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Showing 100 Latest Publications
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Environmental preconditioning rejuvenates adult stem cells' proliferation and chondrogenic potential.Tuesday, December 06, 2016
Pei M,
Biomaterials. 25-Nov-2016
Adult stem cells are a promising cell source for cartilage regeneration. Unfortunately, due to donor age and ex vivo expansion, stem cell senescence becomes a huge hurdle for these cells to be used clinically. Increasing evidence indicates that environmental preconditioning is a powerful approach in promoting stem cells' ability to resist a harsh environment post-engraftment, such as hypoxia and inflammation. However, few reports organize and evaluate the literature regarding the rejuvenation effect of environmental preconditioning on stem cell proliferation and chondrogenic differentiation capacity, which are important variables for stem cell based tissue regeneration. This report aims to identify several critical environmental factors such as oxygen concentration, growth factors, and extracellular matrix and to discuss their preconditioning influence on stem cells' rejuvenation including proliferation and chondrogenic potential as well as underlying molecular mechanisms. We believe that environmental preconditioning based rejuvenation is a simpler and safer strategy to program pre-engraftment stem cells for better survival and enhanced proliferation and differentiation capacity without the undesired effects of some treatments, such as genetic manipulation.
Folic acid-grafted bovine serum albumin decorated graphene oxide: An efficient drug carrier for targeted cancer therapy.Tuesday, December 06, 2016
Ma N, Liu J, He W, Li Z, Luan Y, Song Y, Garg S,
Journal of colloid and interface science. 29-Nov-2016
Targeting drug carrier systems based on graphene oxide (GO) are of great interest, since it can selectively deliver anticancer drugs to tumor cells, and enhance therapeutic activities with minimized side effects. However, direct grafting target molecules on GO usually results in aggregation of physiological fluid, limiting its biomedical applications. Here, we propose a new strategy to construct targeting GO drug carrier using folic acid grafted bovine serum albumin (FA-BSA) as both the stabilizer and targeting agent. FA-BSA decorated graphene oxide-based nanocomposite (FA-BSA/GO) was fabricated by the physical adsorption of FA-BSA on GO, which was developed as a targeting drug delivery carrier. FA-BSA/GO as the drug carrier was associated with anticancer drug doxorubicin (DOX) through π-π and hydrogen-bond interactions, resulting in high drug loading (up to 437.43μgDOX/mgFA-BSA/GO). FA-BSA/GO/DOX systems demonstrated pH responsive and sustained drug release. The hemolysis ratio of FA-BSA/GO was less than 5%, demonstrating its safety as drug carrier for intravenous injection. Moreover, in vitro cell cytotoxicity and cellular uptake analysis suggested that the constructed FA-BSA/GO/DOX nanohybrids could significantly enhance the anticancer activity. The present work has confirmed the potential for fabrication of highly stable and dispersible GO-based targeting delivery systems for efficient cancer therapy.
Basal Cell-Extracellular Matrix Adhesion Regulates Force Transmission during Tissue Morphogenesis.Tuesday, December 06, 2016
Goodwin K, Ellis SJ, Lostchuck E, Zulueta-Coarasa T, Fernandez-Gonzalez R, Tanentzapf G,
Developmental cell. 05-Dec-2016
Tissue morphogenesis requires force-generating mechanisms to organize cells into complex structures. Although many such mechanisms have been characterized, we know little about how forces are integrated across developing tissues. We provide evidence that integrin-mediated cell-extracellular matrix (ECM) adhesion modulates the transmission of apically generated tension during dorsal closure (DC) in Drosophila. Integrin-containing adhesive structures resembling focal adhesions were identified on the basal surface of the amnioserosa (AS), an extraembryonic epithelium essential for DC. Genetic modulation of integrin-mediated adhesion results in defective DC. Quantitative image analysis and laser ablation experiments reveal that basal cell-ECM adhesions provide resistance to apical cell displacements and force transmission between neighboring cells in the AS. Finally, we provide evidence for integrin-dependent force transmission to the AS substrate. Overall, we find that integrins regulate force transmission within and between cells, thereby playing an essential role in transmitting tension in developing tissues.
Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis.Tuesday, December 06, 2016
Brunmeir R, Wu J, Peng X, Kim SY, Julien SG, Zhang Q, Xie W, Xu F,
PLoS genetics. Dec-2016
Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes. Through these analyses, we found that in brown adipocytes, brown lineage-specific genes are pre-marked by both H3K4me1 and H3K27me3, and the removal of H3K27me3 at the late stage is necessary but not sufficient to promote brown gene expression, while the pre-deposition of H3K4me1 plays an essential role in poising the brown genes for expression in mature brown cells. Moreover, we identify SOX13 as part of a p38 MAPK dependent transcriptional response mediating early brown cell lineage commitment. We also identify and subsequently validate PIM1, SIX1 and RREB1 as novel regulators promoting brown adipogenesis. Finally, we show that SIX1 binds to adipogenic and brown marker genes and interacts with C/EBPα, C/EBPβ and EBF2, suggesting their functional cooperation during adipogenesis.
Patient-derived induced pluripotent stem cells in cancer research and precision oncology.Tuesday, December 06, 2016
Papapetrou EP,
Nature medicine. 06-Dec-2016
Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.
The Effect of Uniaxial Mechanical Stretch on Wnt/β-Catenin Pathway in Bone Mesenchymal Stem Cells.Tuesday, December 06, 2016
Zhao C, Li Y, Wang X, Zou S, Hu J, Luo E,
The Journal of craniofacial surgery. 05-Dec-2016
Wnt/β-catenin signal is required in bone formation and remodling, but little is known about whether Wnt/β-catenin signal could promote osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) after uniaxial mechanical stretch. In this study, rat BMSCs were identified by flow cytometry and used for mechanical stretch. A custom-made uniaxial dynamic stretch apparatus was applied for rat BMSCs stretch. There were 2 groups in the study: the mechanical stretch group and the nonstretch control group. Cell morphology, alkaline phosphatase (ALP) activity, mRNA levels (Wnt3a, Lrp5, β-catenin, as well as Runx2 were evaluated using quantitative real-time reverse transcription-polymerase chain reaction) and protein levels (β-catenin and Runx2 were examined using western blot) were observed in both groups. The authors finally found that not only the cell proliferation, ALP activity, but also mRNA expression of Wnt3a, Lrp5, β-catenin, and Runx2 in BMSCs were markedly elevated by mechanical stretch than the controls. Protein levels of β-catenin and Runx2 were significantly higher than that of control as well. Activation of mechanical stretch was partially reversed by DKK-1, a classical inhibitor of Wnt/β-catenin signal. These results demonstrate that uniaxial mechanical stretch could stimulate osteogenic differentiation and proliferation of BMSCs by activating the Wnt/β-catenin signaling.
Lung regeneration: steps toward clinical implementation and use.Tuesday, December 06, 2016
Calle EA, Leiby KL, Raredon MB, Niklason LE,
Current opinion in anaesthesiology. 05-Dec-2016
Ultimately, the goal of the research described herein is to create a useful clinical product. In the intermediate time, however, the tools described here may be employed to advance our knowledge of lung biology and the organ-specific regenerative capacity of lung stem and progenitor cells.
Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes.Tuesday, December 06, 2016
Baraibar MA, Hyzewicz J, Rogowska-Wrzesinska A, Bulteau AL, Prip-Buus C, Butler-Browne G, Friguet B,
Aging. 04-Dec-2016
Accumulation of oxidized proteins is a hallmark of cellular and organismal aging. Adult muscle stem cell (or satellite cell) replication and differentiation is compromised with age contributing to sarcopenia. However, the molecular events related to satellite cell dysfunction during aging are not completely understood. In the present study we have addressed the potential impact of oxidatively modified proteins on the altered metabolism of senescent human satellite cells. By using a modified proteomics analysis we have found that proteins involved in protein quality control and glycolytic enzymes are the main targets of oxidation (carbonylation) and modification with advanced glycation/lipid peroxidation end products during the replicative senescence of satellite cells. Inactivation of the proteasome appeared to be a likely contributor to the accumulation of such damaged proteins. Metabolic and functional analyses revealed an impaired glucose metabolism in senescent cells. A metabolic shift leading to increased mobilization of non-carbohydrate substrates such as branched chain amino acids or long chain fatty acids was observed. Increased levels of acyl-carnitines indicated an increased turnover of storage and membrane lipids for energy production. Taken together, these results support a link between oxidative protein modifications and the altered cellular metabolism associated with the senescent phenotype of human myoblasts.
New Therapies for Asthma and COPD.Tuesday, December 06, 2016
Gross NJ, Barnes PJ,
American journal of respiratory and critical care medicine. 06-Dec-2016
Asthma and COPD (chronic obstructive pulmonary disease) are two common diseases for which current treatments are less than optimal and for which new drugs are greatly needed. Better understanding of the cellular and molecular mechanisms of these diseases has identified new targets for therapy and several new drugs are in development. Although most new treatments on the market are improvements in existing classes of drug or new combination of treatments, the website indicates 50 and 100 new medications for both asthma and COPD and many of these are entirely new. We report here on some of the new treatments now entering the market and in clinical development. Several new long-acting inhaled bronchodilators and their combinations have been developed, including triple inhalers. Major unmet needs are more effective treatments for severe asthma and disease-modifying (anti-inflammatory) therapies for COPD. More specific treatments, such as antibodies that block eosinophilic or neutrophilic inflammation are in development, together with mediator antagonists and selective kinase inhibitors. However, progress has been very slow suggesting that better understanding of disease or better models and biomarkers and greater investment are needed.
Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.Tuesday, December 06, 2016
Hu Y, Xiong LL, Zhang P, Wang TH,
International journal of molecular medicine. 06-Dec-2016
Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.
Immature myeloid-derived suppressor cells: A bridge between inflammation and cancer (Review).Tuesday, December 06, 2016
Musolino C, Allegra A, Pioggia G, Gangemi S,
Oncology reports. 05-Dec-2016
Chronic inflammation is considered to be one of the hallmarks of tumor initiation and progression. Changes occurring in the microenvironment of progressing tumors resemble the process of chronic inflammation, which begins with ischemia followed by interstitial and cellular edema, appearance of immune cells, growth of blood vessels and tissue repair, and development of inflammatory infiltrates. Moreover, long‑term production and accumulation of inflammatory factors lead to local and systemic immunosuppression associated with cancer progression. Of the several mechanisms described to explain this anergy, the accumulation of myeloid cells in the tumor, spleen, and peripheral blood of cancer patients has gained considerable interest. A population of suppressive CD11b+Gr-1+ cells has in fact been designated as myeloid-derived suppressor cells (MDSCs). MDSCs are a unique category of the myeloid lineage, and they induce the prevention of the development of cytotoxic T lymphocytes (CTLs) in vitro, and the induction of antigen-specific CD8+ T-cell tolerance in vivo. Therapeutic approaches directed toward the manipulation of the MDSC population and their function may improve chemoimmune-enhancing therapy for advanced malignancies.
2'-Hydroxycinnamaldehyde induces apoptosis through HSF1-mediated BAG3 expression.Tuesday, December 06, 2016
Nguyen HA, Kim SA,
International journal of oncology. 06-Dec-2016
BAG3, a member of BAG co-chaperone family, is induced by stressful stimuli such as heat shock and heavy metals. Through interaction with various binding partners, BAG3 is thought to play a role in cellular adaptive responses against stressful conditions in normal and neoplastic cells. 2'-Hydroxycinnamaldehyde (HCA) is a natural derivative of cinnamaldehyde and has antitumor activity in various cancer cells. In the present study, for the first time, we identified that HCA induced BAG3 expression and BAG3-mediated apoptosis in cancer cells. The apoptotic cell death induced by HCA was demonstrated by caspase-7, -9 and PARP activation, and confirmed by Annexin V staining in both SW480 and SW620 colon cancer cells. Notably, both the mRNA and protein levels of BAG3 were largely induced by HCA in a dose- and time-dependent manner. By showing transcription factor HSF1 activation, we demonstrated that HCA induces the expression of BAG3 through HSF1 activation. More importantly, knockdown of BAG3 expression using siRNA largely inhibited HCA-induced apoptosis, suggesting that BAG3 is actively involved in HCA-induced cancer cell death. Considering the importance of the stress response mechanism in cancer progression, our results strongly suggest that BAG3 could be a potential target for anticancer therapy.
