor LED acts as the exciting light source, the luminescence light detector and simultaneously as an optical filter. As luminescence material various phosphor materials or crystals can be used, depending on the physical property to be sensed. Possible applications will be discussed.

  15. Rapamycin and mTORC1 Inhibition in the Mouse: Skin Cancer Prevention

    Science.gov (United States)

    Athar, Mohammad; Kopelovich, Levy

    2011-01-01

    Therapeutic and preventive effects of rapamycin include reduced risk of non-melanoma skin cancer (NMSC). In this issue of the journal (beginning on page XXX), Checkley et al. report that rapamycin inhibits mammalian target of rapamycin (mTOR) complex 1 in murine epidermis, thereby inhibiting tumor promotion mediated by tetradecanoyl phorbol-13 acetate (TPA) in association with a strong anti-inflammatory effect. Rapamycin is an immunosuppressive drug for preventing graft rejection in organ transplant recipients and reduces the risk of NMSC and Kaposi’s sarcoma in this population, albeit by mechanisms distinct from immunosuppression. Important future directions include identifying molecular predictors of rapamycin/rapalog sensitivity or resistance (potentially, for example, PI3K pathway alterations and KRAS mutations) and combined non-rapalog, mTOR-targeting approaches, all of which should increase efficacy and minimize toxicity. PMID:21733819

  16. Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells.

    Science.gov (United States)

    Soares, Heloisa P; Ni, Yang; Kisfalvi, Krisztina; Sinnett-Smith, James; Rozengurt, Enrique

    2013-01-01

    The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis.

  17. Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study.

    Science.gov (United States)

    Bee, Janet; Fuller, Sharon; Miller, Suzanne; Johnson, Simon R

    2017-10-09

    Mechanistic target of rapamycin inhibitors reduce loss of lung function in lymphangioleiomyomatosis (LAM), although their benefit varies between individuals. We examined lung function response and side effects to rapamycin in a national cohort. Subjects were receiving rapamycin for progressive lung disease. Clinical evaluation, detailed phenotyping, serial lung function, rapamycin and safety monitoring were performed according to a clinical protocol. Lung function change, measured as FEV1 slope (ΔFEV1), was reported for those treated for 1 year or longer. Rapamycin was associated with improved ΔFEV1 in 21 individuals where pretreatment data were available (p<0.0001). In 47 treated for a mean duration of 35.8 months, mean ΔFEV1 was +11 (SD 75) mL/year, although it varied from +254 to -148 mL/year. The quartile with the highest positive ΔFEV1 had greater pretreatment FEV1 (p=0.02) and shorter disease durations (p=0.02) than the lowest quartile. Serum rapamycin level was positively associated with side effects (p=0.02) but not ΔFEV1 over 1 year. Within the first month of therapy, apthous ulcers, nausea and diarrhoea were associated with higher rapamycin levels. Acne, oedema and menstrual irregularities tended to increase over the first year of therapy. At the end of observation, the prevalence of side effects was 5% or less. Rapamycin reduces lung function loss in LAM, although in some, ΔFEV1 continues to fall at an accelerated rate. Poor response to rapamycin was associated with lower pretreatment lung function and longer disease duration but not serum level. Early intervention with low-dose rapamycin may preserve lung function and reduce side effects. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats.

    Science.gov (United States)

    Lin, Jue; Liu, Lingqi; Wen, Quan; Zheng, Chunming; Gao, Yang; Peng, Shuxian; Tan, Yalun; Li, Yanqin

    2014-01-01

    The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.

  19. Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1.

    Science.gov (United States)

    Kwon, Sora; Jeon, Ji-Sook; Kim, Su Bin; Hong, Young-Kwon; Ahn, Curie; Sung, Jung-Suk; Choi, Inho

    2016-02-27

    Although the prolonged use of rapamycin may cause unwanted side effects such as hyperlipidemia, the underlying mechanism remains unknown. Prox1 is a transcription factor responsible for the development of several tissues including lymphatics and liver. There is growing evidences that Prox1 participates in metabolism in addition to embryogenesis. However, whether Prox1 is directly related to lipid metabolism is currently unknown. HepG2 human hepatoma cells were treated with rapamycin and total lipids were analyzed by thin layer chromatography. The effect of rapamycin on the expression of Prox1 was determined by western blotting. To investigate the role of Prox1 in triglycerides regulation, siRNA and overexpression system were employed. Rapamycin was injected into mice for 2 weeks and total lipids and proteins in liver were measured by thin layer chromatography and western blot analysis, respectively. Rapamycin up-regulated the amount of triglyceride and down-regulated the expression of Prox1 in HepG2 cells by reducing protein half-life but did not affect its transcript. The loss-of-function of Prox1 was coincident with the increase of triglycerides in HepG2 cells treated with rapamycin. The up-regulation of triglycerides by rapamycin in HepG2 cells reverted to normal levels by the compensation of Prox1 using the overexpression system. Rapamycin also down-regulated Prox1 expression but increased triglycerides in mouse liver. This study suggests that rapamycin can increase the amount of triglycerides by down-regulating Prox1 expression in hepatocytes, which means that the mammalian target of rapamycin (mTOR) signaling is important for the regulation of triglycerides by maintaining Prox1 expression.

  20. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation.

    NARCIS (Netherlands)

    van Vliet, E.A.; Forte, G.; Holtman, L.; den Burger, J.C.G.; Sinjewel, A.; de Vries, H.E.; Aronica, E.; Gorter, J.A.

    2012-01-01

    Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant

  1. Rapamycin-binding FKBP25 associates with diverse proteins that form large intracellular entities

    Energy Technology Data Exchange (ETDEWEB)

    Galat, Andrzej, E-mail: galat@dsvidf.cea.fr; Thai, Robert

    2014-08-08

    Highlights: • The hFKBP25 interacts with diverse components of macromolecular entities. • We show that the endogenous human FKBP25 is bound to polyribosomes. • The endogenous hFKBP25 co-immunoprecipitated with nucleosomal proteins. • FKBP25 could induce conformational switch in macromolecular complexes. - Abstract: In this paper, we show some evidence that a member of the FK506-binding proteins, FKBP25 is associated to diverse components that are part of several different intracellular large-molecular mass entities. The FKBP25 is a high-affinity rapamycin-binding immunophilin, which has nuclear translocation signals present in its PPIase domain but it was detected both in the cytoplasm compartment and in the nuclear proteome. Analyses of antiFKBP25-immunoprecipitated proteins have revealed that the endogenous FKBP25 is associated to the core histones of the nucleosome, and with several proteins forming spliceosomal complexes and ribosomal subunits. Using polyclonal antiFKBP25 we have detected FKBP25 associated with polyribosomes. Added RNAs or 0.5 M NaCl release FKBP25 that was associated with the polyribosomes indicating that the immunophilin has an intrinsic capacity to form complexes with polyribonucleotides via its charged surface patches. Rapamycin or FK506 treatments of the polyribosomes isolated from porcine brain, HeLa and K568 cells caused a residual release of the endogenous FKBP25, which suggests that the immunophilin also binds to some proteins via its PPIase cavity. Our proteomics study indicates that the nuclear pool of the FKBP25 targets various nuclear proteins that are crucial for packaging of DNA, chromatin remodeling and pre-mRNA splicing whereas the cytosolic pool of this immunophilin is bound to some components of the ribosome.

  2. Temporary placement of a paclitaxel or rapamycin-eluting stent is effective to reduce stenting induced inflammatory reaction and scaring in benign cardia stricture models.

    Science.gov (United States)

    Wang, Lin; Zhu, Yue-Qi; Cheng, Ying-Sheng; Cui, Wen-Guo; Chen, Ni-Wei

    2014-12-01

    To investigate whether temporary placement of a paclitaxel or rapamycin eluting stent is more effective to reduce stenting induced inflammatory reaction and scaring than a bared stent in benign cardia stricture models. Eighty dog models of stricture were randomly divided into a control group (CG, n=20, no stent insertion), a bare stent group (BSG, n=20), a paclitaxel eluting (Pacl-ESG, n=20) and a rapamycin eluting stent group (Rapa-ESG, n=20), with one-week stent retention. Lower-oesophageal-sphincter pressure (LOSP), 5-minute barium height (5-mBH) and cardia diameter were assessed before, immediately after the procedure, and regularly for 6 months. Five dogs in each group were euthanized for histological examination at each follow-up assessment. Stent insertion was well tolerated, with similar migration rates in three groups. At 6 months, LOSP and 5-mBH improved in Pacl-ESG and Rapa-ESG compared to BSG (pESG and Rapa-ESG (p>0.05). Cardia kept more patency in the Pacl-ESG and Rapa-ESG than in BSG (pESG and Rapa-ESG compared to BSG (pESG and Rapa-ESG (p>0.05). Paclitaxel or rapamycin-eluting stents insertion led to better outcomes than bare stents in benign cardia stricture models.

  3. Led-sukellusvalaisin

    OpenAIRE

    Saarelainen, Mikko

    2012-01-01

    Opinnäytetyön aiheena on LED ja sen käyttö sukellusvalaisimissa. Työn tarkoitus oli tutkia miten LED toimii ja miten se soveltuu käytettäväksi sukellusvalaisimessa, sekä syventää omaa tietoutta valosta, mitä se on ja miten sitä mitataan. Työssä käydään läpi LEDin ominaisuuksia ja miten se eroaa muista sukellusvalaisimissa käytetyistä lampuista. Työ on toteutettu tutustumalla LEDiin ja valoon käyttämällä erilaisia lähteitä ja päivittämällä nykyinen sukellusvalaisimeni LED-sukellusvalaisime...

  4. Nurse-led discharge.

    Science.gov (United States)

    Page, Carole

    2010-12-01

    Delayed discharges have financial implications for hospital trusts and cause dissatisfaction for patients and their families. This article looks at nurse-led discharge pathways at Milton Keynes Hospital's ambulatory care unit. It explains how giving nurses the responsibility to discharge has improved the patient experience, made nurses more accountable and saved money for the trust.

  5. LED system reliability

    NARCIS (Netherlands)

    Driel, W.D. van; Yuan, C.A.; Koh, S.; Zhang, G.Q.

    2011-01-01

    This paper presents our effort to predict the system reliability of Solid State Lighting (SSL) applications. A SSL system is composed of a LED engine with micro-electronic driver(s) that supplies power to the optic design. Knowledge of system level reliability is not only a challenging scientific

  6. Comparison of rapamycin schedules in mice on high-fat diet.

    Science.gov (United States)

    Leontieva, Olga V; Paszkiewicz, Geraldine M; Blagosklonny, Mikhail V

    2014-01-01

    At a wide range of doses, rapamycin extends life span in mice. It was shown that intraperitoneal injections (i.p.) of rapamycin prevent weight gain in mice on high-fat diet (HFD). We further investigated the effect of rapamycin on weight gain in female C57BL/6 mice on HFD started at the age of 7.5 months. By the age of 16 and 23 months, mice on HFD weighed significantly more (52 vs 33 g; p = 0.0001 and 70 vs 38 g; p applications are discussed.

  7. Rapamycin Loaded Solid Lipid Nanoparticles as a New Tool to Deliver mTOR Inhibitors: Formulation and in Vitro Characterization.

    Science.gov (United States)

    Polchi, Alice; Magini, Alessandro; Mazuryk, Jarosław; Tancini, Brunella; Gapiński, Jacek; Patkowski, Adam; Giovagnoli, Stefano; Emiliani, Carla

    2016-05-09

    Recently, the use of mammalian target of rapamycin (mTOR) inhibitors, in particular rapamycin (Rp), has been suggested to improve the treatment of neurodegenerative diseases. However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, we fabricated new Rp loaded solid lipid nanoparticles (Rp-SLN) stabilized with polysorbate 80 (PS80), comparing two different methods and lipids. The formulations were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), wide angle X-ray scattering (WAXS), cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1) was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals. Compritol Rp-SLN resulted more stable and possessing proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lβ, sub-Lα and Lβ' arrangements. PS80 was stably anchored on particle surface. No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was higher with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and stability to be considered for further investigation as Rp brain delivery system.

  8. Rapamycin Loaded Solid Lipid Nanoparticles as a New Tool to Deliver mTOR Inhibitors: Formulation and in Vitro Characterization

    Directory of Open Access Journals (Sweden)

    Alice Polchi

    2016-05-01

    Full Text Available Recently, the use of mammalian target of rapamycin (mTOR inhibitors, in particular rapamycin (Rp, has been suggested to improve the treatment of neurodegenerative diseases. However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, we fabricated new Rp loaded solid lipid nanoparticles (Rp-SLN stabilized with polysorbate 80 (PS80, comparing two different methods and lipids. The formulations were characterized by differential scanning calorimetry (DSC, nuclear magnetic resonance (NMR, wide angle X-ray scattering (WAXS, cryo-transmission electron microscopy (cryo-TEM, dynamic light scattering (DLS and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1 was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals. Compritol Rp-SLN resulted more stable and possessing proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lβ, sub-Lα and Lβ′ arrangements. PS80 was stably anchored on particle surface. No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was higher with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and stability to be considered for further investigation as Rp brain delivery system.

  9. Rapamycin inhibits CaCl2-induced thoracic aortic aneurysm formation in rats through mTOR-mediated suppression of proinflammatory mediators.

    Science.gov (United States)

    Cao, Jiumei; Wu, Qihong; Geng, Liang; Chen, Xiaonan; Shen, Weifeng; Wu, Fang; Chen, Ying

    2017-08-01

    The aim of the present study was to investigate the effect of the mammalian target of rapamycin (mTOR) signaling pathway on thoracic aortic aneurysm (TAA) development. The study used a calcium chloride (CaCl2)‑induced rat TAA model to explore the potential role of mTOR signaling pathway in the disease development. Adult male Sprague‑Dawley rats underwent the periarterial exposure of thoracic aorta to either 0.5 M CaCl2 or normal saline, and a subgroup of CaCl2‑treated rats received rapamycin 1 day prior to surgery. Without pre‑administering rapamycin, significantly enhanced phosphorylation of mTOR and expression of proinflammatory cytokines [i.e., tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), and interleukin (IL)‑1β] were observed in the CaCl2‑treated aortic segments 2 days post‑treatment compared with the NaCl‑treated segments. At 2 weeks post‑treatment, hematoxylin and eosin and Verhoeff‑Van Gieson staining revealed aneurysmal alteration and disappearance of normal wavy elastic structures in the aortic segments exposed to CaCl2. In contrast, the CaCl2‑induced TAA formation was inhibited by pre‑administering rapamycin to CaCl2‑treated rats, which demonstrated attenuated mTOR phosphorylation and downregulation of the proinflammatory mediators (i.e., TNF‑α, IL‑6, IL‑1β, matrix metallopeptidases 2 and 9) to the control level. Further in vitro cell culture experiments using aortic smooth muscle cell (SMC) suggested that the inhibition of the mTOR signaling pathway by rapamycin could promote the differentiation of SMCs, as reflected by the reduced expression of S100A4 and osteopontin. The present study indicated that the early enhanced mTOR signaling pathway in the TAA development and mTOR inhibitor rapamycin may inhibit CaCl2‑induced TAA formation.

  10. Thermal management for LED applications

    CERN Document Server

    Poppe, András

    2014-01-01

    Thermal Management for LED Applications provides state-of-the-art information on recent developments in thermal management as it relates to LEDs and LED-based systems and their applications. Coverage begins with an overview of the basics of thermal management including thermal design for LEDs, thermal characterization and testing of LEDs, and issues related to failure mechanisms and reliability and performance in harsh environments. Advances and recent developments in thermal management round out the book with discussions on advances in TIMs (thermal interface materials) for LED applications, advances in forced convection cooling of LEDs, and advances in heat sinks for LED assemblies. This book also: Presents a comprehensive overview of the basics of thermal management as it relates to LEDs and LED-based systems Discusses both design and thermal management considerations when manufacturing LEDs and LED-based systems Covers reliability and performance of LEDs in harsh environments Has a hands-on applications a...

  11. ‘No Blue’ White LED

    DEFF Research Database (Denmark)

    Ou, Haiyan; Corell, Dennis Dan; Dam-Hansen, Carsten

    2010-01-01

    This paper explored the feasibility of making a white LED light source by color mixing method without using the blue color. This ‘no blue’ white LED has potential applications in photolithography room illumination, medical treatment and biophotonics research. A no-blue LED was designed......, and the prototype was fabricated. The spectral power distribution of both the LED bulb and the yellow fluorescent tube was measured. Based on that, colorimetric values were calculated and compared on terms of chromatic coordinates, correlated color temperature, color rendering index, and chromatic deviation....... Gretagmacbeth color charts were used as a more visual way to compare the two light sources, which shows that our no-blue LED bulb has much better color rendering ability than the YFT. Furthermore, LED solution has design flexibility to improve it further. The prototype has been tested with photoresist SU8...

  12. The effect of community health worker-led education on women's health and treatment-seeking: A cluster randomised trial and nested process evaluation in Gujarat, India.

    Science.gov (United States)

    Desai, Sapna; Mahal, Ajay; Sinha, Tara; Schellenberg, Joanna; Cousens, Simon

    2017-12-01

    A community-based health insurance scheme operated by the Self-Employed Women's Association in Gujarat, India reported that the leading reasons for inpatient hospitalisation claims by its members were diarrhoea, fever and hysterectomy - the latter at the average age of 37. This claims pattern raised concern regarding potentially unnecessary hospitalisation amongst low-income women. A cluster randomised trial and mixed methods process evaluation were designed to evaluate whether and how a community health worker-led education intervention amongst insured and uninsured adult women could reduce insurance claims, as well as hospitalisation and morbidity, related to diarrhoea, fever and hysterectomy. The 18-month intervention consisted of health workers providing preventive care information to women in a group setting in 14 randomly selected clusters, while health workers continued with regular activities in 14 comparison clusters. Claims data were collected from an administrative database, and four household surveys were conducted amongst a cohort of 1934 randomly selected adult women. 30% of insured women and 18% of uninsured women reported attending sessions. There was no evidence of an intervention effect on the primary outcome, insurance claims (risk ratio (RR) = 1.03; 95% confidence interval (CI) 0.81, 1.30) or secondary outcomes amongst insured and uninsured women, hospitalisation (RR = 1.05; 95% CI 0.58, 1.90) and morbidity (RR = 1.09; 95% CI 0.87, 1.38) related to the three conditions. The process evaluation suggested that participants retained knowledge from the sessions, but barriers to behaviour change were not overcome. We detected no evidence of an effect of this health worker-led intervention to decrease claims, hospitalisation and morbidity related to diarrhoea, fever and hysterectomy. Strategies that capitalise on health workers' role in the community and knowledge, as well as those that address the social determinants of diarrhoea, fever

  13. Rapamycin bypasses vesicle-mediated signaling events to activate Gln3 in Saccharomyces cerevisiae

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    Puria, Rekha

    2008-01-01

    Growth of Saccharomyces cerevisiae in poor nitrogen sources or exposure to the Tor inhibitor rapamycin results in expression of the nitrogen catabolite repressed (NCR) genes whose products are involved in scavenging and metabolizing nitrogen. The NCR genes are regulated by the GATA-like transactivators Gln3 and Gat1, which are thought to be under control of the rapamycin-sensitive Tor complex 1 (TORC1). We have recently shown that Gln3 nuclear translocation in response to nitrogen source quality but not in response to rapamycin requires Golgi to endosome trafficking. These and previous findings that several TORC1 components localize to low density endomembranes are discussed in a model that underscores a prominent role for the vesicular trafficking system in facilitating molecular interactions in response to nitrogen source. In addition, these findings have important implications for Tor signaling and rapamycin mechanism of action, both in yeast and in metazoans. PMID:19430540

  14. Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.

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    Lana, D; Di Russo, J; Mello, T; Wenk, G L; Giovannini, M G

    2017-01-01

    The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective

  15. The effect of Bortezomib and Rapamycin on Telomerase Activity in Mantle Cell Lymphoma

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    Orit Uziel

    2014-12-01

    In the light of the crucial role of telomerase in cancer cells, it was important to characterize the possible relations between telomerase and bortezomib and to distinguish the biochemical mechanisms of its regulation and its interactions with other signal transduction inhibitors such as rapamycin. The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients.

  16. Combinatorial Antitumor Effect of Rapamycin and β-Elemene in Follicular Thyroid Cancer Cells

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    Jun Zhou

    2016-01-01

    Full Text Available Background. mTOR signaling would be a promising target for thyroid cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in most cancer types was modest. A new focus on development of combinatorial strategies with rapalogs is increasing. Objective. Investigating the combinatorial antitumor effect of rapamycin and β-elemene in follicular thyroid cancer cells. Methods. MTT assay was used to determine the FTC-133 cell proliferation after culturing with rapamycin and/or β-elemene. To analyze their combinatorial effect, immunoblotting was performed to analyze the activation status of AKT. Moreover, β-elemene attenuated rapamycin-induced immunosuppression was tested in mice. Results. Combination of rapamycin and β-elemene exerted significant synergistic antiproliferative effects in FTC-133 cell lines in vitro, based on inhibiting the AKT feedback activation induced by rapamycin. In vivo, the β-elemene could attenuate rapamycin-induced immunosuppression via reversing imbalance of Treg/Th17, with the underlying mechanism needed to be declared. Conclusions. We demonstrate that the novel combination of mTOR inhibitor with β-elemene synergistically attenuates tumor cell growth in follicular thyroid cancer, which requires additional preclinical validation.

  17. Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract.

    Science.gov (United States)

    Baluk, Peter; Yao, Li-Chin; Flores, Julio C; Choi, Dongwon; Hong, Young-Kwon; McDonald, Donald M

    2017-08-17

    Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, β-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C-driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics.

  18. Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin.

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    Lun, Xue Qing; Zhou, Hongyuan; Alain, Tommy; Sun, Beichen; Wang, Limei; Barrett, John W; Stanford, Marianne M; McFadden, Grant; Bell, John; Senger, Donna L; Forsyth, Peter A

    2007-09-15

    We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.

  19. Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

    Science.gov (United States)

    Yuan, Shiaulou; Li, Jade; Diener, Dennis R.; Choma, Michael A.; Rosenbaum, Joel L.; Sun, Zhaoxia

    2012-01-01

    The cilium serves as a cellular antenna by coordinating upstream environmental cues with numerous downstream signaling processes that are indispensable for the function of the cell. This role is supported by the revelation that defects of the cilium underlie an emerging class of human disorders, termed “ciliopathies.” Although mounting interest in the cilium has demonstrated the essential role that the organelle plays in vertebrate development, homeostasis, and disease pathogenesis, the mechanisms regulating cilia morphology and function remain unclear. Here, we show that the target-of-rapamycin (TOR) growth pathway modulates cilia size and function during zebrafish development. Knockdown of tuberous sclerosis complex 1a (tsc1a), which encodes an upstream inhibitor of TOR complex 1 (Torc1), increases cilia length. In contrast, treatment of embryos with rapamycin, an inhibitor of Torc1, shortens cilia length. Overexpression of ribosomal protein S6 kinase 1 (S6k1), which encodes a downstream substrate of Torc1, lengthens cilia. Furthermore, we provide evidence that TOR-mediated cilia assembly is evolutionarily conserved and that protein synthesis is essential for this regulation. Finally, we demonstrate that TOR signaling and cilia length are pivotal for a variety of downstream ciliary functions, such as cilia motility, fluid flow generation, and the establishment of left-right body asymmetry. Our findings reveal a unique role for the TOR pathway in regulating cilia size through protein synthesis and suggest that appropriate and defined lengths are necessary for proper function of the cilium. PMID:22308353

  20. Rapamycin inhibits IGF-1-mediated up-regulation of MDM2 and sensitizes cancer cells to chemotherapy.

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    Wei Du

    Full Text Available The Murine Double Minute 2 (MDM2 protein is a key regulator of cell proliferation and apoptosis that acts primarily by inhibiting the p53 tumor suppressor. Similarly, the PI3-Kinase (PI3K/AKT pathway is critical for growth factor-mediated cell survival. Additionally, it has been reported that AKT can directly phosphorylate and activate MDM2. In this study, we show that IGF-1 up-regulates MDM2 protein levels in a PI3K/AKT-dependent manner. Inhibition of mTOR by rapamycin or expression of a dominant negative eukaryotic initiation factor 4E binding protein 1 (4EBP1 mutant protein, as well as ablation of eukaryotic initiation factor 4E (eIF4E, efficiently abolishes IGF-1-mediated up-regulation of MDM2. In addition, we show that rapamycin effectively inhibits MDM2 expression and sensitizes cancer cells to chemotherapy. Taken together, this study reveals a novel mechanism by which IGF-1 activates MDM2 via the mTOR pathway, and that pharmacologic inhibition of mTOR combined with chemotherapy may be more effective in treatment of a subset of cancers harboring increased MDM2 activation.

  1. Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.

    Science.gov (United States)

    Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Danielski, Lucineia G; Petronilho, Fabricia; Carvalho, André F; Quevedo, João

    2017-09-01

    Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against

  2. Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.

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    Chenggang Li

    Full Text Available Tuberous sclerosis syndrome (TSC is an autosomal dominant tumor suppressor gene syndrome affecting multiple organs, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM. LAM is a female-predominant interstitial lung disease characterized by the progressive cyst formation and respiratory failure, which is also seen in sporadic patients without TSC. Mutations in TSC1 or TSC2 cause TSC, result in hyperactivation of mammalian target of rapamycin (mTOR, and are also seen in LAM cells in sporadic LAM. We recently reported that prostaglandin biosynthesis and cyclooxygenase-2 were deregulated in TSC and LAM. Phospholipase A2 (PLA2 is the rate-limiting enzyme that catalyzes the conversion of plasma membrane phospholipids into prostaglandins. In this study, we identified upregulation of adipocyte AdPLA2 (PLA2G16 in LAM nodule cells using publicly available expression data. We showed that the levels of AdPLA2 transcript and protein were higher in LAM lungs compared with control lungs. We then showed that TSC2 negatively regulates the expression of AdPLA2, and loss of TSC2 is associated with elevated production of prostaglandin E2 (PGE2 and prostacyclin (PGI2 in cell culture models. Mouse model studies also showed increased expression of AdPLA2 in xenograft tumors, estrogen-induced lung metastatic lesions of Tsc2 null leiomyoma-derived cells, and spontaneous renal cystadenomas from Tsc2+/- mice. Importantly, rapamycin treatment did not affect the expression of AdPLA2 and the production of PGE2 by TSC2-deficient mouse embryonic fibroblast (Tsc2-/-MEFs, rat uterine leiomyoma-derived ELT3 cells, and LAM patient-associated renal angiomyolipoma-derived "mesenchymal" cells. Furthermore, methyl arachidonyl fluorophosphate (MAFP, a potent irreversible PLA2 inhibitor, selectively suppressed the growth and induced apoptosis of TSC2-deficient LAM patient-derived cells relative to TSC2-addback cells. Our findings suggest that AdPLA2 plays an

  3. Effect of rapamycin on spleen size in longstanding renal transplant recipients.

    Science.gov (United States)

    Araújo, N C; Sampaio Gonçalves de Lucena, S B; da Silveira Rioja, S

    2014-06-01

    Based on evidence available in the literature, rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, but not calcineurin inhibitors (CNIs), has been shown to decrease spleen size. Small spleen, in some instances, is associated with hyposplenism, a condition recently reported in patients with longstanding renal transplant. Accordingly, the effect of immunosuppressive drugs on spleen size was evaluated. Renal transplant recipients (35 taking mTOR and 68 CNI) were included, in whom a standardized investigation of the kidney allograft and spleen with the use of color Doppler ultrasound was performed and a peripheral smear were reviewed for the presence of Howell-Jolly bodies (HJBs). We enrolled 103 patients (64 men; 66 from a deceased donor). The mean age was 47.7 years (range, 23.0-74.0 y). Mean transplant duration was 1,899 days (range, 181-6,883 d). According to the presence of HJBs, the prevalence of hyposplenism was 47.6% for the entire cohort. The differences between the mTOR and CNI groups regarding sex and the presence of HJBs were not statistically significant (P > .05). Age, creatinine, hemoglobin, leukocytes, platelets, and Doppler parameters in spleen and kidney were similar in both groups (P > .05). mTOR patients had a decreased spleen length size (90.09 ± 13.02 mm vs 111.95 ± 18.66 mm; P < .001), a longer transplant duration (3,576 ± 1,594 d vs 1,036 ± 1,369 d; P < .001) and higher serum cholesterol (227.50 ± 38.75 mg/dL vs 182.67 ± 37.74 mg/dL; P < .001) and triglycerides (194.23 ± 79.88 mg/dL vs 148.70 ± 55.54 mg/dL; P = .003) levels compared with the CNI group. A multivariate analysis showed mTOR inhibitor to be the most important predictor of spleen size. In both the mTOR and CNI groups, the comparison between the subgroups of present and absent HJBs did not show any difference. The findings of this study suggest that small spleens in transplant recipients may be linked to treatment with an mTOR inhibitor, although this apparently does

  4. Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.

