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Alessandra Lo Cicero, Anne-Laure Jaskowiak, Anne-Laure Egesipe, Johana Tournois, Benjamin Brinon, Patricia R Pitrez, Lino Ferreira, Annachiara de Sandre-Giovannoli, Nicolas Levy, Xavier Nissan
Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation...
October 14, 2016: Scientific Reports
Ketaki Apte, Reimer Stick, Manfred Radmacher
The lamina is a filamentous meshwork beneath the inner nuclear membrane that confers mechanical stability to nuclei. The E145K mutation in lamin A causes Hutchinson-Gilford progeria syndrome (HGPS). It affects lamin filament assembly and induces profound changes in the nuclear architecture. Expression of wild-type and E145K lamin A in Xenopus oocytes followed by atomic force microscopy (AFM) probing of isolated oocyte nuclei has shown significant changes in the mechanical properties of the lamina. Nuclei of oocytes expressing E145K lamin A are stiffer than those expressing wild-type lamin A...
September 28, 2016: Journal of Molecular Recognition: JMR
Su-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-Mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M P Freije, Carlos López-Otín, Gyu Yong Song, Bum-Joon Park
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding...
October 3, 2016: Journal of Clinical Investigation
Alexander Kaltenborn, Harald Schrem, Benedikt Reichert, Felix Braun, Nikos Emmanouilidis, Jürgen Klempnauer, Thomas Becker, Nils Heits
AIM: This study aimed to evaluate whether the Glasgow Prognostic Score (GPS) and its variants are able to predict mortality in live donor and deceased donor liver transplantation for hepatocellular carcinoma. METHODS: Data of 29 live donor and 319 deceased donor transplantations from two German transplant centers was analyzed. The GPS, modified GPS, hepatic GPS, and Abe score were investigated. Receiver operating characteristic (ROC) curve analysis was carried out to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model...
September 6, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Dan M Livovsky, Orit Pappo, Galina Skarzhinsky, Asaf Peretz, Elliot Turvall, Zvi Ackerman
BACKGROUND: We recently observed patients with chronic liver disease (CLD) or chronic reflux symptoms (CRS) who developed gastric polyps (GPs) while undergoing surveillance gastroscopies for the detection of esophageal varices or Barrett's esophagus, respectively. OBJECTIVES: To identify risk factors for GP growth and estimate its growth rate. METHODS: GP growth rate was defined as the number of days since the first gastroscopy (without polyps) in the surveillance program, until the gastroscopy when a GP was discovered...
May 2016: Israel Medical Association Journal: IMAJ
Karim Harhouri, Claire Navarro, Camille Baquerre, Nathalie Da Silva, Catherine Bartoli, Frank Casey, Guedenon Koffi Mawuse, Yassamine Doubaj, Nicolas Lévy, Annachiara De Sandre-Giovannoli
Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients...
2016: Cells
Chun-Xiao Zhang, Shu-Yi Wang, Shuang-Qian Chen, Shuai-Long Yang, Lu Wan, Bin Xiong
BACKGROUND: Glasgow prognostic score (GPS) is widely known as a systemic inflammatory-based marker. The relationship between pretreatment GPS and gastric cancer (GC) survival and clinicopathological features remains controversial. The aim of the study was to conduct a meta-analysis of published studies to evaluate the association between pretreatment GPS and survival and clinicopathological features in GC patients. METHODS: We searched PubMed, Embase, MEDLINE, and BioMed databases for relevant studies...
2016: OncoTargets and Therapy
Susana Gonzalo, Ray Kreienkamp, Peter Askjaer
Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies...
June 29, 2016: Ageing Research Reviews
Clara Soria-Valles, Dido Carrero, Elisabeth Gabau, Gloria Velasco, Víctor Quesada, Clea Bárcena, Marleen Moens, Karen Fieggen, Silvia Möhrcken, Martina Owens, Diana A Puente, Óscar Asensio, Bart Loeys, Ana Pérez, Valerie Benoit, Wim Wuyts, Nicolas Lévy, Raoul C Hennekam, Annachiara De Sandre-Giovannoli, Carlos López-Otín
BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in LMNA leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause. METHODS AND RESULTS: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia...
