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Showing 100 Latest Publications
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Repair of bone defects in vivo using tissue engineered hypertrophic cartilage grafts produced from nasal chondrocytes.Saturday, October 22, 2016
Bardsley K, Kwarciak A, Freeman C, Brook I, Hatton P, Crawford A,
Biomaterials. 11-Oct-2016
The regeneration of large bone defects remains clinically challenging. The aim of our study was to use a rat model to use nasal chondrocytes to engineer a hypertrophic cartilage tissue which could be remodelled into bone in vivo by endochondral ossification. Primary adult rat nasal chondrocytes were isolated from the nasal septum, the cell numbers expanded in monolayer culture and the cells cultured in vitro on polyglycolic acid scaffolds in chondrogenic medium for culture periods of 5-10 weeks. Hypertrophic differentiation was assessed by determining the temporal expression of key marker genes and proteins involved in hypertrophic cartilage formation. The temporal changes in the genes measured reflected the temporal changes observed in the growth plate. Collagen II gene expression increased 6 fold by day 7 and was then significantly downregulated from day 14 onwards. Conversely, collagen X gene expression was detectable by day 14 and increased 100-fold by day 35. The temporal increase in collagen X expression was mirrored by increases in alkaline phosphatase gene expression which also was detectable by day 14 with a 30-fold increase in gene expression by day 35. Histological and immunohistochemical analysis of the engineered constructs showed increased chondrocyte cell volume (31-45 μm), deposition of collagen X in the extracellular matrix and expression of alkaline phosphatase activity. However, no cartilage mineralisation was observed in in vitro culture of up to 10 weeks. On subcutaneous implantation of the hypertrophic engineered constructs, the grafts became vascularised, cartilage mineralisation occurred and loss of the proteoglycan in the matrix was observed. Implantation of the hypertrophic engineered constructs into a rat cranial defect resulted in angiogenesis, mineralisation and remodelling of the cartilage tissue into bone. Micro-CT analysis indicated that defects which received the engineered hypertrophic constructs showed 38.48% in bone volume compared to 7.01% in the control defects. Development of tissue engineered hypertrophic cartilage to use as a bone graft substitute is an exciting development in regenerative medicine. This is a proof of principal study demonstrating the potential of nasal chondrocytes to engineer hypertrophic cartilage which will remodel into bone on in vivo transplantation. This approach to making engineered hypertrophic cartilage grafts could form the basis of a new potential future clinical treatment for maxillofacial reconstruction.
Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective.Saturday, October 22, 2016
Zhao D, Witte F, Lu F, Wang J, Li J, Qin L,
Biomaterials. 11-Oct-2016
As a new generation of medical metallic material, magnesium (Mg) and its alloys with or without surface coating have attracted a great deal of attention due to its biodegradability and potential for avoiding a removal operation after the implant has fulfilled its function for surgical fixation of injured musculoskeletal tissues. Although a few clinical cases on Mg-based orthopaedic implants were reported more than a century ago, it was not until recently that clinical trials using these implants with improved physicochemical properties were carried out in Germany, China and Korea for bone fracture fixation. The promising results so far suggest a bright future for biodegradable Mg-based orthopaedic implants and would warrant large scale phase II/III studies. Given the increasing interest on this emerging biomaterials and intense effort to improve its properties for various clinical applications, this review covers the evolution, current strategies, and future perspectives in the development of Mg-based orthopaedic implants. We also highlight a few clinical cases performed in China that may be unfamiliar to the general orthopaedic community.
3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair.Saturday, October 22, 2016
Jang J, Park HJ, Kim SW, Kim H, Park JY, Na SJ, Kim HJ, Park MN, Choi SH, Park SH, Kim SW, Kwon SM, Kim PJ, Cho DW,
Biomaterials. 14-Oct-2016
Stem cell therapy is a promising therapeutic method for the treatment of ischemic heart diseases; however, some challenges prohibit the efficacy after cell delivery due to hostile microenvironment of the injured myocardium. 3D printed pre-vascularized stem cell patch can enhance the therapeutic efficacy for cardiac repair through promotion of rapid vascularization after patch transplantation. In this study, stem cell-laden decellularized extracellular matrix bioinks are used in 3D printing of pre-vascularized and functional multi-material structures. The printed structure composed of spatial patterning of dual stem cells improves cell-to-cell interactions and differentiation capability and promotes functionality for tissue regeneration. The developed stem cell patch promoted strong vascularization and tissue matrix formation in vivo. The patterned patch exhibited enhanced cardiac functions, reduced cardiac hypertrophy and fibrosis, increased migration from patch to the infarct area, neo-muscle and capillary formation along with improvements in cardiac functions. Therefore, pre-vascularized stem cell patch provides cardiac niche-like microenvironment, resulting in beneficial effects on cardiac repair.
In vivo evaluation of stem cell aggregates on osteochondral regeneration.Saturday, October 22, 2016
Sridharan B, Laflin AD, Holtz MA, Pacicca DM, Wischmeier NK, Detamore MS,
Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 22-Oct-2016
To date, many osteochondral regenerative approaches have utilized varied combinations of biocompatible materials and cells to engineer cartilage. Even in cell-based approaches, to date, no study has utilized stem cell aggregates alone for regenerating articular cartilage. Thus, the purpose of this study was to evaluate the performance of a novel stem cell-based aggregate approach in a fibrin carrier to regenerate osteochondral defects in the Sprague-Dawley rat trochlear groove model. Two different densities of rat bone marrow mesenchymal stem cell (rBMSC) aggregates were fabricated by the hanging drop technique. At 8 weeks, the cell aggregates supported the defects and served as a catalyst for neo-cartilage synthesis, and the experimental groups may have been beneficial for bone and cartilage regeneration compared to the fibrin-only control and sham groups, as evidenced by histological assessment. The cell density of rBMSC aggregates may thus directly impact chondrogenesis. The usage of cell aggregates with fibrin as a cell-based technology is a promising and translational new treatment strategy for repair of cartilage defects. This article is protected by copyright. All rights reserved.
