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https://www.readbyqxmd.com/read/28918366/a-progressive-reduction-in-autophagic-capacity-contributes-to-induction-of-replicative-senescence-in-hs68-cells
#1
Byeal-I Han, Sung-Hee Hwang, Michael Lee
Autophagy has been implicated in delayed aging and extended longevity. Here, we aimed to study the possible effects of autophagy during the progression of replicative senescence, which is one of the major features of aging. Human foreskin fibroblasts, Hs68 cells, at an initial passage of 15 were serially cultured for several months until they reached cellular senescence. A decrease in cell proliferation was observed during the progression of senescence. Induction of replicative senescence in aged cells (at passage 40) was confirmed by senescence-associated β-galactosidase (SA-β-gal) activity that represents a sensitive and reliable marker for quantifying senescent cells...
September 13, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28918027/adeno-associated-viral-vector-mediated-mtor-inhibition-by-short-hairpin-rna-suppresses-laser-induced-choroidal-neovascularization
#2
Tae Kwann Park, Si Hyung Lee, Jun Sub Choi, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Heuiran Lee, Steven Hyun Seung Lee, Keerang Park
Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28911171/sirtuin-3-promotes-adipogenesis-osteoclastogenesis-and-bone-loss-in-aging-male-mice
#3
Linh Ho, Liping Wang, Theresa M Roth, Yong Pan, Eric M Verdin, Edward C Hsiao, Robert A Nissenson
Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice...
September 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28894028/mtorc1-regulates-both-general-autophagy-and-mitophagy-induction-after-oxidative-phosphorylation-uncoupling
#4
Alberto Bartolomé, Ana García-Aguilar, Shun-Ichiro Asahara, Yoshiaki Kido, Carlos Guillén, Utpal B Pajvani, Manuel Benito
The mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2 -/-), which show constitutive MTORC1 activation. TSC2 -/- cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial protein aging and accumulation of p62/SQSTM1 positive mitochondria...
September 11, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28891034/rheb1-insufficiency-in-aged-male-mice-is-associated-with-stress-induced-seizures
#5
Qi Tian, Pavel Gromov, Joachim H Clement, Yingming Wang, Marc Riemann, Falk Weih, Xiao-Xin Sun, Mu-Shui Dai, Lev M Fedorov
The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs...
September 10, 2017: GeroScience
https://www.readbyqxmd.com/read/28889246/the-preliminary-radiogenomics-association-between-mr-perfusion-imaging-parameters-and-genomic-biomarkers-and-their-predictive-performance-of-overall-survival-in-patients-with-glioblastoma
#6
Xiang Liu, Rajiv Mangla, Wei Tian, Xing Qiu, Dongmei Li, Kevin A Walter, Sven Ekholm, Mahlon D Johnson
The radiogenomics association of neovascularization is important for overall survival (OS) in glioblastoma patients and remains unclear. The purpose of this study is to assess the association between MR perfusion imaging derived parameters and genomic biomarkers of glioblastoma, and to evaluate their prognostic value. This retrospective study enrolled 41 patients with newly diagnosed glioblastoma. The mean and maximal relative cerebral blood volume (rCBV) ratio (rCBVmean and rCBVmax), derived from MR perfusion weighted imaging, of the enhancing tumor, as well as maximal rCBV ratio of peri-enhancing tumor area (rCBVperi-tumor) were measured...
September 9, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28889220/rapamycin-treatment-attenuates-age-associated-periodontitis-in-mice
#7
Jonathan Y An, Ellen K Quarles, Surapat Mekvanich, Alex Kang, Anthony Liu, Danielle Santos, Richard A Miller, Peter S Rabinovitch, Timothy C Cox, Matt Kaeberlein
Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people...
September 9, 2017: GeroScience
https://www.readbyqxmd.com/read/28888905/selective-interference-of-mtorc1-raptor-protects-against-human-disc-cellular-apoptosis-senescence-and-extracellular-matrix-catabolism-with-akt-and-autophagy-induction
#8
Masaaki Ito, Takashi Yurube, Kenichiro Kakutani, Koichiro Maeno, Toru Takada, Yoshiki Terashima, Yuji Kakiuchi, Yoshiki Takeoka, Shingo Miyazaki, Ryosuke Kuroda, Kotaro Nishida
OBJECTIVE: The mTOR is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing RAPTOR and mTORC2 containing RICTOR. To analyze their functions in human disc nucleus pulposus cells, RNA interference (RNAi) of mTOR targeting mTORC1 and mTORC2, RAPTOR targeting mTORC1, or RICTOR targeting mTORC2 or rapamycin, a pharmacological mTORC1 inhibitor, was applied...