    Science.gov (United States)

    Sun, Jiandong; Liu, Yan; Moreno, Stephanie; Baudry, Michel; Bi, Xiaoning

    2015-03-18

    Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated 1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi-chronic treatment of AS mice with rapamycin not only improved their motor performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2 complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1-S6K1 pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS. Copyright © 2015 the authors 0270-6474/15/354706-13$15.00/0.

  5. Mammalian Target of Rapamycin Inhibitor Induced Complete Remission of a Recurrent Subependymal Giant Cell Astrocytoma in a Patient Without Features of Tuberous Sclerosis Complex.

    Science.gov (United States)

    Appalla, Deepika; Depalma, Andres; Calderwood, Stanley

    2016-07-01

    The majority of patients with subependymal giant cell astrocytoma (SEGA) have tuberous sclerosis complex (TSC). In such patients, the mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to induce responses. Isolated SEGA have been reported in patients without clinical or genetic features of TSC. The treatment of these patients with everolimus has not previously been reported. We treated a patient with a recurrent isolated SEGA with an mTOR inhibitor. The patient tolerated therapy well and had a sustained complete remission. MTOR inhibitors may be useful for the treatment of isolated SEGA. Further study is warranted. © 2016 Wiley Periodicals, Inc.

  6. Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

    Science.gov (United States)

    Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M.; Dardik, Alan

    2017-01-01

    Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

  7. E-selectin targeted immunoliposomes for rapamycin delivery to activated endothelial cells.

    Science.gov (United States)

    Gholizadeh, Shima; Visweswaran, Ganesh Ram R; Storm, Gert; Hennink, Wim E; Kamps, Jan A A M; Kok, Robbert J

    2017-10-13

    Activated endothelial cells play a pivotal role in the pathology of inflammatory disorders and thus present a target for therapeutic intervention by drugs that intervene in inflammatory signaling cascades, such as rapamycin (mammalian target of rapamycin (mTOR) inhibitor). In this study we developed anti-E-selectin immunoliposomes for targeted delivery to E-selectin over-expressing tumor necrosis factor-α (TNF-α) activated endothelial cells. Liposomes composed of 1,2-dipalmitoyl-sn-glycero-3.;hosphocholine (DPPC), Cholesterol, and 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]-maleimide (DSPE-PEG-Mal) were loaded with rapamycin via lipid film hydration, after which they were further functionalized by coupling N-succinimidyl-S-acetylthioacetate (SATA)-modified mouse anti human E-selectin antibodies to the distal ends of the maleimidyl (Mal)-PEG groups. In cell binding assays, these immunoliposomes bound specifically to TNF-α activated endothelial cells. Upon internalization, rapamycin loaded immunoliposomes inhibited proliferation and migration of endothelial cells, as well as expression of inflammatory mediators. Our findings demonstrate that rapamycin-loaded immunoliposomes can specifically inhibit inflammatory responses in inflamed endothelial cells. Copyright © 2017. Published by Elsevier B.V.

  8. Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

    Energy Technology Data Exchange (ETDEWEB)

    Knight, Steven D.; Adams, Nicholas D.; Burgess, Joelle L.; Chaudhari, Amita M.; Darcy, Michael G.; Donatelli, Carla A.; Luengo, Juan I.; Newlander, Ken A.; Parrish, Cynthia A.; Ridgers, Lance H.; Sarpong, Martha A.; Schmidt, Stanley J.; Aller, Glenn S.Van; Carson, Jeffrey D.; Diamond, Melody A.; Elkins, Patricia A.; Gardiner, Christine M.; Garver, Eric; Gilbert, Seth A.; Gontarek, Richard R.; Jackson, Jeffrey R.; Kershner, Kevin L.; Luo, Lusong; Raha, Kaushik; Sherk, Christian S.; Sung, Chiu-Mei; Sutton, David; Tummino, Peter J.; Wegrzyn, Ronald J.; Auger, Kurt R.; Dhanak, Dashyant (GSKPA)

    2010-09-30

    Phosphoinositide 3-kinase {alpha} (PI3K{alpha}) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{l_brace}2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl{r_brace}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3K{alpha} and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.

  9. The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy.

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    Yu, Ruichao; Bo, Hong; Villani, Vincenzo; Spencer, Philip J; Fu, Ping

    2016-01-01

    the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology. © 2016 The Author(s) Published by S. Karger AG, Basel.

  10. The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Ruichao Yu

    2016-02-01

    activation of Th17 cells. Rapamycin may attenuate DN via reduction of the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology.

  11. Transcriptional Profiling of Rapamycin-Treated Fibroblasts From Hypertrophic and Keloid Scars

    Science.gov (United States)

    Wong, Victor W.; You, Fanglei; Januszyk, Michael; Gurtner, Geoffrey C.; Kuang, Anna A.

    2016-01-01

    Excess scar formation after cutaneous injury can result in hypertrophic scar (HTS) or keloid formation. Modern strategies to treat pathologic scarring represent nontargeted approaches that produce suboptimal results. Mammalian target of rapamycin (mTOR), a central mediator of inflammation, has been proposed as a novel target to block fibroproliferation. To examine its mechanism of action, we performed genomewide microarray on human fibroblasts (from normal skin, HTS, and keloid scars) treated with the mTOR inhibitor, rapamycin. Hypertrophic scar and keloid fibroblasts demonstrated overexpression of collagen I and III that was effectively abrogated with rapamycin. Blockade of mTOR specifically impaired fibroblast expression of the collagen biosynthesis genes PLOD, PCOLCE, and P4HA, targets significantly overexpressed in HTS and keloid scars. These data suggest that pathologic scarring can be abrogated via modulation of mTOR pathways in procollagen and collagen processing. PMID:24835866

  12. Paradigmenwechsel in der Anti-Aging-Medizin: Hormesis, Target-of-Rapamycin-Komplex und erste Anti-Aging-Pillen // Paradigm Shift in Anti-Aging Medicine: Hormesis, Target of Rapamycin Complex and First Human Anti-Aging-Pills

    Directory of Open Access Journals (Sweden)

    Römmler A

    2016-01-01

    Full Text Available Studies in model organisms have shown that some drugs and lifestyle practices (calorie-restricted diets, regular exercise, e.g. can extend life and health span and protect against the onset of age-related chronic diseases by targeting physiological pathways.brA common mode of action was found via mTOR (mechanistic Target Of Rapamycin pathway signalling. This intracellular protein kinase complex plays a key role in stimulating anabolic and cell growth promoting processes, while inhibiting autophagy. On the other hand, downregulation results in antiproliferative, anticancer and intensive cell-repairing effects leading to life and health span extension and stress resistance. The mTOR complex regulates such basic cell activities and integrates signals from nutrition sensing, energy metabolism, insulin and growth factors, stress and hypoxia.brImportantly, mTOR can be inhibited by some molecules and their analogs (rapamycin, resveratrol, metformin, e.g., which are released naturally from plants, yeast or bacteria to protect against natural enemies. Its dosage resembles an adaptive hormetic response relationship, as high concentrations are toxic and mild doses are associated with anticancer and antiaging effects. This opens up new avenues for their use as „anti-aging pills“ in humans.brRecent human data suggest that metformin, rapamycin and other mTOR-inhibitors could delay heart disease, cancer, cognitive decline and improve survival time in people with diabetes mellitus. In addition, response to influenca vaccine was enhanced by rapamycin in adults with immunosenescence, indicating beneficial anti-aging effects in the elderly.br“Treat aging” is an actual call to recognize aging as an indication appropriate for clinical trials and treatments, as it was recently approved by the Federal Drug Administration (FDA USA. p bKurzfassung/b: Die ansteigende Morbidität und Invalidität in alternden Industrienationen stößt an die Grenzen der Ressourcen

  13. Positively charged amphiphilic chitosan derivative for the transscleral delivery of rapamycin.

    Science.gov (United States)

    Elsaid, Naba; Jackson, Timothy L; Gunic, Mirza; Somavarapu, Satyanarayana

    2012-12-13

    We explored the potential of an amphiphilic chitosan derivative to facilitate the transscleral delivery of rapamycin, a potential multitherapeutic agent with poor water solubility. The amphiphilic chitosan derivative, O-octanoyl-chitosan-polyethylene glycol (OChiPEG) graft copolymer, was analyzed using Fourier-transform infrared spectroscopy (FT-IR). OChiPEG micelles were prepared via the thin film method and characterized for their size using dynamic light scattering (DLS), zeta potential using laser Doppler velocimetry (LDV), morphology using transmission electron microscopy (TEM), drug entrapment efficiency (EE), and drug loading (DL) efficiency using reversed-phase high performance liquid chromatography (RP-HPLC), critical micelle concentration (CMC) using spectrofluorometry, and thermal properties using differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD). Scleral permeation and retention of rapamycin from the drug-loaded micelles were determined in porcine sclera clamped in Ussing chambers, using RP-HPLC. Conjugation of hydrophilic and hydrophobic groups to chitosan was confirmed using FT-IR. Rapamycin-loaded micelles of particle size 40.6 nm and zeta potential + 6.84 mV were prepared successfully. These carriers exhibited a high EE and DL of 85.6 and 16.3%, respectively, and a CMC of 16.6 μM. OChiPEG micelles showed a high rapamycin scleral retention (14.8 ± 0.81 μg/g) with successful transscleral permeation (5.57 ± 1.04 × 10(-8) cm(2) · s(-1)). Positively charged OChiPEG micelles loaded with rapamycin were prepared successfully. These showed a high scleral retention and successful permeation of rapamycin, and therefore may be useful for the topical delivery of other hydrophobic agents.

  14. Rapamycin facilitates fracture healing through inducing cell autophagy and suppressing cell apoptosis in bone tissues.

    Science.gov (United States)

    Yin, Z-Y; Yin, J; Huo, Y-F; Yu, J; Sheng, L-X; Dong, Y-F

    2017-11-01

    To investigate the changes in cell autophagy and the molecular mechanism of rapamycin affecting the fracture healing. Sprague-Dawley (SD) rats were used to establish the right femoral shaft fracture models, and then underwent immunofluorescence assay to detect the autophagy level in bone tissues. After model establishment, SD rats were divided into two groups, the control group and the rapamycin group (1 mg/kg/d). Respectively, at the 2nd, 4th, and 6th week, rats were randomly selected from each group for X-ray and Micro-computed tomography (Micro-CT) examinations to determine callus growth, immunofluorescence assay to detect the protein expression of light chain 3 II (LC3 II), immunohistochemistry to evaluate the autophagy level through detecting the expression of Beclin1 in rats, Western blotting assay to detect cell apoptosis in tissues, hematoxylin and eosin staining (HE staining) to evaluate the osteoblastic activity through count of osteoblast in bone tissue at the end of fracture, and measure the expression of vascular endothelial growth factors (VEGF). Significant increases were seen in protein expression of cells in bone tissues at the end of fracture. In rapamycin group, callus formation and calcification level in rats were all higher than those in control group; compared with control group, for rats in rapamycin group, cell autophagy was significantly elevated in bone tissues, while cell apoptosis at the end of fracture was reduced with a significant increase in osteoblastic activity. The expression of VEGF in rapamycin group was higher than that in control group. Rapamycin can facilitate fracture healing through inducing cell apoptosis and suppressing cell apoptosis in bone tissues.

  15. Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Walpen, Thomas; Kalus, Ina [Research Unit, Division Internal Medicine, University Hospital Zuerich, 8091 Zuerich (Switzerland); Schwaller, Juerg [Department of Biomedicine, University of Basel, 4031 Basel (Switzerland); Peier, Martin A. [Research Unit, Division Internal Medicine, University Hospital Zuerich, 8091 Zuerich (Switzerland); Battegay, Edouard J. [Research Unit, Division Internal Medicine, University Hospital Zuerich, 8091 Zuerich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), 8057 Zuerich (Switzerland); Humar, Rok, E-mail: Rok.Humar@usz.ch [Research Unit, Division Internal Medicine, University Hospital Zuerich, 8091 Zuerich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), 8057 Zuerich (Switzerland)

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer Pim1{sup -/-} endothelial cell proliferation displays increased sensitivity to rapamycin. Black-Right-Pointing-Pointer mTOR inhibition by rapamycin enhances PIM1 cytosolic and nuclear protein levels. Black-Right-Pointing-Pointer Truncation of Pim1 beyond serine 276 results in nuclear localization of the kinase. Black-Right-Pointing-Pointer Nuclear PIM1 increases endothelial proliferation independent of rapamycin. -- Abstract: The PIM serine/threonine kinases and the mTOR/AKT pathway integrate growth factor signaling and promote cell proliferation and survival. They both share phosphorylation targets and have overlapping functions, which can partially substitute for each other. In cancer cells PIM kinases have been reported to produce resistance to mTOR inhibition by rapamycin. Tumor growth depends highly on blood vessel infiltration into the malignant tissue and therefore on endothelial cell proliferation. We therefore investigated how the PIM1 kinase modulates growth inhibitory effects of rapamycin in mouse aortic endothelial cells (MAEC). We found that proliferation of MAEC lacking Pim1 was significantly more sensitive to rapamycin inhibition, compared to wildtype cells. Inhibition of mTOR and AKT in normal MAEC resulted in significantly elevated PIM1 protein levels in the cytosol and in the nucleus. We observed that truncation of the C-terminal part of Pim1 beyond Ser 276 resulted in almost exclusive nuclear localization of the protein. Re-expression of this Pim1 deletion mutant significantly increased the proliferation of Pim1{sup -/-} cells when compared to expression of the wildtype Pim1 cDNA. Finally, overexpression of the nuclear localization mutant and the wildtype Pim1 resulted in complete resistance to growth inhibition by rapamycin. Thus, mTOR inhibition-induced nuclear accumulation of PIM1 or expression of a nuclear C-terminal PIM1 truncation mutant is sufficient to increase endothelial cell proliferation

  16. Rapamycin Maintains the Chondrocytic Phenotype and Interferes with Inflammatory Cytokine Induced Processes

    Directory of Open Access Journals (Sweden)

    Andrea De Luna-Preitschopf

    2017-07-01

    Full Text Available Osteoarthritis (OA is hallmarked by a progressive degradation of articular cartilage. Besides risk factors including trauma, obesity or genetic predisposition, inflammation has a major impact on the development of this chronic disease. During the course of inflammation, cytokines such as tumor necrosis factor-alpha(TNF-α and interleukin (IL-1β are secreted by activated chondrocytes as well as synovial cells and stimulate the production of other inflammatory cytokines and matrix degrading enzymes. The mTORC1 inhibitor rapamycin is a clinical approved immunosuppressant and several studies also verified its chondroprotective effects in OA. However, the effect of blocking the mechanistic target of rapamycin complex (mTORC1 on the inflammatory status within OA is not well studied. Therefore, we aimed to investigate if inhibition of mTORC1 by rapamycin can preserve and sustain chondrocytes in an inflammatory environment. Patient-derived chondrocytes were cultured in media supplemented with or without the mTORC1 inhibitor rapamycin. To establish an inflammatory environment, either TNF-α or IL-1β was added to the media (=OA-model. The chondroprotective and anti-inflammatory effects of rapamycin were evaluated using sulfated glycosaminoglycan (sGAG release assay, Caspase 3/7 activity assay, lactate dehydrogenase (LDH assay and quantitative real time polymerase chain reaction (PCR. Blocking mTORC1 by rapamycin reduced the release and therefore degradation of sGAGs, which are components of the extracellular matrix secreted by chondrocytes. Furthermore, blocking mTORC1 in OA chondrocytes resulted in an enhanced expression of the main chondrogenic markers. Rapamycin was able to protect chondrocytes from cell death in an OA-model shown by reduced Caspase 3/7 activity and diminished LDH release. Furthermore, inhibition of mTORC1 preserved the chondrogenic phenotype of OA chondrocytes, but also reduced inflammatory processes within the OA-model. This study

  17. Combination of rapamycin, CI-1040, and 17-AAG inhibits metastatic capacity of prostate cancer via Slug inhibition.

    Directory of Open Access Journals (Sweden)

    Guanxiong Ding

    Full Text Available Though prostate cancer (PCa has slow progression, the hormone refractory (HRCP and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

  18. Induction of biogenic magnetization and redox control by a component of the target of rapamycin complex 1 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Keiji Nishida

    Full Text Available Most organisms are simply diamagnetic, while magnetotactic bacteria and migratory animals are among organisms that exploit magnetism. Biogenic magnetization not only is of fundamental interest, but also has industrial potential. However, the key factor(s that enable biogenic magnetization in coordination with other cellular functions and metabolism remain unknown. To address the requirements for induction and the application of synthetic bio-magnetism, we explored the creation of magnetism in a simple model organism. Cell magnetization was first observed by attraction towards a magnet when normally diamagnetic yeast Saccharomyces cerevisiae were grown with ferric citrate. The magnetization was further enhanced by genetic modification of iron homeostasis and introduction of ferritin. The acquired magnetizable properties enabled the cells to be attracted to a magnet, and be trapped by a magnetic column. Superconducting quantum interference device (SQUID magnetometry confirmed and quantitatively characterized the acquired paramagnetism. Electron microscopy and energy-dispersive X-ray spectroscopy showed electron-dense iron-containing aggregates within the magnetized cells. Magnetization-based screening of gene knockouts identified Tco89p, a component of TORC1 (Target of rapamycin complex 1, as important for magnetization; loss of TCO89 and treatment with rapamycin reduced magnetization in a TCO89-dependent manner. The TCO89 expression level positively correlated with magnetization, enabling inducible magnetization. Several carbon metabolism genes were also shown to affect magnetization. Redox mediators indicated that TCO89 alters the intracellular redox to an oxidized state in a dose-dependent manner. Taken together, we demonstrated that synthetic induction of magnetization is possible and that the key factors are local redox control through carbon metabolism and iron supply.

  19. Nobel Prize for blue LEDs

    Science.gov (United States)

    Kraftmakher, Yaakov

    2015-05-01

    A brief review of lighting technologies is presented. Unavoidable restrictions for incandescent light bulbs caused by the Planck distribution and properties of the human eye are illustrated. The efficiency and luminous efficacy of thermal radiation are calculated for various temperatures; the results clearly show the limitations for thermal radiators. The only way to overcome these limitations is using non-thermal radiators, such as fluorescent lamps and light-emitting diodes (LEDs). Unique advantages of LEDs undoubtedly made a revolution in this field. A crucial element of this progress is the blue LEDs (Nobel Prize 2014). Some experiments with a blue and a green LED are described: (i) the luminescence triggered in a green-yellow phosphor inside a white LED by the blue LED; (ii) radiant spectra and ‘efficiency droop’ in the LEDs; (iii) modulation of the blue LED up to 4 MHz; and (iv) the h/e ratio from the turn-on voltage of the green LED. The experiments are suitable for undergraduate laboratories and usable as classroom demonstrations.

  20. LED driver for stroboscopic interferometry

    Science.gov (United States)

    Paulin, T.; Heikkinen, V.; Kassamakov, I.; Hæggström, E.

    2012-04-01

    Three different types of white light emitting diodes (LEDs) and three types of single color LEDs were tested as light sources for stroboscopic scanning white light interferometry (SSWLI) for dynamic (MEMS) characterization. Short, intense, light pulses and low duty cycle (DC-10 MHz), and can drive single LEDs at 5A peak current (0.7% duty cycle at 1 MHz). The shortest measured electrical pulses were 6.2 +/- 0.1 ns FDHM. The minimum measured Full Duration at Half Maximum (FDHM) of the optical pulse was 8.4 +/- 0.1 ns using nonphosphor white LED and 32.1 +/- 0.1 ns using white phosphor-converted LED (0.7 % duty cycle at 1 MHz in both cases). The minimum optical pulse FDHM for a single color blue/green LED was 6.4 +/- 0.1 ns. The maximum intensity of these pulses was 630 +/- 40 μW and 540 +/- 30 μW, respectively. All types of white LEDs could be used for stroboscopic SWLI measurements at frequencies up to 2 MHz. For higher frequencies, non-phosphor white LEDs must be used together with a cyan LED to avoid ringing in the SWLI interferogram.

  1. Protective Effects of the Mechanistic Target of Rapamycin against Excess Iron and Ferroptosis in Cardiomyocytes.

    Science.gov (United States)

    Baba, Yuichi; Higa, Jason K; Shimada, Briana K; Horiuchi, Kate M; Suhara, Tomohiro; Kobayashi, Motoi; Woo, Jonathan D; Aoyagi, Hiroko; Marh, Karra S; Kitaoka, Hiroaki; Matsui, Takashi

    2017-11-10

    Clinical studies suggest that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction (MI). Ferroptosis was recently reported as a mechanism of iron-dependent non-apoptotic cell death. However, ferroptosis in the heart is not well understood. The mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic (mTOR-Tg), cardiac-specific mTOR knockout (mTOR-KO), or control mice. CMs were treated with ferric iron [Fe (III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras Selective Lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/Dead Cell Viability Assays revealed that Fe (III)-citrate, erastin, and RSL3 induced cell death. Co-treatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe (III)-citrate, erastin, and RSL3-induced cell death, while mTOR deletion exaggerated cell death in these conditions. H2DCFDA (2',7'-dichlorodihydrofluorescein diacetate) measurement of reactive oxygen species (ROS) production showed that erastin-induced ROS production was significantly lower in mTOR-Tg versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs, and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with MI. Copyright © 2017, American Journal of Physiology-Heart and Circulatory Physiology.

  2. Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol.

    Science.gov (United States)

    Gul, Rukhsana; Mahmood, Abuzar; Luck, Christian; Lum-Naihe, Kelly; Alfadda, Assim A; Speth, Robert C; Pulakat, Lakshmi

    2015-11-01

    Resistance to obesity is observed in rodents and humans treated with rapamycin (Rap) or nebivolol (Neb). Because cardiac miR-208a promotes obesity, this study tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a. Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a. Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pretreatment with an AT1 receptor (AT1R) antagonist, losartan (1 μM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10 μM), and an NADPH oxidase inhibitor, apocynin (0.5 mM), did not. Ang II-induced increase in miR-208a was suppressed by Rap (10 nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1 μM), a 3rd generation β-blocker that suppressed bioavailable AT1R binding of (125) I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750 μg kg(-1)  day(-1) ; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity. Rap and Neb suppressed cardiac miR-208a. Suppression of miR-208a and increase in MED13 correlated with attenuated weight gain despite leptin resistance. © 2015 The Obesity Society.

  3. Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2.

    Science.gov (United States)

    Karuppasamy, Manikandan; Kusmider, Beata; Oliveira, Taiana M; Gaubitz, Christl; Prouteau, Manoel; Loewith, Robbie; Schaffitzel, Christiane

    2017-11-23

    The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Avo3/Rictor is unique to TORC2, but interacts with the same HEAT repeats of Tor2 that are engaged by Kog1/Raptor in mammalian TORC1, explaining the mutual exclusivity of these two proteins. Density, which we conclude is Avo3, occludes the FKBP12-rapamycin-binding site of Tor2's FRB domain rendering TORC2 rapamycin insensitive and recessing the kinase active site. Although mobile, Avo1/hSin1 further restricts access to the active site as its conserved-region-in-the-middle (CRIM) domain is positioned along an edge of the TORC2 active-site-cleft, consistent with a role for CRIM in substrate recruitment.

  4. GSK-3/Rb12 Pathway as a Novel Target of Rapamycin in Prostate Cancer

    Science.gov (United States)

    2005-11-01

    that also have a potent tumor suppressor effect. These drugs are currently being evaluated in clinical trials to treat human cancers including...tumors to inhibition of FRAP /mTOR." Proc Natl Acad Sci U S A 98(18): 10314-9. Noh, W. C., W. H. Mondesire, et al. (2004). "Determinants of rapamycin

  5. Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin.

    Science.gov (United States)

    Lun, XueQing; Alain, Tommy; Zemp, Franz J; Zhou, Hongyuan; Rahman, Masmudur M; Hamilton, Mark G; McFadden, Grant; Bell, John; Senger, Donna L; Forsyth, Peter A

    2010-01-15

    Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity against human brain tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate the oncolytic potential of MYXV in immunocompetent racine glioma models. Here, we report that MYXV infects and kills all racine cell glioma lines and that its effects are enhanced by rapamycin. Intratumoral administration of MYXV with rapamycin improved viral replication in the tumor and significantly prolonged host survival. Similarly, coadministration via a method of convection-enhanced delivery (CED) enhanced viral replication and efficacy in vivo. Mechanisms by which rapamycin improved MYXV oncolysis included an inhibition of type I IFN production in vitro and a reduction of intratumoral infiltration of CD68(+) microglia/macrophages and CD163(+) macrophages in vivo. Our findings define a method to improve MYXV efficacy against gliomas by rapamycin coadministration, which acts to promote immune responses engaged by viral delivery.

  6. New approach for local delivery of rapamycin by bioadhesive PLGA-carbopol nanoparticles.

    Science.gov (United States)

    Zou, Weiwei; Cao, Guangqing; Xi, Yanwei; Zhang, Na

    2009-01-01

    Local delivery of antiproliferative drugs encapsulated in biodegradable nanoparticles has shown promise as an experimental strategy for preventing vascular restenosis development. The general aim of this work was to develop polymeric nanoparticle carriers with bioadhesive properties, and to evaluate its adjuvant potential for local, intramural delivery of rapamycin for inhibition of restenosis. The bioadhesive rapamycin-loaded PLGA nanoparticles were obtained by applying carbopol 940 of different concentrations as stabilizer and bioadhesive agent. The resultant nanoparticles were characterized concerning physicochemical properties such as morphology, particle size, zeta potential, entrapment efficiency, drug loading, drug release in vitro, stability in vitro as well as the arterial uptake and retention ability in an ex-vivo model. The results revealed that carbopol could serve as a better stabilizer in the preparation of rapamycin-loaded PLGA nanoparticles compared with PVA, and the physicochemical characteristics of the obtained PLGA nanoparticles were affected by the concentration of carbopol. Furthermore, it was found that carbopol could impart the nanoparticles with bioadhesive properties, improving the rentention and uptake of nanoparticles in the arterial wall, benefiting the nanoparticles for efficient localization of therapeutic agents in restenosis site. Cell viability assay results showed that blank PLGA-carbopol nanoparticles exhibited low toxicity and excellent biocompatibility and rapamycin-loaded nanoparticles with a smaller particle size (carbopol stabilized bioadhesive nanoparticles against restenosis in vivo.

  7. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance

    DEFF Research Database (Denmark)

    Widlund, Anne Lykkegaard; Vang, Ole; Ye, Lan

    2013-01-01

    and compromise the function of mitochondria in cultured muscle cells, implying that defects in bioenergetics might be an unavoidable consequence of targeting mTORC1 in vivo. Therefore, we tested whether rapamycin, at the same doses used to extend lifespan, affects mitochondrial function in skeletal muscle. While...