RD Lawrence Lecture 2015. Old habits are hard to break: lessons from the study of hypoglycaemia.Saturday, October 22, 2016
McCrimmon RJ,
Diabetic medicine : a journal of the British Diabetic Association. 22-Oct-2016
Despite the introduction of newer technologies and improved insulin formulations, recurrent hypoglycaemia continues to affect the lives of many people with Type 1 and Type 2 diabetes. Developing strategies or therapies designed to prevent or minimize hypoglycaemia risk is of utmost importance to help individuals safely achieve glycaemic targets. Novel, educational or behavioural approaches need to be based on a clear understanding of the mechanisms underpinning both the detection of hypoglycaemia and why repeated exposure to hypoglycaemia leads to the development of a clinical syndrome referred to as impaired awareness of hypoglycaemia. In the present review, I propose that impaired awareness of hypoglycaemia may represent a form of learning called habituation, a response that, at a cellular level, represents a biological adaptation designed to protect the organism from future exposure to that stressor. In diabetes, this survival response to low glucose is, however, overwhelmed by high systemic insulin levels resulting from exogenous insulin therapy, leading to progressively more severe hypoglycaemia. A recognition of the underlying mechanism means that the development of impaired awareness of hypoglycaemia can perhaps be better understood and explained to individuals with diabetes, and novel therapeutic approaches such as dishabituation or cognitive behavioural therapies can be considered. This article is protected by copyright. All rights reserved.
Skeletal Muscle Patch Engineering on Synthetic and Acellular Human Skeletal Muscle Originated Scaffolds.Saturday, October 22, 2016
Ay B, Karaoz E, Kesemenli CC, Kenar H,
Journal of biomedical materials research. Part A. 22-Oct-2016
The reconstruction of skeletal muscle tissue is currently performed by transplanting a muscle tissue graft from local or distant sites of the patient`s body, but this practice leads to donor site morbidity in case of large defects. With the aim of providing an alternative treatment approach, skeletal muscle tissue formation potential of human myoblasts and human menstrual blood derived mesenchymal stem cells (hMB-MSCs) on synthetic (poly(L-lactide-co-caprolactone), 70:30) scaffolds with oriented microfibers, human muscle extracellular matrix (ECM), and their hybrids was investigated in this study. The reactive muscle ECM pieces were chemically crosslinked to the synthetic scaffolds to produce the hybrids. Cell proliferation assay WST-1, Scanning Electron Microscopy (SEM), and immunostaining were carried out after culturing the cells on the scaffolds. The ECM and the synthetic scaffolds were effective in promoting spontaneous myotube formation from human myoblasts. Anisotropic muscle patch formation was more successful when human myoblasts were grown on the synthetic scaffolds. Nonetheless, spontaneous differentiation could not be induced in hMB-MSCs on any type of the scaffolds. Human myoblast-synthetic scaffold combination is promising as a skeletal muscle patch, and can be improved further to serve as a fast integrating functional patch by introducing vascular and neuronal networks to the structure. This article is protected by copyright. All rights reserved.
Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2α.Saturday, October 22, 2016
Zaki Dizaji M, Ghaffari SH, Hosseini E, Alizadeh N, Rostami S, Momeny M, Alimoghaddam K, Ghavamzadeh A,
Asia-Pacific journal of clinical oncology. 22-Oct-2016
Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2α) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO.
Acute Physical Exercise and Long-Term Individual Shear Rate Therapy Increase Telomerase Activity in Human Peripheral Blood Mononuclear Cells.Saturday, October 22, 2016
Zietzer A, Buschmann EE, Janke D, Li L, Brix M, Meyborg H, Stawowy P, Jungk C, Buschmann I, Hillmeister P,
Acta physiologica (Oxford, England). 22-Oct-2016
In summary, we show that acute exercise and long-term ISRT counterpulsation positively affect PBMC telomerase activity, which is indicative for an improved regenerative potential of immune cells and vascular tissues. Long-term ISRT also enhances the gene expression of the telomere protective factor TRF2. This article is protected by copyright. All rights reserved.
Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum.Saturday, October 22, 2016
Piao X, Yamazaki S, Komazawa-Sakon S, Miyake S, Nakabayashi O, Kurosawa T, Mikami T, Tanaka M, Van Rooijen N, Ohmuraya M, Oikawa A, Kojima Y, Kakuta S, Uchiyama Y, Tanaka M, Nakano H,
Hepatology (Baltimore, Md.). 22-Oct-2016
These findings indicate an unexpected role of myeloid cells in decreasing serum IL-6, TNFα, and histone H3 levels via the suppression of TNFα-induced hepatocyte apoptosis. This article is protected by copyright. All rights reserved.
Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy.Saturday, October 22, 2016
Liu M, Zhou J, Chen Z, Cheng AS,
The Journal of pathology. 22-Oct-2016
The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence underscores the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ("epimutations"), there is also growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells toward an immunosuppressive state. Pharmacological inhibition of DNA methylation and histone modifications can reduce the efficiency of immune checkpoint blockage, and unleash anti-tumour T-cell responses. However, these non-specific agents also represent a "double-edged sword", as they can also reactivate gene transcription of checkpoint molecules, interrupting immune surveillance programmes. By understanding the impact of epigenetic control on the tumour microenvironment, rational combinatorial epigenetic and checkpoint blockage therapies have potential to harness the immune system for the treatment of cancer.
Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia.Saturday, October 22, 2016
Chao CM, Yahya F, Moiseenko A, Tiozzo C, Shrestha A, Ahmadvand N, El Agha E, Quantius J, Dilai S, Kheirollahi V, Jones M, Wilhem J, Carraro G, Ehrhardt H, Zimmer KP, Barreto G, Ahlbrecht K, Morty RE, Herold S, Abellar RG, Seeger W, Schermuly R, Zhang JS, Minoo P, Bellusci S,
The Journal of pathology. 22-Oct-2016
Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10(+/-) versus Fgf10(+/+) pups was investigated. In normoxia, no lethality of Fgf10(+/+) or Fgf10(+/-) pups was observed. By contrast, all Fgf10(+/-) pups died within 8 days of hyperoxic injury, with lethality starting at day 5, whereas Fgf10(+/+) pups were all alive. Lungs of pups from the two genotypes were collected on postnatal day 3 following normoxia or hyperoxia exposure for further analysis. In hyperoxia, Fgf10(+/-) lungs exhibited increased hypoalveolarization. Analysis by FACS of the Fgf10(+/-) versus control lungs in normoxia, revealed a decreased ratio of alveolar epithelial type II (AECII) cells over total Epcam-positive cells. In addition, gene array analysis indicated reduced AECII and increased AECI transcriptome signatures in isolated AECII cells from Fgf10(+/-) lungs. Such an imbalance in differentiation is also seen in hyperoxia and associated with reduced mature surfactant protein B and C expression. Attenuation of the activity of Fgfr2b ligands post-natally in the context of hyperoxia lead also to increased lethality with decreased surfactant expression. In summary, decreased Fgf10 mRNA levels leads to congenital lung defects, which are compatible with postnatal survival, but which compromise the ability of the lungs to cope with sub-lethal hyperoxic injury. Fgf10 deficiency affects quantitatively and qualitatively the formation of AECII cells. In addition, Fgfr2b ligands are also important for repair after hyperoxia exposure in neonates. Deficient AECII cells could be an additional complication for patients with BPD.
