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https://www.readbyqxmd.com/read/28342808/role-of-mtorc1-s6k1-signaling-pathway-in-regulation-of-hematopoietic-stem-cell-and-acute-myeloid-leukemia
#1
REVIEW
Joydeep Ghosh, Reuben Kapur
Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions...
March 22, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28336518/bmp-9-interferes-with-liver-regeneration-and-promotes-liver-fibrosis
#2
Katja Breitkopf-Heinlein, Christoph Meyer, Courtney König, Haristi Gaitantzi, Annalisa Addante, Maria Thomas, Eliza Wiercinska, Chen Cai, Qi Li, Fengqi Wan, Claus Hellerbrand, Nektarios A Valous, Maximilian Hahnel, Christian Ehlting, Johannes G Bode, Stephanie Müller-Bohl, Ursula Klingmüller, Jutta Altenöder, Iryna Ilkavets, Marie-José Goumans, Lukas J A C Hawinkels, Se-Jin Lee, Matthias Wieland, Carolin Mogler, Matthias P Ebert, Blanca Herrera, Hellmut Augustin, Aránzazu Sánchez, Steven Dooley, Peter Ten Dijke
OBJECTIVE: Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN: Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice...
March 23, 2017: Gut
https://www.readbyqxmd.com/read/28335073/clinical-characteristics-and-whole-exome-transcriptome-sequencing-of-coexisting-chronic-myeloid-leukemia-and-myelofibrosis
#3
Malathi Kandarpa, Yi-Mi Wu, Dan Robinson, Patrick William Burke, Arul M Chinnaiyan, Moshe Talpaz
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera or myelofibrosis (ET/PV/MF) or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent...
March 23, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28334032/does-hysteroscopy-worsen-prognosis-in-women-with-type-ii-endometrial-carcinoma
#4
Jiao Chen, Leslie H Clark, Wei-Min Kong, Zhen Yan, Chao Han, Hui Zhao, Ting-Ting Liu, Tong-Qing Zhang, Dan Song, Si-Meng Jiao, Chunxiao Zhou
BACKGROUND: Prior studies evaluating the impact of hysteroscopy on outcomes in endometrial cancer have predominantly evaluated type I tumors. We sought to evaluate whether hysteroscopy worsens prognosis in type II endometrial cancer. METHODS: A retrospective cohort analysis of 140 patients from two institutions with type II endometrial cancer was performed. Women who underwent either diagnostic hysteroscopy (HSC) or dilation and curettage (D&C) for cancer diagnosis from June 2001 until June 2010 were included...
2017: PloS One
https://www.readbyqxmd.com/read/28332284/ezh2-mediated-repression-of-dkk1-promotes-hepatic-stellate-cell-activation-and-hepatic-fibrosis
#5
Yang Yang, Xiao-Xia Chen, Wan-Xia Li, Xiao-Qin Wu, Cheng Huang, Juan Xie, Yu-Xin Zhao, Xiao-Ming Meng, Jun Li
EZH2, a histone H3 lysine-27-specific methyltransferase, is involved in diverse physiological and pathological processes including cell proliferation and differentiation. However, the role of EZH2 in liver fibrosis is largely unknown. In this study, it was identified that EZH2 promoted Wnt pathway-stimulated fibroblasts in vitro and in vivo by repressing Dkk-1, which is a Wnt pathway antagonist. The expression of EZH2 was increased in CCl4 -induced rat liver and primary HSCs as well as TGF-β1-treated HSC-T6, whereas the expression of Dkk1 was reduced...
March 23, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28330619/efficient-ex%C3%A2-vivo-engineering-and-expansion-of-highly-purified-human-hematopoietic-stem-and-progenitor-cell-populations-for-gene-therapy
#6
Erika Zonari, Giacomo Desantis, Carolina Petrillo, Francesco E Boccalatte, Maria Rosa Lidonnici, Anna Kajaste-Rudnitski, Alessandro Aiuti, Giuliana Ferrari, Luigi Naldini, Bernhard Gentner
Ex vivo gene therapy based on CD34(+) hematopoietic stem cells (HSCs) has shown promising results in clinical trials, but genetic engineering to high levels and in large scale remains challenging. We devised a sorting strategy that captures more than 90% of HSC activity in less than 10% of mobilized peripheral blood (mPB) CD34(+) cells, and modeled a transplantation protocol based on highly purified, genetically engineered HSCs co-infused with uncultured progenitor cells. Prostaglandin E2 stimulation allowed near-complete transduction of HSCs with lentiviral vectors during a culture time of less than 38 hr, mitigating the negative impact of standard culture on progenitor cell function...
March 13, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330618/latexin-inactivation-enhances-survival-and-long-term-engraftment-of%C3%A2-hematopoietic-stem-cells-and-expands-the-entire-hematopoietic-system-in-mice
#7
Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret St Clair, Jinze Liu, Changguo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang
Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner...