  8. Surface engineering of porous silicon microparticles for intravitreal sustained delivery of rapamycin.

    Science.gov (United States)

    Nieto, Alejandra; Hou, Huiyuan; Moon, Sang Woong; Sailor, Michael J; Freeman, William R; Cheng, Lingyun

    2015-01-22

    To understand the relationship between rapamycin loading/release and surface chemistries of porous silicon (pSi) to optimize pSi-based intravitreal delivery system. Three types of surface chemical modifications were studied: (1) pSi-COOH, containing 10-carbon aliphatic chains with terminal carboxyl groups grafted via hydrosilylation of undecylenic acid; (2) pSi-C12, containing 12-carbon aliphatic chains grafted via hydrosilylation of 1-dodecene; and (3) pSiO2-C8, prepared by mild oxidation of the pSi particles followed by grafting of 8-hydrocarbon chains to the resulting porous silica surface via a silanization. The efficiency of rapamycin loading follows the order (micrograms of drug/milligrams of carrier): pSiO2-C8 (105 ± 18) > pSi-COOH (68 ± 8) > pSi-C12 (36 ± 6). Powder X-ray diffraction data showed that loaded rapamycin was amorphous and dynamic drug-release study showed that the availability of the free drug was increased by 6-fold (compared with crystalline rapamycin) by using pSiO2-C8 formulation (P = 0.0039). Of the three formulations in this study, pSiO2-C8-RAP showed optimal performance in terms of simultaneous release of the active drug and carrier degradation, and drug-loading capacity. Released rapamycin was confirmed with the fingerprints of the mass spectrometry and biologically functional as the control of commercial crystalline rapamycin. Single intravitreal injections of 2.9 ± 0.37 mg pSiO2-C8-RAP into rabbit eyes resulted in more than 8 weeks of residence in the vitreous while maintaining clear optical media and normal histology of the retina in comparison to the controls. Porous silicon-based rapamycin delivery system using the pSiO2-C8 formulation demonstrated good ocular compatibility and may provide sustained drug release for retina. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  9. Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis.

    Science.gov (United States)

    Saiprasad, Gowrikumar; Chitra, Palanivel; Manikandan, Ramar; Sudhandiran, Ganapasam

    2014-09-01

    Abnormalities in the homeostasis mechanisms involved in cell survival and apoptosis are contributing factors for colon carcinogenesis. Interventions of these mechanisms by pharmacologically safer agents gain predominance in colon cancer prevention. We previously reported the chemopreventive efficacy of hesperidin against colon carcinogenesis. In the present study, we aimed at investigating the potential of hesperidin over the abrogated Aurora-A coupled pro-survival phosphoinositide-3-kinase (PI3K)/Akt signalling cascades. Further, the role of hesperidin over apoptosis and mammalian target of rapamycin (mTOR) mediated autophagic responses were studied. Azoxymethane (AOM) induced mouse model of colon carcinogenesis was involved in this study. Hesperidin treatment was provided either in initiation/post-initiation mode respectively. Hesperidin significantly altered AOM mediated anti-apoptotic scenario by modulating Bax/Bcl-2 ratio together with enhanced cytochrome-c release and caspase-3, 9 activations. In addition, hesperidin enhanced p53-p21 axis with concomitant decrease in cell cycle regulator. Hesperidin treatment caused significant up-regulation of tumour suppressor phosphatase and tensin homologue (PTEN) with a reduction in the expression of AOM mediated p-PI3K and p-Akt. Additionally, hesperidin administration exhibited inhibition against p-mTOR expression which in turn led to stimulation of autophagic markers Beclin-1 and LC3-II. Aurora-A an upstream regulator of PI3K/Akt pathway was significantly inhibited by hesperidin. Furthermore, hesperidin administration restored glycogen synthase kinase-3 beta (GSK-3β) activity which in turn prevented the accumulation of oncoproteins β-catenin, c-jun and c-myc. Taken together, hesperidin supplementation initiated apoptosis via targeted inhibition of constitutively activated Aurora-A mediated PI3K/Akt/GSK-3β and mTOR pathways coupled with autophagic stimulation against AOM induced colon carcinogenesis. Copyright

  10. Rapamycin protects testes against germ cell apoptosis and oxidative stress induced by testicular ischemia-reperfusion.

    Science.gov (United States)

    Ghasemnejad-Berenji, Morteza; Ghazi-Khansari, Mahmoud; Yazdani, Iraj; Saravi, Seyed Soheil Saeedi; Nobakht, Maliheh; Abdollahi, Alireza; Ansari, Javad Mohajer; Ghasemnejad-Berenji, Hojjat; Pashapour, Sarvin; Dehpour, Ahmad Reza

    2017-08-01

    Rapamycin is an immunosuppressant compound with a broad spectrum of pharmaco-logical activities. In recent years, it has been used successfully to decrease ischemia-reperfusion injury in several organ systems. The purpose of the present study was to examine the effect of rapamycin on testicular ischemia-reperfusion injury. Seventy-two adult male Wistar rats were divided into six groups: control (group1), sham-operated (Group2), T/D + DMSO as vehicle group (group3), and groups 4-6; respectively received 0.5, 1, and 1.5 mgkg-1 of rapamycin, IP 30 min before detorsion. Ischemia was achieved by twisting the right testis 720° clockwise for 1 hr. The right testis of 6 animals from each group were excised 4 hr after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and TUNEL test in right testis of 6 animals per group, 24 hr after detorsion. Testicular T/D caused increases in the apoptosis, malondialdehyde (MDA), and caspase-3 levels and decreases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in ipsilateral testis (P<0.001). The rats treated with rapamycin had significant decreases in the MDA and caspase-3 levels and significant increases in the SOD, CAT and GPx activities in ipsilateral testis compared with the T/D group (P<0.001); germ cell apoptosis was decreased, and MSTD was improved. Rapamycin administration during testicular torsion decreased ischemia/reperfusion (I/R) cellular damage.

  11. Evaluation of an AAV2-based rapamycin-regulated glial cell line-derived neurotrophic factor (GDNF expression vector system.

    Directory of Open Access Journals (Sweden)

    Piotr Hadaczek

    Full Text Available Effective regulation of transgene product in anatomically circumscribed brain tissue is dependent on the pharmacokinetics of the regulating agent, the kinetics of transcriptional activation and degradation of the transgene product. We evaluated rapamycin-regulated AAV2-GDNF expression in the rat brain (striatum. Regulated (a dual-component system: AAV2-FBZhGDNF + AAV2-TF1Nc and constitutive (CMV-driven expression vectors were compared. Constitutively active AAV2-GDNF directed stable GDNF expression in a dose-dependent manner and it increased for the first month, thereafter reaching a plateau that was maintained over a further 3 months. For the AAV2-regGDNF, rapamycin was administered in a 3-days on/4-days off cycle. Intraperitoneal, oral, and direct brain delivery (CED of rapamycin were evaluated. Two cycles of rapamycin at an intraperitoneal dose of 10 mg/kg gave the highest GDNF level (2.75±0.01 ng/mg protein. Six cycles at 3 mg/kg resulted in lower GDNF values (1.36±0.3 ng/mg protein. Interestingly, CED of rapamycin into the brain at a very low dose (50 ng induced GDNF levels comparable to a 6-week intraperitoneal rapamycin cycle. This study demonstrates the effectiveness of rapamycin regulation in the CNS. However, the kinetics of the transgene in brain tissue, the regulator dosing amount and schedule are critical parameters that influence the kinetics of accumulation and zenith of the encoded transgene product.

  12. The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Pinelopi Argyriou

    2012-01-01

    Full Text Available Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

  13. Laser and LED external teeth-bleaching

    Science.gov (United States)

    Zanin, Fatima A.; Brugnera, Aldo, Jr.; Marchesan, Melissa A.; Pecora, Jesus D.

    2004-09-01

    Teeth-bleaching is an initial phase in the reproduction of an aesthetic smile; thus, it is very important that the dentist knows how to diagnose the causes of color changes and indicate whitening before proposing dental treatment. Technological advances in teeth-whitening lead to the development of new techniques, improving comfort, security and decreasing time of execution: argon laser, diode Laser, LED whitening, xenon light whitening. The clearing agent used in all techniques, including home whitening, is hydrogen peroxide (H2O2) in different concentrations. In this study, the authors describe mechanisms of gel activation, the use of Laser and LED"s for teeth-bleaching, the importance of diagnosis and the comfort of the patient in in-office teeth-bleaching techniques.

  14. Diagnosis, monitoring and treatment of tuberous sclerosis complex ...

    African Journals Online (AJOL)

    mammalian target of rapamycin) inhibitors to treat subependymal giant cell astrocytomas not amenable to surgery and renal angiomyolipomas larger than 3 cm, and as adjunctive treatment for refractory focal seizures. We await with interest results from ...

  15. Light pipes for LED measurements

    Science.gov (United States)

    Floyd, S. R.; Thomas, E. F., Jr.

    1976-01-01

    Light pipe directly couples LED optical output to single detector. Small area detector measures total optical output of diode. Technique eliminates thermal measurement problems and channels optical output to remote detector.

  16. Practical lighting design with LEDs

    CERN Document Server

    Lenk, Ron

    2016-01-01

    The second edition of Practical Lighting Design with LEDs has been revised and updated to provide the most current information for developing light-emitting diodes products. The authors, noted authorities in the field, offer a review of the most relevant topics including optical performance, materials, thermal design, and modeling and measurement. Comprehensive in scope, the text covers all the information needed to design LEDs into end products.

  17. Celebrity-led Development Organisations

    DEFF Research Database (Denmark)

    Budabin, Alexandra Cosima; Rasmussen, Louise Mubanda; Richey, Lisa Ann

    2017-01-01

    The past decade has seen a frontier open up in international development engagement with the entrance of new actors such as celebrity-led organisations. We explore how such organisations earn legitimacy with a focus on Madonna’s Raising Malawi and Ben Affleck’s Eastern Congo Initiative. The study...... for funding, endorsements, and expertise. We argue that the ways in which celebrity-led organisations establish themselves as legitimate development actors illustrate broader dynamics of the machinery of development....

  18. LED minilidar for Mars rover

    Science.gov (United States)

    Shiina, Tatsuo; Yamada, Sonoko; Senshu, Hiroki; Otobe, Naohito; Hashimoto, George; Kawabata, Yasuhiro

    2016-10-01

    A mini-lidar to observe the activity of Martian atmosphere is developed. The 10cm-cube LED mini-lidar was designed to be onboard a Mars rover. The light source of the mini-lidar is a high powered LED of 385nm. LED was adopted as light source because of its toughness against circumference change and physical shock for launch. The pulsed power and the pulse repetition frequency of LED beam were designed as 0.75W (=7.5nJ/10ns) and 500kHz, respectively. Lidar echoes were caught by the specially designed Cassegrain telescope, which has the shorter telescope tube than the usual to meet the 10cm-cube size limit. The high-speed photon counter was developed to pursue to the pulse repetition frequency of the LED light. The measurement range is no shorter than 30m depending back-ground condition. Its spatial resolution was improved as 0.15m (=1ns) by this photon counter. The demonstrative experiment was conducted at large wind tunnel facility of Japan Meteorological Agency. The measurement target was smoke of glycerin particles. The smoke was flowed in the wind tunnel with wind speed of 0 - 5m. Smoke diffusion and its propagation due to the wind flow were observed by the LED mini-lidar. This result suggests that the developed lidar can pursue the structure and the motion of dust devil of >2m.

  19. Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia.

    Science.gov (United States)

    Xu, Shiyu; Stern, Michael; McNew, James A

    2017-01-15

    The locomotor deficits in the group of diseases referred to as hereditary spastic paraplegia (HSP) reflect degeneration of upper motor neurons, but the mechanisms underlying this neurodegeneration are unknown. We established a Drosophila model for HSP, atlastin (atl), which encodes an ER fusion protein. Here, we show that neuronal atl loss causes degeneration of specific thoracic muscles that is preceded by other pathologies, including accumulation of aggregates containing polyubiquitin, increased generation of reactive oxygen species and activation of the JNK-Foxo stress response pathway. We show that inhibiting the Tor kinase, either genetically or by administering rapamycin, at least partially reversed many of these pathologies. atl loss from muscle also triggered muscle degeneration and rapamycin-sensitive locomotor deficits, as well as polyubiquitin aggregate accumulation. These results indicate that atl loss triggers muscle degeneration both cell autonomously and nonautonomously. © 2017. Published by The Company of Biologists Ltd.

  20. ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines

    Energy Technology Data Exchange (ETDEWEB)

    Zask, Arie; Verheijen, Jeroen C.; Curran, Kevin; Kaplan, Joshua; Richard, David J.; Nowak, Pawel; Malwitz, David J.; Brooijmans, Natasja; Bard, Joel; Svenson, Kristine; Lucas, Judy; Toral-Barza, Lourdes; Zhang, Wei-Guo; Hollander, Irwin; Gibbons, James J.; Abraham, Robert T.; Ayral-Kaloustian, Semiramis; Mansour, Tarek S.; Yu, Ker; (Wyeth)

    2009-09-18

    The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

  1. MobiLED: mobile-led and leading via mobile

    CSIR Research Space (South Africa)

    Ford, M

    2009-03-01

    Full Text Available the past three years it has become evident that many of the initiative's innovations have a wider application than originally envisaged. This paper will discuss the results of the education-related MobiLED pilots and expands on the possibilities of using...

  2. Campylobacter jejuni induces colitis through activation of mammalian target of rapamycin signaling.

    Science.gov (United States)

    Sun, Xiaolun; Threadgill, Deborah; Jobin, Christian

    2012-01-01

    Campylobacter jejuni is the worldwide leading cause of bacterial-induced enteritis. The molecular and cellular events that lead to campylobacteriosis are poorly understood. We identify mammalian target of rapamycin (mTOR) as a signaling pathway that leads to C jejuni-induced intestinal inflammation. Germ-free (control) or conventionally derived Il10(-/-) mice that express enhanced green fluorescent protein (EGFP) under the control of nuclear factor κB (Il10(-/-); NF-κB(EGFP) mice) were infected with C jejuni (10(9) colony-forming units/mouse) for 12 days; their responses were determined using histologic, semiquantitative reverse-transcription polymerase chain reaction, fluorescence in situ hybridization, transmission electron microscopy, and tissue culture analyses. mTOR signaling was blocked by daily intraperitoneal injections of the pharmacologic inhibitor rapamycin (1.5 mg/kg). CD4(+) T cells were depleted by intraperitoneal injections of antibodies against CD4 (0.5 mg/mouse every 3 days). Bacterial survival in splenocytes was measured using a gentamycin killing assay. C jejuni induced intestinal inflammation, which correlated with activation of mTOR signaling and neutrophil infiltration. The inflamed intestines of these mice had increased levels of interleukin-1β, Cxcl2, interleukin-17a, and EGFP; C jejuni localized to colons and extraintestinal tissues of infected Il10(-/-); NF-κB(EGFP) mice compared with controls. Rapamycin, administered before or after introduction of C jejuni, blocked C jejuni-induced intestinal inflammation and bacterial accumulation. LC3II processing and killing of C jejuni were increased in splenocytes incubated with rapamycin compared with controls. mTOR signaling mediates C jejuni-induced colitis in Il10(-/-) mice, independently of T-cell activation. Factors involved in mTOR signaling might be therapeutic targets for campylobacteriosis. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism

    OpenAIRE

    Huber, Kimberly M.; Klann, Eric; Costa-Mattioli, Mauro; Zukin, R. Suzanne

    2015-01-01

    The mammalian target of rapamycin (mTOR) is a central regulator of a diverse array of cellular processes, including cell growth, proliferation, autophagy, translation, and actin polymerization. Components of the mTOR cascade are present at synapses and influence synaptic plasticity and spine morphogenesis. A prevailing view is that the study of mTOR and its role in autism spectrum disorders (ASDs) will elucidate the molecular mechanisms by which mTOR regulates neuronal function under physiolo...

  4. Transmittance measurement using scanning LED

    Science.gov (United States)

    Ping, Yao; Mohan, Rosmin Elsa; Lau, Gih-Keong; Asundi, Anand Krishna

    2017-06-01

    In order to measure the transmittance for a large field of view (FOV), a system based on scanning LED is developed. The system mainly consists of tunable LEDs, a glass diffuser and a camera. The LED panel would display different colors in the CIE color space. An algorithm of converting the light wavelength to the RGB values is adopted. The images are captured using a monochrome camera. Depending on the number of colors displayed, the transmittance map for the entire spread of visible colors can be determined. Results are compared with those measured through a spectrometer. The spectral transmittance for the two methods exhibit good similarity. The system provides a means of measuring transmittance with no moving parts and can be extended to other hyperspectral imaging applications.

  5. LED power reduction trade-offs for ambulatory pulse oximetry.

    Science.gov (United States)

    Peláez, Eduardo Aguilar; Villegas, Esther Rodríguez

    2007-01-01

    The development of ambulatory arterial pulse oximetry is key to longer term monitoring and treatment of cardiovascular and respiratory conditions. The investigation presented in this paper will assist the designer of an ambulatory pulse oximetry monitor in minimizing the overall LED power consumption (P LED,TOT) levels by analyzing the lowest achievable limit as constrained by the optical components, circuitry implementation and final SpO2 reading accuracy required. LED duty cycle (D LED) reduction and light power (P LED,ON) minimization are proposed as methods to reduce P LED,TOT. Bandwidth and signal quality calculations are carried out in order to determine the required P LED,TOT as a function of the different noise sources.

  6. Addition of rapamycin to anti-CD3 antibody improves long-term glycaemia control in diabetic NOD mice.

    Directory of Open Access Journals (Sweden)

    Shira Perl

    Full Text Available Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia.Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control.Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35. Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05.The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice.

  7. Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer.

    Science.gov (United States)

    Castillo-Pichardo, Linette; Dharmawardhane, Suranganie F

    2012-01-01

    We recently reported that a combination of dietary grape polyphenols resveratrol, quercetin, and catechin (RQC), at low concentrations, was effective at inhibiting metastatic cancer progression. Herein, we investigate the molecular mechanisms of RQC in breast cancer and explore the potential of RQC as a potentiation agent for the epidermal growth factor receptor (EGFR) therapeutic gefitinib. Our in vitro experiments showed RQC induced apoptosis in gefitinib-resistant breast cancer cells via regulation of a myriad of proapoptotic proteins. Because the Akt/mammalian target of rapamycin (mTOR) signaling pathway is often elevated during development of anti-EGFR therapy resistance, the effect of RQC on the mTOR upstream effector Akt and the negative regulator AMP kinase (AMPK) was investigated. RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells. Combined RQC and gefitinib decreased gefitinib resistant breast cancer cell viability to a greater extent than RQC or gefitinib alone. Moreover, RQC inhibited Akt and mTOR and activated AMPK even in the presence of gefitinib. Our in vivo experiments showed combined RQC and gefitinib was more effective than the individual treatments at inhibiting mammary tumor growth and metastasis in nude mice. Therefore, RQC treatment inhibits breast cancer progression and may potentiate anti-EGFR therapy by inhibition of Akt/mTOR signaling.

  8. Importance of EEG in validating the chronic effects of drugs: suggestions from animal models of epilepsy treated with rapamycin.

    Science.gov (United States)

    Cambiaghi, Marco; Magri, Laura; Cursi, Marco

    2015-04-01

    The development of new drugs for the treatment of epilepsy is a major challenge for modern neurology and its first steps demand basic research. Preclinical studies on animal models of epilepsy are mainly based on the analysis of brain electrical activity to detect seizures, when they are not just limited to behavioral tests like the Racine scale. In the present review, we discuss the importance of using time-locked video and EEG recordings (Video-EEG) coupled with behavioral tests as tools to monitor and analyze the effects of anti-epileptic drugs in pre-clinical research. Particularly, we focus on the utility of a multimodal approach based on EEG/behavioral analysis to study the beneficial effects of chronic rapamycin treatment as a potential anti-epileptogenic therapy for a broad spectrum of epilepsy, including both genetic (as in tuberous sclerosis complex) and acquired diseases. Changes and synchronization of neuronal activity of different areas have been correlated with specific behavior in both physiological and pathological conditions. In the epileptic brain, during a seizure there is an abnormal activation of many cells all at once, altering different networks. A multimodal approach based on video, EEG analysis and behavioral tests would be the best option in preclinical studies of epilepsy. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  9. Activated mammalian target of rapamycin is associated with T regulatory cell insufficiency in nasal polyps

    Directory of Open Access Journals (Sweden)

    Shi Jianbo

    2009-02-01

    Full Text Available Abstract Background Decreased infiltration of Foxp3+ T regulatory cell (Treg is considered to be critical for the Th1/Th2 dysregulation of nasal polyps, while the cellular mechanism underlying Foxp3+ Treg insufficiency is currently not well defined. Methods We attempted to investigate the tissue expression of phosphorylated mammalian target of rapamycin (pmTOR and infiltration of Foxp3+ Tregs in 28 nasal polyps and 16 controls by histological staining. We also evaluated the effects of blocking the mTOR signaling pathway with rapamycin on T cell phenotype selection and Foxp3+CD4+ Tregs expansion in a tissue culture system. Results Significantly increased infiltration of pmTOR+ inflammatory cells and decreased infiltration of Foxp3+CD4+ Tregs into nasal polyps was observed, with an inverse association. In the tissue culture system, we detected significantly elevated Foxp3 expression and IL-10 production, as well as an increased percentage of Foxp3+ Tregs in nasal polyps after blocking the mTOR signaling pathway with rapamycin. Conclusion Here we demonstrate for the first time that the mTOR signaling pathway is associated with Foxp3+ Tregs insufficiency in nasal polyps. Inhibition of the mTOR signaling pathway may be helpful for enhancement of Foxp3+ Treg expansion, as well as modulation of T cell phenotype imbalances in nasal polyps.

  10. Rapamycin protects testes against germ cell apoptosis and oxidative stress induced by testicular ischemia-reperfusion

    Directory of Open Access Journals (Sweden)

    Morteza Ghasemnejad-berenji

    2017-08-01

    Full Text Available Objective(s:Rapamycin is an immunosuppressant compound with a broad spectrum of pharmaco-logical activities. In recent years, it has been used successfully to decrease ischemia-reperfusion injury in several organ systems. The purpose of the present study was to examine the effect of rapamycin on testicular ischemia-reperfusion injury. Materials and Methods: Seventy-two adult male Wistar rats were divided into six groups: control (group1, sham-operated (Group2, T/D + DMSO as vehicle group (group3, and groups 4–6; respectively received 0.5, 1, and 1.5 mgkg-1 of rapamycin , IP 30 min before detorsion. Ischemia was achieved by twisting the right testis 720o clockwise for 1 hr. The right testis of 6 animals from each group were excised 4 hr after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD and TUNEL test in right testis of 6 animals per group, 24 hr after detorsion. Results: Testicular T/D caused increases in the apoptosis, malondialdehyde (MDA, and caspase-3 levels and decreases in the superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GPx activities in ipsilateral testis (P

  11. p21WAF1/CIP1 Expression is Differentially Regulated by Metformin and Rapamycin

    Directory of Open Access Journals (Sweden)

    Zoltan Molnar

    2014-01-01

    Full Text Available The mammalian target of rapamycin (mTOR pathway plays an important role in the development of diabetic nephropathy and other age-related diseases. One of the features of DN is the elevated expression of p21WAF1/CIP1. However, the importance of the mTOR signalling pathway in p21 regulation is poorly understood. Here we investigated the effect of metformin and rapamycin on mTOR-related phenotypes in cell lines of epithelial origin. This study reports that metformin inhibits high glucose-induced p21 expression. High glucose opposed metformin in regulating cell size, proliferation, and protein synthesis. These effects were associated with reduced AMPK activation, affecting downstream mTOR signalling. However, the inhibition of the mTOR pathway by rapamycin did not have a negative effect on p21 expression, suggesting that metformin regulates p21 upstream of mTOR. These findings provide support for the hypothesis that AMPK activation may regulate p21 expression, which may have implications for diabetic nephropathy and other age-related pathologies.

  12. LED-belysning och brukaren

    OpenAIRE

    Adanko, Carina; Küller, Marianne

    2014-01-01

    Ljusforskning är om något diversifierad och omfattar teorier och metoder från skilda discipliner som teknik, medicin och samhällsvetenskap. Det finns också en förväntan att erhållna forskningsresultat skall kunna appliceras direkt i verkliga miljöer. I och med introduktionen av LED har många tidigare studier som behandlat glödlampor, lysrör och andra ljuskällor inaktualiserats. Ny kunskap - och ny forskning - krävs. En inventering av aktuell humanrelaterad LED-forskning genomfördes under 2013...

  13. Semiconductor lasers and herterojunction leds

    CERN Document Server

    Kressel, Henry

    2012-01-01

    Semiconductor Lasers and Heterojunction LEDs presents an introduction to the subject of semiconductor lasers and heterojunction LEDs. The book reviews relevant basic solid-state and electromagnetic principles; the relevant concepts in solid state physics; and the p-n junctions and heterojunctions. The text also describes stimulated emission and gain; the relevant concepts in electromagnetic field theory; and the modes in laser structures. The relation between electrical and optical properties of laser diodes; epitaxial technology; binary III-V compounds; and diode fabrication are also consider

  14. mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation.

    Science.gov (United States)

    Lin, Yu; Wang, Binsheng; Shan, Wei; Tan, Yamin; Feng, Jingjing; Xu, Lin; Wang, Limengmeng; Han, Biqing; Zhang, Mingming; Yu, Jian; Yu, Xiaohong; Huang, He

    2017-11-10

    The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus-host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD. RAPA treatment can enhance the suppressive function of PMN-MDSCs via up-regulation of arginase1 (Arg1) and induced nitric oxide synthase (iNOS) at later time points. Moreover, RAPA can also induce a strong immunosuppressive function in PMN-MDSCs from murine bone marrow in vitro, but has a contrary effect on monocytic MDSCs (M-MDSCs). We found that RAPA-treated PMN-MDSCs can restrain the differentiation of Th1/Th2 cells and promote induction of regulatory T cells in in vitro studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. White LED motorcycle headlamp design

    Science.gov (United States)

    Sun, Wen-Shing

    2015-09-01

    The motorcycle headlamp is composed of a white LED module, an elliptical reflector, a parabolic reflector and a toric lens. We use non-sequential ray to improve the optical efficiency of the compound reflectors. Using the toric lens can meet ECE_113 regulation and obtain a good uniformity.

  16. Architecture-Led Safety Process

    Science.gov (United States)

    2016-12-01

    Contents Acknowledgments iv Abstract v 1 Introduction 1 2 Architecture -Led Processes and ALSA 2 3 ALSA Practices 5 3.1 Example System 8 4 Identify... Architecture Models 13 5 Identify Operational Hazards and Hazard Contributors 15 5.1 System Partitioning 15 5.2 Operational Context as a Control

  17. Testing intravitreal toxicity of rapamycin in rabbit eyes Toxicidade intravítrea da rapamicina em olhos de coelhos

    Directory of Open Access Journals (Sweden)

    Roberta Pereira de Almeida Manzano

    2009-02-01

    Full Text Available PURPOSE: To evaluate retinal toxicity of varying doses of rapamycin when injected intravitreally in rabbits. Rapamycin is a potent immunosuppressive agent with significant antitumor and antiangiogenic properties, clinically approved for prevention of organ transplant rejection. METHODS: Twelve New Zealand albino rabbits were divided into four groups. Four different doses of rapamycin were prepared in 0.1 ml: 20 µg, 50 µg, 200 µg, and 1000 µg. Each concentration was injected in one eye of three rabbits, and 0.1 ml volume of sterile BSS was injected into the contralateral eye of the three rabbits. Slit-lamp and fundoscopic examinations were performed and the animals were observed for 2 weeks for signs of infection, inflammation, and toxicity. A baseline ERG was performed before drug treatment and at day 14, after which the rabbits were euthanized. Histology of the enucleated eyes was studied to look for retinal toxicity. RESULTS: ERG results showed some decrease in scotopic response; however this was not dose related. ERG results were normal at 20 µg. Histological results showed no retinal toxicity in all groups. CONCLUSION: Although ERG changes were identified at dosages between 50-1000 µg, the histology of all groups up to 1000 µg did not show any discernable abnormalities.OBJETIVO: Avaliar a toxicidade da injeção intravítrea de diferentes doses de rapamicina para a retina de coelhos. Rapamicina é uma potente droga imunossupressora aprovada clinicamente para a prevenção da rejeição de transplantes de orgãos. MÉTODOS: Doze coelhos albinos da Nova Zelândia foram usados neste estudo. Foram divididos em quatro grupos. Quatro diferentes doses de rapamicina foram preparadas nas seguintes concentrações: 20 µg, 50 µg, 200 µg, 1000 µg. Foram realizadas injeções intravítreas de 0,1 ml de cada concentração em um olho de três coelhos e 0,1 ml de solução salina foi injetada no olho contralateral de cada coelho. Foram

  18. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1.