Pituitary sex hormones enhance the pro‑metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase‑1.Tuesday, December 06, 2016
Abdelbaset-Ismail A, Pedziwiatr D, Schneider G, Niklinski J, Charkiewicz R, Moniuszko M, Kucia M, Ratajczak MZ,
International journal of oncology. 02-Dec-2016
We report that human lung cancer cell lines express functional receptors for pituitary sex hormones (SexHs) and respond to stimulation by follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). Expression of these receptors has also been confirmed in patient lung cancer samples at the mRNA level. Stimulation of human lung cancer cell lines with FSH, LH, or PRL stimulated migration and chemotaxis, and some cell lines responded by enhanced proliferation. Moreover, priming of human lung cancer cells by exposing them to pituitary SexHs resulted in enhanced seeding efficiency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodeficient mouse model. The chemotaxis of lung cancer cell lines corresponded with the activity of heme oxygenase‑1 (HO‑1), as stimulation of these cells by FSH, LH, and PRL downregulated its expression in a p38 MAPK‑dependent manner. Moreover, while downregulation of HO‑1 by the small‑molecule inhibitor tin protoporphyrin (SnPP) promoted migration, upregulation of HO‑1 by the small‑molecule activator cobalt protoporphyrin (CoPP) showed the opposite effect. Based on this finding, we propose that pituitary SexHs play a significant role in the pathogenesis of lung cancer, particularly when the blood level of FSH increases due to gonadal dysfunction with advanced age. Finally, we propose that upregulation of HO‑1 expression by a small‑molecule activator may be effective in controlling SexH‑induced cell migration in lung cancer.
Factors Associated With Intestinal Constipation in Chronic Patients With Stroke Sequelae Undergoing Rehabilitation.Tuesday, December 06, 2016
Engler TM, Aguiar MH, Furtado ÍA, Ribeiro SP, de Oliveira P, Mello PA, Padula MP, Beraldo PS,
Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates. 02-12-2016
The objective of this study was to define which stroke-related factors constitute independent variables in the incidence of intestinal constipation (IC) of chronic patients admitted to a hospital rehabilitation program. All patients consecutively admitted for rehabilitation were recruited for the study. In the Poisson multiple regression analysis using a hierarchical model, sociodemographic variables, comorbidities, medication, previous history of constipation, life habits, and stroke-related variables were considered for defining factors associated with IC. A 31% prevalence (95% confidence interval [CI]: 25.3-37.1) of IC was detected. Among the factors associated, female gender (adjusted prevalence ratio [PRadjusted] = 1.79; 95% CI: 1.20-2.68), intestinal complaints prior to stroke (PRadjusted = 3.71; 95% CI: 2.60-5.31), intake of less than 800 ml of fluid per day (PRadjusted = 1.72; 95% CI: 1.20- 2.45), age greater than 65 years at brain injury (PRadjusted = 1.67; 95% CI: 1.01-2.75), and partially impaired anterior brain circulation (PRadjusted = 3.35; 95% CI: 1.02-10.97) were associated with IC. Female gender, elderly, prior history of IC, low fluid intake, and partial impairment of anterior brain circulation were factors independently associated with IC in stroke survivors undergoing rehabilitation. These findings require further validation and may serve toward improving bowel retraining programs for this patient group.
Internal Consistency and Convergent Validity of the Portuguese Versions of the Global Appraisal of Individual Needs-Initial and Short Screener: Validity of the Portuguese GAIN-I and SS.Tuesday, December 06, 2016
Garcia Claro H, Ferreira de Oliveira MA, de Almeida Lopes Fernandes IF, Titus JC, Ribeiro Tarifa R, Fernandes Rojas T, Hayasi Pinho P,
Journal of addictions nursing. 7-12-2016
The Brazilian Portuguese instrument scales showed evidence for internal consistency and convergent validity performing similarly to the American English versions.
Reliability and Validity of the Work and Social Adjustment Scale in Treatment-Seeking Problem Gamblers.Tuesday, December 06, 2016
Tolchard B,
Journal of addictions nursing. 7-12-2016
The WSAS has excellent reliability and sound validity among a treatment-seeking problem gambling population. Understanding disability related to gambling may offer insights into the long-term success of gamblers completing treatment. This instrument needs further refinement in a more rigorous experimental setting.
Ionizing Radiation Impairs Endogenous Regeneration of Infarcted Heart: An In Vivo (18)F-FDG PET/CT and (99m)Tc-Tetrofosmin SPECT/CT Study in Mice.Tuesday, December 06, 2016
Luo L, Nishi K, Urata Y, Yan C, Hasan AS, Goto S, Kudo T, Li ZL, Li TS,
Radiation research. 06-Dec-2016
Epidemiological studies have suggested that ionizing radiation increases cardiovascular disease risk, but the relevant mechanism is poorly understood. We recently demonstrated that adult mice exposed to whole-body irradiation with 3 Gy gamma rays significantly decreases the number and quality of cardiac stem cells. To further determine if radiation impairs myocardial regenerative potency, a myocardial infarction model was established in adult C57BL/6 mice by ligating the left anterior descending artery approximately 6 h after sham- or whole-body gamma irradiation (0 or 3 Gy). To evaluate the regenerative potency of the infarcted heart, we measured the myocardial perfusion and remodeling by (18)F-FDG PET/CT and (99m)Tc-tetrofosmin SPECT/CT at 1-2 days (baseline) and 14-15 days (end point) after infarction, respectively. Mice were sacrificed at day 15 after infarction, and heart tissue was collected for histological analysis. The infarct area of the left ventricle was significantly larger in irradiated mice than healthy controls 14 days after infarction, although it was similar between the groups at the baseline. However, histological analysis showed that the infarct size and left ventricle wall thickness were not significantly different among the groups. Compared to the healthy controls, irradiated mice had significantly less c-kit-positive stem cells, less Sca-1-positive stem cells, less proliferating cells, more apoptotic cells and lower vessel density within the infarcted heart. The results of this study suggest that whole-body irradiation with 3 Gy gamma rays impairs the endogenous regeneration of infarcted heart, which may indirectly predict future cardiovascular disease risk.
Current practices for screening, consent and care of related donors in France: Haematopoietic stem cell transplantation coordinator nurses' perceptions.Tuesday, December 06, 2016
Polomeni A, Bompoint C, Gomez A, Brissot E, Ruggeri A, Belhocine R, Mohty M,
European journal of cancer care. 06-Dec-2016
Haematopoietic stem cell transplantation-coordinating nurses (HSCT-CNs) play an important role in informing related donors (RDs) and in organising human leucocyte antigen (HLA) tests, pre-donation workup and stem cells collection. Our pilot study aimed to explore French HSCT-CNs' perceptions of RD care issues. Twenty-nine French HSCT adult units were sent a questionnaire on the subject of donation procedures, HSCT-CNs' data and their professional experience of related donation issues. Twenty-two HSCT-CNs returned a completed questionnaire, and 90% of HSCT units were involved to some degree in both patient and donor care. Responses indicated that the provision of information to potential donors prior to HLA tests was insufficient, while donors were given a medical consultation only during the pre-donation workup. Questions were raised about the consent and voluntary status of RDs. None of the HSCT teams organised a post-donation consultation, while 57% provided follow-up by phone or via a questionnaire. Our results draw attention to the conflict of interest experienced by HSCT-CNs when caring simultaneously for patients and donors. The specific psychosocial difficulties associated with becoming an RD are also highlighted. French HSCT-CNs' perceptions of related donation reveal many ethical and clinical problems that have yet to be fully explored. Data on this topic remain scarce, and our pilot study may contribute to the current debate on the organisation of RD care.
Mitomycin C-treated human-induced pluripotent stem cells as a safe delivery system of gold nanorods for targeted photothermal therapy of gastric cancer.Tuesday, December 06, 2016
Yang M, Liu Y, Hou W, Zhi X, Zhang C, Jiang X, Pan F, Yang Y, Ni J, Cui D,
Nanoscale. 06-Dec-2016
Human-induced pluripotent stem cells (iPS) possess an intrinsic tumor tropism ability. However, iPS cells are impeded in clinical applications of tumor therapy due to the formation of teratomas and their survival in normal organs such as the liver, lungs, spleen and kidneys. Mitomycin C (MMC) can overcome this limitation by suppressing iPS proliferation. Herein, we fabricated a safe delivery system of iPS cells treated with MMC loading with gold nanorods (AuNRs) for the targeted photothermal treatment of gastric cancer. Our results showed that the tumor cells were efficiently killed by the heat generated from the gold nanorods, and the iPS cells ultimately died due to the action of MMC seven days after the photothermal treatment. This suggested that pre-treated iPS cells with MMC can be used as a novel and safe approach for targeted tumor therapy. This paves the road for clinical translation in the future.
Thermo-sensitive hydrogels combined with decellularised matrix deliver bFGF for the functional recovery of rats after a spinal cord injury.Tuesday, December 06, 2016
Xu HL, Tian FR, Lu CT, Xu J, Fan ZL, Yang JJ, Chen PP, Huang YD, Xiao J, Zhao YZ,
Scientific reports. 06-Dec-2016
Because of the short half-life, either systemic or local administration of bFGF shows significant drawbacks to spinal injury. In this study, an acellular spinal cord scaffold (ASC) was encapsulated in a thermo-sensitive hydrogel to overcome these limitations. The ASC was firstly prepared from the spinal cord of healthy rats and characterized by scanning electronic microscopy and immunohistochemical staining. bFGF could specifically complex with the ASC scaffold via electrostatic or receptor-mediated interactions. The bFGF-ASC complex was further encapsulated into a heparin modified poloxamer (HP) solution to prepare atemperature-sensitive hydrogel (bFGF-ASC-HP). bFGF release from the ASC-HP hydrogel was more slower than that from the bFGF-ASC complex alone. An in vitro cell survival study showed that the bFGF-ASC-HP hydrogel could more effectively promote the proliferation of PC12 cells than a bFGF solution, with an approximate 50% increase in the cell survival rate within 24 h (P < 0.05). Compared with the bFGF solution, bFGF-ASC-HP hydrogel displayed enhanced inhibition of glial scars and obviously improved the functional recovery of the SCI model rat through regeneration of nerve axons and the differentiation of the neural stem cells. In summary, an ASC-HP hydrogel might be a promising carrier to deliver bFGF to an injured spinal cord.
Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I.Tuesday, December 06, 2016
Chen GL, Tian YQ, Wu JL, Li N, Guo MQ,
Scientific reports. 06-Dec-2016
Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.
Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD.Tuesday, December 06, 2016
Kennelly H, Mahon BP, English K,
Scientific reports. 06-Dec-2016
Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emphysema the efficacy of human MSC therapy and optimal cell dose were investigated. Protective effects were examined in the lung through histological examination. Further in vivo experiments examined the reparative abilities of MSCs after tissue damage was established and the role played by soluble factors secreted by MSCs. The mechanism of MSC action was determined in using shRNA gene knockdown. Human MSC therapy and MSC conditioned media exerted significant cytoprotective effects when administered early at the onset of the disease. These protective effects were due to significant anti-inflammatory, anti-fibrotic and anti-apoptotic mechanisms, mediated in part through MSC production of hepatocyte growth factor (HGF). When MSC administration was delayed, significant protection of the lung architecture was observed but this was less extensive. MSC cell therapy was more effective than MSC conditioned medium in this emphysema model.
Blood flow controls bone vascular function and osteogenesis.Tuesday, December 06, 2016
Ramasamy SK, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, Gamrekelashvili J, Limbourg A, Medvinsky A, Santoro MM, Limbourg FP, Adams RH,
Nature communications. 06-Dec-2016
While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.
Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.Tuesday, December 06, 2016
Katsushima K, Natsume A, Ohka F, Shinjo K, Hatanaka A, Ichimura N, Sato S, Takahashi S, Kimura H, Totoki Y, Shibata T, Naito M, Kim HJ, Miyata K, Kataoka K, Kondo Y,
Nature communications. 06-Dec-2016
Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.
House Dust Mites Confer a Distinct Immunological Feature among Dermatitis.Tuesday, December 06, 2016
Baris S, Ozen A, Akdeniz T, Karakoc-Aydiner E, Aydin O, Ercan H, Ogulur I, Camcioglu Y, Cengizlier R, Demirkesen C, Yucelten D, Demirel G, Barlan IB,
Iranian journal of allergy, asthma, and immunology. Aug-2016
Atopic dermatitis (AD) is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM)-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL)-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ)+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively). Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3) and T-cell-specific transcription factor (T-bet) (p=0.018, p=0.018, p=0.018, respectively). HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.