Effect of enzymatic degradation of chitosan in polyhydroxybutyrate/chitosan/calcium phosphate composites on in vitro osteoblast response.Saturday, October 22, 2016
Giretova M, Medvecky L, Stulajterova R, Sopcak T, Briancin J, Tatarkova M,
Journal of materials science. Materials in medicine. Dec-2016
Polyhydroxybutyrate/chitosan/calcium phosphate composites are interesting biomaterials for utilization in regenerative medicine and they may by applied in reconstruction of deeper subchondral defects. Insufficient informations were found in recent papers about the influence of lysozyme degradation of chitosan in calcium phosphate/chitosan based composites on in vitro cytotoxicity and proliferation activity of osteoblasts. The effect of enzymatic chitosan degradation on osteoblasts proliferation was studied on composite films in which the porosity of origin 3D scaffolds was eliminated and the surface texture was modified. The significantly enhanced proliferation activity with faster population growth of osteoblasts were found on enzymatically degraded biopolymer composite films with α-tricalcium phosphate and nanohydroxyapatite. No cytotoxicity of composite films prepared from lysozyme degraded scaffolds containing a large fraction of low molecular weight chitosans (LMWC), was revealed after 10 days of cultivation. Contrary to above in the higher cytotoxicity origin untreated nanohydroxyapatite films and porous composite scaffolds. The results showed that the synergistic effect of surface distribution, morphology of nanohydroxyapatite particles, microtopography and the presence of LMWC due to chitosan degradation in composite films were responsible for compensation of the cytotoxicity of nanohydroxyapatite composite films or porous composite scaffolds.
Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure.Saturday, October 22, 2016
Nagy G, Baksa V, Kiss A, Turani M, Banfalvi G,
Apoptosis : an international journal on programmed cell death. 22-Oct-2016
The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd(3+) ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd(3+) treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO2), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd(3+) concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd(3+) ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages.
Cell-based therapies for neonatal lung disease.Saturday, October 22, 2016
O'Reilly M, Thébaud B,
Cell and tissue research. 22-Oct-2016
Preterm birth occurs in approximately 11 % of all births worldwide. Advances in perinatal care have enabled the survival of preterm infants born as early as 23-24 weeks of gestation. However, many are affected by bronchopulmonary dysplasia (BPD)-a common respiratory complication of preterm birth, which has life-long consequences for lung health. Currently, there is no specific treatment for BPD. Recent advances in stem cell research have opened new therapeutic avenues for prevention/repair of lung damage. This review summarizes recent pre-clinical data and early clinical translation of cell-based therapies for BPD.
Combined effects of electromagnetic field and low-level laser increase proliferation and alter the morphology of human adipose tissue-derived mesenchymal stem cells.Saturday, October 22, 2016
Nurković J, Zaletel I, Nurković S, Hajrović Š, Mustafić F, Isma J, Škevin AJ, Grbović V, Filipović MK, Dolićanin Z,
Lasers in medical science. 21-Oct-2016
In recent years, electromagnetic field (EMF) and low-level laser (LLL) have been found to affect various biological processes, the growth and proliferation of cells, and especially that of stem cells. The aim of this study was to investigate the effects of EMF and LLL on proliferation of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and thus to examine the impact of these therapeutic physical modalities on stem cell engraftment. hAT-MSCs were isolated from subcutaneous adipose tissue of six persons ranging in age from 21 to 56 years. EMF was applied for a period of 7 days, once a day for 30 min, via a magnetic cushion surface at a frequency of 50 Hz and an intensity of 3 mT. LLL was applied also for 7 days, once a day for 5 min, at radiation energies of 3 J/cm(2), with a wavelength of 808 nm, power output of 200 mW, and power density of 0.2 W/cm(2). Nonexposed cells (control) were cultivated under the same culture conditions. Seven days after treatment, the cells were examined for cell viability, proliferation, and morphology. We found that after 7 days, the number of EMF-treated hAT-MSCs was significantly higher than the number of the untreated cells, LLL-treated hAT-MSCs were more numerous than EMF-treated cells, and hAT-MSCs that were treated with the combination of EMF and LLL were the most numerous. EMF and/or LLL treatment did not significantly affect hAT-MSC viability by itself. Changes in cell morphology were also observed, in terms of an increase in cell surface area and fractal dimension in hAT-MSCs treated with EMF and the combination of EMF and LLL. In conclusion, EMF and/or LLL treatment accelerated the proliferation of hAT-MSCs without compromising their viability, and therefore, they may be used in stem cell tissue engineering.
3D Cell Culturing and Possibilities for Myometrial Tissue Engineering.Saturday, October 22, 2016
Heidari Kani M, Chan EC, Young RC, Butler T, Smith R, Paul JW,
Annals of biomedical engineering. 21-Oct-2016
Research insights into uterine function and the mechanisms of labour have been hindered by the lack of suitable animal and cellular models. The use of traditional culturing methods limits the exploration of complex uterine functions, such as cell interactions, connectivity and contractile behaviour, as it fails to mimic the three-dimensional (3D) nature of uterine cell interactions in vivo. Animal models are an option, however, use of these models is constrained by ethical considerations as well as translational limitations to humans. Evidence indicates that these limitations can be overcome by using 3D culture systems, or 3D Bioprinters, to model the in vivo cytological architecture of the tissue in an in vitro environment. 3D cultured or 3D printed cells can be used to form an artificial tissue. This artificial tissue can not only be used as an appropriate model in which to study cellular function and organisation, but could also be used for regenerative medicine purposes including organ or tissue transplantation, organ donation and obstetric care. The current review describes recent developments in cell culture that can facilitate the development of myometrial 3D structures and tissue engineering applications.