    Science.gov (United States)

    Li, Hui; Li, Xiaoqiang; Liu, Shuang; Guo, Lei; Zhang, Bo; Zhang, Jubo; Ye, Qinghai

    2017-12-01

    Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920-1933). © 2017 by the American Association for the Study of Liver Diseases.

  19. LED lamp power management system and method

    Science.gov (United States)

    Gaines, James; Clauberg, Bernd; Van Erp, Josephus A. M.

    2013-03-19

    An LED lamp power management system and method including an LED lamp having an LED controller 58; a plurality of LED channels 60 operably connected to the LED controller 58, each of the plurality of LED channels 60 having a channel switch 62 in series with at least one shunted LED circuit 83, the shunted LED circuit 83 having a shunt switch 68 in parallel with an LED source 80. The LED controller 58 reduces power loss in one of the channel switch 62 and the shunt switch 68 when LED lamp electronics power loss (P.sub.loss) exceeds an LED lamp electronics power loss limit (P.sub.lim); and each of the channel switches 62 receives a channel switch control signal 63 from the LED controller 58 and each of the shunt switches 68 receives a shunt switch control signal 69 from the LED controller 58.

  20. LED lamp color control system and method

    Science.gov (United States)

    Gaines, James; Clauberg, Bernd; Van Erp, Josephus A.M.

    2013-02-05

    An LED lamp color control system and method including an LED lamp having an LED controller 58; and a plurality of LED channels 60 operably connected to the LED controller 58, each of the plurality of LED channels 60 having a channel switch 62 in series with at least one shunted LED circuit 83, the shunted LED circuit 83 having a shunt switch 68 in parallel with an LED source 80. The LED controller 58 determines whether the LED source 80 is in a feedback controllable range, stores measured optical flux for the LED source 80 when the LED source 80 is in the feedback controllable range, and bypasses storing the measured optical flux when the LED source 80 is not in the feedback controllable range.

  1. CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Li L

    2016-09-01

    Full Text Available Leiming Li,1,* Yan Li,2,* Jiansong Zhao,2 Shuli Fan,3 Liguo Wang,1 Xu Li1 1Department of Joint Surgery and Sports Medicine, The First Affiliated Hospital, 2Department of Spine and Joint Surgery, Sheng Jing Hospital, 3Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China *These authors contributed equally to this work Abstract: Osteosarcoma (OS is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines. Autophagic vacuoles could be observed in electron microscopy and 3-methyladenine prevented cell death mediated by CX-5461. Moreover, it significantly augmented phosphorylated AMP-Activated Protein Kinases α (p-AMPK α. (Thr172 expression in U2-OS cells and decreased p-Akt (Ser473 expression in MNNG cells, respectively, which repressed their downstream effector, mammalian target of rapamycin. On the other hand, CX-5461 increased p53 accumulation and messenger RNA level of its target genes, p21, MDM2, and Sestrin1/2 in U2-OS cells. Knockdown of p53 expression markedly impaired cell death as well as the expression of light chain 3-II and p21 induced by CX-5461. It also significantly enhanced doxorubicin-mediated cytotoxic effect in vitro and in vivo together with additive expression of p53, p21, and light chain 3-II in U2-OS cells. Our data indicate that CX-5461 might induce autophagy via mammalian target of rapamycin-associated signaling pathways

  2. Branched Chain Amino Acid Suppresses Hepatocellular Cancer Stem Cells through the Activation of Mammalian Target of Rapamycin

    Science.gov (United States)

    Nishitani, Shinobu; Horie, Mayumi; Ishizaki, Sonoko; Yano, Hirohisa

    2013-01-01

    Differentiation of cancer stem cells (CSCs) into cancer cells causes increased sensitivity to chemotherapeutic agents. Although inhibition of mammalian target of rapamycin (mTOR) leads to CSC survival, the effect of branched chain amino acids (BCAAs), an mTOR complex 1 (mTORC1) activator remains unknown. In this study, we examined the effects of BCAA on hepatocellular carcinoma (HCC) cells expressing a hepatic CSC marker, EpCAM. We examined the effects of BCAA and/or 5-fluorouracil (FU) on expression of EpCAM and other CSC-related markers, as well as cell proliferation in HCC cells and in a xenograft mouse model. We also characterized CSC-related and mTOR signal-related molecule expression and tumorigenicity in HCC cells with knockdown of Rictor or Raptor, or overexpression of constitutively active rheb (caRheb). mTOR signal-related molecule expression was also examined in BCAA-treated HCC cells. In-vitro BCAA reduced the frequency of EpCAM-positive cells and improved sensitivity to the anti-proliferative effect of 5-FU. Combined 5-FU and BCAA provided better antitumor efficacy than 5-FU alone in the xenograft model. Stimulation with high doses of BCAA activated mTORC1. Knockdown and overexpression experiments revealed that inhibition of mTOR complex 2 (mTORC2) or activation of mTORC1 led to decreased EpCAM expression and little or no tumorigenicity. BCAA may enhance the sensitivity to chemotherapy by reducing the population of cscs via the mTOR pathway. This result suggests the utility of BCAA in liver cancer therapy. PMID:24312415

  3. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions.

    Science.gov (United States)

    O'Neil, T K; Duffy, L R; Frey, J W; Hornberger, T A

    2009-07-15

    Resistance exercise induces a hypertrophic response in skeletal muscle and recent studies have begun to shed light on the molecular mechanisms involved in this process. For example, several studies indicate that signalling by the mammalian target of rapamycin (mTOR) is necessary for a hypertrophic response. Furthermore, resistance exercise has been proposed to activate mTOR signalling through an upstream pathway involving the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB); however, this hypothesis has not been thoroughly tested. To test this hypothesis, we first evaluated the temporal pattern of signalling through PI3K-PKB and mTOR following a bout of resistance exercise with eccentric contractions (EC). Our results indicated that the activation of signalling through PI3K-PKB is a transient event (12 h). Furthermore, inhibition of PI3K-PKB activity did not prevent the activation of mTOR signalling by ECs, indicating that PI3K-PKB is not part of the upstream regulatory pathway. These observations led us to investigate an alternative pathway for the activation of mTOR signalling involving the synthesis of phosphatidic acid (PA) by phospholipase D (PLD). Our results demonstrate that ECs induce a sustained elevation in [PA] and inhibiting the synthesis of PA by PLD prevented the activation of mTOR. Furthermore, we determined that similar to ECs, PA activates mTOR signalling through a PI3K-PKB-independent mechanism. Combined, the results of this study indicate that the activation of mTOR following eccentric contractions occurs through a PI3K-PKB-independent mechanism that requires PLD and PA.

  4. Branched chain amino acid suppresses hepatocellular cancer stem cells through the activation of mammalian target of rapamycin.

    Directory of Open Access Journals (Sweden)

    Shinobu Nishitani

    Full Text Available Differentiation of cancer stem cells (CSCs into cancer cells causes increased sensitivity to chemotherapeutic agents. Although inhibition of mammalian target of rapamycin (mTOR leads to CSC survival, the effect of branched chain amino acids (BCAAs, an mTOR complex 1 (mTORC1 activator remains unknown. In this study, we examined the effects of BCAA on hepatocellular carcinoma (HCC cells expressing a hepatic CSC marker, EpCAM. We examined the effects of BCAA and/or 5-fluorouracil (FU on expression of EpCAM and other CSC-related markers, as well as cell proliferation in HCC cells and in a xenograft mouse model. We also characterized CSC-related and mTOR signal-related molecule expression and tumorigenicity in HCC cells with knockdown of Rictor or Raptor, or overexpression of constitutively active rheb (caRheb. mTOR signal-related molecule expression was also examined in BCAA-treated HCC cells. In-vitro BCAA reduced the frequency of EpCAM-positive cells and improved sensitivity to the anti-proliferative effect of 5-FU. Combined 5-FU and BCAA provided better antitumor efficacy than 5-FU alone in the xenograft model. Stimulation with high doses of BCAA activated mTORC1. Knockdown and overexpression experiments revealed that inhibition of mTOR complex 2 (mTORC2 or activation of mTORC1 led to decreased EpCAM expression and little or no tumorigenicity. BCAA may enhance the sensitivity to chemotherapy by reducing the population of cscs via the mTOR pathway. This result suggests the utility of BCAA in liver cancer therapy.

  5. Rapamycin combined with anti-CD45RB mAb and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation.

    Directory of Open Access Journals (Sweden)

    Nicola Gagliani

    Full Text Available BACKGROUND: A large pool of preexisting alloreactive effector T cells can cause allogeneic graft rejection following transplantation. However, it is possible to induce transplant tolerance by altering the balance between effector and regulatory T (Treg cells. Among the various Treg-cell types, Foxp3(+Treg and IL-10-producing T regulatory type 1 (Tr1 cells have frequently been associated with tolerance following transplantation in both mice and humans. Previously, we demonstrated that rapamycin+IL-10 promotes Tr1-cell-associated tolerance in Balb/c mice transplanted with C57BL/6 pancreatic islets. However, this same treatment was unsuccessful in C57BL/6 mice transplanted with Balb/c islets (classified as a stringent transplant model. We accordingly designed a protocol that would be effective in the latter transplant model by simultaneously depleting effector T cells and fostering production of Treg cells. We additionally developed and tested a clinically translatable protocol that used no depleting agent. METHODOLOGY/PRINCIPAL FINDINGS: Diabetic C57BL/6 mice were transplanted with Balb/c pancreatic islets. Recipient mice transiently treated with anti-CD45RB mAb+rapamycin+IL-10 developed antigen-specific tolerance. During treatment, Foxp3(+Treg cells were momentarily enriched in the blood, followed by accumulation in the graft and draining lymph node, whereas CD4(+IL-10(+IL-4(- T (i.e., Tr1 cells localized in the spleen. In long-term tolerant mice, only CD4(+IL-10(+IL-4(- T cells remained enriched in the spleen and IL-10 was key in the maintenance of tolerance. Alternatively, recipient mice were treated with two compounds routinely used in the clinic (namely, rapamycin and G-CSF; this drug combination promoted tolerance associated with CD4(+IL-10(+IL-4(- T cells. CONCLUSIONS/SIGNIFICANCE: The anti-CD45RB mAb+rapamycin+IL-10 combined protocol promotes a state of tolerance that is IL-10 dependent. Moreover, the combination of rapamycin+G-CSF induces

  6. Inhibition of p70S6K does not mimic the enhancement of Akt phosphorylation by rapamycin.

    Science.gov (United States)

    Wang, Xuerong; Yue, Ping; Tao, Hui; Sun, Shi-Yong

    2017-08-01

    It has been suggested that the mTOR complex 1 (mTORC1)/p70S6K axis represses upstream PI3K/Akt signaling through phosphorylation of IRS-1 and its subsequent degradation. One potential and current model that explains Akt activation induced by the mTOR inhibitor rapamycin is the relief of mTORC1/p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling, although this has not been experimentally proven. In this study, we found that chemical inhibition of p70S6K did not increase Akt phosphorylation. Surprisingly, knockdown of p70S6K even substantially inhibited Akt phosphorylation. Hence, p70S6K inhibition clearly does not mimic the activation of Akt by rapamycin. Inhibition or enforced activation of p70S6K did not affect the ability of rapamycin to increase Akt phosphorylation. Moreover, inhibition of mTORC1 with either rapamycin or raptor knockdown did not elevate IRS-1 levels, despite potently increasing Akt phosphorylation. Critically, knockdown or knockout of IRS-1 or IRS-2 failed to abolish the ability of rapamycin to increase Akt phosphorylation. Therefore, IRS-1 and IRS-2 are not essential for mediating rapamycin-induced Akt activation. Collectively, our findings suggest that Akt activation by rapamycin or mTORC1 inhibition is unlikely due to relief of p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling.

  7. Potential role for mammalian target of rapamycin inhibitors as first-line therapy in hormone receptor–positive advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Beck JT

    2015-12-01

    Full Text Available J Thaddeus Beck Highlands Oncology Group, Fayetteville, AR, USA Abstract: Despite advances in cytotoxic chemotherapy and targeted therapies, 5-year ­survival rates remain low for patients with advanced breast cancer at diagnosis. This highlights the limited effectiveness of current treatment options. An improved understanding of cellular functions associated with the development and progression of breast cancer has resulted in the creation of a number of novel targeted molecular therapies. However, more work is needed to improve outcomes, particularly in the first-line recurrent or metastatic hormone receptor–positive breast cancer setting. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR pathway is a major intracellular signaling pathway that is often upregulated in breast cancer, and overactivation of this pathway has been associated with primary or developed resistance to endocrine treatment. Clinical data from the Phase III Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2 study of the mTOR inhibitor everolimus combined with exemestane in hormone receptor–positive advanced breast cancer were very promising, highlighting the potential role of mTOR inhibitors in combination with endocrine therapies as a first-line treatment option for these patients. It is hoped that the use of mTOR inhibitors combined with current standard-of-care endocrine therapies, such as aromatase inhibitors, in the first-line advanced breast cancer setting may result in greater antitumor effects and also delay or reverse treatment resistance. Keywords: mammalian target of rapamycin, everolimus, hormone receptor–positive breast cancer, first-line

  8. Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

    Science.gov (United States)

    Nair, Vijayalekshmi; Sreevalsan, Sandeep; Basha, Riyaz; Abdelrahim, Maen; Abudayyeh, Ala; Rodrigues Hoffman, Aline; Safe, Stephen

    2014-01-01

    The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively. PMID:25143389

  9. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  10. Life-long rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling

    Science.gov (United States)

    Majumder, Smita; Caccamo, Antonella; Medina, David X.; Benavides, Adriana D.; Javors, Martin A.; Kraig, Ellen; Strong, Randy; Richardson, Arlan; Oddo, Salvatore

    2012-01-01

    Summary Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1β, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. It remains to be established, however, whether extending lifespan with rapamycin is accompanied by an improvement in cognitive function. In this study, we show that 18-month-old mice treated with rapamycin starting at two months of age perform significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15-month-old mice with pre-existing, age-dependent learning and memory deficits. We further show that the rapamycin-mediated improvement in learning and memory is associated with a decrease in IL-1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age-dependent learning and memory deficits. PMID:22212527

  11. Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability.

    Science.gov (United States)

    Sivertsson, Ebba; Friederich-Persson, Malou; Öberg, Carl M; Fasching, Angelica; Hansell, Peter; Rippe, Bengt; Palm, Fredrik

    2017-09-27

    Increased kidney oxygen consumption causing tissue hypoxia is suggested as a common pathway to chronic kidney disease. Mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors, e.g. rapamycin, are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. We therefore investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin and the functional consequences studied fourteen days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1), and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates to increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway to development of chronic kidney disease, mTOR inhibition to patients with pre-existing nephropathy should be used with caution since it may accelerate the progression of disease. Copyright © 2017, American Journal of Physiology-Renal Physiology.

  12. Rapamycin-Sensitive Late-LTP is Enhanced in the Hippocampus of IL-6 Transgenic Mice.

    Science.gov (United States)

    Olde Engberink, Anneke; Hernandez, Ruben; de Graan, Pierre; Gruol, Donna L

    2017-11-10

    The neuroimmune factor IL-6 has been shown to regulate hippocampal long-term potentiation (LTP), an activity-dependent enhancement of synaptic transmission that plays a central role in memory and learning. This IL-6 action was demonstrated with relatively short IL-6 exposure, and may reflect physiological actions of IL-6. IL-6 is also expressed chronically at elevated levels in the central nervous system (CNS) under pathological conditions such as neurological disorders. Little is known about the effects IL-6 on LTP under such conditions, an issue that we are addressing by electrophysiological recordings from CA1 pyramidal neurons of hippocampal slices from transgenic mice that persistently express elevated levels of IL-6 in the CNS (IL-6 tg). The current studies examined the long-lasting phase of LTP (late LTP; L-LTP) and the potential involvement mammalian target of rapamycin (mTOR), a known regulator of L-LTP and a downstream partner of IL-6 signal transduction pathways. Results show that basal synaptic transmission and L-LTP were increased in hippocampal slices from IL-6 tg mice compared to slices from non-transgenic (non-tg) control mice. An inhibitor of mTOR, rapamycin, reduced L-LTP in slices from both genotypes, and eliminated the difference in magnitude of L-LTP between IL-6 and non-tg hippocampus. There were no genotypic effect of rapamycin on basal synaptic transmission, but synaptic responses during the LTP induction protocol were reduced in IL-6 tg slices, an effect that could contribute to the reduction of L-LTP in the IL-6 tg slices. These results indicate that persistently increased levels of IL-6 can lead to alterations in mTOR regulation of L-LTP, possibly affecting learning and memory. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Aortic eNOS expression and phosphorylation in Apo-E knockout mice: differing effects of rapamycin and simvastatin.

    Science.gov (United States)

    Naoum, Joseph J; Zhang, Shu; Woodside, Kenneth J; Song, Wei; Guo, Qian; Belalcazar, Ligia M; Hunter, Glenn C

    2004-08-01

    The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. Apo-E -/- mice (n = 38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean +/- SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents. Copyright 2004 Elsevier Inc.

  14. Critical analysis of the potential for therapeutic targeting of mammalian target of rapamycin (mTOR in gastric cancer

    Directory of Open Access Journals (Sweden)

    Inokuchi M

    2014-04-01

    Full Text Available Mikito Inokuchi,1 Keiji Kato,1 Kazuyuki Kojima,2 Kenichi Sugihara1 1Department of Surgical Oncology, 2Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, Tokyo, Japan Abstract: Multidisciplinary treatment including chemotherapy has become the global standard of care for patients with metastatic gastric cancer (mGC; nonetheless, survival remains poor. Although many molecular-targeted therapies have been developed for various cancers, only anti-HER2 treatment has produced promising results in patients with mGC. Mammalian target of rapamycin (mTOR plays a key role in cell proliferation, antiapoptosis, and metastasis in signaling pathways from the tyrosine kinase receptor, and its activation has been demonstrated in gastric cancer (GC cells. This review discusses the clinical relevance of mTOR in GC and examines its potential as a therapeutic target in patients with mGC. Preclinical studies in animal models suggest that suppression of the mTOR pathway inhibits the proliferation of GC cells and delays tumor progression. The mTOR inhibitor everolimus has been evaluated as second- or third-line treatment in clinical trials. Adverse events were well tolerated although the effectiveness of everolimus alone was limited. Everolimus is now being evaluated in combination with chemotherapy in Phase III clinical studies in this subgroup of patients. Two Phase III studies include exploratory biomarker research designed to evaluate the predictive value of the expression or mutation of molecules related to the Akt/mTOR signaling pathway. These biomarker studies may lead to the realization of targeted therapy for selected patients with mGC in the future. Keywords: gastric cancer, mTOR, everolimus

  15. [Combined rapamycin eye drop in nanometer vector and poly (lactic acid) wafers of cyclosporine A effectively prevents high-risk corneal allograft rejection in rabbits].

    Science.gov (United States)

    Jiang, Wei; Sun, Hui-Min; Li, Xiao-Rong; Yuan, Xu-Bo; Wang, Yu-Qing; Zhang, Shu-Xian; Tian, En-Jiang; Yuan, Jia-Qin

    2009-06-01

    To evaluate the combined effect of topical rapamycin (RAPA) eye drop in nanometer vector and poly (lactic acid) (PLA) wafers of cyclosporine A (CsA) in the prevention of acute allograft rejection after rabbit corneal transplantation. Methods It was an experimental study. RAPA was incorporated into the nanometer particles and CsA was incorporated into PLA wafers. A was syngeneic control whose both donor and recipient are New Zealand rabbit. Gray donor corneas were implanted into the 102 recipients of New Zealand albino rabbits with corneal neovascularization who were randomly divided into B, C, D, E, F, G 6 groups to receive the different types of therapy: B was no therapy control; C was eye drop of nanometer vector but no RAPA twice a day, 28 days; D was PLA wafers in the anterior chamber of rabbit eyes but no drugs; E was 0.5% RAPA eye drop of nanometer vector twice a day, 28 days; F was PLA wafers of CsA in the anterior chamber of rabbit eyes; G was PLA wafers of CsA in the anterior chamber of rabbit eyes and 0.5% RAPA eye drop of nanometer vector eye drop twice a day for 28 days together. Postoperative evaluation included slit-lamp biomicroscopy, histopathology and immunohistology, Cytokines related with neovascularization and immunosuppression in the corneal tissue by RT-PCR. The graft survival was assessed by One-Way ANOVA and q test. Corneal allograft survival time: A (100.00 +/- 0.00), B (8.44 +/- 1.24), C (8.89 +/- 2.57), D (8.56 +/- 2.30), E (43.11 +/- 5.58), F (43.67 +/- 9.54), G (72.00 +/- 15.34) d. Group G led to a statistically significant prolongation of transplant survival and was superior than group E and F which was a statistical prolongation compared with group B, C and D (qGE = 11.42, qGF = 11.24, qEB = 13.64, qEC = 13.38, qED = 13.46, qFB = 13.82, qFC = 13.56, qFD = 13.64; P < 0.01). Immunohistopathologically, the grafts were subjected to an immune response contained a dense infiltrate of neutrophils, CD4+ and CD8+ T lymphocytes in the group B

  16. Two mTOR inhibitors, rapamycin and Torin 1, differentially regulate iron-induced generation of mitochondrial ROS.

    Science.gov (United States)

    Huang, Hui; Chen, Jun; Lu, Huiru; Zhou, Mengxue; Chai, Zhifang; Hu, Yi

    2017-12-01

    It is generally believed that gene-environment interaction may contribute to neurodegeneration. Of particular note is that iron overload may be one of the risk factors for neurodegeneration. However, the mechanisms underlying iron-associated neurotoxicity are not fully understood. Here we explored the effects of mechanistic target of rapamycin (mTOR) inhibition in iron-stressed human neuroblastoma cells. Two mTOR inhibitors, rapamycin and Torin 1, had similar effects in cells exposed to a relatively low concentration of iron. At a higher concentration of iron, Torin 1, instead of rapamycin, could further aggravate iron-induced cytotoxicity, and mitochondrial ROS levels were significantly higher in Torin 1-treated cells. These results suggest that mTOR inhibition may not be able to alleviate iron-induced neurotoxicity.

  17. Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin

    DEFF Research Database (Denmark)

    Paul, David S; Grevengoed, Trisha J; Pascual, Florencia

    2014-01-01

    In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1(H-/-)), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy...... of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i.......p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin...

  18. Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1.

    Directory of Open Access Journals (Sweden)

    Gokhan Demirkan

    Full Text Available Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR complex 1 (mTORC1, which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood.We developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides from rat liver homogenates. Using the anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated by refeeding following 48 hr of starvation. Using protein and peptide fractionation methods, TiO(2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 62 new rapamycin-responsive candidate phosphorylation sites. Among these were PRAS40, gephyrin, and AMP kinase 2. We observed similar proportions of increased and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTOR pathway components among rapamycin-sensitive phosphopeptide candidates.In addition to identifying potential new mTORC1-mediated phosphorylation events, and providing information relevant to the biology of this signaling network, our experimental and analytical approaches indicate the feasibility of large-scale phosphoproteomic profiling of tissue samples to study physiological signaling events in vivo.

  19. Enhancement of rapamycin production by metabolic engineering in Streptomyces hygroscopicus based on genome-scale metabolic model.

    Science.gov (United States)

    Dang, Lanqing; Liu, Jiao; Wang, Cheng; Liu, Huanhuan; Wen, Jianping

    2017-02-01

    Rapamycin, as a macrocyclic polyketide with immunosuppressive, antifungal, and anti-tumor activity produced by Streptomyces hygroscopicus, is receiving considerable attention for its significant contribution in medical field. However, the production capacity of the wild strain is very low. Hereby, a computational guided engineering approach was proposed to improve the capability of rapamycin production. First, a genome-scale metabolic model of Streptomyces hygroscopicus ATCC 29253 was constructed based on its annotated genome and biochemical information. The model consists of 1003 reactions, 711 metabolites after manual refinement. Subsequently, several potential genetic targets that likely guaranteed an improved yield of rapamycin were identified by flux balance analysis and minimization of metabolic adjustment algorithm. Furthermore, according to the results of model prediction, target gene pfk (encoding 6-phosphofructokinase) was knocked out, and target genes dahP (encoding 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase) and rapK (encoding chorismatase) were overexpressed in the parent strain ATCC 29253. The yield of rapamycin increased by 30.8% by knocking out gene pfk and increased by 36.2 and 44.8% by overexpression of rapK and dahP, respectively, compared with parent strain. Finally, the combined effect of the genetic modifications was evaluated. The titer of rapamycin reached 250.8 mg/l by knockout of pfk and co-expression of genes dahP and rapK, corresponding to a 142.3% increase relative to that of the parent strain. The relationship between model prediction and experimental results demonstrates the validity and rationality of this approach for target identification and rapamycin production improvement.

  20. Practical lighting design with LEDs

    CERN Document Server

    Lenk, Ron

    2011-01-01

    "This book covers all of the information needed to design LEDs into end-products. It is a practical guide, primarily explaning how things are done by practicing engineers. Equations are used only for practical calculations, and are kept to the level of high-school algebra. There are numerous drawings and schematics showing how things such as measurements are actually made, and showing curcuits that actually work. There are practical notes and examples embedded in the text that give pointers and how-to guides on many of the book's topics. After reading each chapter of the book, readers will have the knowledge to implement practical designs. This book will be kept as a reference tool for years to come"--

  1. Chronic exposure to rapamycin and episodic serum starvation modulate ageing of human fibroblasts in vitro.

    Science.gov (United States)

    Sodagam, Lakshman; Lewinska, Anna; Wnuk, Maciej; Rattan, Suresh I S

    2017-10-01

    Mild stress-induced activation of stress response (SR) pathways, such as autophagy, heat shock response, oxidative SR, DNA damage response, and inflammatory response, can be potentially health beneficial. Using the model system of cellular ageing and replicative senescence in vitro, we have studied the ageing modulatory effects of the two conditions, rapamycin and serum starvation. Chronic exposure to 0.1, 1 and 10 nM rapamycin positively modulated the survival, growth, morphology, telomere length, DNA methylation levels, 8-oxo-dG level in DNA, N6-methyl-adenosine level in RNA, and ethanol stress tolerance of serially passaged normal human skin fibroblasts. Furthermore, episodic (once a week) serum starvation of human skin fibroblasts extended their replicative lifespan by about 22%, along with the maintenance of early passage youthful morphology even in late passage cultures. Although the results of this study may be considered preliminary, it can be inferred that intermittent and episodic induction of SR, rather than chronic up-regulation of SR, is more effective and applicable in the practice of hormesis for healthy ageing and longevity.

