المؤلفون: Yu Sogo, Lue Sun, Kumi Morikawa, Yuki Sugiura

المصدر: Journal of Radiation Research

مصطلحات موضوعية: 0301 basic medicine, Senescence, senescence, Morpholines, Health, Toxicology and Mutagenesis, Apoptosis, medicine.disease_cause, Carcinoma, Lewis Lung, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Radiology, Nuclear Medicine and imaging, Fundamental Radiation Science, Radiosensitivity, Cellular Senescence, Tumor Stem Cell Assay, PI3K/AKT/mTOR pathway, Radiation, Triazines, Chemistry, TOR Serine-Threonine Kinases, Endoplasmic reticulum, mammalian target of rapamycin (mTOR), Cell Cycle, Endoplasmic Reticulum Stress, Genes, p53, Mitochondria, Neoplasm Proteins, Genes, ras, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer research, Unfolded protein response, AcademicSubjects/SCI00960, MHY1485, AcademicSubjects/MED00870, Lipid Peroxidation, Drug Screening Assays, Antitumor, Oxidative stress, Signal Transduction

الوصف: The mammalian target of rapamycin (mTOR) is a sensor of nutrient status and plays an important role in cell growth and metabolism. Although inhibition of mTOR signaling promotes tumor cell death and several mTOR inhibitors have been used clinically, recent reports have shown that co-treatment with MHY1485, an mTOR activator, enhances the anti-cancer effects of anti-PD-1 antibody and 5-fluorouracil. However, it remains unclear whether MHY1485 treatment alters the effects of radiation on tumor cells. In this study, the radiosensitizing effects of MHY1485 were investigated using murine CT26 and LLC cell lines. We examined mTOR signaling, tumor cell growth, colony formation, apoptosis, senescence, oxidative stress, p21 accumulation and endoplasmic reticulum (ER) stress levels in cells treated with MHY1485 and radiation, either alone or together. We found that MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485’s known role in activating mTOR signaling. Furthermore, we found that combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone. Our results suggested that MHY1485 enhances the radiosensitivity of tumor cells by a mechanism that may differ from MHY1485’s role in mTOR activation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96d9fb71f10d7fcd49dc94d4e158f3adTest
https://doi.org/10.1093/jrr/rrab057Test

المؤلفون: Divya Vohora, Preeti Vyas, Rajkumar Tulsawani

المصدر: Frontiers in Immunology
Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: Male, Morpholines, Immunology, Buparlisib, Aminopyridines, Apoptosis, mTORC1, Pharmacology, Hippocampus, mTORC2, Cell Line, Mice, chemistry.chemical_compound, Seizures, Animals, Immunology and Allergy, Kinase activity, Protein kinase B, Neuroinflammation, PI3K/AKT/mTOR pathway, Phosphoinositide-3 Kinase Inhibitors, Original Research, Membrane Potential, Mitochondrial, Sirolimus, PI3K/Akt/p-p70S6 pathway, Phosphoinositide 3-kinase, biology, Chemistry, TOR Serine-Threonine Kinases, mammalian target of rapamycin (mTOR), lipopolysaccharide, Imidazoles, phosphoinositide-3-kinase (PI3K), RC581-607, cytokines, Mice, Inbred C57BL, pilocarpine, kinase inhibition, Oxidative Stress, Neuroinflammatory Diseases, Quinolines, biology.protein, neuronal inflammation, Immunologic diseases. Allergy, Immunosuppressive Agents, Signal Transduction