Texture analysis in radiology: Does the emperor have no clothes?Saturday, October 22, 2016
Summers RM,
Abdominal radiology (New York). 21-Oct-2016
Texture analysis is more and more frequently used in radiology research. Is this a new technology, and if not, what has changed? Is texture analysis the great diagnostic and prognostic tool we have been searching for in radiology? This commentary answers these questions and places texture analysis into its proper perspective.
UK must act quickly to become world leader in regenerative medicine, MPs hear.Saturday, October 22, 2016
O'Dowd A,
BMJ (Clinical research ed.). 21-Oct-2016
Atorvastatin enhances endothelial cell function in post transplant poor graft function.Saturday, October 22, 2016
Shi MM, Kong Y, Song Y, Sun YQ, Wang Y, Zhang XH, Xu LP, Liu KY, Huang XJ,
Blood. 21-Oct-2016
Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells (HSCs) in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF post-allotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cAMP-responsive element-binding protein (CREB) were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through down-regulation of the p38 mitogen-activated protein kinase (MAPK) pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through down-regulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF post-allotransplant.
Rapid and Minimally-Traumatic Replacement of Stimulator Extension Cables: Technical Note on a Novel Use for Sternal Wire.Saturday, October 22, 2016
Henderson F, Takacs I,
World neurosurgery. 18-Oct-2016
A less expensive and faster technique for passing pulse generator extension cables may be the use of a sternal wire. Using the described technique, pulse generators may be quickly and safely adjusted from side-to-side and site-to-site as the clinical situation dictates.
Human-derived extracellular matrix from Wharton's jelly: an untapped substrate to build up a standardized and homogeneous coating for vascular engineering.Saturday, October 22, 2016
Dan P, Velot É, Francius G, Menu P, Decot V,
Acta biomaterialia. 18-Oct-2016
Discovery and design of biomaterial surface are a hot spot in the tissue engineering field. Natural matrix is preferred to mimic native cell microenvironment but its use is limited due to poor resource availability. Moreover, current studies often use single or several components of natural polymers, which is not the case in human body. This paper reports a natural extracellular matrix with full components derived from healthy human tissue: Wharton's jelly of umbilical cord. Reconstituting this matrix as a culture surface, our easily-prepared coating provides superior biocompatibility for stem and mature cells. Furthermore, we observed improved cell performance on this coating under both static and dynamic condition. This novel human derived ECM would be a promising choice for regenerative medicine.
Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming.Saturday, October 22, 2016
Gu R, Zhang F, Chen G, Han C, Liu J, Ren Z, Zhu Y, Waddington JL, Tai Zheng L, Zhen X,
Brain, behavior, and immunity. 18-Oct-2016
Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1(+/-) mice after treatment with MPTP, a rodent model of Parkinson's disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1(+/-) DA cells to MPP(+), the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1(+/-) mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.
Autocrine Semaphorin3A signaling is essential for the maintenance of stem-like cells in lung cancer.Saturday, October 22, 2016
Yamada D, Takahashi K, Kawahara K, Takehiko M,
Biochemical and biophysical research communications. 18-Oct-2016
Cancer stem-like cells (CSCs) exist in tumor tissues composed of heterogeneous cell population and are characterized by their self-renewal capacity and tumorigenicity. Many studies demonstrate that eradication of CSCs prevents development and recurrences of tumor; yet, molecules critical for the maintenance of CSCs have not been completely understood. We previously reported that Semaphorin3A (Sema3a) knockdown suppressed the tumorigenicity and proliferative capacity of Lewis lung carcinoma (LLC) cells. Therefore, we identified Sema3a as an essential factor for the establishment or maintenance of CSCs derived from LLC (LLC-stem cell). shRNA against Sema3a was introduced into LLC cells to establish a LLC-stem cell line and its effects on tumorigenesis, sphere formation, and mTORC1 activity were tested. Sema3a knockdown completely abolished tumorigenicity and the sphere-formation and self-renewal ability of LLC-stem cells. The Sema3a knockdown was also associated with decreased expression of mRNA for stem cell markers. The self-renewal ability abolished by Sema3a knockdown could not be recovered by exogenous addition of recombinant SEMA3A. In addition, the activity of mammalian target of rapamycin complex 1 (mTORC1) and the expression of its substrate p70S6K1 were also decreased. These results demonstrate that Sema3a is a potential therapeutic target in eradication of CSCs.
Responsiveness of the active wrist joint position sense test after distal radius fracture intervention.Saturday, October 22, 2016
Karagiannopoulos C, Sitler M, Michlovitz S, Tucker C, Tierney R,
Journal of hand therapy : official journal of the American Society of Hand Therapists. 18-Oct-2016
Keap1 as the redox sensor of the antioxidant response.Saturday, October 22, 2016
Sihvola V, Levonen AL,
Archives of biochemistry and biophysics. 18-Oct-2016
Reactive oxygen species (ROS) and products of their reactions with cellular macromolecules such as unsaturated fatty acids have been implicated to be important regulators of signalling processes via oxidation or alkylation of redox active thiol residues in target proteins. One of key redox-sensitive signalling proteins mediating the response to oxidant stress is Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is a negative regulator of transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and the central hub for sensing endogenous and environmental oxidative and electrophilic stress. In this review, we provide an overview of the mechanisms by which Keap1 orchestrates the antioxidant response and how the system can be targeted for therapy.
Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells.Saturday, October 22, 2016
Eyvani H, Moghaddaskho F, Kabuli M, Zekri A, Momeny M, Tavakkoly-Bazzaz J, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH,
Life sciences. 18-Oct-2016
These data suggest that demethylation and alteration in the expression level of the cell cycle-related genes may be possible mechanisms in As2O3-induced cell cycle arrest in colorectal cancer cells.
Aaryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis.Saturday, October 22, 2016
Xue J, Zhao Q, Sharma V, Nguyen LP, Lee YN, Pham KL, Edderkaoui M, Pandol SJ, Park W, Habtezion A,
Gastroenterology. 18-Oct-2016
AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis, via upregulation of IL22. This pathway might be targeted for treatment of CP and serve as biomarker of disease.
The association of cumulative discrimination on quality of care, patient-centered care, and dissatisfaction with care in adults with type 2 diabetes.Saturday, October 22, 2016
Cykert DM, Williams JS, Walker RJ, Davis KS, Egede LE,
Journal of diabetes and its complications. 30-Sep-2016
Increased cumulative discrimination was associated with decreased feeling of patient-centeredness and increased dissatisfaction with care. However, these perceptions of discrimination were not significantly associated with quality indicators.