June 22, 2016: Journal of Medical Genetics
Nard Kubben, Weiqi Zhang, Lixia Wang, Ty C Voss, Jiping Yang, Jing Qu, Guang-Hui Liu, Tom Misteli
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading, through unknown mechanisms, to diverse morphological, epigenetic, and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen, we identify the NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress...
June 2, 2016: Cell
Vera Gorbunova, Sarallah Rezazadeh, Andrei Seluanov
Progerin, a mutated lamin A, causes the severe premature-aging syndrome Hutchinson-Gilford progeria (HGPS). Kubben et al. present a driving mechanism for HGPS involving trapping of NRF2 at the nuclear periphery by progerin. This local restriction results in impaired NRF2 signaling and chronic oxidative stress.
June 2, 2016: Cell
Qizhou Lian, Yuelin Zhang, Xiaoting Liang, Fei Gao, Hung-Fat Tse
Multipotent stromal cells, also known as mesenchymal stem cells (MSCs), possess great potential to generate a wide range of cell types including endothelial cells, smooth muscle cells, bone, cartilage, and lipid cells. This protocol describes in detail how to perform highly efficient, lineage-specific differentiation of human-induced pluripotent stem cells (iPSCs) with an MSCs fate. The approach uses a clinically compliant protocol with chemically defined media, feeder-free conditions, and a CD105 positive and CD24 negative selection to achieve a single cell-based MSCs derivation from differentiating human pluripotent cells in approximately 20 days...
2016: Methods in Molecular Biology
Ray Kreienkamp, Monica Croke, Martin A Neumann, Gonzalo Bedia-Diaz, Simona Graziano, Adriana Dusso, Dale Dorsett, Carsten Carlberg, Susana Gonzalo
Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence...
May 24, 2016: Oncotarget
Veronika Eisch, Xiang Lu, Diana Gabriel, Karima Djabali
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke. The most common mutation in HGPS is at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, producing a truncated farnesylated protein called progerin. Lamins play important roles in the organization and structure of the nucleus...
April 26, 2016: Oncotarget
John M Lee, Chika Nobumori, Yiping Tu, Catherine Choi, Shao H Yang, Hea-Jin Jung, Timothy A Vickers, Frank Rigo, C Frank Bennett, Stephen G Young, Loren G Fong
The alternatively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in similar amounts in most tissues and have largely redundant functions. This redundancy suggests that diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that are caused by prelamin A-specific mutations could be treated by shifting the output of LMNA more toward lamin C. Here, we investigated mechanisms that regulate LMNA mRNA alternative splicing and assessed the feasibility of reducing prelamin A expression in vivo...
April 1, 2016: Journal of Clinical Investigation
Camilla Evangelisti, Vittoria Cenni, Giovanna Lattanzi
The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, such signaling pathway has come to the attention of the scientific community due to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends life-span in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome that recapitulates most of the traits of physiological ageing, the Hutchinson-Gilford Progeria (HGPS)...
March 8, 2016: British Journal of Clinical Pharmacology
Yuichi Ikeda, Hidetoshi Kumagai, Yoshihiro Motozawa, Jun-Ichi Suzuki, Hiroshi Akazawa, Issei Komuro
Early human mummies examined recently by computed tomography demonstrated a high prevalence of vascular calcification, a pathognomonic sign of atherosclerosis, which was correlated with estimated age at death. Early populations had little exposure to modern-day metabolic risk factors: these observations thus suggest that humans have an inherent age-dependent predisposition to atherosclerosis. Premature aging syndromes are extremely rare genetic disorders that exhibit clinical phenotypes resembling accelerated aging, including severe atherosclerosis, but those phenotypes are usually segmental...
May 2016: Canadian Journal of Cardiology
Olga Moiseeva, Stéphane Lopes-Paciencia, Geneviève Huot, Frédéric Lessard, Gerardo Ferbeyre
Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation...
February 2016: Aging
S Blondel, A-L Egesipe, P Picardi, A-L Jaskowiak, M Notarnicola, J Ragot, J Tournois, A Le Corf, B Brinon, P Poydenot, P Georges, C Navarro, P R Pitrez, L Ferreira, G Bollot, C Bauvais, D Laustriat, A Mejat, A De Sandre-Giovannoli, N Levy, M Bifulco, M Peschanski, X Nissan
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules...
2016: Cell Death & Disease
Sandra Vidak, Roland Foisner
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation...
April 2016: Histochemistry and Cell Biology
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