الوصف: Emerging evidence suggests the association of seizures and inflammation; however, underlying cell signaling mechanisms are still not fully understood. Overactivation of phosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, we speculate the PI3K/Akt/mTOR pathway as a promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in a lipopolysaccharide (LPS)-primed pilocarpine (PILO) model. We then evaluated the effects of 7-day treatment of buparlisib (PI3K inhibitor, 25 mg/kg p.o.), dactolisib (PI3K/mTOR inhibitor, 25 mg/kg p.o.), and rapamycin (mTORC1 inhibitor, 10 mg/kg p.o.) in an LPS-primed PILO model of seizures in C57BL/6 mice. LPS priming resulted in enhanced seizure severity and reduced latency. Buparlisib and dactolisib, but not rapamycin, prolonged latency to seizures and reduced neuronal loss, while all drugs attenuated seizure severity. Buparlisib and dactolisib further reduced cellular redox, mitochondrial membrane potential, cleaved caspase-3 and p53, nuclear integrity, and attenuated NF-κB, IL-1β, IL-6, TNF-α, and TGF-β1 and TGF-β2 signaling both in vitro and in vivo post-PILO and LPS+PILO inductions; however, rapamycin mitigated the same only in the PILO model. Both drugs protected against neuronal cell death demonstrating the contribution of this pathway in the seizure-induced neuronal pyknosis; however, rapamycin showed resistance in a combination model. Furthermore, LPS and PILO exposure enhanced pAkt/Akt and phospho-p70S6/total-p70S6 kinase activity, while buparlisib and dactolisib, but not rapamycin, could reduce it in a combination model. Partial rapamycin resistance was observed possibly due to the reactivation of the pathway by a functionally different complex of mTOR, i.e., mTORC2. Our study substantiated the plausible involvement of PI3K-mediated apoptotic and inflammatory pathways in LPS-primed PILO-induced seizures and provides evidence that its modulation constitutes an anti-inflammatory mechanism by which seizure inhibitory effects are observed. We showed dual inhibition by dactolisib as a promising approach. Targeting this pathway at two nodes at a time may provide new avenues for antiseizure therapies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ed26d5fbbbcd9031337e5666c995aecTest
https://doi.org/10.3389/fimmu.2021.739452Test

المؤلفون: Ling Chen, Ya Wang, Guoxi Li, Qi Wan, Tingting Di, Huanxian Chang, Wenfeng Yu, Xianying Zeng

المصدر: Neurobiology of Disease, Vol 127, Iss, Pp 350-361 (2019)

مصطلحات موضوعية: 0301 basic medicine, BSCL2, Tau protein, Hyperphosphorylation, tau Proteins, Tau phosphorylation, Hippocampus, Protein Aggregation, Pathological, Seipin, lcsh:RC321-571, Congenital generalized lipodystrophy, 03 medical and health sciences, Mice, 0302 clinical medicine, GTP-Binding Protein gamma Subunits, Peroxisome proliferator-activated receptor-γ (PPARγ), medicine, Animals, Phosphorylation, Protein kinase B, Mammalian target of rapamycin (mTOR), lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, PI3K/AKT/mTOR pathway, Mice, Knockout, Neurons, Glycogen Synthase Kinase 3 beta, biology, Chemistry, TOR Serine-Threonine Kinases, GSK3β, Insulin resistance, medicine.disease, Axons, Cell biology, PPAR gamma, 030104 developmental biology, Neurology, biology.protein, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Signal Transduction

الوصف: Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr212/Ser214 and Ser202/Thr205 and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARγ. Neuronal seipin deletion increased activities of GSK3β and Akt/mTOR signaling, which were corrected by the administration of PPARγ agonist rosiglitazone for 7 days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3β inhibitors for 7 days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser396 and JNK, which were corrected by treatment with rosiglitazone for 30 days rather than 7 days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser396. The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARγ to enhance GSK3β and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::05e9c26c8af25986e1d0768233a2ccb9Test
http://www.sciencedirect.com/science/article/pii/S0969996119300762Test

المؤلفون: Jun Wada, Yizhen Sang, Kazuhiko Fukushima, Shinji Kitamura, Kenji Tsuji

المصدر: International Journal of Molecular Sciences
Volume 21
Issue 11
International Journal of Molecular Sciences, Vol 21, Iss 4054, p 4054 (2020)