Core-shell silk hydrogels with spatially tuned conformations as drug-delivery system.Tuesday, December 06, 2016
Yan LP, Oliveira JM, Oliveira AL, Reis RL,
Journal of tissue engineering and regenerative medicine. 05-Dec-2016
Hydrogels of spatially controlled physicochemical properties are appealing platforms for tissue engineering and drug delivery. In this study, core-shell silk fibroin (SF) hydrogels of spatially controlled conformation were developed. The core-shell structure in the hydrogels was formed by means of soaking the preformed (enzymatically crosslinked) random coil SF hydrogels in methanol. When increasing the methanol treatment time from 1 to 10 min, the thickness of the shell layer can be tuned from about 200 to about 850 μm as measured in wet status. After lyophilization of the rehydrated core-shell hydrogels, the shell layer displayed compact morphology and the core layer presented porous structure, when observed by scanning electron microscopy. The conformation of the hydrogels was evaluated by Fourier transform infrared spectroscopy in wet status. The results revealed that the shell layer possessed dominant β-sheet conformation and the core layer maintained mainly random coil conformation. Enzymatic degradation data showed that the shell layers presented superior stability to the core layer. The mechanical analysis displayed that the compressive modulus of the core-shell hydrogels ranged from about 25 kPa to about 1.1 MPa by increasing the immersion time in methanol. When incorporated with albumin, the core-shell SF hydrogels demonstrated slower and more controllable release profiles compared with the non-treated hydrogel. These core-shell SF hydrogels of highly tuned properties are useful systems as drug-delivery system and may be applied as cartilage substitute. Copyright © 2016 John Wiley & Sons, Ltd.
pH-Responsive Triblock Copolymeric Micelles Decorated with a Cell-Penetrating Peptide Provide Efficient Doxorubicin Delivery.Tuesday, December 06, 2016
Ng KE, Amin MC, Katas H, Amjad MW, Butt AM, Kesharwani P, Iyer AK,
Nanoscale research letters. Dec-2016
This study developed novel triblock pH-responsive polymeric micelles (PMs) using cholic acid-polyethyleneimine-poly-L-arginine (CA-PEI-pArg) copolymers. PEI provided pH sensitivity, while the hydrophilic cell-penetrating pArg peptide promoted cellular PM internalization. The copolymers self-assembled into PMs in aqueous solution at above the critical micelle concentration (2.98 × 10(-7) M) and encapsulated doxorubicin in the core region, with a 34.2% (w/w) entrapment efficiency. PMs showed pH-dependent swelling, increasing in size by almost sevenfold from pH 7.4 to 5.0. Doxorubicin release was pH-dependent, with about 65% released at pH 5.0, and 32% at pH 7.4. Cellular uptake, assessed by confocal microscopy and flow cytometry, was enhanced by using doxorubicin-loaded CA-PEI-pArg PMs, as compared to free doxorubicin and DOX-loaded CA-PEI PMs. Moreover, 24-h incubation of these PMs with a human breast cancer cell line produced greater cytotoxicity than free doxorubicin. These results indicate that pH-responsive CA-PEI-pArg micelles could provide a versatile delivery system for targeted cancer therapy using hydrophobic drugs. Graphical of CA-PEI-pArg polymeric micelles as a pH-responsive drug delivery system.
Leaving IJH: joining to fly.Tuesday, December 06, 2016
Kitamura T, Takaori-Kondo A,
International journal of hematology. 05-Dec-2016
A new era of disease modeling and drug discovery using induced pluripotent stem cells.Tuesday, December 06, 2016
Suh W,
Archives of pharmacal research. 05-Dec-2016
In 2006, Shinya Yamanaka first reported that in vitro reprogramming of somatic cells toward pluripotency was achieved by simple induction of specific transcription factors. Induced pluripotent stem cell (iPSC) technology has since revolutionized the ways in which we explore the mechanisms of human diseases and develop therapeutics. Here, I describe the recent advances in human iPSC-based disease modeling and drug discovery and discuss the current challenges. Additionally, I outline potential future applications of human iPSCs in classifying patients based on their response to drugs in clinical trials and elucidating optimal patient-specific therapeutic strategies, which will contribute to reduced attrition rates and the development of precision medicine.
Human Mesenchymal Stem Cells from Adipose Tissue Differentiated into Neuronal or Glial Phenotype Express Different Aquaporins.Tuesday, December 06, 2016
Avola R, Graziano AC, Pannuzzo G, Cardile V,
Molecular neurobiology. 05-Dec-2016
Aquaporins (AQPs) are 13 integral membrane proteins that provide selective pores for the rapid movement of water and other uncharged solutes, across cell membranes. Recently, AQPs have been focused for their role in production, circulation, and homeostasis of the cerebrospinal fluid and their importance in several human diseases is becoming clear. This study investigated the time course (0, 14, and 28 days) of AQP1, 4, 7, 8, and 9 during the neural differentiation of human mesenchymal stem cells (MSCs) from adipose tissue (AT). For this purpose, two different media, enriched with serum or B-27 and N1 supplements, were applied to give a stimulus toward neural lineage. After 14 days, the cells were cultured with neuronal or glial differentiating medium for further 14 days. The results confirmed that AT-MSCs could be differentiated into neurons, astrocytes, and oligodendrocytes, expressing not only the typical neural markers but also specific AQPs depending on differentiated cell type. Our data demonstrated that at 28 days, AT-MSCs express only AQP1; astrocytes AQP1, 4, and 7; oligodendrocytes AQP1, 4, and 8; and finally neurons AQP1 and 7. This study provides fundamental insight into the biology of the mesenchymal stem cells and it suggests that AQPs can be potential neural markers.
Transplantation of collagen scaffold with autologous bone marrow mononuclear cells promotes functional endometrium reconstruction via downregulating ΔNp63 expression in Asherman's syndrome.Tuesday, December 06, 2016
Zhao G, Cao Y, Zhu X, Tang X, Ding L, Sun H, Li J, Li X, Dai C, Ru T, Zhu H, Lu J, Lin C, Wang J, Yan G, Wang H, Wang L, Dai Y, Wang B, Li R, Dai J, Zhou Y, Hu Y,
Science China. Life sciences. 01-Dec-2016
Asherman's syndrome (AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells (BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.
A Novel Fluorescent Quantum Dot Probe for the Rapid Diagnostic High Contrast Imaging of Tumor in Mice.Tuesday, December 06, 2016
Vibin M, Vinayakan R, Fernandez FB, John A, Abraham A,
Journal of fluorescence. 05-Dec-2016
A simple probe - antibody conjugated silica over coated cadmium selenide quantum dots (QD-Ab probe) for efficient and rapid diagnostic in vivo imaging of tumors is developed. Compared to unconjugated quantum dots (QD), these probes underwent efficient cellular internalization and tumor targeting behavior, retaining bright emission under in vivo cancer models. Silica over coated cadmium selenide quantum dots were conjugated with Epidermal growth factor receptor (EGFR) monoclonal antibody to detect the over expression of EGFR in cancer models. The in vitro cellular internalization efficiency of QD and QD-Ab probe in cultured stem cells (RADMSCs) and cancer cells (HeLa) were assessed by ICP-OES and cLSM. Results demonstrated a greater internalization efficiency of CdSe-Silica QD-Ab probe than CdSe-Silica QDs. For in vivo imaging solid tumor bearing mice was subjected to tail vein injection of QD and QD-Ab probe. After the specific time interval of injection, mice were anesthetized and subjected into Xenogen IVIS®200 imaging system, followed by ex vivo imaging. Subsequently, ultrathin sections of tumor were imaged by using cLSM. Both in vivo and ex vivo imaging results confirmed the tumor-targeted imaging efficiency of QD-Ab probes compared to unconjugated QDs.
Endogenous Stem Cells Were Recruited by Defocused Low-Energy Shock Wave in Treating Diabetic Bladder Dysfunction.Tuesday, December 06, 2016
Jin Y, Xu L, Zhao Y, Wang M, Jin X, Zhang H,
Stem cell reviews. 05-Dec-2016
Defocused low-energy shock wave (DLSW) has been shown effects on activating mesenchymal stromal cells (MSCs) in vitro. In this study, recruitment of endogenous stem cells was firstly examined as an important pathway during the healing process of diabetic bladder dysfunction (DBD) treated by DLSW in vivo. Neonatal rats received intraperitoneal injection of 5-ethynyl-2-deoxyuridine (EdU) and then DBD rat model was created by injecting streptozotocin. Four weeks later, DLSW treatment was performed. Afterward, their tissues were examined by histology. Meanwhile, adipose tissue-derived stem cells (ADSCs) were treated by DLSW in vitro. Results showed DLSW ameliorated voiding function of diabetic rats by recruiting EdU(+)Stro-1(+)CD34(-) endogenous stem cells to release abundant nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). Some EdU(+) cells overlapped with staining of smooth muscle actin. After DLSW treatment, ADSCs showed higher migration ability, higher expression level of stromal cell-derived factor-1 and secreted more NGF and VEGF. In conclusion, DLSW could ameliorate DBD by recruiting endogenous stem cells. Beneficial effects were mediated by secreting NGF and VEGF, resulting into improved innervation and vascularization in bladder.
MCP1 triggers monocyte dysfunctions during abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis.Tuesday, December 06, 2016
Xie Z, Wang P, Li J, Li Y, Wang S, Wu X, Sun S, Cen S, Su H, Deng W, Liu Z, Ouyang Y, Wu Y, Shen H,
Journal of molecular medicine (Berlin, Germany). 05-Dec-2016
ASMSCs secreted more MCP1 during abnormal osteogenic differentiation. MCP1 overexpression leads to monocyte dysfunctions. Pathological osteogenesis can lead to inflammation in AS.
Effect of L-carnitine on in vitro developmental rate, the zona pellucida and hatching of blastocysts and their cell numbers in mouse embryos.Tuesday, December 06, 2016
Khanmohammadi N, Movahedin M, Safari M, Sameni HR, Yousefi B, Jafari B, Zarbakhsh S,
International journal of reproductive biomedicine (Yazd, Iran). Oct-2016
The results suggest that LC may increase the number of blastocyst cells, which probably helps to expand the blastocyst and thinning of the ZP thickness and, therefore, creating a successful hatching for implantation.
Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury.Tuesday, December 06, 2016
Tan RJ, Zhou D, Liu Y,
Kidney diseases (Basel, Switzerland). Oct-2016
The discovery of a complex and intricate system of communication between tubular cells and fibroblasts is a new paradigm in our understanding of renal fibrosis. An appreciation of both their regenerative and pathologic functions will inform the development and use of targeted therapeutic interventions.
The Collection of Adipose Derived Stem Cells using Water-Jet Assisted Lipoplasty for their Use in Plastic and Reconstructive Surgery: A Preliminary Study.Tuesday, December 06, 2016
Purpura V, Bondioli E, Melandri D, Parodi PC, Valenti L, Riccio M,
Frontiers in cell and developmental biology. 2016
The graft of autologous fat for the augmentation of soft tissue is a common practice frequently used in the field of plastic and reconstructive surgery. In addition, the presence of adipose derived stem cells (ASCs) in adipose tissue stimulates the regeneration of tissue in which it is applied after the autologous fat grafting improving the final clinical results. Due to these characteristics, there is an increasing interest in the use of ASCs for the treatment of several clinical conditions. As a consequence, the use of clean room environment is required for the production of cell-based therapies. The present study is aimed to describe the biological properties of adipose tissue and cells derived from it cultured in vitro in clean room environment according to current regulation. The collection of adipose tissue was performed using the water-jet assisted liposuction in order to preserve an high cell viability increasing their chances of future use for different clinical application in the field of plastic and reconstructive surgery.
Amniotic Epithelial Cells: A New Tool to Combat Aging and Age-Related Diseases?Tuesday, December 06, 2016
Di Germanio C, Bernier M, de Cabo R, Barboni B,
Frontiers in cell and developmental biology. 2016
The number of elderly people is growing at an unprecedented rate and this increase of the aging population is expected to have a direct impact on the incidence of age-related diseases and healthcare-associated costs. Thus, it is imperative that new tools are developed to fight and slow age-related diseases. Regenerative medicine is a promising strategy for the maintenance of health and function late in life; however, stem cell-based therapies face several challenges including rejection and tumor transformation. As an alternative, the placenta offers an extraordinary source of fetal stem cells, including the amniotic epithelial cells (AECs), which retain some of the characteristics of embryonic stem cells, but show low immunogenicity, together with immunomodulatory and anti-inflammatory activities. Because of these characteristics, AECs have been widely utilized in regenerative medicine. This perspective highlights different mechanisms triggered by transplanted AECs that could be potentially useful for anti-aging therapies, which include: Graft and differentiation for tissue regeneration in age-related settings, anti-inflammatory behavior to combat "inflammaging," anti-tumor activity, direct lifespan and healthspan extension properties, and possibly rejuvenation in a manner reminiscent of heterochronic parabiosis. Here, we critically discuss benefits and limitation of AECs-based therapies in age-related diseases.
Describing the Stem Cell Potency: The Various Methods of Functional Assessment and In silico Diagnostics.Tuesday, December 06, 2016
Singh VK, Saini A, Kalsan M, Kumar N, Chandra R,
Frontiers in cell and developmental biology. 2016
Stem cells are defined by their capabilities to self-renew and give rise to various types of differentiated cells depending on their potency. They are classified as pluripotent, multipotent, and unipotent as demonstrated through their potential to generate the variety of cell lineages. While pluripotent stem cells may give rise to all types of cells in an organism, Multipotent and Unipotent stem cells remain restricted to the particular tissue or lineages. The potency of these stem cells can be defined by using a number of functional assays along with the evaluation of various molecular markers. These molecular markers include diagnosis of transcriptional, epigenetic, and metabolic states of stem cells. Many reports are defining the particular set of different functional assays, and molecular marker used to demonstrate the developmental states and functional capacities of stem cells. The careful evaluation of all these methods could help in generating standard identifying procedures/markers for them.