  2. Chemical Genetics of Rapamycin-Insensitive TORC2 in S. cerevisiae

    Directory of Open Access Journals (Sweden)

    Joseph I. Kliegman

    2013-12-01

    Full Text Available Current approaches for identifying synergistic targets use cell culture models to see if the combined effect of clinically available drugs is better than predicted by their individual efficacy. New techniques are needed to systematically and rationally identify targets and pathways that may be synergistic targets. Here, we created a tool to screen and identify molecular targets that may synergize with new inhibitors of target of rapamycin (TOR, a conserved protein that is a major integrator of cell proliferation signals in the nutrient-signaling pathway. Although clinical results from TOR complex 1 (TORC1-specific inhibition using rapamycin analogs have been disappointing, trials using inhibitors that also target TORC2 have been promising. To understand this increased therapeutic efficacy and to discover secondary targets for combination therapy, we engineered Tor2 in S. cerevisiae to accept an orthogonal inhibitor. We used this tool to create a chemical epistasis miniarray profile (ChE-MAP by measuring interactions between the chemically inhibited Tor2 kinase and a diverse library of deletion mutants. The ChE-MAP identified known TOR components and distinguished between TORC1- and TORC2-dependent functions. The results showed a TORC2-specific interaction with the pentose phosphate pathway, a previously unappreciated TORC2 function that suggests a role for the complex in balancing the high energy demand required for ribosome biogenesis.

  3. Target of rapamycin signaling orchestrates growth-defense trade-offs in plants.

    Science.gov (United States)

    De Vleesschauwer, David; Filipe, Osvaldo; Hoffman, Gena; Seifi, Hamed Soren; Haeck, Ashley; Canlas, Patrick; Van Bockhaven, Jonas; De Waele, Evelien; Demeestere, Kristof; Ronald, Pamela; Hofte, Monica

    2018-01-01

    Plant defense to microbial pathogens is often accompanied by significant growth inhibition. How plants merge immune system function with normal growth and development is still poorly understood. Here, we investigated the role of target of rapamycin (TOR), an evolutionary conserved serine/threonine kinase, in the plant defense response. We used rice as a model system and applied a combination of chemical, genetic, genomic and cell-based analyses. We demonstrate that ectopic expression of TOR and Raptor (regulatory-associated protein of mTOR), a protein previously demonstrated to interact with TOR in Arabidopsis, positively regulates growth and development in rice. Transcriptome analysis of rice cells treated with the TOR-specific inhibitor rapamycin revealed that TOR not only dictates transcriptional reprogramming of extensive gene sets involved in central and secondary metabolism, cell cycle and transcription, but also suppresses many defense-related genes. TOR overexpression lines displayed increased susceptibility to both bacterial and fungal pathogens, whereas plants with reduced TOR signaling displayed enhanced resistance. Finally, we found that TOR antagonizes the action of the classic defense hormones salicylic acid and jasmonic acid. Together, these results indicate that TOR acts as a molecular switch for the activation of cell proliferation and plant growth at the expense of cellular immunity. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  4. PEGylated lipid bilayer-wrapped nano-graphene oxides for synergistic co-delivery of doxorubicin and rapamycin to prevent drug resistance in cancers

    Science.gov (United States)

    Thapa, Raj Kumar; Byeon, Jeong Hoon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2017-07-01

    Nano-graphene oxide (nGO) is a carbon allotrope studied for its potential as carrier for chemotherapeutic delivery and its photoablation effects. However, interaction of nGO with blood components and the subsequent toxicities warrant a hybrid system for effective cancer drug delivery. Combination chemotherapy aids in effective cancer treatment and prevention of drug resistance. Therefore, in this study, we attempted to prepare polyethylene glycosylated (PEGylated) lipid bilayer-wrapped nGO co-loaded with doxorubicin (DOX) and rapamycin (RAPA), GOLDR, for the prevention and treatment of resistant cancers. Our results revealed a stable GOLDR formulation with appropriate particle size (∼170 nm), polydispersity (∼0.19) and drug loading. Free drug combination (DOX and RAPA) presented synergistic anticancer effects in MDA-MB-231, MCF-7, and BT474 cells. Treatment with GOLDR formulation maintained this synergism in treated cancer cells, which was further enhanced by the near infrared (NIR) laser irradiation-induced photothermal effects of nGO. Higher chromatin condensation and apoptotic body formation, and enhanced protein expression of apoptosis-related markers (Bax, p53, p21, and c-caspase 3) following GOLDR treatment in the presence of NIR laser treatment clearly suggests its superiority in effective chemo-photothermal therapy of resistant cancers. The hybrid nanosystem that we developed provides a basis for the effective use of GOLDR treatment in the prevention and treatment of resistant cancer types.

  5. Implementation of PIC Based LED Displays

    OpenAIRE

    Htet Htet Thit San; Chaw Myat Nwe; Hla Myo Tun

    2014-01-01

    This paper explains the project which is a special kind of LED Display Board for performing dance movement according to the rhythm of music. Nowadays, LED display boards are widely used in advertising and other applications. LED display boards can also be used indoors or outdoors. The objective of this system is to design a display panel by using several dozens of LED matrix display. The display pattern can desire to be changed easily and modified by the user. This LED display...

  6. MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.

    Science.gov (United States)

    Zhang, Zi-Wei; Guo, Rui-Wei; Lv, Jin-Lin; Wang, Xian-Mei; Ye, Jin-Shan; Lu, Ni-Hong; Liang, Xing; Yang, Li-Xia

    2017-04-29

    Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. LEDs light up the world

    Energy Technology Data Exchange (ETDEWEB)

    Mather, N.

    2004-06-30

    A lighting system using light-emitting diodes, and privately financed by a Canadian engineering professor at the University of Calgary, has been set up in a village in Nepal in 2000. Since then, through the efforts of the 'Light Up The World' Foundation, established by Dr. Irvine-Halliday, projects have lit up thousands of homes in the Philippines, India, Afghanistan, the Galapagos Islands, Mexico, Sri Lanka, and Angola. Although the goal of the project is primarily to provide lighting for reading and writing for school-children, the project has been the source of many other advantages; creation of enterprise, increased employment, enhanced income, gender equality, and improvements in health and safety among them. Since LED lamps in most cases replace kerosene lamps, the system also has significant environmental benefits. The system as originally envisioned creates electricity by pedal-powered generator, or by solar panels connected to a battery, depending on what is available at each home. Each home is connected to the power supply and supplied with low-energy diode lamps. The lights are extremely efficient and many homes can be equipped with them using less energy than it takes to power a single 100-watt light bulb. 5 photos.

  8. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR pathway.

    Directory of Open Access Journals (Sweden)

    Delia M Talos

    Full Text Available Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1 signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46, phospho-p70S6K (Thr389 and phospho-S6 (Ser235/236, as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308 and phospho-ERK (Thr202/Tyr204. Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures.

  9. Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Helmschrott M

    2017-06-01

    Full Text Available Matthias Helmschrott,1 Rasmus Rivinius,1 Thomas Bruckner,2 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: A calcineurin inhibitor (CNI-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs seems to be attractive in patients after heart transplantation (HTX in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC-based vs cyclosporine-A (CSA-based immunosuppression (in combination with mycophenolate mofetil. However, data regarding renal function after HTX in mTOR/CNI patients remain limited. Aim: Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. Methods: Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR calculated from Modification of Diet in Renal Disease equation. Results: Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant. Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. Conclusion: The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen. Keywords: heart transplantation, cyclosporine A, tacrolimus, risk factors

  10. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application.

    Science.gov (United States)

    Zhao, Pan; Sui, Bing-Dong; Liu, Nu; Lv, Ya-Jie; Zheng, Chen-Xi; Lu, Yong-Bo; Huang, Wen-Tao; Zhou, Cui-Hong; Chen, Ji; Pang, Dan-Lin; Fei, Dong-Dong; Xuan, Kun; Hu, Cheng-Hu; Jin, Yan

    2017-10-01

    Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age-related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti-aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR-based anti-aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  11. In vitro antimicrobial activity of LED irradiation on Pseudomonas aeruginosa.

    Science.gov (United States)

    Petrini, Morena; Trentini, Paolo; Tripodi, Domenico; Spoto, Giuseppe; D'Ercole, Simonetta

    2017-03-01

    Pseudomonas aeruginosa is an opportunistic pathogen responsible of many deaths due to nosocomial pneumonia each year. It is particularly resistant to many different classes of antibiotics and disinfectants. For all these reasons, there is the necessity to find novel approaches of treatment. The aim of this study was to evaluate the effect of 880nm light emitting diodes (LED) irradiation on P. aeruginosa, in vitro. Different LED irradiation parameters (time, energy output and the addition of methylene blue and chlorhexidine) have been tested in order to evaluate the effects on this bacterium. After treatment, the colony forming units per milliliter (CFU mL-1) were recorded and the data were submitted to ANOVA and Bonferroni post hoc tests at a level of significance of 5%. A statistical significant reduction of bacterial count has been registered after 5min of LED irradiation. The antibacterial effect was directly proportional to irradiation time and the output energy. The pre-treatment with methylene blue, seems to be not effective against P. aeruginosa, independently from irradiation parameters. On the contrary, the contemporary action of LED and chlorhexidine has shown a great reduction of bacterial count that was statistical significant respect chlorhexidine and LED alone. The effect of LED irradiation was visible also after 24h, when a lower bacterial count characterized all irradiated samples respect controls. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells.

    Directory of Open Access Journals (Sweden)

    Tatiana N Golovina

    Full Text Available Natural T regulatory cells (Tregs are challenging to expand ex vivo, and this has severely hindered in vivo evaluation of their therapeutic potential. All trans retinoic acid (ATRA plays an important role in mediating immune homeostasis in vivo, and we investigated whether ATRA could be used to promote the ex vivo expansion of Tregs purified from adult human peripheral blood. We found that ATRA helped maintain FOXP3 expression during the expansion process, but this effect was transient and serum-dependent. Furthermore, natural Tregs treated with rapamycin, but not with ATRA, suppressed cytokine production in co-cultured effector T cells. This suppressive activity correlated with the ability of expanded Tregs to induce FOXP3 expression in non-Treg cell populations. Examination of CD45RA+ and CD45RA- Treg subsets revealed that ATRA failed to maintain suppressive activity in either population, but interestingly, Tregs expanded in the presence of both rapamycin and ATRA displayed more suppressive activity and had a more favorable epigenetic status of the FOXP3 gene than Tregs expanded in the presence of rapamycin only. We conclude that while the use of ATRA as a single agent to expand Tregs for human therapy is not warranted, its use in combination with rapamycin may have benefit.

  13. Neuroprotective effect of rapamycin on spinal cord injury via activation of the Wnt/β-catenin signaling pathway

    Directory of Open Access Journals (Sweden)

    Kai Gao

    2015-01-01

    Full Text Available The Wnt/β-catenin signaling pathway plays a crucial role in neural development, axonal guidance, neuropathic pain remission and neuronal survival. In this study, we initially examined the effect of rapamycin on the Wnt/β-catenin signaling pathway after spinal cord injury, by intraperitoneally injecting spinal cord injured rats with rapamycin over 2 days. Western blot analysis and immunofluorescence staining were used to detect the expression levels of β-catenin protein, ca-spase-3 protein and brain-derived neurotrophic factor protein, components of the Wnt/β-catenin signaling pathway. Rapamycin increased the levels of β-catenin and brain-derived neurotrophic factor in the injured spinal cord, improved the pathological morphology at the injury site, reduced the loss of motor neurons, and promoted motor functional recovery in rats after spinal cord injury. Our experimental findings suggest that the neuroprotective effect of rapamycin intervention is mediated through activation of the Wnt/β-catenin signaling pathway after spinal cord injury.

  14. Role of adenosine 5'-monophosphate-activated protein kinase subunits in skeletal muscle mammalian target of rapamycin signaling

    DEFF Research Database (Denmark)

    Deshmukh, Atul S.; Treebak, Jonas Thue; Long, Yun Chau

    2008-01-01

    AMP-activated protein kinase (AMPK) is an important energy-sensing protein in skeletal muscle. Mammalian target of rapamycin (mTOR) mediates translation initiation and protein synthesis through ribosomal S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). AMPK activ...

  15. Co-Localization of Insulin-Like Growth Factor Binding Protein-1, Casein Kinase-2β, and Mechanistic Target of Rapamycin in Human Hepatocellular Carcinoma Cells as Demonstrated by Dual Immunofluorescence and in Situ Proximity Ligation Assay.

    Science.gov (United States)

    Singal, Sahil S; Nygard, Karen; Dhruv, Manthan R; Biggar, Kyle; Abu Shehab, Majida; Shun-Cheng Li, Shawn; Jansson, Thomas; Gupta, Madhulika B

    2017-10-14

    Insulin-like growth factor binding protein (IGFBP)-1 influences fetal growth by modifying insulin-like growth factor-I (IGF-I) bioavailability. IGFBP-1 phosphorylation, which markedly increases its affinity for IGF-I, is regulated by mechanistic target of rapamycin (mTOR) and casein kinase (CSNK)-2. However, the underlying molecular mechanisms remain unknown. We examined the cellular localization and potential interactions of IGFBP-1, CSNK-2β, and mTOR as a prerequisite for protein-protein interaction. Analysis of dual immunofluorescence images indicated a potential perinuclear co-localization between IGFBP-1 and CSNK-2β and a nuclear co-localization between CSNK-2β and mTOR. Proximity ligation assay (PLA) indicated proximity between IGFBP-1 and CSNK-2β as well as mTOR and CSNK-2β but not between mTOR and IGFBP-1. Three-dimensional rendering of the PLA images validated that IGFBP-1 and CSNK-2β interactions were in the perinuclear region and mTOR and CSNK-2β interactions were predominantly perinuclear rather than nuclear as indicated by mTOR and CSNK-2β co-localization. Compared with control, hypoxia and rapamycin treatment showed markedly amplified PLA signals for IGFBP-1 and CSNK-2β (approximately 18-fold, P = 0.0002). Stable isotope labeling with multiple reaction monitoring-mass spectrometry demonstrated that hypoxia and rapamycin treatment increased IGFBP-1 phosphorylation at Ser98/Ser101/Ser119/Ser174 but most considerably (106-fold) at Ser169. We report interactions between CSNK-2β and IGFBP-1 as well as mTOR and CSNK-2β, providing strong evidence of a mechanistic link between mTOR and IGF-I signaling, two critical regulators of cell growth via CSNK-2. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action.

    Science.gov (United States)

    Soliman, Ghada A; Acosta-Jaquez, Hugo A; Dunlop, Elaine A; Ekim, Bilgen; Maj, Nicole E; Tee, Andrew R; Fingar, Diane C

    2010-03-12

    The mammalian target of rapamycin (mTOR) Ser/Thr kinase signals in at least two multiprotein complexes distinguished by their different partners and sensitivities to rapamycin. Acute rapamycin inhibits signaling by mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), which both promote cell growth, proliferation, and survival. Although mTORC2 regulation remains poorly defined, diverse cellular mitogens activate mTORC1 signaling in a manner that requires sufficient levels of amino acids and cellular energy. Before the identification of distinct mTOR complexes, mTOR was reported to autophosphorylate on Ser-2481 in vivo in a rapamycin- and amino acid-insensitive manner. These results suggested that modulation of mTOR intrinsic catalytic activity does not universally underlie mTOR regulation. Here we re-examine the regulation of mTOR Ser-2481 autophosphorylation (Ser(P)-2481) in vivo by studying mTORC-specific Ser(P)-2481 in mTORC1 and mTORC2, with a primary focus on mTORC1. In contrast to previous work, we find that acute rapamycin and amino acid withdrawal markedly attenuate mTORC1-associated mTOR Ser(P)-2481 in cycling cells. Although insulin stimulates both mTORC1- and mTORC2-associated mTOR Ser(P)-2481 in a phosphatidylinositol 3-kinase-dependent manner, rapamycin acutely inhibits insulin-stimulated mTOR Ser(P)-2481 in mTORC1 but not mTORC2. By interrogating diverse mTORC1 regulatory input, we find that without exception mTORC1-activating signals promote, whereas mTORC1-inhibitory signals decrease mTORC1-associated mTOR Ser(P)-2481. These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity and reveal that rapamycin inhibits mTORC1 signaling in vivo by reducing mTORC1 catalytic activity.

  17. Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway.

    Science.gov (United States)

    Lim, Hyung-Kyu; Choi, Young-Ae; Park, Wan; Lee, Taehoon; Ryu, Sung Ho; Kim, Seong-Yong; Kim, Jae-Ryong; Kim, Jung-Hye; Baek, Suk-Hwan

    2003-11-14

    Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the production of nitric oxide, prostaglandin E2, which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.

  18. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature.

    Science.gov (United States)

    Caccamo, Antonella; De Pinto, Vito; Messina, Angela; Branca, Caterina; Oddo, Salvatore

    2014-06-04

    Elevated mammalian target of rapamycin (mTOR) signaling has been found in Alzheimer's disease (AD) patients and is linked to diabetes and aging, two known risk factors for AD. However, whether hyperactive mTOR plays a role in the cognitive deficits associated with AD remains elusive. Here, we genetically reduced mTOR signaling in the brains of Tg2576 mice, a widely used animal model of AD. We found that suppression of mTOR signaling reduced amyloid-β deposits and rescued memory deficits. Mechanistically, the reduction in mTOR signaling led to an increase in autophagy induction and restored the hippocampal gene expression signature of the Tg2576 mice to wild-type levels. Our results implicate hyperactive mTOR signaling as a previous unidentified signaling pathway underlying gene-expression dysregulation and cognitive deficits in AD. Furthermore, hyperactive mTOR signaling may represent a molecular pathway by which aging contributes to the development of AD. Copyright © 2014 the authors 0270-6474/14/347988-11$15.00/0.

  19. Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Lianjun Zhang

    2016-02-01

    Full Text Available Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs and memory precursor cells (MPECs. The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2, regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

  20. LEDs for Street Lighting—Here Today

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-11-29

    Fact sheet that provides a brief overview of the viability of LED street lighting in municipalities and highlights case studies of two cities—Los Angeles and Seattle—that have invested in LED street lighting.

  1. Metallic nanostructures for efficient LED lighting

    NARCIS (Netherlands)

    Lozano, G.; Rodriguez, S. R. K.; Verschuuren, M. A.; J. Gomez Rivas,

    2016-01-01

    Light-emitting diodes (LEDs) are driving a shift toward energy-efficient illumination. Nonetheless, modifying the emission intensities, colors and directionalities of LEDs in specific ways remains a challenge often tackled by incorporating secondary optical components. Metallic nanostructures

  2. Fokusgruppeinterview som led i en evalueringsproces

    DEFF Research Database (Denmark)

    Andersen-Mølgaard, Hanna; Harrit, Ole

    2006-01-01

    Teoretiske begrundelser og perspektiver, responsiv-konstruktivistisk evaluering, fokusgruppeinterview som led i BIKVAmodellen, eksempler, vurdering og perspektivering......Teoretiske begrundelser og perspektiver, responsiv-konstruktivistisk evaluering, fokusgruppeinterview som led i BIKVAmodellen, eksempler, vurdering og perspektivering...

  3. Evaluation of LED vehicular and pedestrian modules.

    Science.gov (United States)

    2009-04-01

    This study was conducted to verify the compliance of vehicular and pedestrian LED traffic signal modules with the Institute : of Transportation Engineers specifications; and to assess drivers preferences of the LED modules. Four vehicular modules ...

  4. The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling.

    Science.gov (United States)

    Yoon, Mee-Sup

    2017-10-27

    The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR). In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

  5. The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease

    Science.gov (United States)

    Talboom, Joshua S; Velazquez, Ramon; Oddo, Salvatore

    2015-01-01

    Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer’s disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD. PMID:28721257

  6. The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer's disease.

    Science.gov (United States)

    Talboom, Joshua S; Velazquez, Ramon; Oddo, Salvatore

    2015-01-01

    Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer's disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD.

  7. Methylglyoxal activates the target of rapamycin complex 2-protein kinase C signaling pathway in Saccharomyces cerevisiae.

    Science.gov (United States)

    Nomura, Wataru; Inoue, Yoshiharu

    2015-04-01

    Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. We show here that methylglyoxal activates the Pkc1-Mpk1 mitogen-activated protein (MAP) kinase cascade in a target of rapamycin complex 2 (TORC2)-dependent manner in the budding yeast Saccharomyces cerevisiae. We demonstrate that TORC2 phosphorylates Pkc1 at Thr(1125) and Ser(1143). Methylglyoxal enhanced the phosphorylation of Pkc1 at Ser(1143), which transmitted the signal to the downstream Mpk1 MAP kinase cascade. We found that the phosphorylation status of Pkc1(T1125) affected the phosphorylation of Pkc1 at Ser(1143), in addition to its protein levels. Methylglyoxal activated mammalian TORC2 signaling, which, in turn, phosphorylated Akt at Ser(473). Our results suggest that methylglyoxal is a conserved initiator of TORC2 signaling among eukaryotes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. eIF4E-Overexpression imparts perillyl alcohol and rapamycin-mediated regulation of telomerase reverse transcriptase.

    Science.gov (United States)

    Sundin, Tabetha; Peffley, Dennis; Hentosh, Patricia

    2013-08-01

    Translation is mediated partly by regulation of free eukaryotic initiation factor 4E (eIF4E) levels through PI3K-Akt-mTOR signaling. Cancer cells treated with the plant-derived perillyl alcohol (POH) or the mechanistic target of rapamycin (mTOR) inhibitor rapamycin dephosphorylate eIF4E-binding protein (4E-BP1) and attenuate cap-dependent translation. We previously showed in cancer cell lines with elevated eIF4E that POH and rapamycin regulate telomerase activity through this pathway. Here, immortalized Chinese hamster ovary (CHO) control cells and CHO cells with forced eIF4E expression (rb4E) were used to elucidate eIF4E's role in telomerase regulation by POH and rapamycin. Despite 5-fold higher eIF4E amounts in rb4E, telomerase activity, telomerase reverse transcriptase (TERT) mRNA, and TERT protein were nearly equivalent in control and rb4E cells. In control cells, telomerase activity, TERT mRNA and protein levels were unaffected by either compound. In contrast, telomerase activity and TERT protein were both attenuated by either agent in rb4E cells, but without corresponding TERT mRNA decreases indicating a translational/post-translational process. S6K, Akt, and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E. Thus, eIF4E-overexpression in rb4E cells enables inhibitory effects of POH and rapamycin on telomerase and TERT protein. Importantly, eIF4E-overexpression modifies cellular protein synthetic processes and gene regulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders.

    Science.gov (United States)

    Burket, Jessica A; Benson, Andrew D; Tang, Amy H; Deutsch, Stephen I

    2014-01-01

    Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+)Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p.×four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Goniometric characterization of LED based greenhouse lighting

    DEFF Research Database (Denmark)

    Thorseth, Anders; Lindén, Johannes; Corell, Dennis Dan

    2015-01-01

    This paper describes a demonstration of goniospectroradiometry for characterizations of new light emitting diode (LED) based luminaries for enhanced photosynthesis in greenhouses. It highlights the differences between measurement of the traditional high pressure sodium (HPS) luminaries and the LED...... based luminaries. The LED based luminaries are compared to traditional HPS luminaries; in terms of energy efficiency with regard to the photosynthetic photon flux, and the LED luminaries were found to be more effective than the HPS luminaries...

  11. Harmonics Monitoring Survey on LED Lamps

    OpenAIRE

    Abdelrahman Ahmed Akila; Kamelia Youssef; Ibrahim Yassin

    2017-01-01

    Light Emitting Diode (LED) lamps are being increasingly used in many applications. These LED lamps operate using a driver, which is a switching device. Hence, LED lamps will be a source of harmonics in the power system. These harmonics if not well treated, may cause severe performance and operational problems. In this paper, harmonics (amplitude and phase angles) generated by both LED lamps and conventional fluorescent lamps will be studied practically. Then they will be analyzed and evaluate...

  12. Impact of rapamycin on phenotype and tolerogenic function of dendritic cells via intravital optical imaging

    Science.gov (United States)

    Luo, Meijie; Zhang, Zhihong

    2014-03-01

    Rapamycin (RAPA) as a unique tolerance-promoting therapeutic drug is crucial to successful clinical organ transplantation. DC (Dendritic cells) play a critical role in antigen presentation to T cells to initiate immune responses involved in tissue rejection. Although the influence of RAPA on DC differentiation and maturation had been reported by some research groups, it is still controversial and unclear right now. In addition, it is also lack of study on investigating the role of DC in DTH reaction via intravital optical imaging. Herein, we investigated the effect of rapamycin on phenotype and function of bone marrow monocyte-derived DC both in vitro and in vivo. In vitro experiments by flow cytometry (FACS) showed that DC displayed decreased cell size and lower expression levels of surface molecule CD80 induced by RAPA; Furthermore, the phagocytic ability to OVA of DC was inhibited by RAPA started from 1 h to 2 h post co-incubation, but recovered after 4 h; In addition, the capacity of DC to activate naïve OT-II T cell proliferation was also inhibited at 3 day post co-incubation, but had no effect at 5 day, the data indicated this effect was reversible when removing the drug. More importantly, the DC-T interaction was monitored both in vitro and in intravital lymph node explant, and showed that RAPA-DC had a significant lower proportion of long-lived (>15min) contacts. Thus, RAPA displayed immunosuppressive to phenotypic and functional maturation of DC, and this phenomenon induced by RAPA may favorable in the clinical organ transplantation in future.

  13. An approach to analyse the specific impact of rapamycin on mRNA-ribosome association

    Directory of Open Access Journals (Sweden)

    Jaquier-Gubler Pascale

    2008-08-01

    Full Text Available Abstract Background Recent work, using both cell culture model systems and tumour derived cell lines, suggests that the differential recruitment into polysomes of mRNA populations may be sufficient to initiate and maintain tumour formation. Consequently, a major effort is underway to use high density microarray profiles to establish molecular fingerprints for cells exposed to defined drug regimes. The aim of these pharmacogenomic approaches is to provide new information on how drugs can impact on the translational read-out within a defined cellular background. Methods We describe an approach that permits the analysis of de-novo mRNA-ribosome association in-vivo during short drug exposures. It combines hypertonic shock, polysome fractionation and high-throughput analysis to provide a molecular phenotype of translationally responsive transcripts. Compared to previous translational profiling studies, the procedure offers increased specificity due to the elimination of the drugs secondary effects (e.g. on the transcriptional read-out. For this pilot "proof-of-principle" assay we selected the drug rapamycin because of its extensively studied impact on translation initiation. Results High throughput analysis on both the light and heavy polysomal fractions has identified mRNAs whose re-recruitment onto free ribosomes responded to short exposure to the drug rapamycin. The results of the microarray have been confirmed using real-time RT-PCR. The selective down-regulation of TOP transcripts is also consistent with previous translational profiling studies using this drug. Conclusion The technical advance outlined in this manuscript offers the possibility of new insights into mRNA features that impact on translation initiation and provides a molecular fingerprint for transcript-ribosome association in any cell type and in the presence of a range of drugs of interest. Such molecular phenotypes defined pre-clinically may ultimately impact on the evaluation of

  14. Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway.

    Science.gov (United States)

    Altamirano, Francisco; Oyarce, César; Silva, Patricio; Toyos, Marcela; Wilson, Carlos; Lavandero, Sergio; Uhlén, Per; Estrada, Manuel

    2009-08-01

    Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (Akt) phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt-inhibitor-X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP(3)) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of beta-myosin heavy chain, alpha-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP(3)/Ca(2+) and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.

  15. Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy.

    Science.gov (United States)

    Pereyra, Andrea S; Hasek, Like Y; Harris, Kate L; Berman, Alycia G; Damen, Frederick W; Goergen, Craig J; Ellis, Jessica M

    2017-11-10

    Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2 M-/- ) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M -/- mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60-90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M -/- hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M -/- mice. Lysine acetylation was reduced by ∼50% in Cpt2M -/- hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M -/- hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M -/- hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion.

    Science.gov (United States)

    Griner, Samantha E; Joshi, Jayashree P; Nahta, Rita

    2013-01-01

    Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease.