مصطلحات موضوعية: 0301 basic medicine, sodium glucose co-transporter 2 inhibitor, obesity, Mitochondrion, Lamellar granule, lcsh:Chemistry, Kidney Tubules, Proximal, Mice, 0302 clinical medicine, lcsh:QH301-705.5, Spectroscopy, TOR Serine-Threonine Kinases, mammalian target of rapamycin (mTOR), General Medicine, Immunohistochemistry, Computer Science Applications, medicine.medical_specialty, autophagy, Normal diet, Urinary system, Sodium, chemistry.chemical_element, 030209 endocrinology & metabolism, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Sodium-Glucose Transporter 2, Internal medicine, medicine, Empagliflozin, Animals, Physical and Theoretical Chemistry, Molecular Biology, Sodium-Glucose Transporter 2 Inhibitors, multi lamellar body, business.industry, Organic Chemistry, Autophagy, Autophagosomes, Transporter, Epithelial Cells, Lipid Metabolism, 030104 developmental biology, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, chemistry, business, Lysosomes, Biomarkers

الوصف: Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i&ndash
HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ab0c369b4b4180251198e80af404feb5Test
https://pubmed.ncbi.nlm.nih.gov/32517059Test

المؤلفون: Yukari Kyumoto-Nakamura, Kento Nishida, Soichiro Sonoda, Sara Murata, Shion Hama, Toshio Kukita, Takayoshi Yamaza, Haruyoshi Yamaza, Kazuaki Nonaka, Yosuke Tanaka, Norihisa Uehara

المصدر: Stem Cell Research & Therapy
Stem Cell Research & Therapy, Vol 9, Iss 1, Pp 1-12 (2018)

مصطلحات موضوعية: Male, 0301 basic medicine, Small interfering RNA, Bone Regeneration, Cell, Medicine (miscellaneous), Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Osteogenesis, lcsh:QD415-436, Phosphorylation, lcsh:R5-920, biology, Chemistry, Cell Differentiation, Phosphoinositide 3 kinase (PI3K), Up-Regulation, Cell biology, medicine.anatomical_structure, Molecular Medicine, Stem cell, lcsh:Medicine (General), Signal Transduction, Scaffold-free spheroidal calcified construct, Stem cells from apical papilla (SCAP), Biochemistry, Genetics and Molecular Biology (miscellaneous), lcsh:Biochemistry, Young Adult, 03 medical and health sciences, Spheroids, Cellular, medicine, Animals, Humans, Mammalian target of rapamycin (mTOR), Dental Papilla, Protein kinase B, PI3K/AKT/mTOR pathway, Sirolimus, Phosphoinositide 3-kinase, Research, AKT, Multipotent Stem Cells, Regeneration (biology), Mesenchymal stem cell, Mesenchymal Stem Cells, 030206 dentistry, Cell Biology, Dentinogenesis, 030104 developmental biology, Dentin, biology.protein, Proto-Oncogene Proteins c-akt

الوصف: Background Stem cells from apical papilla (SCAP) are a subpopulation of mesenchymal stem cells (MSCs) isolated from the apical papilla of the developing tooth root apex of human teeth. Because of their osteogenic/dentinogenic capacity, SCAP are considered as a source for bone and dentin regeneration. However, little is understood about the molecular mechanism of osteogenic/dentinogenic differentiation of SCAP. Phosphoinositide 3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signal pathway participates in regulating the differentiation of various cell types, such as MSCs. In this study, we examined the role of the PI3K-AKT-mTOR signal pathway in the osteogenic/dentinogenic differentiation of SCAP. Moreover, we challenge to fabricate scaffold-free SCAP-based spheroidal calcified constructs. Methods SCAP were pretreated with or without small interfering RNA for AKT (AKT siRNA), PI3K inhibitor LY294402, and mTOR inhibitor rapamycin and were cultured under osteogenic/dentinogenic differentiation to examine in vitro and in vivo calcified tissue formation. Moreover, SCAP-based cell aggregates were pretreated with or without LY294402 and rapamycin. The cell aggregates were cultured under osteogenic/dentinogenic condition and were analyzed the calcification of the aggregates. Results Pretreatment with AKT siRNA, LY294402, and rapamycin enhances the in vitro and in vivo calcified tissue-forming capacity of SCAP. SCAP were fabricated as scaffold-free spheroids and were induced into forming calcified 3D constructs. The calcified density of the spheroidal constructs was enhanced when the spheroids were pretreated with LY294402 and rapamycin. Conclusions Our findings indicate that the suppression of PI3K-AKT-mTOR signal pathway plays a role in not only enhancing the in vivo and in vitro osteogenic/dentinogenic differentiation of SCAP, but also promoting the calcification of scaffold-free SCAP-based calcified constructs. These findings suggest that a suppressive regulation of PI3K-AKT-mTOR signal pathway is a novel approach for SCAP-based bone and dentin regeneration. Electronic supplementary material The online version of this article (10.1186/s13287-018-1077-9) contains supplementary material, which is available to authorized users.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6da87115e32aceab171d86993f9bb56bTest
https://doi.org/10.1186/s13287-018-1077-9Test