Assessing the hyperthermic properties of magnetic heterostructures: the case of gold-iron oxide composites.Tuesday, December 06, 2016
Fantechi E, Castillo PM, Conca E, Cugia F, Sangregorio C, Casula MF,
Interface focus. 06-Dec-2016
Gold-iron oxide composites were obtained by in situ reduction of an Au(III) precursor by an organic reductant (either potassium citrate or tiopronin) in a dispersion of preformed iron oxide ultrasmall magnetic (USM) nanoparticles. X-ray diffraction, transmission electron microscopy, chemical analysis and mid-infrared spectroscopy show the successful deposition of gold domains on the preformed magnetic nanoparticles, and the occurrence of either citrate or tiopronin as surface coating. The potential of the USM@Au nanoheterostructures as heat mediators for therapy through magnetic fluid hyperthermia was determined by calorimetric measurements under sample irradiation by an alternating magnetic field with intensity and frequency within the safe values for biomedical use. The USM@Au composites showed to be active heat mediators for magnetic fluid hyperthermia, leading to a rapid increase in temperature under exposure to an alternating magnetic field even under the very mild experimental conditions adopted, and their potential was assessed by determining their specific absorption rate (SAR) and compared with the pure iron oxide nanoparticles. Calorimetric investigation of the synthesized nanostructures enabled us to point out the effect of different experimental conditions on the SAR value, which is to date the parameter used for the assessment of the hyperthermic efficiency.
Exogenous Secreted Frizzled-Related Protein-4 Modulates Steroidogenesis of Rat Granulosa Cells through Wnt/β-catenin and PI3K/AKT Signaling Pathways.Tuesday, December 06, 2016
Hossein G, Khanmohammadi M, Sahranavard Fard P, Heidarian Y, Kazemnejad S, Akhondi MM,
Avicenna journal of medical biotechnology. 7-12-2016
Taken together, our results showed that rhSFRP-4 could directly induce terminal differentiation in GCs via the modulation of β-catenin and PKB/AKT pathways and that it does so in a dose-dependent manner.
Paroxetine Can Enhance Neurogenesis during Neurogenic Differentiation of Human Adipose-derived Stem Cells.Tuesday, December 06, 2016
Jahromi M, Razavi S, Amirpour N, Khosravizadeh Z,
Avicenna journal of medical biotechnology. 7-12-2016
Our results provide evidence that Paroxetine can promote proliferation and differentiation rate during neurogenic differentiation of hADSCs. Moreover, Paroxetine can reduce gliogenesis of induced hADSCs during neurogenic differentiation.
Anti-anaphylactic effects of Trichilia monadelpha (Thonn.) J. J. De Wilde extracts on rodent models of anaphylaxis.Tuesday, December 06, 2016
Ben IO, Woode E, Koffuor GA, Asiamah EA,
Research in pharmaceutical sciences. Oct-2016
Effects of petroleum ether and ethanolic extracts of Trichilia monadelpha stem bark (PEE and EAE) on compound 48/80-induced systemic and passive anaphylaxis were determined. Survival rate, extravasation, degranulation of mast cells, and secretion of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured after pre-treatment with extracts (10-100 mg/kg) and disodium chromoglycate (2.5-250 μg/kg) and induction of anaphylaxis in C57BL/6 mice or Sprague-Dawley rats with compound 48/80. Histopathological assessments were made from skin biopsies of rats. Data was analyzed by Kaplan-Meier Survival Log-Rank Analysis, or One-way ANOVA and Holm-Sidak's post hoc test. PEE and EAE inhibited (P ≤ 0.0001) tremors in systemic anaphylaxis passive cutaneous anaphylactic reactions and extravasation, stabilized or prevented (P ≤ 0.001-0.0001) mast cell degranulation, and inhibited (P ≤ 0.001-0.0001) TNF-α and IL-6 secretion. Per the findings, PEE and EAE of T. monadelpha have exhibited substantial anti-anaphylactic and anti-inflammatory property (with PEE performing better) which substantiates its use traditionally in management of allergies and other inflammatory disorders.
Connecting Sarcomere Protein Mutations to Pathogenesis in Cardiomyopathies: The Development of "Disease in a Dish" Models.Tuesday, December 06, 2016
Zaunbrecher R, Regnier M,
Frontiers in physiology. 2016
Recent technological and protocol developments have greatly increased the ability to utilize stem cells transformed into cardiomyocytes as models to study human heart muscle development and how this is affected by disease associated mutations in a variety of sarcomere proteins. In this perspective we provide an overview of these emerging technologies and how they are being used to create better models of "disease in a dish" for both research and screening assays. We also consider the value of these assays as models to explore the seminal processes in initiation of the disease development and the possibility of early interventions.
Getting miRNA Therapeutics into the Target Cells for Neurodegenerative Diseases: A Mini-Review.Tuesday, December 06, 2016
Wen MM,
Frontiers in molecular neuroscience. 2016
miRNAs play important roles in modulating gene expression in varying cellular processes and disease pathogenesis, including neurodegenerative diseases. Several miRNAs are expressed in the brain, control brain development and are identified as important biomarkers in the pathogenesis of motor-and neuro-cognitive diseases such as Alzheimer's (AD), Huntington's and Parkinson's diseases (PD) and amyotrophic lateral sclerosis. These remarkable miRNAs could be used as diagnostic markers and therapeutic targeting potential for many stressful and untreatable progressive neurodegenerative diseases. To modulate these miRNA activities, there are currently two strategies involved; first one is to therapeutically restore the suppressed miRNA level by miRNA mimics (agonist), and the other one is to inhibit miRNA function by using anti-miR (antagonist) to repress overactive miRNA function. However, RNAi-based therapeutics often faces in vivo instability because naked nucleic acids are subject to enzyme degradation before reaching the target sites. Therefore, an effective, safe and stable bio-responsive delivery system is necessary to protect the nucleic acids from serum degradation and assist their entrance to the cells. Since neuronal cells are non-regenerating, to design engineered miRNAs to be delivered to the central nervous system (CNS) for long term gene expression and knockdown is representing an enormous challenge for scientists. This article provides an insight summary on some of the innovative strategies employed to deliver miRNA into target cells. These viral and non-viral carrier systems hold promise in RNA therapy delivery for neurodegenerative diseases.
Successful Treatment of Small Intestinal Bleeding in a Crohn's Patient with Noncirrhotic Portal Hypertension by Transjugular Portosystemic Shunt Placement and Infliximab Treatment.Tuesday, December 06, 2016
Heimgartner B, Dawson H, De Gottardi A, Wiest R, Niess JH,
Case reports in gastroenterology. 22-11-2016
Small intestinal bleeding in Crohn's disease patients with noncirrhotic portal hypertension and partial portal and superior mesenteric vein thrombosis is a life-threatening event. Here, a case is reported in which treatment with azathioprine may have resulted in nodular regenerative hyperplasia, portal hypertension and portal vein thrombosis. The 56-year-old patient with Crohn's disease developed nodular regenerative hyperplasia under treatment with azathioprine. He was admitted with severe bleeding. Gastroscopy showed small esophageal varices without bleeding stigmata. Blood was detected in the terminal ileum. CT scan revealed a partial portal vein thrombosis with extension to the superior mesenteric vein, thickening of the jejunal wall and splenomegaly. Because intestinal bleeding could not be controlled by conservative treatment, the thrombus was aspirated and a transjugular intrahepatic portosystemic shunt (TIPS) was placed. Switching the immunosuppressive medication to infliximab controlled Crohn's disease activity. Bleeding was stopped, hemoglobin normalized, and thrombocytopenia and bowel movements improved. In summary, small intestinal bleeding in a Crohn's patient with nodular regenerative hyperplasia, portal hypertension and portal vein thrombosis can be efficiently treated by TIPS. TIPS placement together with infliximab treatment led to the improvement of the blood panel and remission in this patient.
Endocrinological Abnormalities Are a Main Feature of 17p13.1 Microduplication Syndrome: A New Case and Literature Review.Tuesday, December 06, 2016
Maini I, Ivanovski I, Iodice A, Rosato S, Pollazzon M, Mussini M, Belligni EF, Coutton C, Marinelli M, Barbieri V, Napoli M, Pascarella R, Sartori C, Madia F, Fusco C, Franchi F, Street ME, Garavelli L,
Molecular syndromology. Nov-2016
To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.
Lesch-Nyhan Syndrome: Models, Theories, and Therapies.Tuesday, December 06, 2016
Bell S, Kolobova I, Crapper L, Ernst C,
Molecular syndromology. Nov-2016
Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by mutations in HPRT1, an important enzyme in the purine salvage pathway. Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in hypoxanthine and guanine recycling can lead to such a profound neurological phenotype. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients, though none have led to a satisfactory explanation of the disease. New technologies such as next-generation sequencing, optogenetics, genome editing, and induced pluripotent stem cells provide a unique opportunity to map the precise sequential pathways leading from genotype to phenotype.
The effect of magnetic nanoparticles on neuronal differentiation of induced pluripotent stem cell-derived neural precursors.Tuesday, December 06, 2016
Jiráková K, Šeneklová M, Jirák D, Turnovcová K, Vosmanská M, Babič M, Horák D, Veverka P, Jendelová P,
International journal of nanomedicine. 2016
Our results show that cells labeled with PLL-coated γ-Fe2O3 are suitable for MR detection, did not affect the differentiation potential of iPSC-NPs and are suitable for in vivo cell therapies in experimental models of central nervous system disorders.
Fabrication and characterization of drug-loaded nano-hydroxyapatite/polyamide 66 scaffolds modified with carbon nanotubes and silk fibroin.Tuesday, December 06, 2016
Yao MZ, Huang-Fu MY, Liu HN, Wang XR, Sheng X, Gao JQ,
International journal of nanomedicine. 2016
Nano-hydroxyapatite/polyamide 66 (nHA/PA66) porous scaffolds were fabricated by a phase inversion method. Carbon nanotubes (CNTs) and silk fibroin (SF) were used to modify the surface of the nHA/PA66 scaffolds by freeze-drying and cross-linking. Dexamethasone was absorbed to the CNTs to promote the osteogenic differentiation of bone mesenchymal stem cells (BMSCs). The cell viability of BMSCs was investigated by changing the concentration of the CNT dispersion, and the most biocompatible scaffold was selected. In addition, the morphology and mechanical property of the scaffolds were investigated. The results showed that the nHA/PA66 scaffolds modified with CNTs and SF met the requirements of bone tissue engineering scaffolds. The dexamethasone-loaded CNT/SF-nHA/PA66 composite scaffold promoted the osteogenic differentiation of BMSCs, and the drug-loaded scaffolds are expected to function as effective bone tissue engineering scaffolds.
Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.Tuesday, December 06, 2016
Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L,
Scientific reports. Dec-2016
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 μM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.
Intensive care unit stress ulcer prophylaxis: is it still needed?Tuesday, December 06, 2016
Almadi MA, Barkun AN,
Annals of Saudi medicine. 05-12-2016
Experimentally Induced Preterm Birth in Sheep Following a Clinical Course of Antenatal Betamethasone: Effects on Growth and Long-Term Survival.Tuesday, December 06, 2016
Nguyen VB, De Matteo R, Harding R, Stefanidis A, Polglase GR, Black MJ,
Reproductive sciences (Thousand Oaks, Calif.). 05-Dec-2016
Preterm births account for approximately 10% of births worldwide, with the majority (∼80%) being moderate preterm. Our aim was to determine the effects of moderate preterm birth on survival and long-term growth of male and female offspring using an ovine model of preterm birth that was preceded by a clinically relevant dose of corticosteroids. Ewes were induced to deliver preterm or at term; those assigned to deliver preterm were administered antenatal betamethasone (11.4 mg, 2 doses, 24 hours apart). The growth (body weight and body dimensions) of offspring was monitored to adulthood (62 weeks) when the animals were humanely killed for organ collection. Survival in the immediate period following preterm birth was high (75% for both sexes). However, there were unexpected deaths between 5 and 12 weeks of age, as a result of vitamin E/selenium deficiency; this only occurred in preterm offspring. From birth until adolescence, preterm lambs were lighter than term lambs (controls). After this time, there was gradual catch-up in body weight in preterm females, whereas in preterm males, body weight remained lower than in controls. Preterm sheep were smaller in stature than controls throughout life. This clinically relevant model of preterm birth leads to equally high survival rates in both sexes and is an excellent animal model in which to examine the effects of moderate preterm birth on growth and development of organ systems into adulthood.