    Science.gov (United States)

    Tang, Zhi; Bereczki, Erika; Zhang, Haiyan; Wang, Shan; Li, Chunxia; Ji, Xinying; Branca, Rui M; Lehtiö, Janne; Guan, Zhizhong; Filipcik, Peter; Xu, Shaohua; Winblad, Bengt; Pei, Jin-Jing

    2013-05-31

    Previous evidence from post-mortem Alzheimer disease (AD) brains and drug (especially rapamycin)-oriented in vitro and in vivo models implicated an aberrant accumulation of the mammalian target of rapamycin (mTor) in tangle-bearing neurons in AD brains and its role in the formation of abnormally hyperphosphorylated tau. Compelling evidence indicated that the sequential molecular events such as the synthesis and phosphorylation of tau can be regulated through p70 S6 kinase, the well characterized immediate downstream target of mTor. In the present study, we further identified that the active form of mTor per se accumulates in tangle-bearing neurons, particularly those at early stages in AD brains. By using mass spectrometry and Western blotting, we identified three phosphoepitopes of tau directly phosphorylated by mTor. We have developed a variety of stable cell lines with genetic modification of mTor activity using SH-SY5Y neuroblastoma cells as background. In these cellular systems, we not only confirmed the tau phosphorylation sites found in vitro but also found that mTor mediates the synthesis and aggregation of tau, resulting in compromised microtubule stability. Changes of mTor activity cause fluctuation of the level of a battery of tau kinases such as protein kinase A, v-Akt murine thymoma viral oncogene homolog-1, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and tau protein phosphatase 2A. These results implicate mTor in promoting an imbalance of tau homeostasis, a condition required for neurons to maintain physiological function.

  18. LED belichting tijdens het voortrekken van lelie

    NARCIS (Netherlands)

    Kok, B.J.; Wildschut, J.

    2010-01-01

    De laatste jaren staat het gebruik van LED-lampen in de tuinbouw in de belangstelling. Uit vele onderzoeken is al gebleken dat LED-lampen op dit moment nog geen alternatief zijn voor de SON-T lampen. Het grote voordeel van LED-lampen is dat ze monochromatisch licht van alle mogelijke golflengtes

  19. A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration.

    Science.gov (United States)

    Mejia, Pedro; Treviño-Villarreal, J Humberto; Reynolds, Justin S; De Niz, Mariana; Thompson, Andrew; Marti, Matthias; Mitchell, James R

    2017-11-09

    Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

  20. Low-dose rapamycin reduces kidney volume angiomyolipomas and prevents the loss of renal function in a patient with tuberous sclerosis complex.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Cuesta-López, Emilio; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Azorín, Sebastián; Selgas, Rafael

    2010-11-01

    Tuberous sclerosis complex (TSC) is caused by constitutively activated mammalian target of rapamycin (mTOR) resulting in non-malignant tumours of several organs including renal angiomyolipomas (AMLs). AMLs may originate renal failure, hypertension and spontaneous life-threatening bleeding. Recent reports suggest a possible beneficial role of the mTOR inhibitor rapamycin for TSC. However, safety and efficiency of rapamycin in TSC patients as an anti-proliferative agent are still undefined. A 40-year-old man with sporadic TSC and a history of spontaneous bleeding from his left kidney AMLs received low-dose rapamycin for 12 months, and this was associated with a reduction in bilateral kidney AML volume, stabilization and even improvement of renal function. There was also a reduction of facial angiofibromas, improvement of blood pressure control and absence of AML bleeding over this time period. Brain lesion images remained stable, and no significant rapamycin-associated side effects were noted. To the best of our knowledge, this is the first report of a case of reduction in renal AML volume together with preservation of renal function in a patient with TSC receiving low-dose rapamycin. These data suggest that it could be the result of the anti-angiogenic, anti-fibrotic and anti-proliferative effects of rapamycin.

  1. Effect of Led Lighting Colors for Laying Japanese Quails

    Directory of Open Access Journals (Sweden)

    KC Nunes

    Full Text Available ABSTRACT Time of exposure and light intensity rearing house may affect the performance and egg quality of laying quails. This research aimed at evaluating the live performance, egg quality, biometry of the reproductive system, and the gastrointestinal tract of Japanese quails (Coturnix coturnix japonica exposed to artificial light-emitting diodes (LED of different colors in comparison with fluorescent lamps. A total of 240 Japanese quails were distributed in completely randomized experimental design with four treatments (fluorescent lamp, and green, red, or blue LED lamps with six replicates of 10 birds each. Average egg weight and eggshell thickness were different (p0.05. The oviduct of 64-d-old hens exposed to green LED lighting was shorter (p<0.05 than those exposed to the fluorescent lamp. Red LED can be used to replace the fluorescent lamps, as they promote the same live performance, egg quality, and morphological development of the reproductive tract of laying Japanese quails.

  2. Effects of nurse-led motivational interviewing of patients with chronic musculoskeletal pain in preparation of rehabilitation treatment (PREPARE) on societal participation, attendance level, and cost-effectiveness: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Mertens, Vera-Christina; Goossens, Mariëlle E J B; Verbunt, Jeanine A; Köke, Albere J; Smeets, Rob J E M

    2013-04-02

    Non-adherence and drop-out are major problems in pain rehabilitation. For patients with various health problems, motivational interviewing (MI) has shown promising effects to tackle these problems. In chronic pain patients, the effectiveness of MI is however unknown. Therefore, a MI-based pre-pain rehabilitation intervention (MIP) addressing motivation, expectations, and beliefs has been developed to prepare eligible patients for rehabilitation treatment. A parallel randomized controlled trial including two interventions: a motivational interviewing pre-pain rehabilitation intervention (MIP) and a usual care (UC) control arm. Follow-up will be 6 months after completion of rehabilitation treatment. One hundred and sixty (n = 80 per arm) patients with chronic non-specific musculoskeletal pain visiting an outpatient rehabilitation department, who are eligible to participate in an outpatient cognitive behavioral pain rehabilitation program. MIP consists of two sessions to prepare and motivate the patient for pain rehabilitation treatment and its bio psychosocial approach. UC consists of information and education about the etiology and the general rehabilitation approach of chronic pain. Both the MIP and UC contain two sessions of 45 to 60 minutes each. The aim of the current study is to evaluate the effectiveness of MIP compared to UC in terms of an increase in the long-term level of societal participation and decrease of drop-out during rehabilitation treatment.Main study endpoints: Primary outcome is the change in level of participation (according to the ICF-definition: 'involvement in a life situation') 6 months after completion of rehabilitation treatment. Secondary outcomes are adherence and treatment drop-out, disability, pain intensity, self-reported main complaints, (pain-specific) self-efficacy, motivation, and quality of life. Costs are calculated including the costs of the pre-treatment intervention, productivity losses, and healthcare utilization. Potential

  3. Molecular insights into the stabilization of protein-protein interactions with small molecule: The FKBP12-rapamycin-FRB case study

    Science.gov (United States)

    Chaurasia, Shilpi; Pieraccini, Stefano; De Gonda, Riccardo; Conti, Simone; Sironi, Maurizio

    2013-11-01

    Targetting protein-protein interactions is a challenging task in drug discovery process. Despite the challenges, several studies provided evidences for the development of small molecules modulating protein-protein interactions. Here we consider a typical case of protein-protein interaction stabilization: the complex between FKBP12 and FRB with rapamycin. We have analyzed the stability of the complex and characterized its interactions at the atomic level by performing free energy calculations and computational alanine scanning. It is shown that rapamycin stabilizes the complex by acting as a bridge between the two proteins; and the complex is stable only in the presence of rapamycin.

  4. Fatigue Intervention by Nurses Evaluation – The FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610

    Directory of Open Access Journals (Sweden)

    Dunn G

    2006-04-01

    Full Text Available Abstract Background Chronic fatigue syndrome, also known as ME (CFS/ME, is a condition characterised primarily by severe, disabling fatigue, of unknown origin, which has a poor prognosis and serious personal and economic consequences. Evidence for the effectiveness of any treatment for CFS/ME in primary care, where most patients are seen, is sparse. Recently, a brief, pragmatic treatment for CFS/ME, based on a physiological dysregulation model of the condition, was shown to be successful in improving fatigue and physical functioning in patients in secondary care. The treatment involves providing patients with a readily understandable explanation of their symptoms, from which flows the rationale for a graded rehabilitative plan, developed collaboratively with the therapist. The present trial will test the effectiveness and cost-effectiveness of pragmatic rehabilitation when delivered by specially trained general nurses in primary care. We selected a client-centred counselling intervention, called supportive listening, as a comparison treatment. Counselling has been shown to be as effective as cognitive behaviour therapy for treating fatigue in primary care, is more readily available, and controls for supportive therapist contact time. Our control condition is treatment as usual by the general practitioner (GP. Methods and design This study protocol describes the design of an ongoing, single-blind, pragmatic randomized controlled trial of a brief (18 week self-help treatment, pragmatic rehabilitation, delivered by specially trained nurse-therapists in patients' homes, compared with nurse-therapist delivered supportive listening and treatment as usual by the GP. An economic evaluation, taking a societal viewpoint, is being carried out alongside the clinical trial. Three adult general nurses were trained over a six month period to deliver the two interventions. Patients aged over 18 and fulfilling the Oxford criteria for CFS are assessed at baseline

  5. In vitro inactivation of Enterococcus faecalis with a led device.

    Science.gov (United States)

    D'Ercole, S; Spoto, G; Trentini, P; Tripodi, D; Petrini, M

    2016-07-01

    Non-coherent light-emitting diodes (LEDs) are effective in a large variety of clinical indications; however, the bactericidal activity of LEDs is unclear, although the effectiveness of such lights is well known. Currently, no studies have examined the effects of NIR-LED on bacteria. The aims of this study were to verify the antibacterial activity of 880-nm LED irradiation on a bacterial suspension of Enterococcus faecalis and to compare it with the actions of sodium hypochlorite (NaOCl) and the concurrent use of both treatments. Before we proceeded with the main experiment, we first performed preliminary tests to evaluate the influence of such parameters as the distance of irradiation, the energy density, the irradiation time and the presence of photosensitizers on the antimicrobial effects of LEDs. After treatment, the colony forming units per milliliter (CFU/mL) was recorded and the data were submitted to ANOVA and Bonferroni post hoc tests at a level of significance of 5%. The results showed that LED irradiation, at the parameters used, is able to significantly decrease E. faecalis viability in vitro. The total inhibition of E. faecalis was obtained throughout concurrent treatment of LED and NaOCl (1%) for 5min. The same antimicrobial activity was confirmed in all of the experiments (p<0.05), but no statistically significant differences were found by varying such parameters as the distance of irradiation (from 0.5mm to 10mm), energy density (from 2.37 to 8.15mJ/s), irradiation time (from 5min to 20min) or by adding toluidine blue O (TBO). Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Testing Finance-Led, Export-Led and Import-Led Growth Hypotheses on Four Sub-Saharan African Economies

    OpenAIRE

    Evans, Olaniyi

    2013-01-01

    This study carries out an empirical examination of the finance-led, export-led and import-led growth hypothesis for four of the largest Sub-Saharan African economies namely South Africa, Nigeria, Ghana and Kenya. Within a multivariate Vector-Auto Regressive (VAR) framework, the concept of Granger causality is employed to determine the direction of causation between exports and output, duly taking into account the stationarity properties of the time series data. With further substantiation fro...

  7. PENGEMBANGAN LAMPU LED DENGAN TEKNOLOGI PHOTOVOLTAIC (LED-PV SEBAGAI ALAT BANTU PENGUMPUL IKAN PADA PERIKANAN BAGAN

    Directory of Open Access Journals (Sweden)

    Mochamad Arief Sofijanto

    2015-03-01

    mengetahui perbedaan jumlah hasil tangkapan pada bagan tancap akibat perlakuan warna lampu LED yang berbeda. Metode penelitian yang digunakan adalah deskriptif dan experimental fishing dimana rancangan penelitiannya adalah Rancangan Acak Lengkap (RAL dengan perlakuan warna lampu LED sebanyak 5 jenis warna yaitu merah (A, kuning (B, hijau (C, biru (D, dan putih (E dengan 6 kali ulangan. Secara deskriptif hasil penelitian menunjukkan lampu LED dapat digunakan untuk menggantikan lampu petromaks dan lampu LHE. Diperoleh 17 jenis ikan laut yang tertarik pada cahaya lampu LED yang digunakan. Hasil analisis statistik menunjukkan terdapat perbedaan nyata terhadap hasil tangkapan bagan dengan perlakuan warna lampu LED. Berdasarkan Uji Nyata Terkecil dinyatakan bahwa bagan yang menggunakan warna lampu LED biru mendapatkan hasil tangkapan tertinggi kemudian diikuti oleh warna kuning, hijau, putih dan merah.  The set ‘bagan’ (liftnet fishing gear is a kind of fishing gears which using atificial light as fishes gathering. This fishing gear uses an electric generator to turn on the energy saving lamp which hang on under the set ‘bagan’. The price of gasoline more expensive due to the Indonesia government’s fuel subsidy reduced and this make fishing operation costs more expensive for fishermen. This research using the LED lamps that do not use gasoline as fuel because the LED lamps can use the photovoltaic technology (solar cell system. The purposes of this study were: 1 to find out whether the LED lamps can replace the kerosene lamps and saving energy lamps, 2 to know the different in cath using different colours of LED lamps. The reserach methods are descriptive and experimental fishing which used Completely Randomized Design with LED lamps colour treatments i.e: red (A, yellow (B, green (C, blue (D, and white (E, the number of replications are 6 times. LED lamps can be used to replace the kerosene and saving energy lamps. There were 17 species of

  8. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice.

    Science.gov (United States)

    Makki, Kassem; Taront, Solenne; Molendi-Coste, Olivier; Bouchaert, Emmanuel; Neve, Bernadette; Eury, Elodie; Lobbens, Stéphane; Labalette, Myriam; Duez, Hélène; Staels, Bart; Dombrowicz, David; Froguel, Philippe; Wolowczuk, Isabelle

    2014-01-01

    The "mechanistic target of rapamycin" (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel

  9. A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease

    Directory of Open Access Journals (Sweden)

    Han-Hyuk Lim

    2017-12-01

    Full Text Available A major obstacle to enzyme replacement therapy (ERT with recombinant human acid-α-glucosidase (rhGAA for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa during the first 3 weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX per week for the first 3 weeks. Empty nanoparticles (NP were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Body weight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes.

  10. Update on etiopathogenesis and treatment of Acne

    Directory of Open Access Journals (Sweden)

    Yasmeen Jabeen Bhat

    2017-01-01

    Full Text Available Acne, the most common skin disease, is a disorder of pilosebaceous units that affects adolescents mainly and adults occasionally. The pathogenesis is multifactorial. Besides genetic predisposition, other major factors include the action of androgens, pro-inflammatory lipids acting as ligands of peroxisome proliferator-activated receptors in the sebocytes, toll-like receptor-2 acting on keratinocytes, recognition of pathogen-associated molecular patterns, cytokines, chemokines, inflammasomes, neuroendocrine regulatory mechanisms, diet and other pro-inflammatory targets implicated in the activation of immune detection and response. Most of these factors converge on mammalian target of rapamycin complex1 (mTORC1 activation which is further enhanced by the nutrient signaling of Western diet. This multitude of pathogenic factors has led to a new armamentarium of drugs for the treatment of acne. Topical anti-androgens, insulin-like growth factor-1 inhibitors, peroxisome proliferator-activated receptor-modulators, acetylcholine inhibitors, topical retinoic acid metabolism-blocking agents, vitamin D analogues, antimicrobial peptides, interleukin-1α and interleukin-1β blockers and immunotherapy are some of the novel treatment options.

  11. Role of everolimus in the treatment of renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Saby George

    2009-08-01

    Full Text Available Saby George1, Ronald M Bukowski21University of Texas Health Sciences Center, MC-8221, Division of Hematology and Oncology, San Antonio, Texas, USA; 2CCF Lerner College of Medicine Division of Hematology and Oncology, Cleveland, Ohio, USAAbstract: The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC. Everolimus (RAD 001 is an oral inhibitor of the mammalian target of rapamycin (mTOR pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1 conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001. Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.Keywords: mTOR inhibitor, mammalian target of rapamycin inhibitor, signal transduction inhibitor, renal cell carcinoma, targeted therapy

  12. Miniature LED endoilluminators for vitreoretinal surgery

    Science.gov (United States)

    Hessling, M.; Koelbl, P. S.; Lingenfelder, C.; Koch, F.

    2015-07-01

    Two innovative approaches for intraocular illumination during vitreoretinal surgery by application of white LEDs are being developed. Both techniques are less harmful to the patient, more convenient for the surgeon and smaller and cheaper compared to conventional illumination by Xenon light sources and optical fibers. These two novel approaches are: I) The miniature LED chandelier endoilluminator consisting of a single white LED with a "light probe" on top of the LED housing that fits in a small incision in the wall of the eye. II) The alternative transscleral LED endoilluminator is integrated into an eye speculum that presses the flat LED top against the eye. The intraocular space is only illuminated by light transmitted through the sclera. In contrast to conventional illumination techniques for vitreoretinal surgery no incision is necessary. Both approaches are evaluated with regard to potential photochemical and thermal risks for the patient's retina and they are tested on porcine eyes.

  13. White LED visible light communication technology research

    Science.gov (United States)

    Yang, Chao

    2017-03-01

    Visible light communication is a new type of wireless optical communication technology. White LED to the success of development, the LED lighting technology is facing a new revolution. Because the LED has high sensitivity, modulation, the advantages of good performance, large transmission power, can make it in light transmission light signal at the same time. Use white LED light-emitting characteristics, on the modulation signals to the visible light transmission, can constitute a LED visible light communication system. We built a small visible optical communication system. The system composition and structure has certain value in the field of practical application, and we also research the key technology of transmitters and receivers, the key problem has been resolved. By studying on the optical and LED the characteristics of a high speed modulation driving circuit and a high sensitive receiving circuit was designed. And information transmission through the single chip microcomputer test, a preliminary verification has realized the data transmission function.

  14. Performance of led linear replacement lamps

    OpenAIRE

    Ryckaert, Wouter; Roelandts, Inge; Gils, Mieke; Durinck, Guy; Forment, Stefaan; Audenaert, Jan; Hanselaer, Peter

    2012-01-01

    Many manufacturers and distributors of LED tubes claim energy savings of 50% and more when replacing T8 fluorescent tubes with LED linear replacement lamps. Above, most distributors pretend that the same visual performance and comfort will be maintained after such replacement. Optical and electrical parameters of twelve commercially available LED tubes have been measured and compared and the evolution in time of these parameters has been monitored. The performance of these lamps with distinct...

  15. System Reliability for LED-Based Products

    Energy Technology Data Exchange (ETDEWEB)

    Davis, J Lynn; Mills, Karmann; Lamvik, Michael; Yaga, Robert; Shepherd, Sarah D; Bittle, James; Baldasaro, Nick; Solano, Eric; Bobashev, Georgiy; Johnson, Cortina; Evans, Amy

    2014-04-07

    Results from accelerated life tests (ALT) on mass-produced commercially available 6” downlights are reported along with results from commercial LEDs. The luminaires capture many of the design features found in modern luminaires. In general, a systems perspective is required to understand the reliability of these devices since LED failure is rare. In contrast, components such as drivers, lenses, and reflector are more likely to impact luminaire reliability than LEDs.

  16. The effect of LED illumination on endodontic biofilms

    DEFF Research Database (Denmark)

    Markvart, Merete

    Within endodontics photodynamic therapy (PDT) has been suggested as a disinfectant procedure during root canal treatment. A photoactive dye (photosensitizer), methylene blue or toluidine blue, are activated by a light source, usually lasers or light emitting diodes (LEDs), thereby forming free...

  17. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review

    NARCIS (Netherlands)

    Boers-Doets, Christine B.; Epstein, Joel B.; Raber-Durlacher, Judith E.; Ouwerkerk, Jan; Logan, Richard M.; Brakenhoff, Jan A.; Lacouture, Mario E.; Gelderblom, Hans

    2012-01-01

    Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal

  18. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review

    NARCIS (Netherlands)

    Boers-Doets, C.B.; Epstein, J.B.; Raber-Durlacher, J.E.; Ouwerkerk, J.; Logan, R.M.; Brakenhoff, J.A.; Lacouture, M.E.; Gelderblom, H.

    2012-01-01

    Background. Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the

  19. Improved Clearance during Treatment of HPV-Positive Head and Neck Cancer through mTOR Inhibition

    Directory of Open Access Journals (Sweden)

    Joseph D. Coppock

    2013-06-01

    Full Text Available Human papillomavirus (HPV-related head and neck squamous cell carcinoma (HNSCC incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic target of rapamycin (mTOR inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/ 6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC.

  20. Blue LEDs feasibility for tissue fluorescence analysis

    Science.gov (United States)

    Dets, Sergiy M.; Denisov, Nikolay A.

    2000-04-01

    We considered the limited number of light-induced fluorescence applications for marketed ultra-bright blue LEDs where they can compete with versatile laser sources. Satisfactory optical output and miniature size as well as low power consumption of blue LEDs emitting at 470 nm allow to consider them as a promising alternatives to metal vapor or gas lasers used in many expires LIF applications. Available to authors LEDs form Hewlett-Packard, Micro Electronics Corp., Nichia Chemical Industries Ltd. and Toyoda Gosei Co. were tested to comply with demands to a tissue excitation source for portable spectroscopes. The optical performance of LEDs has shown that selected group of InGaN LEDs could be successfully used for that. The miniature illuminator that includes LED, focusing condenser, filter set and distal fiberoptic light concentrator was designed and tested in conjunction with portable CCD- equipped spectroscope. Operating in dark condition the proposed LED illuminator provides the level of fluorescence signal sufficient to detect spectral abnormalities in human Caucasian skin and excised gastrointestinal samples. All tissue autofluorescence data taken under LED illumination were compared with readings under He-Cd laser excitation and showed a good match. A new diagnostic designs based on LEDs were considered for clinical use.

  1. Solid State Lighting LED Manufacturing Roundtable Summary

    Energy Technology Data Exchange (ETDEWEB)

    none,

    2010-03-31

    Summary of a meeting of LED experts to develop proposed priority tasks for the Manufacturing R&D initiative, including task descriptions, discussion points, recommendations, and presentation highlights.

  2. Dialysis modality selection: physician guided or patient led?

    OpenAIRE

    Winterbottom, A; Bekker, H; Mooney, A.

    2016-01-01

    The process of choosing dialysis modality for patients is complex and requires input from the expert renal team. Although it is commonplace for nephrologists to recommend dialysis modalities to patients, this might not always lead to the patient receiving treatment which they regard as most suitable. Nephrologists should consider whether it is appropriate for pre-dialysis education to be directive, or whether the choice between treatment options should be led by the patient.

  3. Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids

    Science.gov (United States)

    Zheng, Xu; Liang, Yan; He, Qiburi; Yao, Ruiyuan; Bao, Wenlei; Bao, Lili; Wang, Yanfeng; Wang, Zhigang

    2014-01-01

    Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research. PMID:25402640

  4. Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1 Activation by Growth Factors and Amino Acids

    Directory of Open Access Journals (Sweden)

    Xu Zheng

    2014-11-01

    Full Text Available Mammalian target of rapamycin (mTOR, which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.

  5. Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome.

    Science.gov (United States)

    Andrade-Talavera, Yuniesky; Benito, Itziar; Casañas, Juan José; Rodríguez-Moreno, Antonio; Montesinos, María Luz

    2015-10-01

    Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model. Here, we report that these mice exhibit deficits in both synaptic plasticity (i.e., BDNF-long term potentiation) and the persistence of spatial long-term memory. Interestingly, these deficits were fully reversible using rapamycin, a Food and Drug Administration-approved specific mTOR inhibitor; therefore, rapamycin may be a novel pharmacotherapy to improve cognition in DS. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Hypertrophied myocardium is vulnerable to ischemia reperfusion injury and refractory to rapamycin-induced protection due to increased oxidative/nitrative stress.

    Science.gov (United States)

    Ma, Lei-Lei; Yin, Pei-Pei; Li, Yang; Kong, Fei-Juan; Guo, Jun-Jie; Shi, Hong-Tao; Zhu, Jian-Bin; Zou, Yun-Zeng; Ge, Jun-Bo

    2017-11-24

    Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection are altered in the presence of LVH has yet to be determined. Pressure overload-induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin  10 min before reperfusion. Rapamycin produced marked cardioprotection in normal control mice, whereas pressure overload-induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocytes apoptosis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91phox expression, superoxide production, total NO metabolites and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91phox assembly inhibitor gp91ds-tat or ONOO- scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarction, hindered cardiomyocytes apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects was achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardioprotection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite protects the hypertrophied heart from MI/R. ©2017 The Author(s).

  7. Rapamycin inhibits ox-LDL-induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway.

    Science.gov (United States)

    Sun, Juan-Juan; Yin, Xiao-Wei; Liu, Hui-Hui; Du, Wen-Xiu; Shi, Lu-Yao; Huang, Ya-Bo; Wang, Fen; Liu, Chun-Feng; Cao, Yong-Jun; Zhang, Yan-Lin

    2017-10-26

    Rapamycin and its derivative possess anti-atherosclerosis activity, but its effects on adhesion molecule expression and macrophage adhesion to endothelial cells during atherosclerosis remain unclear. In this study we explored the effects of rapamycin on ox-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells in vitro and the underlying mechanisms. Ox-LDL (6-48 μg/mL) dose-dependently increased the protein levels of two adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and E-selectin, in human umbilical vein endothelial cells (HUVECs), whereas pretreatment with rapamycin (1-10 μmol/L) dose-dependently inhibited ox-LDL-induced increase in the adhesion molecule expression and macrophage adhesion to endothelial cells. Knockdown of mTOR or rictor, rather than raptor, mimicked the effects of rapamycin. Ox-LDL (100 μg/mL) time-dependently increased PKC phosphorylation in HUVECs, which was abolished by rapamycin or rictor siRNA. Pretreatment with PKC inhibitor staurospo¬rine significantly reduced ox-LDL-stimulated adhesion molecule expression and macrophage adhesion to endothelial cells, whereas pretreatment with PKC activator PMA/TPA attenuated the inhibitory effect of rapamycin on adhesion molecule expression. Ox-LDL (100 μg/mL) time-dependently increased c-Fos levels in HUVECs, and pretreatment with rapamycin or rictor siRNA significantly decreased expression of c-Fos. Knockdown of c-Fos antagonized ox-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells. Our results demonstrate that rapamycin reduces ox-LDL-stimulated adhesion molecule expression and macrophage adhesion to endothelial cells by inhibiting mTORC2, but not mTORC1, and mTORC2 acts through the PKC/c-Fos signaling pathway.

  8. Targeting Rapamycin to Podocytes Using a Vascular Cell Adhesion Molecule-1 (VCAM-1-Harnessed SAINT-Based Lipid Carrier System.

    Directory of Open Access Journals (Sweden)

    Ganesh Ram R Visweswaran

    Full Text Available Together with mesangial cells, glomerular endothelial cells and the basement membrane, podocytes constitute the glomerular filtration barrier (GFB of the kidney. Podocytes play a pivotal role in the progression of various kidney-related diseases such as glomerular sclerosis and glomerulonephritis that finally lead to chronic end-stage renal disease. During podocytopathies, the slit-diaphragm connecting the adjacent podocytes are detached leading to severe loss of proteins in the urine. The pathophysiology of podocytopathies makes podocytes a potential and challenging target for nanomedicine development, though there is a lack of known molecular targets for cell selective drug delivery. To identify VCAM-1 as a cell-surface receptor that is suitable for binding and internalization of nanomedicine carrier systems by podocytes, we investigated its expression in the immortalized podocyte cell lines AB8/13 and MPC-5, and in primary podocytes. Gene and protein expression analyses revealed that VCAM-1 expression is increased by podocytes upon TNFα-activation for up to 24 h. This was paralleled by anti-VCAM-1 antibody binding to the TNFα-activated cells, which can be employed as a ligand to facilitate the uptake of nanocarriers under inflammatory conditions. Hence, we next explored the possibilities of using VCAM-1 as a cell-surface receptor to deliver the potent immunosuppressant rapamycin to TNFα-activated podocytes using the lipid-based nanocarrier system Saint-O-Somes. Anti-VCAM-1-rapamycin-SAINT-O-Somes more effectively inhibited the cell migration of AB8/13 cells than free rapamycin and non-targeted rapamycin-SAINT-O-Somes indicating the potential of VCAM-1 targeted drug delivery to podocytes.