المؤلفون: José L. Quiles, Ángel J. De la Rosa, José L. Mauriz, Francisco J. Padillo, Raúl González, José M. Fuentes, Jesús de la Cruz, Javier González-Gallego, Elena Navarro-Villarán, Raquel Ordóñez, L.M. Marín-Gómez, Jordi Muntané, Mario Rodríguez-Arribas, María A. Rodríguez-Hernández, J.M. Álamo-Martínez, Paloma Gallego, Laura Contreras, José A Del Campo

المساهمون: Universidad de Sevilla. Departamento de Genética

المصدر: idUS. Depósito de Investigación de la Universidad de Sevilla
instname

مصطلحات موضوعية: 0301 basic medicine, Sorafenib, Cell signaling, autophagy, Physiology, Clinical Biochemistry, Apoptosis, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, Autophagy, medicine, Biomarkers, Tumor, Animals, Humans, Bcl-2, Protein kinase A, Protein kinase B, PI3K/AKT/mTOR pathway, Chemistry, Caspase 3, mammalian target of rapamycin (mTOR), Liver Neoplasms, apoptosis, JNK Mitogen-Activated Protein Kinases, Cell Biology, Hep G2 Cells, Endoplasmic Reticulum Stress, 5′AMP-activated protein kinase (AMPK), Xenograft Model Antitumor Assays, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, 030220 oncology & carcinogenesis, Unfolded protein response, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Transcription Factor CHOP, medicine.drug, Signal Transduction

الوصف: Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5′AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P-JNK1/2/JNK1/2, Thr172P-AMPKα, Ser413P-Foxo3a, Thr308P-AKt/AKt and Thr32P-Foxo3a/Foxo3a ratios, and reduction of Ser2481P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL, Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation. Ministerio de Economía y Competitividad BFU2016‐75352‐P Instituto de Salud Carlos III PI15/00034, PI13/ 00021, PI16/00090, PI14/01349 Ministerio de Educación FPU16/05127, FPU12/01433, FPU13/01237 Junta de Andalucía CTS-6264, PI-00025-2013, PI-0127-2013, PI-0198-2016

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13faddb9a0c020090635a3ed453ddd5eTest
https://hdl.handle.net/10668/12863Test

المؤلفون: Ji Miao, Sudha B. Biddinger, Ivana Semova, Anthony N. Hollenberg, Hong Kang, Matthew D. Hirschey, David Masson, Yue Hu, Satyapal Chahar, Xiaowei Sun

المساهمون: Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] ( HMS ), Beth Israel Deaconess Medical Center, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Duke University Medical Center

المصدر: Journal of Biological Chemistry
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2018, 293 (6), pp.2006-2014. 〈http://www.jbc.org/content/293/6/2006.longTest〉. 〈10.1074/jbc.M117.782557〉

مصطلحات موضوعية: 0301 basic medicine, Male, medicine.medical_specialty, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biochemistry, metabolic syndrome, fructose, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Gene expression, medicine, Animals, glucose, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Triglycerides, lipogenesis, Mice, Knockout, Fatty liver, dyslipidemia, mammalian target of rapamycin (mTOR), Lipid metabolism, Fructose, Cell Biology, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Metabolism, chemistry, Gene Expression Regulation, Liver, Lipogenesis, Metabolic syndrome, Signal transduction, biological phenomena, cell phenomena, and immunity, 030217 neurology & neurosurgery, Signal Transduction