Fast and automatic identification of particle tilt pairs based on Delaunay triangulation.Saturday, October 22, 2016
Vilas JL, Navas J, Gómez-Blanco J, de la Rosa-Trevín JM, Melero R, Peschiera I, Ferlenghi I, Cuenca J, Marabini R, Carazo JM, Vargas J, Sorzano CO,
Journal of structural biology. 18-Oct-2016
Random conical tilt (RCT) and orthogonal tilt reconstruction (OTR) are two remarkable methods for reconstructing the three-dimensional structure of macromolecules at low resolution. These techniques use two images at two different sample tilts. One of the most demanding steps in these methods at the image processing level is to identify corresponding particles on both micrographs, and manual or semiautomatic matching methods are usually used. Here we present an approach to solve this bottleneck with a fully automatic method for assigning particle tilt pairs. This new algorithm behaves correctly with a variety of samples, covering the range from small to large macromolecules and from sparse to densely populated fields of view. It is also more rapid than previous approaches. The roots of the method lie in a Delaunay triangulation of the set of independently picked coordinates on both the untilted and tilted micrographs. These triangulations are then used to search an affine transfo rmation between the untilted and tilted triangles. The affine transformation that maximizes the number of correspondences between the two micrographs defines the coordinate matching.
Androgens modify Wnt agonists/antagonists expression balance in dermal papilla cells preventing hair follicle stem cell differentiation in androgenetic alopecia.Saturday, October 22, 2016
Leirós GJ, Ceruti JM, Castellanos ML, Kusinsky AG, Balañá ME,
Molecular and cellular endocrinology. 18-Oct-2016
In androgenetic alopecia, androgens impair dermal papilla-induced hair follicle stem cell (HFSC) differentiation inhibiting Wnt signaling. Wnt agonists/antagonists balance was analyzed after dihydrotestosterone (DHT) stimulation in androgen-sensitive dermal papilla cells (DPC) cultured as spheroids or monolayer. In both culture conditions, DHT stimulation downregulated Wnt5a and Wnt10b mRNA while the Wnt antagonist Dkk-1 was upregulated. Notably, tissue architecture of DPC-spheroids lowers Dkk-1 and enhances Wnt agonists' basal expression; probably contributing to DPC inductivity. The role of Wnt agonists/antagonists as mediators of androgen inhibition of DPC-induced HFSC differentiation was evaluated. Inductive DPC-conditioned medium supplemented with DKK-1 impaired HFSC differentiation mimicking androgens' action. This effect was associated with inactivation of Wnt/β-catenin pathway in differentiating HFSC by both DPC-conditioned media. Moreover, addition of WNT10b to DPC-medium conditioned with DHT, overcame androgen inhibition of HFSC differentiation. Our results identify DKK1 and WNT10b as paracrine factors which modulate the HFSC differentiation inhibition involved in androgen-driven balding.
Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy.Saturday, October 22, 2016
Ding C, Chen S, Zhang C, Hu G, Zhang W, Li L, Chen YZ, Tan C, Jiang Y,
Bioorganic & medicinal chemistry. 10-Oct-2016
By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0.49 and 8.76μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.
COMT Val(158)Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.Saturday, October 22, 2016
Winkler EA, Yue JK, Ferguson AR, Temkin NR, Stein MB, Barber J, Yuh EL, Sharma S, Satris GG, McAllister TW, Rosand J, Sorani MD, Lingsma HF, Tarapore PE, Burchard EG, Hu D, Eng C, Wang KK, Mukherjee P, Okonkwo DO, Diaz-Arrastia R, Manley GT,
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 18-Oct-2016
Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val(158)Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met(158) allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val(158)Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings.
The exciting prospects of new therapies with mesenchymal stromal cells.Saturday, October 22, 2016
Prockop DJ,
Cytotherapy. 18-Oct-2016
From the outset, it was apparent that developing new therapies with mesenchymal stem/stromal cells (MSCs) was not a simple or easy task. Among the earliest experiments was administration of MSCs from normal mice to transgenic mice that developed brittle bones because they expressed a mutated gene for type 1 collagen isolated from a patient with osteogenesis imperfecta. The results prompted a clinical trial of MSCs in patients with severe osteogenesis imperfecta. Subsequent work by large numbers of scientists and clinicians has established that, with minor exceptions, MSCs do not engraft or differentiate to a large extent in vivo. Instead the cells produce beneficial effects in a large number of animal models and some clinical trials by secreting paracrine factors and extracellular vesicles in a "hit and run" scenario. The field faces a number of challenges, but the results indicate that we are on the way to effective therapies for millions of patients who suffer from devastating diseases.
Synthesis and cytotoxicity study of novel 3-(triazolyl)coumarins based fluorescent scaffolds.Saturday, October 22, 2016
Sinha S, Kumaran AP, Mishra D, Paira P,
Bioorganic & medicinal chemistry letters. 1-Oct-2016
Recently a choice of fluorescent bioimaging probes have been developed as medical diagnostic tools. Herein, we have introduced a series of coumarin-based target specific probes for cancer theranostic application which play a dual role in the field of both diagnosis and therapy. A fluorogenic version of 1,3-dipolar cycloaddition between azides and alkynes (DBCO) has been introduced to develop the triazolylcoumarin based fluorescent scaffolds. These scaffolds were screened for their anticancer activity against breast cancer (MCF7) and human epitheloid cervix carcinoma (HeLa) cell line. It was established that triazolylcoumarins (5c and 5d) are having electronegative substitution in the benzene ring displayed most effective anticancer profile in both the cell lines. Compounds 5a and 5d exhibited maximum quantum yield and strong cellular uptake in the MCF-7 cell line.
Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells.Saturday, October 22, 2016
Ferreira-Teixeira M, Paiva-Oliveira D, Parada B, Alves V, Sousa V, Chijioke O, Münz C, Reis F, Rodrigues-Santos P, Gomes C,
BMC medicine. 21-Oct-2016
Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression.
Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS.Saturday, October 22, 2016
Chang CF, Lee YC, Lee KH, Lin HC, Chen CL, Shen CJ, Huang CC,
Journal of biomedical science. 21-Oct-2016
We supported an important notion that the traditional herb berberine is a potential alternative therapy for TDP-43-related neuropathology. Here we demonstrated that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. mTOR-autophagy signals plays an important role in berberine-mediated autophagic clearance of TDP-43 aggregates. Exploring the detailed mechanism of berberine on TDP-43 proteinopathy provides a better understanding for the therapeutic development in FTLD and ALS.
Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study.Saturday, October 22, 2016
Agyemang C, Meeks K, Beune E, Owusu-Dabo E, Mockenhaupt FP, Addo J, de Graft Aikins A, Bahendeka S, Danquah I, Schulze MB, Spranger J, Burr T, Agyei-Baffour P, Amoah SK, Galbete C, Henneman P, Klipstein-Grobusch K, Nicolaou M, Adeyemo A, van Straalen J, Smeeth L, Stronks K,
BMC medicine. 21-Oct-2016
Our study shows high risks of obesity and T2D among sub-Saharan African populations living in Europe. In Ghana, similarly high prevalence rates were seen in an urban environment, whereas in rural areas, the prevalence of obesity among women is already remarkable. Similar processes underlying the high burden of obesity and T2D following migration may also be at play in sub-Saharan Africa as a consequence of urbanisation.
Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors.Saturday, October 22, 2016
Merryweather-Clarke AT, Tipping AJ, Lamikanra AA, Fa R, Abu-Jamous B, Tsang HP, Carpenter L, Robson KJ, Nandi AK, Roberts DJ,
BMC genomics. 21-Oct-2016
Together, these data suggest that hiPSC-derived cells may be specified to a primitive erythroid fate, and implies that definitive specification may more accurately reflect adult development. We have therefore identified, for the first time, distinct gene expression dynamics during erythroblast differentiation from hiPSCs which may cause reduced proliferation and enucleation of hiPSC-derived erythroid cells. The data suggest several mechanistic defects which may partially explain the observed aberrant erythroid differentiation from hiPSCs.
Coexistence and Possible Parasitism of Somatic and Germ Cell Lines in Chimeras of the Colonial Urochordate Botryllus schlosseri.Friday, October 21, 2016
Pancer Z, Gershon H, Rinkevich B,
The Biological bulletin. Oct-1995
Fusion between conspecifics (chimerism) is a well-documented phenomenon in a variety of taxa. Chimerism and the subsequent mixing of genetically different stem cell lines may lead to competition between cell lineages for positions in the germ line and to somatic and germ cell parasitism. It is suggested that somatic compatibility systems evolved to alleviate the costs and the threat of such cell lineage competition. Allogeneic colonies of the ascidian Botryllus schlosseri form vascular chimeras based on matching in one or both alleles on one highly polymorphic fusibility haplotype. Thereafter, one of the partners is completely or partially resorbed. Here we used a polymorphic molecular marker (PCR typing at a microsatellite locus) to follow somatic and gametic consequences of chimera formation. Twenty-two chimeras and subclone samples were established from 12 different genotype combinations, in which blood cells, zooids, and gonads were typed 45-130 days thereafter. Somatic coexistence of both partners was recorded in 73% of the subcloned chimeras (83% of chimeric entities) up to 100 days after disconnection between genotypes and in all chimeras where colony-resorption was completed. Both genotypes were present in 23% of the sampled gonads (in 33% of the chimeras), and in 22% of the cases, germ cells of the second partner only were detected. Injection of allogeneic but compatible blood cells into three recipient colonies revealed proliferation of the donor cells in one case, 100 days after injection. To further evaluate somatic and germ cell parasitism in chimeric organisms, we propose four key features that characterize cell lineage competition processes. These include the somatic embryogenesis mode of development, the capability for independent existence of stem cells, the disproportionate share of gametic output within chimeras, and the existence of hierarchial responses.
College urges midwives to resist any pressure to take cord blood.Friday, October 21, 2016
Nursing standard (Royal College of Nursing (Great Britain) : 1987). 17-Mar-2010
The Royal College of Midwives (RCM) has advised midwives to resist pressure and not collect umbilical cord blood in a bid to preserve stem cells.
Regeneration patterns influence hindlimb automutilation after sciatic nerve repair using stem cells in rats.Wednesday, October 19, 2016
Haselbach D, Raffoul W, Larcher L, Tremp M, Kalbermatten DF, di Summa PG,
Neuroscience letters. 17-Oct-2016
Hindlimb autophagy can be used as index of neuropathic pain due to nerve lesion or on-going immature regeneration. dMSC group was characterized by a less targeted regeneration comparing to dASC and primary Schwann cells, which confirmed their effectiveness in regeneration and potential in future clinical applications.
Retinoic acid receptor β enhanced the anti-cancer stem cells effect of β-carotene by down-regulating expression of delta-like 1 homologue in human neuroblastoma cells.Tuesday, October 18, 2016
Kim YS, Kim E, Park YJ, Kim Y,
Biochemical and biophysical research communications. 15-Oct-2016
Neuroblastoma (NB) is childhood malignancy that retains characteristics of cancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. β-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC. Treatment with BC or retinoic acid (RA) upregulated RARβ mRNA expression in two NB cell lines. Inhibition of RARβ using siRNA up-regulated gene expression of delta-like 1 homologue (DLK1), a marker of CSCs. To understand the molecular mechanisms of RARβ-mediated inhibition of DLK1, four retinoic acid receptor elements (RAREs) were identified in the promoter of DLK1. Chromatin immunoprecipitation assays indicated that RARβ bound directly to a RARE in the DLK1 promoter region. Knock-down of RARβ also increased the self-renewal capacity of NB cells, which was suppressed by BC. Taken together, this study provided evidence that the therapeutic anti-CSC effects of BC depend on RARβ and its ability to interact with and down-regulate the CSCs marker, DLK1.