Serum miR-451a Levels Are Significantly Elevated in Women With Endometriosis and Recapitulated in Baboons (Papio anubis) With Experimentally-Induced Disease.Tuesday, December 06, 2016
Nothnick WB, Falcone T, Joshi N, Fazleabas AT, Graham A,
Reproductive sciences (Thousand Oaks, Calif.). 05-Dec-2016
We have previously demonstrated that human microRNA-451a (miR-451a) endometriotic lesion expression is significantly higher compared to that of the corresponding eutopic endometrium. The objective of the current study was to examine the relationship between lesion and serum content of miR-451a and to determine the utility of serum miR-451a in distinguishing between women with and without visible signs of endometriosis. Eighty-one participants were enrolled in this study, 41 with confirmed endometriosis and 40 without visible signs of endometriosis at laparoscopy (n = 20) or symptoms of endometriosis (pain, infertility n = 20). Experimental endometriosis was also induced in 8 baboons. Blood, endometriotic lesions, and eutopic endometrial samples were collected from women undergoing laparoscopy for surgical removal of endometriosis. Blood was also collected from control participants with no signs and symptoms associated with the disease as well as from baboons prior to, and then 1, 3, 6, 9, and 15 months postinduction of endometriosis. MicroRNA-451a was assessed by quantitative real-time polymerase chain reaction in all samples. In humans, serum miR-451a levels positively correlated with endometriotic lesion miR-451a content, and sera levels were significantly higher in these participants compared to controls. The area under the curve (AUC) for miR-451a was 0.8599. In baboons, serum miR-451a reached statistically significant peak levels at 6 months postinduction of endometriosis. We conclude from this study that sera miR-451a levels positively correlated with endometriotic lesion content and are significantly greater compared to sera levels in women without visible signs or symptoms of endometriosis. MicroRNA-451a may serve as a serum diagnostic marker for endometriosis.
The PLETHORA gene regulatory network guides growth and cell differentiation in Arabidopsis roots.Tuesday, December 06, 2016
Santuari L, Sanchez-Perez G, Luijten M, Rutjens B, Terpstra I, Berke L, Gorte M, Prasad K, Bao D, Timmermans-Hereijgers JL, Maeo K, Nakamura K, Shimotohno A, Pencik A, Novák O, Ljung K, van Heesch S, de Bruijn E, Cuppen E, Willemsen V, Mähönen AP, Lukowitz W, Snel B, de Ridder D, Scheres B, Heidstra R,
The Plant cell. 05-Dec-2016
Organ formation in animals and plants relies on precise control of cell state transitions to turn stem cell daughters into fully differentiated cells. In plants, cells cannot rearrange due to shared cell walls. Thus, differentiation progression and the accompanying cell expansion must be tightly coordinated across tissues. PLETHORA (PLT) transcription factor gradients are unique in their ability to guide the progression of cell differentiation at different positions in the growing Arabidopsis root, which contrasts with well-described transcription factor gradients in animals specifying distinct cell fates within an essentially static context. To understand the output of the PLT gradient, we studied the gene set transcriptionally controlled by PLTs. Our work reveals how the PLT gradient can regulate cell state by region-specific induction of cell proliferation genes and repression of differentiation. Moreover, PLT targets include major patterning genes and autoregulatory feedback components, enforcing their role as master regulators of organ development.
PKR mediates inflammatory response induced by hyperosmotic stress.Tuesday, December 06, 2016
Farabaugh KT, Majumder M, Guan BJ, Jobava R, Wu J, Krokowski D, Gao XH, Schuster A, Longworth M, Chan ED, Bianchi M, Dey M, Koromilas AE, Ramakrishnan P, Hatzoglou M,
Molecular and cellular biology. 05-Dec-2016
High extracellular osmolarity results in a switch from an adaptive to an inflammatory gene expression program. We show that hyperosmotic stress activates the protein kinase R (PKR) independently of its RNA binding domain. In turn, PKR stimulated nuclear accumulation of nuclear factor-κB (NF-κB) p65 species phosphorylated at serine-536, which was paralleled by the induction of a subset of inflammatory NF-κB p65- responsive genes including inducible nitric oxide synthase (iNOS), IL-6, and IL-1β. The PKR mediated-hyperinduction of iNOS decreased cell survival in mouse embryonic fibroblasts via mechanisms involving nitric oxide (NO) synthesis and post-translational modification of proteins. Moreover, we demonstrate that the PKR inhibitor C16 ameliorates both iNOS amplification and disease-induced phenotypic breakdown of the intestinal epithelial barrier caused by an increase in extracellular osmolarity induced by dextran sodium sulfate (DSS) in vivo Collectively, these findings indicate that PKR activation is an essential part of the molecular switch from adaptation to inflammation in response to hyperosmotic stress.
Group I Paks promote skeletal myoblast differentiation in vivo and in vitro.Tuesday, December 06, 2016
Joseph GA, Lu M, Radu M, Lee JK, Burden SJ, Chernoff J, Krauss RS,
Molecular and cellular biology. 05-Dec-2016
Skeletal myogenesis is regulated by signal transduction, but the factors and mechanisms involved are not well understood. The group I Paks, Pak1 and Pak2, are related protein kinases and direct effectors of Cdc42 and Rac1. Group I Paks are ubiquitously expressed and specifically required for myoblast fusion in Drosophila We report that both Pak1 and Pak2 are activated during mammalian myoblast differentiation. One pathway of activation is initiated by N-cadherin ligation, and involves the cadherin co-receptor Cdo with its downstream effector, Cdc42. Individual genetic deletion of Pak1 and Pak2 in mice has no overt effect on skeletal muscle development or regeneration. However, combined muscle-specific deletion of Pak1 and Pak2 results in reduced muscle mass and a higher proportion of myofibers with smaller cross-sectional area. This phenotype is exacerbated after repair to acute injury. Furthermore, primary myoblasts lacking Pak1 and Pak2 display delayed expression of myogenic differentiation markers and myotube formation. These results identify Pak1 and Pak2 as redundant regulators of myoblast differentiation in vitro and in vivo and as components of the pro-myogenic Ncad/Cdo/Cdc42 signaling pathway.
Activation of D2 dopamine receptors in CD133+ve cancer stem cells in non-small cell lung carcinoma inhibits proliferation, clonogenic ability and invasiveness of these cells.Tuesday, December 06, 2016
Roy S, Lu K, Nayak MK, Bhuniya A, Ghosh T, Kundu S, Ghosh S, Baral R, Dasgupta PS, Basu S,
The Journal of biological chemistry. 05-Dec-2016
Lung carcinoma is the leading cause of cancer-related death worldwide, and among this cancer, non-small cell lung carcinoma (NSCLC) comprises the majority of cases. Furthermore, recurrence and metastasis of NSCLC correlate well with CD133+ve tumor cells, a small population of tumor cells, which has been designated as cancer stem cells (CSC). We here for the first time have demonstrated high expression of D2 dopamine (DA) receptors in CD133+ve adenocarcinoma NSCLC cells. Also, activation of D2 DA receptors in these cells significantly inhibited their proliferation, clonogenic ability and invasiveness by suppressing extracellular-signal-regulated kinases 1/2 (ERK1/2) and AKT, downregulation of octamer-binding transcription factor 4 (Oct-4) expression and matrix metalloproteinase-9 (MMP-9) secretion by these cells. These results are of significance as D2 DA agonists which are already in clinical use for treatment of other diseases may be useful in combination with conventional chemotherapy and radiotherapy for better management of NSCLC patients by targeting both tumor cells and stem cell compartment in the tumor mass. .
Regulation of turkey myogenic satellite cell migration by MicroRNAs miR-128 and miR-24.Tuesday, December 06, 2016
Velleman SG, Harding RL,
Poultry science. 05-Dec-2016
Myogenic satellite cells are an adult stem cell responsible for all post-hatch muscle growth in poultry. As a stem cell population, satellite cells are highly heterogeneous, but the origin of this heterogeneity remains unclear. Heterogeneity is, in part, regulated by gene expression. One method of endogenous gene regulation that may contribute to heterogeneity is microRNAs (miRNAs). Two miRNAs previously shown to regulate poultry myogenic satellite cell proliferation and differentiation, miR-128 and miR-24, were studied to determine if they also affected satellite cell migration. Satellite cell migration is an essential step for both proliferation and differentiation. During proliferation, satellite cells will migrate and align to form new myofibers or donate their nuclei to existing myofibers leading to muscle fiber hypertrophy or regeneration. Transient transfection of miRNA specific mimics to each miRNA reduced migration of satellite cells following a cell culture scratch at 72 h of proliferation when the cultures were 90 to 100% confluent. However, only the migration in cells transfected with miR-24 mimics at 24 and 30 h following the scratch was significantly reduced (P ≤ 0.05) to around 70% of the distance migrated by controls. Alternately, transfection with inhibitors specific to miR-128 or miR-24 significantly (P ≤ 0.05) increased migration between 147 and 252% compared to their controls between 24 and 48 h following the scratch. These data demonstrate that miR-128 and miR-24 play a role in myogenic satellite cell migration, which will impact muscle development and growth.
Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events.Tuesday, December 06, 2016
Parisi S, Passaro F, Russo L, Musto A, Navarra A, Romano S, Petrosino G, Russo T,
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 05-Dec-2016
Lin28 RNA-binding proteins play important roles in pluripotent stem cells, but the regulation of their expression and the mechanisms underlying their functions are still not definitively understood. Here we address the above-mentioned issues in the first steps of mouse embryonic stem cell (ESC) differentiation. We observed that the expression of Lin28 genes is transiently induced soon after the exit of ESCs from the naive ground state and that this induction is due to the Hmga2-dependent engagement of Otx2 with enhancers present at both Lin28 gene loci. These mechanisms are crucial for Lin28 regulation, as demonstrated by the abolishment of the Lin28 accumulation in Otx2 or Hmga2 knockout cells compared to the control cells. We have also found that Lin28 controls Hmga2 expression levels during ESC differentiation through a let-7-independent mechanism. Indeed, we found that Lin28 proteins bind a highly conserved element in the 3' UTR of Hmga2 mRNA, and this provokes a down-regulation of its translation. This mechanism prevents the inappropriate accumulation of Hmga2 that would modify the proliferation and physiological apoptosis of differentiating ESCs. In summary, we demonstrated that during ESC differentiation, Lin28 transient induction is dependent on Otx2 and Hmga2 and prevents an inappropriate excessive rise of Hmga2 levels.-Parisi, S., Passaro, F., Russo, L., Musto, A., Navarra, A., Romano, S., Petrosino, G., Russo, T. Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events.
Methyl-CpG binding protein MBD1 regulates neuronal lineage commitment through maintaining adult neural stem cell identity.Tuesday, December 06, 2016
Jobe EM, Gao Y, Eisinger BE, Mladucky JK, Giuliani CC, Kelnhofer LE, Zhao X,
The Journal of neuroscience : the official journal of the Society for Neuroscience. 05-Dec-2016
Adult neural stem cells (aNSCs) in the hippocampus self-renew and generate neurons throughout life. We show that MBD1, a DNA methylation "reader", is important for maintaining the integrity of NSCs, which is critical for their neurogenic potency. Our data reveal a novel role for MBD1 in stem cell maintenance and provide insight into how epigenetic regulation preserves the multipotency of stem cells for subsequent differentiation.
SUV4-20 activity in the preimplantation mouse embryo controls timely replication.Tuesday, December 06, 2016
Eid A, Rodriguez-Terrones D, Burton A, Torres-Padilla ME,
Genes & development. 05-Dec-2016
Extensive chromatin remodeling after fertilization is thought to take place to allow a new developmental program to start. This includes dynamic changes in histone methylation and, in particular, the remodeling of constitutive heterochromatic marks such as histone H4 Lys20 trimethylation (H4K20me3). While the essential function of H4K20me1 in preimplantation mouse embryos is well established, the role of the additional H4K20 methylation states through the action of the SUV4-20 methyltransferases has not been addressed. Here we show that Suv4-20h1/h2 are mostly absent in mouse embryos before implantation, underscoring a rapid decrease of H4K20me3 from the two-cell stage onward. We addressed the functional significance of this remodeling by introducing Suv4-20h1 and Suv4-20h2 in early embryos. Ectopic expression of Suv4-20h2 leads to sustained levels of H4K20me3, developmental arrest, and defects in S-phase progression. The developmental phenotype can be partially overcome through inhibition of the ATR pathway, suggesting that the main function for the remodeling of H4K20me3 after fertilization is to allow the timely and coordinated progression of replication. This is in contrast to the replication program in somatic cells, where H4K20me3 has been shown to promote replication origin licensing, and anticipates a different regulation of replication during this early developmental time window.