March 7, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28327550/significant-role-of-collagen-xvii-and-integrin-%C3%AE-4-in-migration-and-invasion-of-the-less-aggressive-squamous-cell-carcinoma-cells
#8
Jyri M Moilanen, Stefanie Löffek, Nina Kokkonen, Sirpa Salo, Juha P Väyrynen, Tiina Hurskainen, Aki Manninen, Pilvi Riihilä, Ritva Heljasvaara, Claus-Werner Franzke, Veli-Matti Kähäri, Tuula Salo, Markus J Mäkinen, Kaisa Tasanen
Collagen XVII and integrin α6β4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin α6β4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin γ2, collagen XVII and integrin β4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen's disease...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322865/palmitic-acid-elicits-hepatic-stellate-cell-activation-through-inflammasomes-and-hedgehog-signaling
#9
Na-Na Duan, Xue-Jing Liu, Jian Wu
AIMS: Activation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult. MAIN METHODS: Inflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs...
March 17, 2017: Life Sciences
https://www.readbyqxmd.com/read/28322443/all-trans-retinoic-acid-ameliorates-hepatic-stellate-cell-activation-via-suppression-of-thioredoxin-interacting-protein-expression
#10
Hiroki Shimizu, Toshiaki Tsubota, Keita Kanki, Goshi Shiota
Activation of hepatic stellate cells (HSCs) is the effector factor of hepatic fibrosis and hepatocellular carcinoma (HCC) development. Accumulating evidence suggests that retinoic acids (RAs), derivatives of vitamin A, contribute to prevention of liver fibrosis and carcinogenesis, however, regulatory mechanisms of RAs still remain exclusive. To elucidate RA signaling pathway, we previously performed a genome-wide screening of RA-responsive genes by in silico analysis of RA-response elements, and identified 26 RA-responsive genes...
March 21, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28322315/quantitative-proteomic-analysis-on-activated-hepatic-stellate-cells-reversion-reveal-stat1-as-a-key-regulator-between-liver-fibrosis-and-recovery
#11
Hongyu Zhang, Fangyan Chen, Xu Fan, Cong Lin, Yunwei Hao, Handong Wei, Weiran Lin, Ying Jiang, Fuchu He
Understanding the changes of activated HSCs reversion is an essential step toward clarifying the potential roles of HSCs in the treatment of liver fibrosis. In this study, we chose adipocyte differentiation mixture to induce LX-2 cells for 2 days in vitro as reversion phase, comparing with normal cultured LX-2 cells as activation phase. Mass spectrometric-based SILAC technology was adopted to study differentially expressed proteome of LX-2 cells between reversion and activation. Compared with activated HSCs, 273 proteins showed significant differences in reverted HSCs...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322247/tricyclic-antidepressants-promote-ceramide-accumulation-to-regulate-collagen-production-in-human-hepatic-stellate-cells
#12
Jennifer Y Chen, Benjamin Newcomb, Chan Zhou, Joshua V Pondick, Sarani Ghoshal, Samuel R York, Daniel L Motola, Nicolas Coant, Jae Kyo Yi, Cungui Mao, Kenneth K Tanabe, Irina Bronova, Evgeny V Berdyshev, Bryan C Fuchs, Yusuf Hannun, Raymond T Chung, Alan C Mullen
Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28320106/ctrp3-attenuates-hepatic-stellate-cell-activation-through-transforming-growth-factor-%C3%AE-smad-signaling-pathway
#13
Chuantao Cheng, Shuo Yu, Ran Kong, Qinggong Yuan, Yuefeng Ma, Wenbin Yang, Gang Cao, Liyi Xie
Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of liver fibrosis. C1q/tumor necrosis factor-related protein 3 (CTRP3), a member of CTRPs, was involved in fibrosis. However, little is known about the role of CTRP3 in liver fibrosis. This study aimed to determine its role in liver fibrosis and explore the possible mechanism. Our results demonstrated that CTRP3 was lowly expressed in liver fibrosis tissues and activated HSCs. Overexpression of CTRP3 inhibited the proliferation and migration of HSCs, as well as suppressed the expression of extracellular matrix (ECM) in transforming growth factor-β1 (TGF-β1)-stimulated HSC-T6 cells...
March 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28320105/anti-fibrotic-potential-of-human-umbilical-cord-mononuclear-cells-and-mouse-bone-marrow-cells-in-ccl4-induced-liver-fibrosis-in-mice
#14
Nageh Ahmed Elmahdy, Samia Salem Sokar, Mohamed Labib Salem, Naglaa Ibrahim Sarhan, Sherin Hamed Abou-Elela
Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl4) induced liver fibrosis in mice and compare it with that of silymarin...
March 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28320086/antifibrotic-effect-of-diethylcarbamazine-combined-with-hesperidin-against-ethanol-induced-liver-fibrosis-in-rats
#15
Alaa El-Din El-Sayed El-Sisi, Samia Salim Sokar, Abdelhadi Mohamed Shebl, Dina Zakaria Mohamed
Chronic alcohol consumption leads to extracellular matrix hyperplasia and liver fibrosis with a great role of hepatic stellate cell (HSC) activation in this process. The present study was designed to investigate the possible protective effects of diethylcarbamazine (DEC) (50mg/kg, acting as an anti-inflammatory drug, interferes with the arachidonic acid metabolism) when administrated in combination with hesperidin (HDN) (200mg/kg, a flavanone glycoside with potent antioxidant and anti-inflammatory activities) against alcoholic liver fibrosis in wistar rats compared to silymarin (Sil) (100mg/kg)...