Evaluation of interleukin 12 and CD56+ lymphocyte cells in pediatric hematopoietic stem cell transplantation for early diagnosis of acute graft versus host disease.Tuesday, October 18, 2016
Tootoonchian R, Pak F, Ardekani AM, Sehati N, Abedi-Valugerdi M, Kokhaei P,
Transplant immunology. 15-Oct-2016
The present study tried to explain CD56+ lymphocyte cells activities and possible prognostic role of these cells in Graft-Versus-Host-Disease (GVHD). The role of IL-12 activation and function is of interest in this study. Peripheral blood samples of 51 Hematopoietic Stem Cell Transplantation (HSCT) recipients collected at before (day -8) and after (days 7 and 14). PBMC were collected by Ficoll separation and analyzed by Flow Cytometry using triple antibody (CD45-PerCP, CD56-FITC, and CD69-PE staining and control antibody. Levels of the cytokine IL-12 in the patient's serum were evaluated by ELISA. Percentage of CD56+ lymphocytes (CD56+(bright)) cells was significantly increased at day 14 in patients with acute GVHD and percentage of lymphocytes expressing CD69 was significantly increased at days 7 and 14 posts HSCT in patients with acute GVHD in comparison to those in non-GVHD patients. Baseline serum IL-12 levels (pre-HSCT, day -8) were significantly higher in those HSCT recipients who did not develop GVHD. This study showed that post-transplant CD56+ lymphocytes and pre-transplant serum levels of IL-12 play significant roles in the induction of and protection against GVHD, respectively. The increase in the percentage of CD69+ cells indicates the activation of lymphocyte in acute GVHD group.
Effects of voluntary exercise on the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups born from morphine- dependent mothers during pregnancy.Monday, October 17, 2016
Haydari S, Safari M, Zarbakhsh S, Bandegi AR, Miladi-Gorji H,
Neuroscience letters. 13-Oct-2016
This study was designed to investigate whether free access to a running wheel during pregnancy in morphine-dependent mothers would influence the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with free access to a running wheel. Male pups are weaned at 21days of birth and their bones marrows were aspirated from the femurs and tibias and also the bone marrow stromal cells (BMSCs) cultured. MTT assay was used to determine cell viability and proliferation rate. The level of BDNF was measured in the supernant of BMSCs culture by ELISA. The sedentary morphine-dependent mothers' pups showed a significant increase in the percentage cell viability and proliferation rate and also a significant decrease in the BDNF protein levels in BMSCs. The rat pups borne from exercising the control and morphine-dependent mothers exhibited an increase in the percentage viability, proliferation rate and BDNF levels of the BMSCs. This study showed that maternal exercise during pregnancy in morphine-dependent and non-dependent mothers, with increasing of BDNF levels increased the proliferation and viability of BMSCs in the rat pups. Also, chronic administration of morphine during pregnancy was able to increase the proliferation and viability of BMSCs in the rat pups.
Is cleaved glucagon-like peptide 1 really inactive? Effects of GLP-1(9-36) on human adipose stem cells.Monday, October 17, 2016
Cantini G, Di Franco A, Mannucci E, Luconi M,
Molecular and cellular endocrinology. 13-Oct-2016
Glucagon-like peptide 1(9-36) [GLP-1(9-36)] is generated by dipeptidyl peptidase-4 (DPP4) cleavage of the gut incretin hormone, GLP-1(7-36). Since GLP-1(9-36) has a very low affinity for the GLP-1 receptor (GLP-1R), it has so far been considered an inactive form of GLP-1. Here we show GLP-1(9-36) activity in human adipose stem cells (ASC) in vitro. GLP-1(9-36) inhibits human ASC proliferation, glucose uptake and adipogenesis, as well as induces cell apoptosis, to a similar extent as GLP-1(7-36) and liraglutide. Since GLP-1(9-36) effects are not reverted by the receptor antagonist exendin(9-39), which conversely reverts the effects of GLP-1(7-36), we hypothesized that the former may be mediated by a GLP-1 receptor different from the classical pancreatic one. This is the first report of GLP-1(9-36) activity in human adipose cells. Nevertheless, these findings deserve further preclinical studies to better elucidate novel and unforeseen GLP-1(9-36) activities, which could allow a better understanding of the clinical profile of DPP4 inhibitors and GLP-1R agonists.
The double life of cardiac mesenchymal cells: Epimetabolic sensors and therapeutic assets for heart regeneration.Saturday, October 15, 2016
Cencioni C, Atlante S, Savoia M, Martelli F, Farsetti A, Capogrossi MC, Zeiher AM, Gaetano C, Spallotta F,
Pharmacology & therapeutics. 11-Oct-2016
Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms. Intriguingly, the heart is emerging as a source of different cells, including pericytes, cardiac progenitors, and cardiac fibroblasts. According to phenotypic, functional, and molecular criteria, these should be classified as mesenchymal cells. Not surprisingly, in recent years, the attention on these cells as therapeutic tools has grown exponentially, although only very preliminary data have been obtained in clinical trials to date. In this review, we summarized the state of the art about the phenotypic features, functions, regenerative properties, and clinical applicability of mesenchymal cells, with a particular focus on those of cardiac origin.
Pathophysiological aldosterone levels modify the secretory activity of cardiac progenitor cells.Saturday, October 15, 2016
Wenzel K, Samal R, Hammer E, Dhople VM, Gross S, Völker U, Felix SB, Könemann S,
Molecular and cellular endocrinology. 12-Oct-2016
Cardiac progenitor cells (CPCs) trigger regenerative processes via paracrine mechanisms in response to changes in their environment. In the present study we explored alterations in the secretory activity of CPCs induced by raised aldosterone levels symptomatic for heart failure. The cytokine profile of the supernatant of CPCs that were treated with the mineralocorticoid showed an induction of interleukin-6 secretion. Mass spectrometric analyses revealed an increase in the abundance of secreted proteins associated with regeneration and cell migration like gelsolin and galectin-1. Differential regulation of proteins associated with the extracellular matrix further points to an activation of cell migration. In response to supernatant, migration and proliferation were induced in CPCs, indicating a potential role of paracrine factors in the activation of CPCs from other regions of the heart or extra-cardiac sources. Changes in the secretory activity of CPCs might aim to compensate for the detrimental actions of aldosterone in heart failure.
Immobilization and delivery of biologically active Lipoxin A4 using electrospinning technology.Wednesday, October 12, 2016
Cianci E, Trubiani O, Diomede F, Merciaro I, Meschini I, Bruni P, Croce F, Romano M,
International journal of pharmaceutics. 11-Oct-2016
Lipoxin (LX)A4 is a lipoxygenase-formed arachidonic acid metabolite with potent anti-inflammatory, pro-resolution properties. Its therapeutic efficacy has been largely demonstrated in a variety of cellular, preclinical and clinical models. Among these, periodontal disease, where LXA4 promotes tissue repair, also by modulating functions of human periodontal ligament stem cells (hPDLSCs). As medicated biomembranes may be particularly useful in clinical settings, where local stimulation of tissue repair is needed, we used electrospinning to embed LXA4 in membranes made of poly(ethylene oxide) (PEO) and poly(d,l-lactide) (PDLLA). These membranes were fully characterized by scanning electron microscopy, differential scanning calorimetry and biocompatibility with hPDLSCs. Here, we report that LXA4 is retained in these membranes and that ∼15-20% of the total LXA4 amount added to the reaction can be eluted from the membranes using an aqueous buffered medium. The eluted LXA4 fully retained its capability to stimulate hPDLSC proliferation. A similar effect was obtained by adding directly the LXA4-containing membranes to cells. These results demonstrate for the first time that LXA4 can be incorporated into biomembranes, which may be useful to combat local inflammation and promote tissue repair in selected clinical settings.