September 6, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28888322/tor-the-gateway-to-cellular-metabolism-cell-growth-and-disease
#9
John Blenis
Michael N. Hall is this year's recipient of the Lasker Basic Medical Research Award for the identification of the target of rapamycin, TOR. TOR is a master regulator of the cell's growth and metabolic state, and its dysregulation contributes to a variety of diseases, including diabetes, obesity, neurodegenerative disorders, aging, and cancer, making the TOR pathway an attractive therapeutic target.
August 22, 2017: Cell
https://www.readbyqxmd.com/read/28888202/iron-accumulation-in-senescent-cells-is-coupled-with-impaired-ferritinophagy-and-inhibition-of-ferroptosis
#10
Shashank Masaldan, Sharnel A S Clatworthy, Cristina Gamell, Peter M Meggyesy, Antonia-Tonia Rigopoulos, Sue Haupt, Ygal Haupt, Delphine Denoyer, Paul A Adlard, Ashley I Bush, Michael A Cater
Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity...
September 1, 2017: Redox Biology
https://www.readbyqxmd.com/read/28884409/chronic-exposure-to-rapamycin-and-episodic-serum-starvation-modulate-ageing-of-human-fibroblasts-in-vitro
#11
Lakshman Sodagam, Anna Lewinska, Maciej Wnuk, Suresh I S Rattan
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, N(6)-methyl-adenosine level in RNA, and ethanol stress tolerance of serially passaged normal human skin fibroblasts...
September 7, 2017: Biogerontology
https://www.readbyqxmd.com/read/28882949/phe354leu-polymorphism-of-lkb1-is-a-potential-prognostic-factor-for-cytogenetically-normal-acute-myeloid-leukemia
#12
Ming-Yu Yang, Hui-Hua Hsiao, Yi-Chang Liu, Cheng-Ming Hsu, Sheng-Fung Lin, Pai-Mei Lin
BACKGROUND/AIM: Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications. PATIENTS AND METHODS: Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing...
September 2017: In Vivo
https://www.readbyqxmd.com/read/28872639/gene-expression-associated-with-suicide-attempts-in-us-veterans
#13
J D Flory, D Donohue, S Muhie, R Yang, S A Miller, R Hammamieh, K Ryberg, R Yehuda
According to a recent report from the Office of Suicide Prevention in the US Department of Veterans Affairs, veterans represent 8.5% of the US population, but account for 18% of all deaths from suicide. The aim of this study of psychiatric patients (n=39; 87% male) was to compare blood gene expression data from veterans with a history of one or more suicide attempts to veterans who had never attempted suicide. The attempter and non-attempter groups were matched for age and race/ethnicity, and both groups included veterans with a diverse psychiatric history that included posttraumatic stress disorder (PTSD) and substance-use disorders...
September 5, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28836934/sirolimus-associated-with-tacrolimus-at-low-doses-in-elderly-kidney-transplant-patients-a-prospective-randomized-controlled-trial
#14
Cristiane Akemi Kojima, Hong Si Nga, Henrique Mochida Takase, Ariane Moyses Bravin, Márcia de Fátima Faraldo Martinez Garcia, Paula Dalsoglio Garcia, Mariana Moraes Contti, Luis Gustavo Modelli de Andrade
OBJECTIVES: There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. MATERIALS AND METHODS: In this single-center prospective randomized study (Trial Registration No...