A role for mitotic bookmarking of SOX2 in pluripotency and differentiation.Tuesday, December 06, 2016
Deluz C, Friman ET, Strebinger D, Benke A, Raccaud M, Callegari A, Leleu M, Manley S, Suter DM,
Genes & development. 05-Dec-2016
Mitotic bookmarking transcription factors remain bound to chromosomes during mitosis and were proposed to regulate phenotypic maintenance of stem and progenitor cells at the mitosis-to-G1 (M-G1) transition. However, mitotic bookmarking remains largely unexplored in most stem cell types, and its functional relevance for cell fate decisions remains unclear. Here we screened for mitotic chromosome binding within the pluripotency network of embryonic stem (ES) cells and show that SOX2 and OCT4 remain bound to mitotic chromatin through their respective DNA-binding domains. Dynamic characterization using photobleaching-based methods and single-molecule imaging revealed quantitatively similar specific DNA interactions, but different nonspecific DNA interactions, of SOX2 and OCT4 with mitotic chromatin. Using ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) to assess the genome-wide distribution of SOX2 on mitotic chromatin, we demonstrate the bookmarking activity of SOX2 on a small set of genes. Finally, we investigated the function of SOX2 mitotic bookmarking in cell fate decisions and show that its absence at the M-G1 transition impairs pluripotency maintenance and abrogates its ability to induce neuroectodermal differentiation but does not affect reprogramming efficiency toward induced pluripotent stem cells. Our study demonstrates the mitotic bookmarking property of SOX2 and reveals its functional importance in pluripotency maintenance and ES cell differentiation.
The Transcellular Propagation and Intracellular Trafficking of α-Synuclein.Tuesday, December 06, 2016
Tofaris GK, Goedert M, Spillantini MG,
Cold Spring Harbor perspectives in medicine. 05-Dec-2016
Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals. Here, we discuss the transcellular propagation and intracellular trafficking of α-synuclein and posit that endosomal processing could be a point of convergence between these two routes. Understanding these events will clarify the therapeutic potential of enzymes that regulate protein trafficking and degradation in synucleinopathies.
Dietary Flavonoids Luteolin and Quercetin Suppressed Cancer Stem Cell Properties and Metastatic Potential of Isolated Prostate Cancer Cells.Tuesday, December 06, 2016
Tsai PH, Cheng CH, Lin CY, Huang YT, Lee LT, Kandaswami CC, Lin YC, Lee KP, Hung CC, Hwang JJ, Ke FC, Chang GD, Lee MT,
Anticancer research. Dec-2016
A highly invasive Du145-III subline was isolated by three successive passages of the parental Du145 prostate tumor cell line (Du145-P) through a Boyden chamber with matrigel-coated membrane support. Du145-III cells showed great invasion potential based on their increased ability to spread/migrate and enhanced expression/secretion of the matrix metalloproteinase 9 (MMP9). Du145-III cells exerted vasculogenic mimicry (VM) properties, reminiscent of endothelial cell characteristics and expressed elevated levels of cancer stem cell (CSC) markers, including Nanog, Sox2, CD44 and ABCG2 and ability to self-renew. Of prominence, MMP9 was required for the induction of VM and for increased stemness in Du145-III cells. Using Du145-III as a model, the effects of dietary flavonoids, luteolin and quercetin, were evaluated on stemness and invasion capacity of Du145-III cells in relation to JNK signaling pathway activation. These flavonoids depressed the malignancy of highly invasive Du145-III cells, VM, anchorage-independent spheroid formation and expression of certain CSC markers. Since luteolin and quercetin were able to target CSC cells and prevent cancer cell invasiveness, may serve as potential anti-angiogenesis and anti-metastasis agents.
Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine.Tuesday, December 06, 2016
Takeda H, Okada M, Suzuki S, Kuramoto K, Sakaki H, Watarai H, Sanomachi T, Seino S, Yoshioka T, Kitanaka C,
Anticancer research. Dec-2016
Small molecule inhibitor-mediated targeting of ROCK may be a viable strategy to overcome cancer chemoresistance through down-regulation of survivin.
Ectopic Myoglobin Expression Is Associated with a Favourable Outcome in Head and Neck Squamous Cell Carcinoma Patients.Tuesday, December 06, 2016
Meller S, VAN Ellen A, Gevensleben H, Bicker A, Hankeln T, Gorr TA, Sailer V, Dröge F, Schröck F, Bootz F, Schröck A, Perner S, Dietrich D, Kristiansen G,
Anticancer research. Dec-2016
MB is differentially expressed in HNSCC and correlates with a better OS.
Intraportal mesenchymal stem cell transplantation prevents acute liver failure through promoting cell proliferation and inhibiting apoptosis.Tuesday, December 06, 2016
Sang JF, Shi XL, Han B, Huang T, Huang X, Ren HZ, Ding YT,
Hepatobiliary & pancreatic diseases international : HBPD INT. Dec-2016
Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC transplantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.
Heparin-hyaluronic acid hydrogel for efficient cellular activities of 3D encapsulated adipose derived stem cells.Tuesday, December 06, 2016
Gwon K, Kim E, Tae G,
Acta biomaterialia. 02-Dec-2016
We have developed stem cell-responsive, heparin-hyaluronic acid (Hep-HA) hydrogel, crosslinked by thiolated heparin (Hep-SH) and methacrylated hyaluronic acid (HA-MA) via visible light mediated, thiol-ene reaction. Physical properties of the hydrogel (gelation time, storage modulus, and swelling ratio) were tunable by adjusting light intensity, initiator/polymer concentration, and precursor pH. Culture of human adipose derived mesenchymal stem cells (ADSCs) using this hydrogel was characterized and compared with the control hydrogels including Hep-PEG hydrogel, PEG-HA hydrogel. Sufficient initial adhesion and continuous proliferation of ADSCs in 2D were observed on both heparin-containing hydrogels (Hep-HA and Hep-PEG hydrogel) in contrast to no adhesion of ADSCs on PEG-HA hydrogel. On the other hand, in the case of 3D culture of encapsulated ADSCs, efficient cellular activities such as spreading, proliferation, migration, and differentiation of ADSCs were only observed in soft Hep-HA hydrogel compared to Hep-PEG or PEG-HA hydrogel with the similar modulus. The upregulated expressions of hyaluronidases in ADSCs encapsulated in Hep-HA hydrogel compared to the control hydrogels and effective degradation of the hydrogel by hyaluronidase imply that the degradation of hydrogel was necessary for 3D cellular activities. Thus, Hep-HA hydrogel, where heparin acts as a binding domain for ADSCs and HA acts as a degradation site by cell secreted enzymes, was efficient for 3D culture of human ADSCs without any additional modification using biological/chemical molecules. [STATEMENT OF SIGNIFICANCE]: Stem cell-responsive hydrogel composed of heparin and hyaluronic acid was prepared by visible light-mediated thiol-ene reaction. Without additional modification using functional peptides for cell adhesion and matrix degradation, ADSCs encapsulated in this hydrogel showed efficient cellular activities such as spreading, proliferation, migration, and differentiation of ADSCs whereas control hydrogels missing heparin or hyaluronic acid could not support cellular activities in 3D. In this hydrogel, heparin mainly acts as a binding domain for stem cells and hyaluronic acid mainly acts as a degradation site by ADSC secreted enzymes, but interrelated synergistic functions of heparin and HA were observed. Therefore, we speculate that this hydrogel can serve as a promising carrier for stem cell based therapy and various tissue engineering applications.
Germ cell proliferation and cluster behavior in ovarioles of Sialis flavilatera (Megaloptera: Sialidae) during larval growth.Tuesday, December 06, 2016
Rübsam R, Büning J,
Arthropod structure & development. 02-Dec-2016
Telotrophic meroistic insect ovaries are assigned to four different types. The Sialis type is found in Sialidae (Megaloptera), Raphidioptera and a coleopteran subgroup (Myxophaga: Hydroscaphidae). King and Büning (1985) proposed a hypothetical model for the development of this ovariole type, a detailed description of ovarian development in Sialis was missing so far. Using light and electron microscopy, we investigated developing ovaries of Sialis flavilatera starting in the 10(th) month of the biennial larval phase until adulthood. At least from the 10(th) month onwards, a Sialis ovariole anlage contains a single germ cell syncytium, whose growth is promoted by a mitotic cell population maintained in its anterior compartment. The stem-like, dividing germ cells form synchronous sub-clusters consisting of 2-16 cystocytes, which are spatially arranged in bigger rosettes that stay connected to each other via cytoplasmic tubes. Within individual rosettes, cells communicate by centrally gathering intercellular bridges. Following each round of cystocyte division and subsequent rosette formation, plasma membrane wrinkles sprout near newborn bridges, elongate, and interdigitate with the preexisting membrane tubes. In this way the membrane labyrinth emerges and grows. Germ cells leaving the proliferation zone posteriorly enter meiotic prophase. Hypotheses on the phylogenetic origin of this ovary type are discussed in the light of our results.
Folic acid-capped PEGylated magnetic nanoparticles enter cancer cells mostly via clathrin-dependent endocytosis.Tuesday, December 06, 2016
Allard-Vannier E, Hervé-Aubert K, Kaaki K, Blondy T, Shebanova A, Shaitan KV, Ignatova AA, Saboungi ML, Feofanov AV, Chourpa I,
Biochimica et biophysica acta. 02-Dec-2016
Composition, magnetic and optical properties of the SFP-FA as well their ability to enter cancer cells are promising for their applications in cancer theranosis. Combination of complementary analytical approaches is relevant to understand the nanoparticles behavior in suspension and in contact with cells.
The bad seed gardener: Deubiquitinases in the cancer stem-cell signaling network and therapeutic resistance.Tuesday, December 06, 2016
Qiu GZ, Sun W, Jin MZ, Lin J, Lu PG, Jin WL,
Pharmacology & therapeutics. 02-Dec-2016
Tumors are comprised of highly heterogeneous populations of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These rare cancer stem cells (CSCs) have been regarded as the "bad seeds" accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. CSC-targeted therapy seems to be a better avenue for radical cure of cancer. Deubiquitinases (DUBs), specifically disassembling ubiquitin chains, have been demonstrated to play an important role in rigidly maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis in normal circumstances. Dysfunction or deregulation of DUBs always leads to a series of disorders, even malignant transformation. Despite the accumulative evidence that DUB inhibitors in cancer remedy mainly target the tumor bulk, side effects like toxicity and resistance are still hard nuts to crack. In this article, we review the concept of ubiquitin proteasome system (UPS) and hallmarks of CSCs related to tumor obstinacy. We primarily summarize the CSC-related factors and signaling pathways and focus on the function of DUBs on biological traits of CSCs. We also illustrate the opportunities and challenges for the application of DUB inhibitors in the CSC-targeted therapy. Finally, we discuss the complexity of cancer stem cell hierarchy complexity and argue that a combination therapy for both CSCs and non-CSCs should be a desirable option.
The potential of induced pluripotent stem cells as a tool to study skeletal dysplasias and cartilage-related pathologic conditions.Tuesday, December 06, 2016
Liu H, Yang L, Yu FF, Wang S, Wu C, Qu C, Guo X, Lammi MJ,
Osteoarthritis and cartilage. 02-Dec-2016
The development of induced pluripotent stem cells (iPSCs) technology has opened up new horizons for development of new research tools especially for skeletal dysplasias, which often lack human disease models. Regenerative medicine and tissue engineering could be the next areas to benefit from refinement of iPSC methods to repair focal cartilage defects, while applications for osteoarthritis (OA) and drug screening have evolved rather slowly. Although the advances in iPSC research of skeletal dysplasias and repair of focal cartilage lesions are not directly relevant to OA, they can be considered to pave the way to future prospects and solutions to OA research, too. The same problems which face the present cell-based treatments of cartilage injuries concern also the iPSC-based ones. However, established iPSC lines, which have no genomic aberrations and which efficiently differentiate into extracellular matrix secreting chondrocytes, could be an invaluable cell source for cell transplantations in the future. The safety issues concerning the recipient risks of teratoma formation and immune response still have to be solved before the potential use of iPSCs in cartilage repair of focal cartilage defects and OA.
Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer.Tuesday, December 06, 2016
Li T, Piperdi B, Walsh WV, Kim M, Beckett LA, Gucalp R, Haigentz M, Bathini VG, Wen H, Zhou K, Pasquinelli PB, Gajavelli S, Sreedhara M, Xie X, Lara PN, Gandara DR, Perez-Soler R,
Clinical lung cancer. 28-Oct-2016
In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.
Targeted delivery of glucocorticoids to macrophages in a mouse model of multiple sclerosis using inorganic-organic hybrid nanoparticles.Tuesday, December 06, 2016
Montes-Cobos E, Ring S, Fischer HJ, Heck J, Strauß J, Schwaninger M, Reichardt SD, Feldmann C, Lühder F, Reichardt HM,
Journal of controlled release : official journal of the Controlled Release Society. 02-Dec-2016
Glucocorticoids (GC) are widely used to treat acute relapses in multiple sclerosis (MS) patients, but their application is accompanied by side effects due to their broad spectrum of action. Here, we report on the therapeutic option to apply GC via inorganic-organic hybrid nanoparticles (IOH-NP) with the composition [ZrO](2+)[(BMP)0.9(FMN)0.1](2-) (designated BMP-NP with BMP: betamethasone phosphate; FMN: flavinmononucleotide). We found that these BMP-NP have an increased cell type-specificity compared to free GC while retaining full therapeutic efficacy in a mouse model of MS. BMP-NP were preferentially taken up by phagocytic cells and modulated macrophages in vivo more efficiently than T cells. When GC were applied in the form of BMP-NP, treatment of neuroinflammatory disease in mice exclusively depended on the control of macrophage function whereas effects on T cells and brain endothelial cells were dispensable for therapeutic efficacy. Importantly, BMP-NP were not only active in mice but also showed strong activity towards monocytes isolated from healthy human volunteers. We conclude that application of GC via IOH-NP has the potential to improve MS therapy in the future.
Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer with amide-conjugated biotin, a potential carrier of anticancer drugs.Tuesday, December 06, 2016
Uram Ł, Szuster M, Filipowicz A, Zaręba M, Wałajtys-Rode E, Wołowiec S,
Bioorganic & medicinal chemistry. 25-Nov-2016
In search for soluble derivatives of PAMAM dendrimers as potential carriers for hydrophobic drugs, the conjugates of PAMAM G3 with biotin, further converted into glycodendrimer with d-glucoheptono-1,4-lactone, were prepared. Polyamidoamine dendrimer (PAMAM) of third generation, G3 was functionalized with four biotin equivalents covalently attached to terminal amine nitrogens via amide bond G3(4B). The remaining 28 amine groups were blocked by glucoheptoamide substituents (gh) to give G3(4B28gh) or with one fluorescein equivalent (attached by reaction of G3(4B) with fluorescein isothiocyanate, FITC) via thiourea bond as FITC followed by exhaustive glucoheptoamidation to get G3(4B27gh1F). As a control the G3 substituted totally with 32 glucoheptoamide residues, G3(gh) and its fluorescein labeled analogue G3(31gh1F) were synthesized. The glucoheptoamidation of PAMAM G0 dendrimer with glucoheptono-1,4-lactone was performed in order to fully characterize the (1)H NMR spectra of glucoheptoamidated PAMAM dendrimers and to control the derivatization of G3 with glucoheptono-1,4-lactone. Another two derivatives of G3, namely G3(4B28gh1F') and G3(32ghF'), with ester bonded fluorescein were also obtained. Biological properties of obtained dendrimer conjugates were estimated in vitro with human cell lines: normal fibroblast (BJ) and two cancer glioblastoma (U-118 MG) and squamous carcinoma (SCC-15), including cytotoxicity by reduction of XTT and neutral red (NR) assays. Cellular uptake of dendrimer conjugates was evaluated with confocal microscopy. Obtained results confirmed, that biotinylated bioconjugates have always lower cytotoxicity and 3-4 times higher cellular uptake than non-biotinylated dendrimer conjugates in all cell lines. Comparison of various cell lines revealed different dose-dependent cell responses and the lower cytotoxicity of examined dendrimer conjugates for normal fibroblasts and squamous carcinoma, as compared with much higher cytotoxic effects seen in glioblastoma cell line. Synthetized multi-functional conjugate (G3(4B27gh1F)) is a promising candidate as biocompatible vehicle for hydrophobic molecules used in anticancer therapy.
Non-fucosylated CB CD34(+) cells represent a good target for enforced fucosylation to improve engraftment following cord blood transplantation.Tuesday, December 06, 2016
Robinson SN, Thomas MW, Simmons PJ, Lu J, Yang H, Javni JA, Shpall EJ, Zweidler-Mckay PA,
Cytotherapy. 02-Dec-2016
The majority of endogenously non-fucosylated CB HSPCs represent a good target for enforced fucosylation with the goal of improving engraftment following CB transplantation.
Nonsteroidal anti-inflammatory drugs may affect cytokine response and benefit healing of combat-related extremity wounds.Tuesday, December 06, 2016
Lisboa FA, Bradley MJ, Hueman MT, Schobel SA, Gaucher BJ, Styrmisdottir EL, Potter BK, Forsberg JA, Elster EA,
Surgery. 02-Dec-2016
Treatment with nonsteroidal anti-inflammatory drugs for postoperative pain management after major combat-related extremity trauma is associated with lesser concentrations of inflammatory cytokines and may contribute to a more favorable inflammatory response leading to successful wound healing.
Effective production of recipient male pigs for spermatogonial stem cell transplantation by intratesticular injection with busulfan.Tuesday, December 06, 2016
Lin Z, Bao J, Kong Q, Bai Y, Luo F, Songyang Z, Wu Y, Huang J,
Theriogenology. 01-Nov-2016
Germ cell transplantation has facilitated spermatogonial stem cell (SSC) and spermatogenesis research and shown great potential in the seed-breeding of domestic livestock. However, little progress has been made in large animals, primarily reflecting the difficulties in preparing sterile recipients. Here, we developed a novel protocol to prepare recipient pigs through the direct injection of busulfan into the cavum vaginale of the scrotums of Landrace-Large bi-crossbreeding male pigs and Seghers male pigs, two economically-important types of pigs, to eliminate endogenous spermatogonia. No severe diseases or weight loss was observed in either pig type after the injection with busulfan. Histologic analysis showed an advanced and dose-dependent germ cell loss, with complete germ cell loss observed in the highest dose group, 3.0 mg/kg in the Landrace-Large bi-crossbreeding pigs and 2.0 mg/kg in the Seghers pigs. A smaller seminiferous tubule diameter, a vacuolized seminiferous epithelium and the overproliferation interstitial cells, frequently observed in mouse germ cell deficiency models, were present in the most of the high-dose busulfan-treated groups. Molecular markers detected in Seghers pigs further confirmed the depletion of endogenous germ cells, providing an accessible niche for exogenous SSCs. This study provides a basis to prepare the transplantation recipients of SSCs in pigs.
Human epidermal stem cells: Role in adverse skin reactions and carcinogenesis from radiation.Tuesday, December 06, 2016
Martin MT, Vulin A, Hendry JH,
Mutation research. 01-11-2016
In human skin, keratinopoiesis is based on a functional hierarchy among keratinocytes, with rare slow-cycling stem cells responsible for the long-term maintenance of the tissue through their self-renewal potential, and more differentiated daughter progenitor cells actively cycling to permit epidermal renewal and turn-over every month. Skin is a radio-responsive tissue, developing all types of radiation damage and pathologies, including early tissue reactions such as dysplasia and denudation in epidermis, and later fibrosis in the dermis and acanthosis in epidermis, with the TGF-beta 1 pathway as a known master switch. Also there is a risk of basal cell carcinoma, which arises from epidermal keratinocytes, notably after oncogenic events in PTCH1 or TP53 genes. This review will cover the mechanisms of adverse human skin reactions and carcinogenesis after various types of exposures to ionizing radiation, with comparison with animal data when necessary, and will discuss the possible role of stem cells and their progeny in the development of these disorders. The main endpoints presented are basal cell intrinsic radiosensitivity, genomic stability, individual factors of risk, dose specific responses, major molecular pathways involved and the cellular origin of skin reactions and cancer. Although major advances have been obtained in recent years, the precise implications of epidermal stem cells and their progeny in these processes are not yet fully characterized.
Consequences of irradiation on adult spermatogenesis: Between infertility and hereditary risk.Tuesday, December 06, 2016
Marjault HB, Allemand I,
Mutation research. 17-08-2016
DNA damage response in adult spermatogenic cells should limit the propagation of mutations to the offspring, without being detrimental to fertility. In differentiating spermatogenic cells, the genomic instability is limited in time, whereas in spermatogonial stem cells it can be maintained all along life. Spermatogonial stem cells are long-lived cells that support normal germ cell differentiation and must be preserved throughout life. However after irradiation spermatogenesis recovery can be impaired as a consequence of the radiation-induced decline in spermatogonial stem cell. In this review, we summarize the differential sensitivities to DNA damage of spermatogenic cell populations, and the DNA repair mechanisms activated in these cells that paradoxically might favour the maintenance of cells with impaired genomic integrity. We describe how the testis tissue collapses in response to irradiation and we discuss the molecular pathways involved in the control of DNA damage response and homeostasis in spermatogonial stem cells.
The role of gene mutations and gene products in intestinal tissue reactions from ionising radiation.Tuesday, December 06, 2016
Hendry JH, Otsuka K,
Mutation research. 19-07-2016
The response of the intestine to (low linear-energy-transfer) ionising radiation is reviewed regarding the cellular basis to the reactions, the regenerative processes which restore the tissue, and external agents which aid its recovery. In the steady-state, it is generally considered that the crypt cell lineages in both small and large intestine are maintained by a small number of stem cells, but there are differences for example in the composition of their niche residence and in the numbers of transit cell generations. Various cell surface markers are now available to indentify particular lineage cell types. Radiation doses up to 1Gy cause apoptotic stem-cell death in particular locations, at higher doses to >6Gy Lgr5(+) stem cells are required for normal intestinal recovery, and at >8Gy some crypts are sterilised and the probability of animal death from intestinal injury increases with higher doses. Mutations in repair genes, tumour suppressor genes, and survival genes cause various degrees of stem cell and clonogenic cell radiosensitisation. Recent evidence is suggesting much plasticity in the crypt cell lineage, potentially contributing to flexibility in the hierarchical lineage, clonogen number variations and the sensitisation differences. Knockout mice for many different genes have been used to detect their role in both steady state and in irradiated conditions, expected to lead to further insight to the damage and restorative processes. Many different external agents have been used to ameliorate intestinal reactions, including prostaglandins, interleukins, angiogenic and epithelial growth factors, other cytokines, and intraluminal factors.
Effects of ionizing radiation on the heart.Tuesday, December 06, 2016
Boerma M, Sridharan V, Mao XW, Nelson GA, Cheema AK, Koturbash I, Singh SP, Tackett AJ, Hauer-Jensen M,
Mutation research. 22-07-2016
This article provides an overview of studies addressing effects of ionizing radiation on the heart. Clinical studies have identified early and late manifestations of radiation-induced heart disease, a side effect of radiation therapy to tumors in the chest when all or part of the heart is situated in the radiation field. Studies in preclinical animal models have contributed to our understanding of the mechanisms by which radiation may injure the heart. More recent observations in human subjects suggest that ionizing radiation may have cardiovascular effects at lower doses than was previously thought. This has led to examinations of low-dose photons and low-dose charged particle irradiation in animal models. Lastly, studies have started to identify non-invasive methods for detection of cardiac radiation injury and interventions that may prevent or mitigate these adverse effects. Altogether, this ongoing research should increase our knowledge of biological mechanisms of cardiovascular radiation injury, identify non-invasive biomarkers for early detection, and potential interventions that may prevent or mitigate these adverse effects.
Tissue reactions to ionizing radiation-Oral mucosa.Tuesday, December 06, 2016
Gruber S, Dörr W,
Mutation research. 10-07-2016
Radiotherapy is one of the most effective treatment strategies for solid malignancies, including head-and-neck tumors (HNT). Oral mucositis is the most frequent, often dose-limiting early adverse event of radio(chemo)therapy for HNT. The oral mucosal response is - like that of typical turnover tissues - based on radiation-induced impairment of epithelial proliferation and cell production, in face of ongoing physiological cell differentiation and cell loss, consequently resulting in hypoplasia and eventually mucosal ulceration. The regenerative epithelial response, i.e. repopulation, and hence the impact of overall treatment time, besides intrinsic radiosensitivity, is the dominant parameter of the radiation tolerance of oral mucosa in fractionated radiotherapy protocols. The epithelial changes are accompanied, at the molecular and cellular level, by various changes in non-epithelial cell populations, i.e. vascular endothelial cells, macrophages, and fibroblasts. An inflammatory response precedes and parallels the epithelial changes; this includes vasodilation associated with rheological consequences and the manifestation of local hypoxia, activation of macrophages and endothelial cells. During these processes, a variety of intra- and intercellular communication pathways are modulated; NF-κB associated signaling is one prominent example. The interactions of these extra-epithelial changes with epithelial hypoplasia, ulceration and regeneration currently remain largely unclear. Research on the molecular mechanisms underlying the clinical manifestation of oral mucositis will allow for identification of potential early biomarkers of oral mucosal morbidity and thus for individualization of patient follow-up and treatment, and also for the development of targeted strategies for prophylaxis and/or mitigation of oral mucositis. This review summarizes the features of the clinical manifestation of oral mucositis and its consequences, the "classical" radiobiological parameters of mucosal radiation sensitivity. It moreover focuses on the underlying "molecular" mechanisms, and on biology-based approaches for the amelioration of radiation-induced oral mucositis.
Effects of ionizing radiation on the mammalian brain.Tuesday, December 06, 2016
Hladik D, Tapio S,
Mutation research. 25-07-2016
Epidemiological studies on the atomic-bomb survivors, cancer survivors and occupational cohorts provide strong evidence for multifaceted damage to brain after ionizing radiation. Radiation-induced late effects may manifest as brain tumors or cognitive impairment. Decreased neurogenesis and differentiation, alteration in neural structure and synaptic plasticity as well as increased oxidative stress and inflammation are suggested to contribute to adverse effects in the brain. In addition to neural stems cells, several brain-specific mature cell types including endothelial and glial cells are negatively affected by ionizing radiation. Radiation-induced enhancement of endothelial cell apoptosis results in disruption of the vascular system and the blood brain barrier. Activated microglia create inflammatory environment that negatively affects neuronal structures and results in decreased synaptic plasticity. Although the molecular mechanisms involved in radiation-induced brain injury remain elusive, first strategies for prevention and amelioration are being developed. Drug-based prevention and treatment focus mainly on the inhibition of oxidative stress and inflammation. Cell replacement therapy holds great promise as first animal studies using transplantation of neural stem cells to irradiated brain have been successful in restoring memory and cognition deficits. This review summarizes the epidemiological and biological data on radiation-induced brain damage and describes prevention and therapy methods to avoid and ameliorate these adverse effects, respectively.
Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides.Tuesday, December 06, 2016
Hallier B, Schiemann R, Cordes E, Vitos-Faleato J, Walter S, Heinisch JJ, Malmendal A, Paululat A, Meyer H,
eLife. 06-Dec-2016
Insulin and IGF signaling are critical to numerous developmental and physiological processes, with perturbations being pathognomonic of various diseases, including diabetes. Although the functional roles of the respective signaling pathways have been extensively studied, the control of insulin production and release is only partially understood. Herein, we show that in Drosophila expression of insulin-like peptides is regulated by neprilysin activity. Concomitant phenotypes of altered neprilysin expression included impaired food intake, reduced body size, and characteristic changes in the metabolite composition. Ectopic expression of a catalytically inactive mutant did not elicit any of the phenotypes, which confirms abnormal peptide hydrolysis as a causative factor. A screen for corresponding substrates of the neprilysin identified distinct peptides that regulate insulin-like peptide expression, feeding behavior, or both. The high functional conservation of neprilysins and their substrates renders the characterized principles applicable to numerous species, including higher eukaryotes and humans.
Derivation of chicken induced pluripotent stem cells tolerant to Newcastle disease virus-induced lysis through multiple rounds of infection.Tuesday, December 06, 2016
Susta L, He Y, Hutcheson JM, Lu Y, West FD, Stice SL, Yu P, Abdo Z, Afonso CL,
Virology journal. 05-Dec-2016
Results demonstrate that ciPSCs are permissive to NDV infection and become increasingly tolerant to NDV under selective pressure, indicating that this system could be applied to study mechanisms of cellular tolerance to NDV.
The unbuilt environment: culture moderates the built environment for physical activity.Tuesday, December 06, 2016
Perrin AJ, Caren N, Skinner AC, Odulana A, Perrin EM,
BMC public health. 05-Dec-2016
Even when PA opportunities existed in this rural county, they were rarely used. This may be the result of culture ("unbuilt environment") that disfavors physical activity even in the presence of features that allow it. Policies promoting built environments designed for healthy lifestyles should consider local culture (shared styles, skills, habits, and beliefs) to maximize positive outcomes.
Perspectives of the AMP-activated kinase (AMPK) signalling pathway in thyroid cancer.Monday, December 05, 2016
Andrade BM, de Carvalho DP,
Bioscience reports. 01-Apr-2014
Approximately 90% of non-medullary thyroid malignancies originate from the follicular cell and are classified as papillary or follicular (well-differentiated) thyroid carcinomas, showing an overall favourable prognosis. However, recurrence or persistence of the disease occurs in some cases associated with the presence of loco-regional or distant metastatic lesions that generally become resistant to radioiodine therapy, while glucose uptake and metabolism are increased. Recent advances in the field of tumor progression have shown that CTC (circulating tumour cells) are metabolic and genetically heterogeneous. There is now special interest in unravelling the mechanisms that allow the reminiscence of dormant tumour lesions that might be related to late disease progression and increased risk of recurrence. AMPK (AMP-activated protein kinase) is activated by the depletion in cellular energy levels and allows adaptive changes in cell metabolism that are fundamental for cell survival in a stressful environment; nevertheless, the activation of this kinase also decreases cell proliferation rate and induces tumour cell apoptosis. In the thyroid field, AMPK emerged as a novel important intracellular pathway, since it regulates both iodide and glucose uptakes in normal thyroid cells. Furthermore, it has recently been demonstrated that the AMPK pathway is highly activated in papillary thyroid carcinomas, although the clinical significance of these findings remains elusive. Herein we review the current knowledge about the role of AMPK activation in thyroid physiology and pathophysiology, with special focus on thyroid cancer.
Establishment and biological characterization of a dermal mesenchymal stem cells line from bovine.Monday, December 05, 2016
Sun T, Yu C, Gao Y, Zhao C, Hua J, Cai L, Guan W, Ma Y,
Bioscience reports. 01-Apr-2014
The DMSCs (dermal mesenchymal stem cells) are multipotent stem cells, which can differentiate in vitro into many cell types. Much work has been done on DMSCs from humans, mice, rabbits and other mammals, but the related literature has not been published about these cells in cattle. In this study, we isolated and established the DMSC lines from cattle, thereby initiating further research on these cells, such as growth kinetics, detection of special surface antigen and RT-PCR (reverse transcription-PCR) assays to identify the biological characterization of the cell line. Furthermore, the DMSCs are induced to differentiate into adipocytes, osteoblasts and neural cells in vitro Our results suggest that DMSCs isolated from cattle possess similar biological characteristics with those from other species. Their multi-lineage differentiation capabilities herald a probable application model in tissue engineering and induced pluripotent stem cells.
Corrigendum: Lens regeneration using endogenous stem cells with gain of visual function.Monday, December 05, 2016
Lin H, Ouyang H, Zhu J, Huang S, Liu Z, Chen S, Cao G, Li G, Signer RA, Xu Y, Chung C, Zhang Y, Lin D, Patel S, Wu F, Cai H, Hou J, Wen C, Jafari M, Liu X, Luo L, Zhu J, Qiu A, Hou R, Chen B, Chen J, Granet D, Heichel C, Shang F, Li X, Krawczyk M, Skowronska-Krawczyk D, Wang Y, Shi W, Chen D, Zhong Z, Zhong S, Zhang L, Chen S, Morrison SJ, Maas RL, Zhang K, Liu Y,
Nature. 30-Nov-2016
Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.Monday, December 05, 2016
Schwörer S, Becker F, Feller C, Baig AH, Köber U, Henze H, Kraus JM, Xin B, Lechel A, Lipka DB, Varghese CS, Schmidt M, Rohs R, Aebersold R, Medina KL, Kestler HA, Neri F, von Maltzahn J, Tümpel S, Rudolph KL,
Nature. 30-Nov-2016
The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.
Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations.Monday, December 05, 2016
Kang E, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, Platero-Luengo A, Martinez-Redondo P, Ma H, Lee Y, Hayama T, Van Dyken C, Wang X, Luo S, Ahmed R, Li Y, Ji D, Kayali R, Cinnioglu C, Olson S, Jensen J, Battaglia D, Lee D, Wu D, Huang T, Wolf DP, Temiakov D, Belmonte JC, Amato P, Mitalipov S,
Nature. 30-Nov-2016
Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.
Stem cells: Aspiring to naivety.Monday, December 05, 2016
Sagi I, Benvenisty N,
Nature. 30-Nov-2016
Stem cells: Cause and consequence in aged-muscle decline.Monday, December 05, 2016
Eliazer S, Brack AS,
Nature. 30-Nov-2016
Specificity protein 1-zinc finger protein 179 pathway is involved in the attenuation of oxidative stress following brain injury.Monday, December 05, 2016
Chuang JY, Kao TJ, Lin SH, Wu AC, Lee PT, Su TP, Yeh SH, Lee YC, Wu CC, Chang WC,
Redox biology. 29-Nov-2016
After sudden traumatic brain injuries, secondary injuries may occur during the following days or weeks, which leads to the accumulation of reactive oxygen species (ROS). Since ROS exacerbate brain damage, it is important to protect neurons against their activity. Zinc finger protein 179 (Znf179) was shown to act as a neuroprotective factor, but the regulation of gene expression under oxidative stress remains unknown. In this study, we demonstrated an increase in Znf179 protein levels in both in vitro model of hydrogen peroxide (H2O2)-induced ROS accumulation and animal models of traumatic brain injury. Additionally, we examined the sub-cellular localization of Znf179, and demonstrated that oxidative stress increases Znf179 nuclear shuttling and its interaction with specificity protein 1 (Sp1). Subsequently, the positive autoregulation of Znf179 expression, which is Sp1-dependent, was further demonstrated using luciferase reporter assay and green fluorescent protein (GFP)-Znf179-expressing cells and transgenic mice. The upregulation of Sp1 transcriptional activity induced by the treatment with nerve growth factor (NGF) led to an increase in Znf179 levels, which further protected cells against H2O2-induced damage. However, Sp1 inhibitor, mithramycin A, was shown to inhibit NGF effects, leading to a decrease in Znf179 expression and lower cellular protection. In conclusion, the results obtained in this study show that Znf179 autoregulation through Sp1-dependent mechanism plays an important role in neuroprotection, and NGF-induced Sp1 signaling may help attenuate more extensive (ROS-induced) damage following brain injury.
Beyond flexibility: controlling stem cells in an ever changing environment.Monday, December 05, 2016
Pfeiffer A, Wenzl C, Lohmann JU,
Current opinion in plant biology. 02-Dec-2016
Developmental plasticity is a defining feature of plants allowing them to colonize a wide range of different ecosystems by promoting environmental adaptation. Their postembryonic development requires life-long maintenance of stem cells, which are embedded into specialized tissues, called meristems. The shoot apical meristem gives rise to all above ground tissues and is a complex and dynamic three-dimensional structure harboring cells of different clonal origins and fates. Functionally divergent subdomains are stably maintained despite permanent cell division, however their relative sizes are modified in response to developmental and environmental signals. In this review, we briefly describe the core regulatory program of the shoot apical meristem and discuss progress in the fields of mechanical and environmental control of its activity.
Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF.Monday, December 05, 2016
Dashnyam K, Jin GZ, Kim JH, Perez R, Jang JH, Kim HW,
Biomaterials. 28-Nov-2016
Angiogenic capacity of biomaterials is a key asset to drive vascular ingrowth during tissue repair and regeneration. Here we design a unique angiogenic microcarrier based on sol-gel derived mesoporous silica. The microspheres offer a potential angiogenic stimulator, Si ion, 'intrinsically' within the chemical structure. Furthermore, the highly mesoporous nature allows the loading and release of angiogenic growth factor 'extrinsically'. The Si ion is released from the microcarriers at therapeutic ranges (over a few ppm per day), which indeed up-regulates the expression of hypoxia inducing factor 1α (HIF1α) and stabilizes it by blocking HIF-prolyl hydroxylase 2 (PHD2) in HUVECs. This in turn activates the expression of a series of proangiogenic molecules, including bFGF, VEGF, and eNOS. VEGF is incorporated effectively within the mesopores of microcarriers and is then released continuously over a couple of weeks. The Si ion and VEGF released from the microcarriers synergistically stimulate endothelial cell functions, such as cell migration, chemotactic homing, and tubular networking. Furthermore, in vivo neo-blood vessel sprouting in chicken chorioallantoic membrane model is significantly promoted by the Si/VEGF releasing microcarriers. The current study demonstrates the synergized effects of Si ion and angiogenic growth factor through a biocompatible mesoporous microsphere delivery platform, and the concept provided here may open the door to a new co-delivery system of utilizing ions with growth factors for tissue repair and regeneration.
Transformation of jaw muscle satellite cells to cardiomyocytes.Monday, December 05, 2016
Daughters RS, Keirstead SA, Slack JM,
Differentiation; research in biological diversity. 02-Dec-2016
In the embryo a population of progenitor cells known as the second heart field forms not just parts of the heart but also the jaw muscles of the head. Here we show that it is possible to take skeletal muscle satellite cells from jaw muscles of the adult mouse and to direct their differentiation to become heart muscle cells (cardiomyocytes). This is done by exposing the cells to extracellular factors similar to those which heart progenitors would experience during normal embryonic development. By contrast, cardiac differentiation does not occur at all from satellite cells isolated from trunk and limb muscles, which originate from the somites of the embryo. The cardiomyocytes arising from jaw muscle satellite cells express a range of specific marker proteins, beat spontaneously, display long action potentials with appropriate responses to nifedipine, norepinephrine and carbachol, and show synchronized calcium transients. Our results show the existence of a persistent cardiac developmental competence in satellite cells of the adult jaw muscles, associated with their origin from the second heart field of the embryo, and suggest a possible method of obtaining cardiomyocytes from individual patients without the need for a heart biopsy.
Roles of L-type calcium channels (CaV1.2) and the distal C-terminus (DCT) in differentiation and mineralization of rat dental apical papilla stem cells (rSCAPs).Monday, December 05, 2016
Gao Q, Ge J, Ju Y, Li C, Gao J, Wu M, Zhao S,
Archives of oral biology. 04-Nov-2016
Our results suggest that CaV1.2 and DCT play important roles in the differentiation of rSCAPs, DCT might act as a transcription factor and regulate the differentiation of rSCAPs.
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