  9. Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite Formation In Vitro

    Directory of Open Access Journals (Sweden)

    Katharina Leitmeyer

    2015-01-01

    Full Text Available Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR by blocking the mTOR complex 1 (mTORC1. mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp. are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzed in vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.

  10. Led Zeppelin reklaamib Narvat / Anti Ronk

    Index Scriptorium Estoniae

    Ronk, Anti

    2007-01-01

    Ilmus Narva-teemaline kahest CD-st koosnev album, kus ühel plaadil on 60 minutit videot linna vaatamisväärsuste ja informatsiooniga, teisel - briti rockansambli Led Zeppelini teosed Narva sümfooniaorkestri ja rockansambli Led R esituses

  11. Reduced Component Count RGB LED Driver

    NARCIS (Netherlands)

    De Pedro, I.; Ackermann, B.

    2008-01-01

    The goal of this master thesis is to develop new drive and contrololutions, for creating white light from mixing the light of different-color LEDs, aiming at a reduced component count resulting in less space required by the electronics and lower cost. It evaluates the LED driver concept proposed in

  12. LED lamps under different EMC environnments

    OpenAIRE

    Gil-de-Castro, Aurora; Larsson, Anders; Rönnberg, Sarah; Bollen, Math

    2015-01-01

    More and more loads are currently connected at the same connection point in industrial, commercial and residential sectors. This paper studies the interaction between a certain LED lamp connected to different industrial environments, and how different LED lamps behave in the same industrial environment. Harmonic emission as well as supraharmonic emission have been considered in the study.

  13. Led-licht biedt mogelijkheden in broeierij

    NARCIS (Netherlands)

    Neefjes, H.; PPO Bomen-bollen,

    2010-01-01

    Onderzoekers van PPO Lisse hebben de mogelijkheden van led-licht verkend bij met name lelie en tulp. Bij lelie bieden leds perspectief in de voortrek. Tulp kan er bijna de hele broeifase van profiteren. Veel licht is niet nodig, maar meerlagenteelt is een voorwaarde.

  14. Anti-CD25 mAb, anti-IL2 mAb, and IL2 block tolerance induction through anti-CD154 mAb and rapamycin in xenogeneic islet transplantation.

    Science.gov (United States)

    Pan, H; Lu, H M; Hu, W-M; Tian, B-L; Liu, X-B; Zhang, Z-D; Mai, G

    2007-12-01

    We have used anti-CD154 monoclonal antibody (mAb; MR1) and rapamycin (rapa) to induce tolerance to islet xenografts. The aim of this study was to investigate whether classical anergy and/or regulation by interleukin (IL)2-dependent CD25+ T regulatory cells played roles in the induction and maintenance of tolerance in this model. Streptozotocin-induced diabetic mice were transplanted with rat islets. We performed the following groups: control group, islet transplantation without therapy; rapamycin group, 0.2 mg/kg by oral gavage on days 0, 1, 2, and every other day to day 14; anti-CD154 mAb (MR1) group, 0.5 mg intraperitoneally on days 0, 2, and 4; combination therapy group with rapa and MR1. We then administered in addition to the combination therapy with early (from days 0 to 14 [for IL2] or to 28 [for anti-IL2 mAb and anti-CD25 mAb] post-transplantation) or late (from days 100 to 114 [for IL2] or to 128 [for anti-IL2 mAb and anti-CD25 mAb] posttransplantation) recombinant IL2 (2000 U, intraperitoneally twice a day), a neutralizing anti-IL2 mAb (S4B6-1, 0.3 mg intraperitoneally twice weekly), and a depleting anti-CD25 mAb (PC61, 0.3 mg intraperitoneally twice weekly), respectively. Histology was performed at time of rejection. Rapa and MR1 therapy alone significantly prolonged xenograft survival compared to the control group: median graft survival was 34 days versus 17 days (P200 days, PIL2 was administered early with MR1 and rapa, rapid rejection developed in 18 of 18 mice (MGS 7 days), whereas when IL2 was given late, only 3 of 10 developed rejection. Early administration of anti-IL2 mAb led to rejection in 10 of 10 mice (MGS 42 days), whereas late administration led to rejection in only one of four mice. Early administration of anti-CD25 mAb led to rejection in eight of nine mice (MGS 49 days), whereas late administration led to rejection in only three of seven mice. Rapa and MR1 allowed indefinite graft survival of islet xenografts. Classical anergy and

  15. Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS).

    Science.gov (United States)

    Wermke, Martin; Schuster, Claudia; Nolte, Florian; Al-Ali, Haifa-Kathrin; Kiewe, Philipp; Schönefeldt, Claudia; Jakob, Christiane; von Bonin, Malte; Hentschel, Leopold; Klut, Ina-Maria; Ehninger, Gerhard; Bornhäuser, Martin; Baretton, Gustavo; Germing, Ulrich; Herbst, Regina; Haase, Detelef; Hofmann, Wolf K; Platzbecker, Uwe

    2016-12-01

    The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients. © 2016 John Wiley & Sons Ltd.

  16. Advances in LEDs for automotive applications

    Science.gov (United States)

    Bhardwaj, Jy; Peddada, Rao; Spinger, Benno

    2016-03-01

    High power LEDs were introduced in automotive headlights in 2006-2007, for example as full LED headlights in the Audi R8 or low beam in Lexus. Since then, LED headlighting has become established in premium and volume automotive segments and beginning to enable new compact form factors such as distributed low beam and new functions such as adaptive driving beam. New generations of highly versatile high power LEDs are emerging to meet these application needs. In this paper, we will detail ongoing advances in LED technology that enable revolutionary styling, performance and adaptive control in automotive headlights. As the standards which govern the necessary lumens on the road are well established, increasing luminance enables not only more design freedom but also headlight cost reduction with space and weight saving through more compact optics. Adaptive headlighting is based on LED pixelation and requires high contrast, high luminance, smaller LEDs with high-packing density for pixelated Matrix Lighting sources. Matrix applications require an extremely tight tolerance on not only the X, Y placement accuracy, but also on the Z height of the LEDs given the precision optics used to image the LEDs onto the road. A new generation of chip scale packaged (CSP) LEDs based on Wafer Level Packaging (WLP) have been developed to meet these needs, offering a form factor less than 20% increase over the LED emitter surface footprint. These miniature LEDs are surface mount devices compatible with automated tools for L2 board direct attach (without the need for an interposer or L1 substrate), meeting the high position accuracy as well as the optical and thermal performance. To illustrate the versatility of the CSP LEDs, we will show the results of, firstly, a reflector-based distributed low beam using multiple individual cavities each with only 20mm height and secondly 3x4 to 3x28 Matrix arrays for adaptive full beam. Also a few key trends in rear lighting and impact on LED light

  17. Harmonics Monitoring Survey on LED Lamps

    Directory of Open Access Journals (Sweden)

    Abdelrahman Ahmed Akila

    2017-03-01

    Full Text Available Light Emitting Diode (LED lamps are being increasingly used in many applications. These LED lamps operate using a driver, which is a switching device. Hence, LED lamps will be a source of harmonics in the power system. These harmonics if not well treated, may cause severe performance and operational problems. In this paper, harmonics (amplitude and phase angles generated by both LED lamps and conventional fluorescent lamps will be studied practically. Then they will be analyzed and evaluated. Compared to each other harmonics generated by both LED and conventional florescent lamps, self mitigation may occur based on the phase angle of these harmonics. All data will be measured using power analyzer and will be done on a sample of actual lamps.

  18. High Performance Green LEDs by Homoepitaxial

    Energy Technology Data Exchange (ETDEWEB)

    Wetzel, Christian; Schubert, E Fred

    2009-11-22

    This work's objective was the development of processes to double or triple the light output power from green and deep green (525 - 555 nm) AlGaInN light emitting diode (LED) dies within 3 years in reference to the Lumileds Luxeon II. The project paid particular effort to all aspects of the internal generation efficiency of light. LEDs in this spectral region show the highest potential for significant performance boosts and enable the realization of phosphor-free white LEDs comprised by red-green-blue LED modules. Such modules will perform at and outperform the efficacy target projections for white-light LED systems in the Department of Energy's accelerated roadmap of the SSL initiative.

  19. Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis.

    Science.gov (United States)

    Ren, Jiafa; Li, Jianzhong; Feng, Ye; Shu, Bingyan; Gui, Yuan; Wei, Wei; He, Weichun; Yang, Junwei; Dai, Chunsun

    2017-08-01

    Mammalian target of rapamycin (mTOR) signalling controls many essential cellular functions. However, the role of Rictor/mTOR complex 2 (mTORC2) in regulating macrophage activation and kidney fibrosis remains largely unknown. We report here that Rictor/mTORC2 was activated in macrophages from the fibrotic kidneys of mice. Ablation of Rictor in macrophages reduced kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction or ischaemia/reperfusion injury. In bone marrow-derived macrophages (BMMs), deletion of Rictor or blockade of protein kinase Cα inhibited cell migration. Additionally, deletion of Rictor or blockade of Akt abolished interleukin-4-stimulated or transforming growth factor (TGF)-β1-stimulated macrophage M2 polarization. Furthermore, deletion of Rictor downregulated TGF-β1-stimulated upregulation of multiple profibrotic cytokines, including platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor, in BMMs. Conditioned medium from TGF-β1-pretreated Rictor-/- macrophages stimulated fibroblast activation less efficiently than that from TGF-β1-pretreated Rictor+/+ macrophages. These results demonstrate that Rictor/mTORC2 signalling can promote macrophage activation and kidney fibrosis. Targeting this signalling pathway in macrophages may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  20. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside

    Directory of Open Access Journals (Sweden)

    Hyun-Jung Kim

    2012-09-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common life-threatening hereditary disease in the USA resulting in chronic kidney disease and the need for dialysis and transplantation. Approximately 85% of cases of ADPKD are caused by a mutation in the Pkd1 gene that encodes polycystin-1, a large membrane receptor. The Pkd1 gene mutation results in abnormal proliferation in tubular epithelial cells, which plays a crucial role in cyst development and/or growth in PKD. Activation of the proliferative mammalian target of rapamycin (mTOR signaling pathway has been demonstrated in polycystic kidneys from rodents and humans. mTOR inhibition with sirolimus or everolimus decreases cysts in most animal models of PKD including Pkd1 and Pkd2 gene deficient orthologous models of human disease. On the basis of animal studies, human studies were undertaken. Two large randomized clinical trials published in the New England Journal of Medicine of everolimus or sirolimus in ADPKD patients were very unimpressive and associated with a high side-effect profile. Possible reasons for the unimpressive nature of the human studies include their short duration, the high drop-out rate, suboptimal dosing, lack of randomization of “fast” and “slow progressors” and the lack of correlation between kidney size and kidney function in ADPKD. The future of mTOR inhibition in ADPKD is discussed.

  1. Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction.

    Science.gov (United States)

    Li, Bingshou; Li, Zhirong; Wang, Pengcheng; Huang, Qizhao; Xu, Lifan; He, Ran; Ye, Lilin; Bai, Qiang

    2017-10-01

    The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. Earlier in vitro studies showed that mTOR signalling regulates B-cell biology by supporting their activation and proliferation. However, how mTOR signalling temporally regulates in vivo germinal centre B (GCB) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not well understood. In this study, we used a combined conditional/inducible knock-out system to investigate the temporal regulation of mTOR complex 1 (mTORC1) in the GCB cell response to acute lymphocytic choriomeningitis virus infection by deleting Raptor, a main component of mTORC1, specifically in B cells in pre- and late GC phase. Early Raptor deficiency strongly inhibited GCB cell proliferation and differentiation and plasma cell differentiation. Nevertheless, late GC Raptor deficiency caused only decreases in the size of memory B cells and long-lived plasma cells through poor maintenance of GCB cells, but it did not change their differentiation. Collectively, our data revealed that mTORC1 signalling supports GCB cell responses at both early and late GC phases during viral infection but does not regulate GCB cell differentiation into memory B cells and plasma cells at the late GC stage. © 2017 John Wiley & Sons Ltd.

  2. Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo.

    Science.gov (United States)

    Dhandhukia, Jugal P; Shi, Pu; Peddi, Santosh; Li, Zhe; Aluri, Suhaas; Ju, Yaping; Brill, Dab; Wang, Wan; Janib, Siti M; Lin, Yi-An; Liu, Shuanglong; Cui, Honggang; MacKay, J Andrew

    2017-11-15

    Recombinant protein-polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility, monodispersity, and multifunctionality. We recently reported that the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth in breast cancer xenografts, and reduces side effects observed with free-drug controls. This new report significantly advances this carrier strategy by demonstrating the coassembly of two different ELP diblock copolymers containing drug-loading and tumor-targeting domains. A new ELP nanoparticle (ISR) was synthesized that includes the canonical integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in a 1:1 molar ratio coassemble into bifunctional nanoparticles containing both the FKBP domain for Rapa loading and the RGD ligand for integrin binding. Coassembled nanoparticles were evaluated for bifunctionality by performing in vitro cell-binding and drug-retention assays and in vivo MDA-MB-468 breast tumor regression and tumor-accumulation studies. The bifunctional nanoparticle demonstrated superior cell target binding and similar drug retention to FSI; however, it enhanced the formulation potency, such that tumor growth was suppressed at a 3-fold lower dose compared to an untargeted FSI-Rapa control. This data suggests that ELP-mediated scaffolds are useful tools for generating multifunctional nanomedicines with potential activity in cancer.

  3. The Role of Mammalian Target of Rapamycin (mTOR in Insulin Signaling

    Directory of Open Access Journals (Sweden)

    Mee-Sup Yoon

    2017-10-01

    Full Text Available The mammalian target of rapamycin (mTOR is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1 and mTOR complex 2 (mTORC2, which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10, insulin receptor substrate (IRS-1, F-box/WD repeat-containing protein 8 (Fbw8, and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR. In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

  4. Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.

    Science.gov (United States)

    Segura-Ibarra, Victor; Amione-Guerra, Javier; Cruz-Solbes, Ana S; Cara, Francisca E; Iruegas-Nunez, David A; Wu, Suhong; Youker, Keith A; Bhimaraj, Arvind; Torre-Amione, Guillermo; Ferrari, Mauro; Karmouty-Quintana, Harry; Guha, Ashrith; Blanco, Elvin

    2017-05-30

    Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism.

    Science.gov (United States)

    Huber, Kimberly M; Klann, Eric; Costa-Mattioli, Mauro; Zukin, R Suzanne

    2015-10-14

    The mammalian target of rapamycin (mTOR) is a central regulator of a diverse array of cellular processes, including cell growth, proliferation, autophagy, translation, and actin polymerization. Components of the mTOR cascade are present at synapses and influence synaptic plasticity and spine morphogenesis. A prevailing view is that the study of mTOR and its role in autism spectrum disorders (ASDs) will elucidate the molecular mechanisms by which mTOR regulates neuronal function under physiological and pathological conditions. Although many ASDs arise as a result of mutations in genes with multiple molecular functions, they appear to converge on common biological pathways that give rise to autism-relevant behaviors. Dysregulation of mTOR signaling has been identified as a phenotypic feature common to fragile X syndrome, tuberous sclerosis complex 1 and 2, neurofibromatosis 1, phosphatase and tensin homolog, and potentially Rett syndrome. Below are a summary of topics covered in a symposium that presents dysregulation of mTOR as a unifying theme in a subset of ASDs. Copyright © 2015 the authors 0270-6474/15/3513836-07$15.00/0.

  6. Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation.

    Science.gov (United States)

    Fine, Nowell M; Kushwaha, Sudhir S

    2016-12-01

    The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review.

  7. Treatment outcomes in palliative care: the TOPCare study. A mixed methods phase III randomised controlled trial to assess the effectiveness of a nurse-led palliative care intervention for HIV positive patients on antiretroviral therapy.

    Science.gov (United States)

    Lowther, Keira; Simms, Victoria; Selman, Lucy; Sherr, Lorraine; Gwyther, Liz; Kariuki, Hellen; Ahmed, Aabid; Ali, Zipporah; Jenkins, Rachel; Higginson, Irene J; Harding, Richard

    2012-11-06

    Patients with HIV/AIDS on Antiretroviral Therapy (ART) suffer from physical, psychological and spiritual problems. Despite international policy explicitly stating that a multidimensional approach such as palliative care should be delivered throughout the disease trajectory and alongside treatment, the effectiveness of this approach has not been tested in ART-experienced populations. This mixed methods study uses a Randomised Controlled Trial (RCT) to test the null hypothesis that receipt of palliative care in addition to standard HIV care does not affect pain compared to standard care alone. An additional qualitative component will explore the mechanism of action and participant experience. The sample size is designed to detect a statistically significant decrease in reported pain, determined by a two tailed test and a p value of ≤0.05. Recruited patients will be adults on ART for more than one month, who report significant pain or symptoms which have lasted for more than two weeks (as measured by the African Palliative Care Association (APCA) African Palliative Outcome Scale (POS)). The intervention under trial is palliative care delivered by an existing HIV facility nurse trained to a set standard. Following an initial pilot the study will be delivered in two African countries, using two parallel independent Phase III clinical RCTs. Qualitative data will be collected from semi structured interviews and documentation from clinical encounters, to explore the experience of receiving palliative care in this context. The data provided by this study will provide evidence to inform the improvement of outcomes for people living with HIV and on ART in Africa.ClinicalTrials.gov Identifier: NCT01608802.

  8. White LED with High Package Extraction Efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Yi Zheng; Matthew Stough

    2008-09-30

    The goal of this project is to develop a high efficiency phosphor converting (white) Light Emitting Diode (pcLED) 1-Watt package through an increase in package extraction efficiency. A transparent/translucent monolithic phosphor is proposed to replace the powdered phosphor to reduce the scattering caused by phosphor particles. Additionally, a multi-layer thin film selectively reflecting filter is proposed between blue LED die and phosphor layer to recover inward yellow emission. At the end of the project we expect to recycle approximately 50% of the unrecovered backward light in current package construction, and develop a pcLED device with 80 lm/W{sub e} using our technology improvements and commercially available chip/package source. The success of the project will benefit luminous efficacy of white LEDs by increasing package extraction efficiency. In most phosphor-converting white LEDs, the white color is obtained by combining a blue LED die (or chip) with a powdered phosphor layer. The phosphor partially absorbs the blue light from the LED die and converts it into a broad green-yellow emission. The mixture of the transmitted blue light and green-yellow light emerging gives white light. There are two major drawbacks for current pcLEDs in terms of package extraction efficiency. The first is light scattering caused by phosphor particles. When the blue photons from the chip strike the phosphor particles, some blue light will be scattered by phosphor particles. Converted yellow emission photons are also scattered. A portion of scattered light is in the backward direction toward the die. The amount of this backward light varies and depends in part on the particle size of phosphors. The other drawback is that yellow emission from phosphor powders is isotropic. Although some backward light can be recovered by the reflector in current LED packages, there is still a portion of backward light that will be absorbed inside the package and further converted to heat. Heat

  9. LED-driven backlights for automotive displays

    Science.gov (United States)

    Strauch, Frank

    2007-09-01

    As a light source the LED has some advantage over the traditionally used fluorescence tube such as longer life or lower space consumption. Consequently customers are asking for the LED lighting design in their products. We introduced in a company owned backlight the white LED technology. This step opens the possibility to have access to the components in the display market. Instead of having a finalized display product which needs to be integrated in the head unit of a car we assemble the backlight, the glass, own electronics and the housing. A major advantage of this concept is the better control of the heat flow generated by the LEDs to the outer side because only a common housing is used for all the components. Also the requirement for slim products can be fulfilled. As always a new technology doesn't come with advantages only. An LED represents a point source compared to the well-known tube thus requiring a mixing zone for the multiple point sources when they enter a light guide. This zone can't be used in displays because of the lack of homogeneity. It's a design goal to minimize this zone which can be helped by the right choice of the LED in terms of slimness. A step ahead is the implementation of RGB LEDs because of their higher color rendering abilities. This allows for the control of the chromaticity point under temperature change but as a drawback needs a larger mixing zone.

  10. High Power UV LED Industrial Curing Systems

    Energy Technology Data Exchange (ETDEWEB)

    Karlicek, Robert, F., Jr; Sargent, Robert

    2012-05-14

    UV curing is a green technology that is largely underutilized because UV radiation sources like Hg Lamps are unreliable and difficult to use. High Power UV LEDs are now efficient enough to replace Hg Lamps, and offer significantly improved performance relative to Hg Lamps. In this study, a modular, scalable high power UV LED curing system was designed and tested, performing well in industrial coating evaluations. In order to achieve mechanical form factors similar to commercial Hg Lamp systems, a new patent pending design was employed enabling high irradiance at long working distances. While high power UV LEDs are currently only available at longer UVA wavelengths, rapid progress on UVC LEDs and the development of new formulations designed specifically for use with UV LED sources will converge to drive more rapid adoption of UV curing technology. An assessment of the environmental impact of replacing Hg Lamp systems with UV LED systems was performed. Since UV curing is used in only a small portion of the industrial printing, painting and coating markets, the ease of use of UV LED systems should increase the use of UV curing technology. Even a small penetration of the significant number of industrial applications still using oven curing and drying will lead to significant reductions in energy consumption and reductions in the emission of green house gases and solvent emissions.

  11. Thermoresponsive scattering coating for smart white LEDs

    Science.gov (United States)

    Cornelissen, Hugo J.; Yu, Joan; Cennini, Giovanni; Bauer, Jurica; Verbunt, Paul P. C.; Bastiaansen, Cees W. M.; Broer, Dirk J.

    2015-09-01

    A novel responsive lighting system is presented capable of lowering the color temperature of emitted light on dimming. It is based on a single white light emitting LED and a thermo-responsive scattering coating. The coated LED automatically emits light of lower correlated color temperature (CCT) when the power is reduced, while maintaining a chromaticity close to the black body curve. Existing systems all use multiple color LEDs, additional control circuitry and mixing optics. An optical ray tracing model can explain the experimental results.

  12. Drosophila insulin and target of rapamycin (TOR pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo

    Directory of Open Access Journals (Sweden)

    Parisi Federica

    2011-09-01

    Full Text Available Abstract Background Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways. Results Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3β a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia. Conclusions Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in Drosophila. At

  13. Stromal liver kinase B1 [STK11] signaling loss induces oviductal adenomas and endometrial cancer by activating mammalian Target of Rapamycin Complex 1.

    Directory of Open Access Journals (Sweden)

    Pradeep S Tanwar

    Full Text Available Germline mutations of the Liver Kinase b1 (LKB1/STK11 tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS, an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Müllerian duct mesenchyme-derived cells of the female reproductive tract and observed expansion of the stromal compartment and hyperplasia and/or neoplasia of adjacent epithelial cells throughout the reproductive tract with paratubal cysts and adenomyomas in oviducts and, eventually, endometrial cancer. Examination of the proliferation marker phospho-histone H3 and mammalian Target Of Rapamycin Complex 1 (mTORC1 pathway members revealed increased proliferation and mTORC1 activation in stromal cells of both the oviduct and uterus. Treatment with rapamycin, an inhibitor of mTORC1 activity, decreased tumor burden in adult Lkb1 mutant mice. Deletion of the genes for Tuberous Sclerosis 1 (Tsc1 or Tsc2, regulators of mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1-deleted stroma contributes to the phenotype. Loss of PTEN, an upstream regulator of mTORC1 signaling, along with Lkb1 deletion significantly increased tumor burden in uteri and induced tumorigenesis in the cervix and vagina. These studies show that LKB1/TSC1/TSC2/mTORC1 signaling in mesenchymal cells is important for the maintenance of epithelial integrity and suppression of carcinogenesis in adjacent epithelial cells. Because similar changes in the stromal population are also observed in human oviductal/ovarian adenoma and endometrial adenocarcinoma patients, we predict that dysregulated mTORC1 activity by upstream mechanisms similar to those described in these model systems contributes to the pathogenesis of these human diseases.

  14. Perceived learning effectiveness of a course Facebook page: teacher-led versus student-led approach

    National Research Council Canada - National Science Library

    Tugba Orten Tugrul

    2017-01-01

    This research aims to compare the perceived effectiveness of teacher -led and student-led content management approaches embraced in a course Facebook page designed to enhance traditional classroom learning...

  15. Kansas highway LED illumination manual : a guide for the use of LED lighting systems : [technical summary].

    Science.gov (United States)

    2015-12-01

    The research project was aimed to assist the Kansas Department of Transportation (KDOT) in the development of a Highway LED Illumination Manual for guiding the upcoming implementation of successful LED roadway lighting systems in Kansas to replace th...

  16. Kansas highway LED illumination manual : a guide for the use of LED lighting systems.

    Science.gov (United States)

    2015-12-01

    The research project was aimed to assist the Kansas Department of Transportation (KDOT) in the development of a Highway LED Illumination Manual for guiding the upcoming implementation of successful LED roadway lighting systems in Kansas to replace th...

  17. The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics.

    Science.gov (United States)

    Di Domenico, Fabio; Barone, Eugenio; Perluigi, Marzia; Butterfield, D Allan

    2017-03-10

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as a metabolic disease, characterized by reduced insulin-stimulated growth and survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. Recent Advances: Reduced glucose utilization and energy metabolism in AD have been associated with the buildup of amyloid-β peptide and hyperphosphorylated tau, increased OS, and the accumulation of unfolded/misfolded proteins. Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance). It is likely that the concomitant and mutual alterations of energy metabolism-mTOR signaling-protein homeostasis might represent a self-sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Intriguingly, the altered cross-talk between the components of such a triangle of death, beyond altering the redox homeostasis of the neuron, is further exacerbated by increased levels of OS that target and impair key components of the pathways involved. Redox proteomic studies in human samples and animal models of AD-like dementia led to identification of oxidatively modified components of the pathways composing the triangle of death, therefore revealing the crucial role of OS in fueling this aberrant vicious cycle. The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. Antioxid

  18. Color tunable hybrid lamp: LED-incandescent and LED-fluorescent

    Science.gov (United States)

    Moreno, Ivan

    2007-03-01

    Light-emitting diodes (LEDs) can be chosen to emit light in a wide variety of highly saturated colors. As a consequence, a hybrid lamp assembled with colored LEDs and with one incandescent or fluorescent source easily allows the user to dynamically select the desired color point without additional filters, with high color rendering index, and at a low cost. We measure some properties of a color tunable lamp that uses both colored LEDs and an incandescent or a fluorescent source. For the LED-incandescent type, we assemble an array of blue LEDs with a typical incandescent bulb source, and to assemble a LED-fluorescent type we used an array of red LEDs with a commercially available compact fluorescent lamp. Incandescent and fluorescent sources have a fixed intensity, while LED intensities are adjusted to tune color. For LED-incandescent lamps, our experimental data show that the correlated color temperature (CCT) can be linearly tuned with the electric current of the LED array. The LED-fluorescent lamp exhibits a CCT that exponentially varies with the drive current of red LEDs.

  19. Significant growth in. LED use predicted.

    Science.gov (United States)

    Simpson, Mike

    2012-03-01

    Although LED lighting has its critics, a number of whom (see article 'LED--panacea or marketing hype', HEJ--February 2012) are concerned about what they claim are some manufacturers' 'exaggerated claims' about lighting efficiency and lamp lifetime, Philips Lighting believes that, such are the advances being made in this innovative lighting technology, that LED's overall share of the European lighting market will have risen from around 7% in 2008 to 25% by 2020 and that, a decade later, it will account for a remarkable 75% of lighting sales. In the UK, Philips' technical and design director for Lighting, Mike Simpson, told HEJ editor, Jonathan Baillie, healthcare estates and facilities managers are increasingly recognising the potential to save energy, reduce carbon emissions, and cut maintenance costs, using LED.