August 28, 2017: Experimental and Clinical Transplantation
https://www.readbyqxmd.com/read/28835921/adult-onset-obesity-is-triggered-by-impaired-mitochondrial-gene-expression
#15
Kara L Perks, Nicola Ferreira, Tara R Richman, Judith A Ermer, Irina Kuznetsova, Anne-Marie J Shearwood, Richard G Lee, Helena M Viola, Victoria P A Johnstone, Vance Matthews, Livia C Hool, Oliver Rackham, Aleksandra Filipovska
Mitochondrial gene expression is essential for energy production; however, an understanding of how it can influence physiology and metabolism is lacking. Several proteins from the pentatricopeptide repeat (PPR) family are essential for the regulation of mitochondrial gene expression, but the functions of the remaining members of this family are poorly understood. We created knockout mice to investigate the role of the PPR domain 1 (PTCD1) protein and show that loss of PTCD1 is embryonic lethal, whereas haploinsufficient, heterozygous mice develop age-induced obesity...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28833536/outcome-of-second-kidney-transplantation-in-patients-with-previous-post-transplantation-kaposi-s-sarcoma-a-french-retrospective-study
#16
Gérôme Bohelay, Nadia Azrouk, Clémentine Rabaté, Laurence Lecleach, Stéphane Barete, Benoît Barrou, Marie-Benedicte Matignon, Sylvie Euvrard, Pierre Lévy, Céleste Lebbé, Camille Francès
This retrospective study concerned 8 patients with post-transplantation Kaposi's sarcoma (pt-KS) after a first kidney transplant who later had a second kidney transplantation. Pt-KS was widespread, with lymph node or visceral involvement in 7 cases. Complete remission was observed in 6 cases and partial remission in 2. After the second kidney transplantation, only 2 cases showed recurrence of skin KS, one with previous complete remission of KS and one with partial remission. The mean delay between stability or complete remission of KS and retransplantation was 2...
August 21, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/28831286/standardized-kaempferia-parviflora-extract-inhibits-intrinsic-aging-process-in-human-dermal-fibroblasts-and-hairless-mice-by-inhibiting-cellular-senescence-and-mitochondrial-dysfunction
#17
Ji-Eun Park, Seon Wook Woo, Mi-Bo Kim, Changhee Kim, Jae-Kwan Hwang
Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE) on H2O2-stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence-associated β-galactosidase activation. KPE inhibited the expression of cell-cycle inhibitors (p53, p21, p16, and pRb) and stimulated the expression of cell-cycle activators (E2F1 and E2F2)...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28823029/experience-of-lung-transplantation-in-patients-with-lymphangioleiomyomatosis-at-a-brazilian-reference-centre
#18
Bruno Guedes Baldi, Marcos Naoyuki Samano, Silvia Vidal Campos, Martina Rodrigues de Oliveira, José Eduardo Afonso Junior, Rafael Medeiros Carraro, Ricardo Henrique Oliveira Braga Teixeira, Isabela Pasqualini Minguini, Roni Burlina, Eduardo Zinoni Silva Pato, Carlos Roberto Ribeiro Carvalho, André Nathan Costa
INTRODUCTION: Lung transplantation (LT) is the standard of care for patients with advanced lung diseases, including lymphangioleiomyomatosis (LAM). LAM accounts for only 1% of all LTs performed in the international registry. As a result, the global experience, including the use of mechanistic target of rapamycin (mTOR) inhibitors before and after LT in LAM, is still limited. METHODS: We conducted a retrospective review of all LAM patients who underwent LT at our centre between 2003 and 2016...
August 19, 2017: Lung
https://www.readbyqxmd.com/read/28815872/a-multimethod-computational-simulation-approach-for-investigating-mitochondrial-dynamics-and-dysfunction-in-degenerative-aging
#19
Timothy E Hoffman, Katherine J Barnett, Lyle Wallis, William H Hanneman
Research in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans...
August 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/28814333/rapamycin-prevents-cyclophosphamide-induced-over-activation-of-primordial-follicle-pool-through-pi3k-akt-mtor-signaling-pathway-in-vivo
#20
Linyan Zhou, Yanqiu Xie, Song Li, Yihua Liang, Qi Qiu, Haiyan Lin, Qingxue Zhang
BACKGROUND: Primordial follicular depletion has thought to be a common adverse effect of chemotherapy especially for female of reproductive age. The study aimed to evaluate the protective effect of rapamycin on the primordial follicles and its potential mechanism for patients receiving chemotherapy. METHODS: 8-week old BALB/c female mice were randomly assigned into four groups (control; rapamycin; cyclophosphamide; and rapamycin combined with cyclophosphamide). Hematoxylin staining, immunohistochemical, TUNEL, western blotting and ELISA were employed to assess inter-group differences using Student's t-test and Mann-Whitney test...
August 16, 2017: Journal of Ovarian Research
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