March 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28319139/identification-of-cell-morphology-parameters-from-automatic-hematology-analyzers-to-predict-the-peripheral-blood-cd34-positive-cell-count-after-mobilization
#16
Saeam Shin, Sung Ran Cho, Sinyoung Kim, Jong Rak Choi, Kyung-A Lee
Optimal timing of apheresis initiation is important for maximizing the hematopoietic stem cell (HSC) yield. This study aimed to identify useful parameters from automatic hematology analyzers for predicting the peripheral blood CD34+ cell count after mobilization. We prospectively enrolled 53 healthy donors and 72 patients, and evaluated 43 cell morphology parameters from Unicel DxH800 (Beckman Coulter, USA) and Advia 2120i (Siemens Healthcare Diagnostics, USA). The correlation of each parameter with the CD34+ cell count in pre-apheresis blood samples was analyzed...
2017: PloS One
https://www.readbyqxmd.com/read/28319048/amino-acid-insensitive-mtorc1-regulation-enables-nutritional-stress-resilience-in-hematopoietic-stem-cells
#17
Demetrios Kalaitzidis, Dongjun Lee, Alejo Efeyan, Youmna Kfoury, Naema Nayyar, David B Sykes, Francois E Mercier, Ani Papazian, Ninib Baryawno, Gabriel D Victora, Donna Neuberg, David M Sabatini, David T Scadden
The mTOR pathway is a critical determinant of cell persistence and growth wherein mTOR complex 1 (mTORC1) mediates a balance between growth factor stimuli and nutrient availability. Amino acids or glucose facilitates mTORC1 activation by inducing RagA GTPase recruitment of mTORC1 to the lysosomal outer surface, enabling activation of mTOR by the Ras homolog Rheb. Thereby, RagA alters mTORC1-driven growth in times of nutrient abundance or scarcity. Here, we have evaluated differential nutrient-sensing dependence through RagA and mTORC1 in hematopoietic progenitors, which dynamically drive mature cell production, and hematopoietic stem cells (HSC), which provide a quiescent cellular reserve...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28315453/defects-in-mitochondrial-energetic-function-compels-fanconi-anemia-cells-to-glycolytic-metabolism
#18
Enrico Cappelli, Paola Cuccarolo, Giorgia Stroppiana, Maurizio Miano, Roberta Bottega, Vanessa Cossu, Paolo Degan, Silvia Ravera
Energetic metabolism plays an essential role in the differentiation of haematopoietic stem cells (HSC). In Fanconi Anaemia (FA), DNA damage is accumulated during HSC differentiation, an event that is likely associated with bone marrow failure (BMF). One of the sources of the DNA damage is altered mitochondrial metabolism and an associated increment of oxidative stress. Recently, altered mitochondrial morphology and a deficit in the energetic activity in FA cells have been reported. Considering that mitochondria are the principal site of aerobic ATP production, we investigated FA metabolism in order to understand what pathways are able to compensate for this energy deficiency...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28303169/diallyl-trisulfide-suppresses-oxidative-stress-induced-activation-of-hepatic-stellate-cells-through-production-of-hydrogen-sulfide
#19
Feng Zhang, Huanhuan Jin, Li Wu, Jiangjuan Shao, Xiaojing Zhu, Anping Chen, Shizhong Zheng
Accumulating data reveal that garlic has beneficial effects against chronic liver disease. We previously reported that diallyl trisulfide (DATS), the primary organosulfur compound in garlic, reduced fibrosis and attenuated oxidative stress in rat fibrotic liver. The present study was aimed at elucidating the underlying mechanisms. The primary rat hepatic stellate cells (HSCs) were cultured and stimulated with hydrogen peroxide (H2O2) for inducing HSC activation under oxidative stress. We examined the effects of DATS on the profibrogenic properties and oxidative stress in H2O2-treated HSCs...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28302560/2-3-7-8-tetrachlorodibenzo-p-dioxin-tcdd-induces-hepatic-stellate-cell-hsc-activation-and-liver-fibrosis-in-c57bl6-mouse-via-activating-akt-and-nf-%C3%AE%C2%BAb-signaling-pathways
#20
Ming Han, Xipeng Liu, Suyi Liu, Guanglei Su, Xikang Fan, Jie Chen, Qianting Yuan, Guangfei Xu
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant that could induce serious toxic effects in both humans and rodents. Some studies suggested that TCDD exposure may facilitate the activation of hepatic stellate cells (HSCs) and liver injury. However, the underlying molecular mechanism by which environmental pollutants promote liver injury remains poorly understood. In the present study, we established an animal model of TCDD exposure by intraperitoneal injection of TCDD in male C57BL/6J mice...
March 13, 2017: Toxicology Letters
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