الوصف: International audience; Although calorically equivalent to glucose, fructose appears to be more lipogenic, promoting dyslipidemia, fatty liver disease, cardiovascular disease, and diabetes. To better understand how fructose induces lipogenesis, we compared the effects of fructose and glucose on mammalian target of rapamycin complex 1 (mTORC1), which appeared to have both positive and negative effects on lipogenic gene expression. We found that fructose acutely and transiently suppressed mTORC1 signalingin vitroandin vivoThe constitutive activation of mTORC1 reduced hepatic lipogenic gene expression and produced hypotriglyceridemia after 1 week of fructose feeding. In contrast, glucose did not suppress mTORC1, and the constitutive activation of mTORC1 failed to suppress plasma triglycerides after 1 week of glucose feeding. Thus, these data reveal fundamental differences in the signaling pathways used by fructose and glucose to regulate lipid metabolism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e0151552b633fb1a9d27448adf7dd3bTest
https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01730773Test

المؤلفون: Paola Muti, Gregory R. Steinberg, Bruce E. Kemp, Andrew J. O'Brien, Vanessa P. Houde, Linda Villani, Theodoros Tsakiridis, Giovanni Blandino, Sandra Galic, Lindsay A. Broadfield

مصطلحات موضوعية: Male, Lung Neoplasms, Sodium Salicylate, AMP-Activated Protein Kinases, Biochemistry, chemistry.chemical_compound, Mice, AMP-activated protein kinase, Mice, Knockout, Aspirin, biology, Anti-Inflammatory Agents, Non-Steroidal, mammalian target of rapamycin (mTOR), Drug Synergism, Metformin, Neoplasm Proteins, Lipogenesis, Female, medicine.drug, acetyl-CoA carboxylase (ACC), medicine.medical_specialty, Cell Survival, aspirin, proliferation, fatty acids, Internal medicine, Cell Line, Tumor, medicine, Animals, Humans, Hypoglycemic Agents, Protein kinase A, Molecular Biology, Sodium salicylate, Fatty acid synthesis, Binding Sites, AMPK, Prostatic Neoplasms, cholesterol, Cell Biology, Fibroblasts, Embryo, Mammalian, Enzyme Activation, Endocrinology, chemistry, biology.protein, Cancer research, 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, Acetyl-CoA Carboxylase

الوصف: Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK β1-subunit, a mechanism that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK–ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::69fa08a800d2106d31457a94d70f7df9Test
https://acuresearchbank.acu.edu.au/item/8825v/salicylate-activates-ampk-and-synergizes-with-metformin-to-reduce-the-survival-of-prostate-and-lung-cancer-cells-ex-vivo-through-inhibition-of-de-novo-lipogenesisTest

المؤلفون: Suhua Zhu, Qing-Ping Li, Xiaowei Wu, Hong-Yi Zhu, Liang Hu, Maojuan Hao

المصدر: International Journal of Molecular Sciences
International Journal of Molecular Sciences; Volume 18; Issue 3; Pages: 614
International Journal of Molecular Sciences, Vol 18, Iss 3, p 614 (2017)

مصطلحات موضوعية: Male, 0301 basic medicine, Nitric Oxide Synthase Type I, AMP-Activated Protein Kinases, lcsh:Chemistry, Mice, Ischemic Postconditioning, lcsh:QH301-705.5, Spectroscopy, chemistry.chemical_classification, TOR Serine-Threonine Kinases, mammalian target of rapamycin (mTOR), General Medicine, Mitochondria, Computer Science Applications, Cell biology, Reperfusion Injury, cardiovascular system, Signal Transduction, medicine.drug, autophagy, adenosine monophosphate-activated protein kinase (AMPK), medicine.medical_specialty, Article, Catalysis, Cell Line, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, medicine, Animals, Physical and Theoretical Chemistry, Protein kinase A, ischemic postconditioning (IPostC), ischemia/reperfusion, neuronal nitric oxide synthase (nNOS), Molecular Biology, PI3K/AKT/mTOR pathway, Reactive oxygen species, Myocardium, Organic Chemistry, Autophagy, AMPK, medicine.disease, Adenosine, 030104 developmental biology, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, chemistry, Apoptosis, Reperfusion injury