  20. Optimized design of LED plant lamp

    Science.gov (United States)

    Chen, Jian-sheng; Cai, Ruhai; Zhao, Yunyun; Zhao, Fuli; Yang, Bowen

    2014-12-01

    In order to fabricate the optimized LED plant lamp we demonstrated an optical spectral exploration. According to the mechanism of higher plant photosynthesis process and the spectral analysis we demonstrate an optical design of the LED plant lamp. Furthermore we built two kins of prototypes of the LED plant lamps which are suitable for the photosynthesis of higher green vegetables. Based on the simulation of the lamp box of the different alignment of the plants we carried out the growing experiment of green vegetable and obtain the optimized light illumination as well as the spectral profile. The results show that only blue and red light are efficient for the green leave vegetables. Our work is undoubtedly helpful for the LED plant lamping design and manufacture.

  1. Eerste LED-proeven met wisselend succes

    NARCIS (Netherlands)

    Sleegers, J.; Dueck, T.A.

    2008-01-01

    Na groentetelers gaan nu ook siertelers met led aan de slag. De eerste praktijkproeven hebben wisselend succes gehad. De fabrikanten zijn vol goede moed en de komende maanden gaan tal van nieuwe proeven van start

  2. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp.

    Science.gov (United States)

    Reinhold, U; Dirschka, T; Ostendorf, R; Aschoff, R; Berking, C; Philipp-Dormston, W G; Hahn, S; Lau, K; Jäger, A; Schmitz, B; Lübbert, H; Szeimies, R-M

    2016-10-01

    Multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun-damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial. To evaluate the efficacy, safety and cosmetic outcome of BF-200 ALA (a nanoemulsion formulation containing 10% aminolaevulinic acid hydrochloride) combined with the BF-RhodoLED(®) lamp for the field-directed treatment of mild-to-moderate AK with PDT. The study was performed as a randomized, multicentre, double-blind, placebo-controlled, parallel-group, phase III trial with BF-200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF-200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF-RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm(-2) was achieved. BF-200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority" should not be skipped since this is an important result. Treatment-emergent adverse events (TEAEs) were experienced by 100% of the BF-200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF-200 ALA group compared with placebo. Field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on

  3. Nurse led venesection: a quality improvement project

    OpenAIRE

    Patel, Chandni; Morgan, Dafydd

    2015-01-01

    Venesection is a widely practised procedure, involving the removal of a unit of blood in order to treat haemochromatosis and polycythaemia. It is still well regarded due to a lack of better alternatives and a small side effect profile. At Barnet General Hospital, venesection has recently been a physician led service, unlike its neighbouring hospital at Chase Farm Hospital, which has a well run nurse led service. The current service being run at Barnet Hospital was beset with problems, includi...

  4. LED til væksthuse

    DEFF Research Database (Denmark)

    Dam-Hansen, Carsten; Thorseth, Anders; Rosenqvist, Eva

    2012-01-01

    Den teknologiske udvikling indenfor Lys Emitterende Dioder (LED) går imod stadig større lysmængder og stadig større effektivitet. Kombineret med fordele som lang levetid, dæmpbarhed og ingen varmestråling gør det, at LED baserede lyskilder/lamper i stigende grad benyttes til belysningsformål og kan...

  5. Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells.

    Directory of Open Access Journals (Sweden)

    Shan He

    Full Text Available BACKGROUND: Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized. DESIGN AND METHODS: Using lymphocytic choriomeningitis virus (LCMV peptide gp33-specific CD8(+ T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo. RESULTS: Antigen-activated CD8(+ T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS. These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells. CONCLUSIONS: Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.

  6. Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer.

    Science.gov (United States)

    Cai, Dongge; Sun, Hongli; Qi, Yanhua; Zhao, Xiaogui; Feng, Minjuan; Wu, Xiaoling

    2016-11-01

    Metformin is a well-tolerated biguanide drug used for decades to treat type 2 diabetes mellitus. In recent years, long-term administration of metformin has been found to reduce carcinogenic risk for cancers derived from various tissues. However, its cellular and molecular mechanisms of anticancer action in the endometrial cancer (EC) have not yet been fully elucidated. Sixty patients diagnosed as endometrial carcinoma were grouped into (n = 30) and non-treatment mixed (n = 30) for analysis. Thirty healthy donors are control groups. We attempt to investigate the interaction of metformin, insulin-like growth factor 1 (IGF-1) expression, and phosphorylated mammalian target of rapamycin (p-mTOR) and AMP-activated protein kinase (p-AMPK). We found that high IGF-1 plasma concentrations in women with EC were reversed by conventional antidiabetic doses of metformin in the present work. In parallel, the activation of AMPK and suppression of mTOR seemed to play an important role for the effect of metformin in patients with EC. This pilot trial presents biological evidence consistent with antiproliferative effects of metformin in women with EC in the clinical setting.

  7. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors.

    Science.gov (United States)

    Nair, Vijayalekshmi; Sreevalsan, Sandeep; Basha, Riyaz; Abdelrahim, Maen; Abudayyeh, Ala; Rodrigues Hoffman, Aline; Safe, Stephen

    2014-10-03

    The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. 2,5-Dimethyl-Celecoxib Extends Drosophila Life Span via a Mechanism That Requires Insulin and Target of Rapamycin Signaling.

    Science.gov (United States)

    Wu, Qi; Lian, Ting; Fan, Xiaolan; Song, Chaochun; Gaur, Uma; Mao, Xueping; Yang, Deying; Piper, Matthew D W; Yang, Mingyao

    2017-10-01

    The search for antiaging drugs is a key component of gerontology research. A few drugs with positive effects on life span in model organisms have been found. Here, we report that 2,5-dimethyl-celecoxib, a derivative of the anti-inflammatory drug celecoxib, can extend Drosophila life span and delay aging by a mechanism involving insulin signaling and target of rapamycin signaling. Importantly, its positive effects were apparent when the treatment window was restricted to the beginning of life or the later half. 2,5-Dimethyl-celecoxib-induced longevity was also associated with improvements in physical activity, intestinal integrity, and increased autophagy. In addition, 2,5-dimethyl-celecoxib exhibited protective effects against several kinds of stress such as starvation and heat. The generally positive effects of 2,5-dimethyl-celecoxib on both health and life span, combined with its mode of action via evolutionarily conserved signaling pathways, indicate that it has the potential to become an effective antiaging drug. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Attenuation of pentylenetrazole-induced acute status epilepticus in rats by adenosine involves inhibition of the mammalian target of rapamycin pathway.

    Science.gov (United States)

    Wang, Yuliang; Liu, Xuewu; Wang, Yuan; Chen, Jinbo; Han, Tao; Su, Lei; Zang, Kejun

    2017-10-18

    Adenosine (ADO) has been characterized as an endogenous anticonvulsant and alternative therapeutic drug, but its mechanism is not entirely clear. This study aimed to examine the relationship of ADO with the mammalian target of rapamycin (mTOR) in a Wistar rat model of pentylenetetrazole (PTZ)-induced acute status epilepticus. ADO (200 mg/kg) was administered intraperitoneally 30 min before PTZ (55-65 mg/kg) treatment, and Western blot assays and immunohistochemistry were performed 3 h after the onset of acute status epilepticus to detect phospho-TOR and the downstream target of mTOR, phospho-S6. The expression of these phosphoproteins in the hippocampus was significantly increased in PTZ-treated rats, but this increase was attenuated by the addition of ADO. To further verify a role for ADO in attenuating mTOR activity, we also evaluated its ability to suppress mTOR activity in normal rats that were not treated with PTZ. Our results suggest that ADO suppresses mTOR and S6 phosphorylation in normal rats and that this suppression can be reversed by the application of Compound C, an inhibitor of AMP-activated protein kinase, which functions as an upstream suppressor of the mTOR pathway. Thus, our results provide a novel antiepileptic mechanism for ADO in suppressing mTOR pathway activation upon PTZ-induced acute status epilepticus.

  10. Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Kuiqing; Chen, Xu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Liu, Cheng [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Gu, Peng; Li, Zhuohang; Wu, Shaoxu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Xu, Kewei [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Lin, Tianxin, E-mail: tianxinl@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Huang, Jian, E-mail: urolhj@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China)

    2015-05-01

    Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients. - Highlights: • Pirarubicin induced autophagy in bladder cancer cells. • Inhibition of autophagy enhanced pirarubicin-induced apoptosis. • Pirarubicin induced autophagy through inhibition of mTOR signaling pathway.

  11. Investigation of Passive Filter for LED Lamp

    Science.gov (United States)

    Sarwono, Edi; Facta, Mochammad; Handoko, Susatyo

    2017-04-01

    Light Emitting Diode lamp or LED lamp is one of the energy saving lamps nowadays widely used by consumers. However, LED lamp has contained harmonics caused by the rectifier circuit inside the lamp. Harmonics cause a quality problem in power system. As the harmonics present in current or voltage, the waveforms are distorted. Harmonics can lead to overheating in magnetic core of electrical equipments. In this paper, several tests are carried out to investigate the harmonic content of voltage and currents, and also the level of light intensity of the two brands of LED lamps. Measurements in this study are conducted by using HIOKI Power Quality Analyzer 3197. The test results show that the total harmonic distortion or THD of voltage on various brands of LED lamps did not exceed 5% as in compliance to the limit of IEEE standard 519-1992. The largest harmonic voltage is 2.9%, while maximum harmonic current for tested brands of LED lamp is 170.6%. The use of low pass filter in the form of LC filter was proposed. Based on experimental results, the application of LC filter at input side of LED lamp has successfully reduced THD current in the range of 85%-88%.

  12. Temperature measurements of high power LEDs

    Science.gov (United States)

    Badalan (Draghici), Niculina; Svasta, Paul; Drumea, Andrei

    2016-12-01

    Measurement of a LED junction temperature is very important in designing a LED lighting system. Depending on the junction temperature we will be able to determine the type of cooling system and the size of the lighting system. There are several indirect methods for junction temperature measurement. The method used in this paper is based on the thermal resistance model. The aim of this study is to identify the best device that would allow measuring the solder point temperature and the temperature on the lens of power LEDs. For this purpose four devices for measuring temperature on a high-power LED are presented and compared according to the acquired measurements: an infrared thermal camera from FLIR Systems, a multimeter with K type thermocouple (Velleman DVM4200), an infrared-spot based noncontact thermometer (Raynger ST) and a measurement system based on a digital temperature sensor (DS1821 type) connected to a PC. The measurements were conducted on an 18W COB (chip-on-board) LED. The measurement points are the supply terminals and the lens of the LED.

  13. Antifibrotic effect of rapamycin containing polyethylene glycol-coated alginate microcapsule in islet xenotransplantation.

    Science.gov (United States)

    Park, Heon-Seok; Kim, Ji-Won; Lee, Seung-Hwan; Yang, Hae Kyung; Ham, Dong-Sik; Sun, Cheng-Lin; Hong, Tae Ho; Khang, Gilson; Park, Chung-Gyu; Yoon, Kun-Ho

    2017-04-01

    Islet microencapsulation is an attractive strategy for the minimization or avoidance of life-long immunosuppression after transplantation. However, the clinical implementation of this technique is currently limited by incomplete biocompatibility. Thus, the aim of the present study was to demonstrate the improved biocompatibility of rapamycin-containing polyethylene glycol (Rapa-PEG)-coating on alginate microcapsules containing xenogeneic islets. The Rapa-PEG-coating on the alginate layer was observed using scanning electron microscopy (SEM) and the molecular cut-off weight of the microcapsules was approximately 70 kDa. The viabilities of the alginate-encapsulated and Rapa-PEG-coated alginate-encapsulated islets were lower than the viability of the naked islets just after encapsulation, but these the differences diminished over time in culture dishes. Rapa-PEG-coating on the alginate capsules effectively decreased the proliferation of macrophage cells compared to the non-coating and alginate coating of xenogeneic pancreas tissues. Glucose-stimulated insulin secretion did not significantly differ among the groups prior to transplantation. The random blood glucose levels of diabetic mice significantly improved following the transplantation of alginate-encapsulated and Rapa-PEG-coated alginate-encapsulated islets, but there were no significant differences between these two groups. However, there was a significant decrease in the number of microcapsules with fibrotic cell infiltration in the Rapa-PEG-coated alginate microcapsule group compared to the alginate microcapsule group. In conclusion, Rapa-PEG-coating might be an effective technique with which to improve the biocompatibility of microcapsules containing xenogeneic islets. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Rapid modification of proteins using a rapamycin-inducible tobacco etch virus protease system.

    Directory of Open Access Journals (Sweden)

    Damian J Williams

    2009-10-01

    Full Text Available The ability to disrupt the function of a specific protein on a rapid time scale provides a powerful tool for biomedical research. Specific proteases provide a potential method to selectively cleave a chosen protein, but rapid control of protease activity is difficult.A heterologous expression system for rapid target-directed proteolysis in mammalian cells was developed. The system consists of an inducible NIa protease from the tobacco etch virus (TEVp and a chosen protein into which a TEVp substrate recognition sequence (TRS has been inserted. Inducible activity was conferred to the TEVp using rapamycin-controlled TEVp fragment complementation. TEVp activity was assayed using a FRET-based reporter construct. TEVp expression was well tolerated by mammalian cells and complete cleavage of the substrate was possible. Cleavage at 37 degrees C proceeded exponentially with a time constant of approximately 150 minutes. Attempts to improve cleavage efficiency were hampered by substantial background activity, which was attributed to inherent affinity between the TEVp fragments. A second TEVp assay, based on changes in inactivation of a modified K(V3.4 channel, showed that functional properties of a channel can be using altered using an inducible TEVp system. Similar levels of background activity and variability were observed in both electrophysiological and FRET assays.The results suggested that an optimum level of TEVp expression leading to sufficient inducible activity (with minimal background activity exists but the variability in expression levels between cells makes the present system rather impractical for single cell experiments. The system is likely to be more suitable for experiments in which the cell-to-cell variability is less of an issue; for example, in experiments involving large populations of cells.

  15. Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.

    Science.gov (United States)

    Wang, Chao; Zhang, Ruiming; Zhou, Le; He, Jintian; Huang, Qiang; Siyal, Farman A; Zhang, Lili; Zhong, Xiang; Wang, Tian

    2017-08-31

    Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined. Intestinal apoptosis, autophagy, and the mechanistic target of rapamycin (mTOR) signaling pathway were analyzed. The results indicated that maternal 50% food restriction reduced maternal serum glucose, bilirubin, and total cholesterol and produced IUGR fetuses, which had decreased body weight; blood glucose; and weights of the small intestine, stomach, spleen, pancreas, and kidney. Decreased Bcl-2 and increased Casp9 mRNA expression was observed in IUGR fetal intestines. Analysis of intestinal autophagy showed that the mRNA expression of WIPI1, MAP1LC3B, Atg5, and Atg14 was also increased, while the protein levels of p62 were decreased in IUGR fetuses. Compared to NW fetuses, IUGR fetuses showed decreased mTOR protein levels and enhanced mRNA expression of ULK1 and Beclin1 in the small intestine. In summary, the results indicated that maternal 50% food restriction on gestational days 10-21 reduced maternal serum glucose, bilirubin, and total cholesterol contents, and produced IUGR fetuses that had low blood glucose and reduced small intestine weight. Intestinal injury of IUGR fetuses caused by maternal food restriction might be due to enhanced apoptosis and autophagy via the mTOR signaling pathway.

  16. BRAF gene alterations and enhanced mammalian target of rapamycin signaling in gangliogliomas.

    Science.gov (United States)

    Kakkar, Aanchal; Majumdar, Atreye; Pathak, Pankaj; Kumar, Anupam; Kumari, Kalpana; Tripathi, Manjari; Sharma, Mehar C; Suri, Vaishali; Tandon, Vivek; Chandra, Sarat P; Sarkar, Chitra

    2017-01-01

    Gangliogliomas (GGs) are slow-growing glioneuronal tumors seen in children and young adults. They are associated with intractable epilepsy, and have recently been found to harbor BRAF (B- rapidly accelerated fibrosarcoma) gene mutations. However, the mammalian target of rapamycin (mTOR) signaling pathway, downstream of BRAF, has not been evaluated extensively in GGs. GG cases were retrieved, clinical data obtained, and histopathological features reviewed. Sequencing for BRAF V600E mutation, analysis of BRAF copy number by quantitative real-time polymerase chain reaction, and immunohistochemistry for mTOR pathway markers p-S6 and p-4EBP1 were performed. Sixty-four cases of GG were identified (0.9% of central nervous system tumors). Of these, 28 had sufficient tumor tissue for further evaluation. Mixed glial and neuronal morphology was the commonest (64%) type. Focal cortical dysplasia was identified in the adjacent cortex (6 cases). BRAF V600E mutation was identified in 30% of GGs; BRAF copy number gain was observed in 50% of them. p-S6 and p-4EBP1 immunopositivity was seen in 57% cases each. Thus, mTOR pathway activation was seen in 81% cases, and was independent of BRAF alterations. 87% patients had Engel grade I outcome, while 13% had Engel grade II outcome. Both the Engel grade II cases analyzed showed BRAF V600E mutation. BRAF V600E mutation is frequent in GGs, as is BRAF gain; the former may serve as a target for personalized therapy in patients with residual tumors, necessitating its assessment in routine pathology reporting of these tumors. Evidence of mTOR pathway activation highlights similarities in the pathogenetic mechanisms underlying GG and focal cortical dysplasia, and suggests that mTOR inhibitors may be of utility in GG patients with persistent seizures after surgery.

  17. Mammalian Target of Rapamycin: Hitting the Bull's-Eye for Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Zhao Zhong Chong

    2010-01-01

    Full Text Available The mammalian target of rapamycin (mTOR and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly,the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens and hormones. Growth factors, amino acids, cellular nutrients and oxygen deficiency can downregulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1 and p70 ribosomal S6 kinase (p70S6K. In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer disease, Parkinson disease and Huntington disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders.

  18. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.

    Science.gov (United States)

    Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian; Banasr, Mounira; Li, Nanxin; Terwilliger, Rose; Sanacora, Gerard; Eid, Tore; Aghajanian, George; Duman, Ronald S

    2013-11-15

    Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists. The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors. The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist. Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents. © 2013 Society of Biological Psychiatry.

  19. LEDS GP Success Story: Fostering Coordinated LEDS Support in Kenya (Fact Sheet)

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2014-03-01

    The LEDS Global Partnership (LEDS GP) strives to advance climate-resilient, low-emission development through catalyzing collaboration, information exchange, and action on the ground. The Government of Kenya is a key LEDS GP member and offers an inspiring example of how LEDS GP is having an impact globally. The 2012 LEDS Collaboration in Action workshop in London provided an interactive space for members to share experiences on cross-ministerial LEDS leadership and to learn about concrete development impacts of LEDS around the world. Inspired by these stories, the Kenya's Ministry of State for Planning, National Development and Vision 2030 (MPND) began to collaborate closely with the Ministry of Environment and Mineral Resources to create strong links between climate change action and development in the country, culminating in the integration of Kenya's National Climate Change Action Plan and the country's Medium Term Development Plan.

  20. Pulsed and Continuous UV LED Reactor for Water Treatment

    Data.gov (United States)

    U.S. Environmental Protection Agency — Numerical data represented in the figures which are graphs. This dataset is associated with the following publication: Spencer, M., M. Miller, J. Richwine, K....

  1. Response of Eustoma Leaf Phenotype and Photosynthetic Performance to LED Light Quality

    Directory of Open Access Journals (Sweden)

    Md Zohurul Kadir Roni

    2017-10-01

    Full Text Available In a controlled environment, light from light-emitting diodes (LEDs has been associated with affecting the leaf characteristics of Eustoma. LEDs help plant growth and development, yet little is known about photosynthetic performance and related anatomical features in the early growth stage of Eustoma leaves. In this study, we examined the effects of blue (B, red (R, and white (W LEDs on the photosynthetic performance of Eustoma leaves, as well as leaf morphology and anatomy including epidermal layer thickness, palisade cells, and stomatal characteristics. Leaves grown under B LEDs were thicker and had a higher chlorophyll content than those grown under the R and W LEDs. Leaves under B LEDs had greater net photosynthetic rates (A, stomatal conductance (gs, and transpiration rates (E, especially at a higher photon flux density (PPFD, that resulted in a decrease in the intercellular CO2 concentration (Ci, than leaves under the W and R LEDs. B LEDs resulted in greater abaxial epidermal layer thickness and palisade cell length and width than the R and W LED treatments. The palisade cells also developed a more cylindrical shape in response to the B LEDs. B LED leaves also showed greater guard cell length, breadth, and area, and stomatal density, than W or R LEDs, which may contribute to increased A, gs and E at higher PPFDs.

  2. Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation.

    Science.gov (United States)

    Jobim, Paulo F C; Pedroso, Thiago R; Werenicz, Aline; Christoff, Raissa R; Maurmann, Natasha; Reolon, Gustavo K; Schröder, Nadja; Roesler, Rafael

    2012-03-01

    The role of the basolateral complex of the amygdala (BLA) in recognition memory remains poorly understood. The mammalian target of rapamycin (mTOR) in the BLA and other brain areas has been implicated in synaptic plasticity and memory. We have recently shown that mTOR signaling in both the BLA and the dorsal hippocampus (DH) is required for formation and reconsolidation of inhibitory avoidance, a fear-motivated memory task. Here we examined the effects of infusions of the mTOR inhibitor rapamycin into the BLA before or after either training or reactivation on retention of novel object recognition (NOR) memory in rats, and compared the effects with those obtained using intra-DH infusions. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after NOR training or reactivation. Rapamycin impaired NOR retention tested 24h after training when given either before or immediately after training into the BLA or DH. Rapamycin also impaired retention measured 24h after reactivation when infused before reactivation into the BLA or DH, or immediately after reactivation into the BLA, but not when given 6h after reactivation into either the BLA or DH. The results suggest that mTOR signaling in the BLA and DH is involved in NOR memory formation and stabilization. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response of 264.7 RAW Macrophages Stimulated by CA-MRSA

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    Rebekah K. H. Shappley

    2014-01-01

    Full Text Available Background. Rapamycin suppresses the RAW264.7 macrophage mediated inflammatory response but in lower doses induces it. In the present study, we tested the suppression of the inflammatory response in the presence of mTOR 1 and 2 inhibitors, Torin and KU63794. Methods. RAW264.7 cells were stimulated for 18 hrs with 106 to 107 CFU/mL inocula of community-acquired- (CA- MRSA isolate, USA400 strain MW2, in the presence of Vancomycin. Then, in sequential experiments, we added Torin, KU63794, and Rapamycin alone and in various combinations. Supernatants were collected and assayed for TNF, IL-1, IL-6, INF, and NO. Results. Rapamycin induces 10–20% of the inflammatory cascade at dose of 0.1 ng/mL and suppresses it by 60% at dose of 10 ng/mL. The induction is abolished in the presence of Torin KU63794. Torin and KU63794 are consistently suppressing cytokine production 50–60%. Conclusions. There is a differential response between Rapamycin (mTOR-1 inhibitor and Torin KU63794 (mTOR 1 and 2 inhibitors. Torin and KU63794 exhibit a dose related suppression. Rapamycin exhibits a significant induction-suppression biphasic response. Knowledge of such response may allow manipulation of the septic inflammatory cascade for clinical advantages.

  4. De Novo Donor-Specific Antibody Formation in Tacrolimus-Based, Mycophenolate Versus Mammalian Target of Rapamycin Immunosuppressive Regimens.

    Science.gov (United States)

    Mithani, Zain; Gralla, Jane; Adebiyi, Oluwafisayo; Klem, Patrick; Cooper, James E; Wiseman, Alexander C

    2017-03-22

    De novo donor-specific antibody formation posttransplant is associated with decreased graft survival. It is not known whether mammalian target of rapamycin inhibitors may be advantageous or detrimental compared with mycophenolate in the prevention of de novo donor-specific antibody formation. We compared 66 kidney and kidney-pancreas transplant recipients who received tacrolimus, mammalian target of rapamycin inhibitor, and prednisone (group 1; 36 of whom received everolimus and 30 of whom received sirolimus) versus 132 patients who received tacrolimus, mycophenolate, and prednisone (group 2) matched for age, sex, race, and type/timing of transplant from 2007 to 2012. Rates of de novo donor-specific antibody formation were comparable between groups at 1, 6, and 12 months (16.7%, 25.8%, and 28.8% for group 1 vs 9.8%, 15.2%, and 22.0% for group 2). There were no significant differences in class (I, II, or mixed), strength (mean fluorescence intensity) of de novo donor-specific antibody, glomerular filtration rate, proteinuria levels, or acute rejection between the groups. In those with de novo donor-specific antibody by 6 months, acute rejection was more common versus those without de novo donor-specific antibody formation (24.3% vs 5.6% at 6 mo; P = .002), with rates of 27.0% versus 6.8% at 1 year (P = .001) and 40.7% versus 11.3% at 2 years (P < .001). An associated reduction in glomerular filtration rate also occurred. Mammalian target of rapamycin inhibitors were neither protective nor permissive for de novo donor-specific antibody formation versus mycophenolate when used with clinically relevant tacrolimus dosing regimens.

  5. Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system

    Directory of Open Access Journals (Sweden)

    Jing eJiang

    2013-08-01

    Full Text Available The mammalian target of rapamycin (mTOR inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA analyses involving single nucleotide polymorphisms (SNPs, mRNA and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs. Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. 127 and 100 SNPs had P<10-4, while 8 and 10 SNPs had P<10-5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.

  6. Rapamycin and CHIR99021 Coordinate Robust Cardiomyocyte Differentiation From Human Pluripotent Stem Cells Via Reducing p53-Dependent Apoptosis.

    Science.gov (United States)

    Qiu, Xiao-Xu; Liu, Yang; Zhang, Yi-Fan; Guan, Ya-Na; Jia, Qian-Qian; Wang, Chen; Liang, He; Li, Yong-Qin; Yang, Huang-Tian; Qin, Yong-Wen; Huang, Shuang; Zhao, Xian-Xian; Jing, Qing

    2017-10-02

    Cardiomyocytes differentiated from human pluripotent stem cells can serve as an unexhausted source for a cellular cardiac disease model. Although small molecule-mediated cardiomyocyte differentiation methods have been established, the differentiation efficiency is relatively unsatisfactory in multiple lines due to line-to-line variation. Additionally, hurdles including line-specific low expression of endogenous growth factors and the high apoptotic tendency of human pluripotent stem cells also need to be overcome to establish robust and efficient cardiomyocyte differentiation. We used the H9-human cardiac troponin T-eGFP reporter cell line to screen for small molecules that promote cardiac differentiation in a monolayer-based and growth factor-free differentiation model. We found that collaterally treating human pluripotent stem cells with rapamycin and CHIR99021 during the initial stage was essential for efficient and reliable cardiomyocyte differentiation. Moreover, this method maintained consistency in efficiency across different human embryonic stem cell and human induced pluripotent stem cell lines without specifically optimizing multiple parameters (the efficiency in H7, H9, and UQ1 human induced pluripotent stem cells is 98.3%, 93.3%, and 90.6%, respectively). This combination also increased the yield of cardiomyocytes (1:24) and at the same time reduced medium consumption by about 50% when compared with the previous protocols. Further analysis indicated that inhibition of the mammalian target of rapamycin allows efficient cardiomyocyte differentiation through overcoming p53-dependent apoptosis of human pluripotent stem cells during high-density monolayer culture via blunting p53 translation and mitochondrial reactive oxygen species production. We have demonstrated that mammalian target of rapamycin exerts a stage-specific and multifaceted regulation over cardiac differentiation and provides an optimized approach for generating large numbers of functional

  7. Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model.

    Science.gov (United States)

    Yang, Chun; Ren, Qian; Qu, Youge; Zhang, Ji-Chun; Ma, Min; Dong, Chao; Hashimoto, Kenji

    2018-01-01

    The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. The intracerebroventricular infusion of rapa