الوصف: Autophagy participates in the progression of many diseases, comprising ischemia/ reperfusion (I/R). It is reported that it is involved in the protective mechanism of ischemic postconditioning (IPostC). According to research, neuronal nitric oxide synthase (nNOS) is also involved in the condition of I/R and IPostC. However, the relationship between nNOS, autophagy and IPostC has not been previously investigated. We hypothesize that IPostC promotes autophagy activity against I/R injury partially through nNOS-mediated pathways. Mouse hearts were subjected to I/R injury through the ligation of the left anterior descending coronary artery. H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. IPostC, compared with I/R, restored nNOS activity, increased the formation of autophagosome and restored the impaired autophagic flux, thus autophagic activity was raised markedly. IPostC increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and suppressed mammalian target of rapamycin (mTOR), but a selective nNOS inhibitor abolished those effects. Similar effects of IPostC were demonstrated in H9c2 cells in vitro. IPostC decreased infarct size and preserved most of the normal structure. The level of reactive oxygen species (ROS) and cell apoptosis were reduced by IPostC with improved cell viability and mitochondrial membrane potential. However, an autophagy inhibitor suppressed the protective effects. These results suggest that IPostC promoted autophagy against I/R injury at least partially via the activation of nNOS/AMPK/mTOR pathway.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b699fa81934a03619a9805f733e92b6dTest
https://doi.org/10.3390/ijms18030614Test

المؤلفون: Wu, Jiangbo, de Theije, Caroline G M, da Silva, Sofia Lopes, Abbring, Suzanne, van der Horst, Hilma, Broersen, Laus M, Willemsen, Linette, Kas, Martien, Garssen, Johan, Kraneveld, Aletta D, Pharmacology, Afd Pharmacology

المساهمون: Pharmacology, Afd Pharmacology, Kas lab

المصدر: Brain, Behavior, and Immunity, 59, 273-287. ACADEMIC PRESS INC ELSEVIER SCIENCE
Brain, Behavior, and Immunity, 59, 273. Academic Press Inc.

مصطلحات موضوعية: Male, Threonine, 0301 basic medicine, Cow’s milk allergy (CMA), Autism Spectrum Disorder, FOOD ALLERGY, DISEASE, Pathogenesis, Mice, Behavioral Neuroscience, 0302 clinical medicine, Intestine, Small, Taverne, AMINO-ACIDS, Mast Cells, Prefrontal cortex, chemistry.chemical_classification, Cow's milk allergy (CMA), Behavior, Animal, TOR Serine-Threonine Kinases, MOUSE MODEL, Autism spectrum disorder (ASD), Amino acid, NEUROPSYCHIATRIC DISORDERS, MAST-CELLS, Amino acids, RAPAMYCIN MTOR, FATTY-ACIDS, Leucine, Gut-brain axis, Food Hypersensitivity, Signal Transduction, medicine.medical_specialty, Immunology, Gut–brain axis, SPECTRUM DISORDERS, Biology, 03 medical and health sciences, Valine, Internal medicine, medicine, Animals, Histidine, Interpersonal Relations, Mammalian target of rapamycin (mTOR), PI3K/AKT/mTOR pathway, Brain Chemistry, Endocrine and Autonomic Systems, Lysine, Immunoglobulin E, Grooming, 030104 developmental biology, Endocrinology, chemistry, MAMMALIAN TARGET, Dietary Supplements, Milk Hypersensitivity, 030217 neurology & neurosurgery

الوصف: Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMC5. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow's milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD. (C) 2016 Published by Elsevier Inc.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2603873901e9edf8665a6b606ab1674Test
https://doi.org/10.1016/j.bbi.2016.09.016Test