Dipeptide-functionalized polyamidoamine dendrimer-mediated apoptin gene delivery facilitates apoptosis of human primary glioma cells.Wednesday, October 12, 2016
Bae Y, Green ES, Kim GY, Song SJ, Mun JY, Lee S, Park JI, Park JS, Ko KS, Han J, Choi JS,
International journal of pharmaceutics. 11-Oct-2016
Glioblastoma multiform (GBM) is the most frequent and aggressive form of brain tumors in adults. However, the development of more efficient and safe nonviral vector gene therapy represents a promising therapeutic approach, using a tumor-specific killer gene, named apoptin. In this study, we describe the efficacy of non-viral gene delivery vectors, the amino acid-conjugated PAMAM derivatives (PAMAM-H-R and PAMAM-H-K) in delivering a therapeutic gene, displaying affinity toward human primary glioma cells (GBL-14 cells) and dermal fibroblasts. We analyzed transfection efficiency, using luciferase (Luci) and a pDNA encoding for enhanced fluorescent protein (EGFP), and cytotoxicity in both cells. The results show that transfection efficiency of PAMAM-H-R improved compared to native PAMAM dendrimer, but cytotoxicity of PAMAM-H-R and PAMAM-H-K were very low. We treated both cells with a polyplex formation of PAMAM-H-R or PAMAM-H-K/apoptin, and analyzed their cellular uptake and localization by flow cytometry and confocal microscopy. Furthermore, we analyzed the endosomal escape effect using TEM images, and found that PAMAM-H-R showed very fast escape from endosome to the cytosol. Caspase 3 activity assay, cell cycle distribution, and JC-1 analysis showed apoptosis induced by apoptin in GBL-14 cells. This indicates that PAMAM-H-R can be a potential nonviral vector gene delivery carrier for brain tumor therapy. The present study demonstrates that PAMAM-H-R/apoptin gene polyplex can be used as an effective therapeutic candidate for GBM due to its selective induction of apoptosis in primary glioma cells as a potential nonviral gene delivery carrier for brain tumor therapy.
Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation.Wednesday, October 12, 2016
Munehira Y, Yang Z, Gozani O,
Journal of molecular biology. 11-Oct-2016
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system. Our analysis identified that LSD1 is the only KDM required for myogenic differentiation and that KDM3B, KDM6A, and KDM8 are the candidate KDMs required for osteoblast differentiation. We find that LSD1, via H3K4me1 demethylation, represses the master regulator of osteoblast differentiation RUNX2 to promote myogenesis in the C2C12 model system. Finally, MLL4 is required for efficient osteoblast differentiation in part by countering LSD1 H3K4me1 demethylation at the RUNX2 enhancer. Together, our findings provide additional mechanisms by which lysine methylation signaling impacts on cell fate decisions.
Development and characterization of a human embryonic stem cell-derived 3D neural tissue model for neurotoxicity testing.Wednesday, October 12, 2016
Sandström J, Eggermann E, Charvet I, Roux A, Toni N, Greggio C, Broyer A, Monnet-Tschudi F, Stoppini L,
Toxicology in vitro : an international journal published in association with BIBRA. 8-Oct-2016
Alternative models for more rapid compound safety testing are of increasing demand. With emerging techniques using human pluripotent stem cells, the possibility of generating human in vitro models has gained interest, as factors related to species differences could be potentially eliminated. When studying potential neurotoxic effects of a compound it is of crucial importance to have both neurons and glial cells. We have successfully developed a protocol for generating in vitro 3D human neural tissues, using neural progenitor cells derived from human embryonic stem cells. These 3D neural tissues can be maintained for two months and undergo progressive differentiation. We showed a gradual decreased expression of early neural lineage markers, paralleled by an increase in markers specific for mature neurons, astrocytes and oligodendrocytes. At the end of the two-month culture period the neural tissues not only displayed synapses and immature myelin sheaths around axons, but electrophysiological measurements also showed spontaneous activity. Neurotoxicity testing - comparing non-neurotoxic to known neurotoxic model compounds - showed an expected increase in the marker of astroglial reactivity after exposure to known neurotoxicants methylmercury and trimethyltin. Although further characterization and refinement of the model is required, these results indicate its potential usefulness for in vitro neurotoxicity testing.
Immunomodulatory/anti-inflammatory effect of ZOE-based dental materials.Tuesday, October 11, 2016
Lee JH, Lee HH, Kim HW, Yu JW, Kim KN, Kim KM,
Dental materials : official publication of the Academy of Dental Materials. 7-Oct-2016
ZOE was highly cytotoxic, especially during setting, to both cells due to Zn(2+) while the immunomodulatory/anti-inflammatory effect of ZOE was induced by eugenol.
Half generations magnetic PAMAM dendrimers as an effective system for targeted gemcitabine delivery.Tuesday, October 11, 2016
Parsian M, Mutlu P, Yalcin S, Tezcaner A, Gunduz U,
International journal of pharmaceutics. 7-Oct-2016
Tumor-specific delivery of anticancer drugs by magnetic nanoparticles will maximize the efficacy of the drug and minimize side effects, and reduce systemic toxicity. The magnetic core of these nanoparticles provides an advantage for selective drug targeting as they can be targeted to the tumor site and accumulated in cancer cells by means of an external magnetic field. Magnetic nanoparticles can be coated with Polyamidoamine (PAMAM) dendrimer and loaded with drugs. However, biomedical applications of PAMAM dendrimers are limited due to their toxicity associated with their multiple cationic charges due to terminal NH2 groups. Modifying the positively charged end groups with negatively charged COOH groups, is a satisfactory strategy for obtaining less toxic PAMAM dendrimers. Gemcitabine being an analogue of deoxycytidine, is an effective anticancer drug. However, clinical benefits of Gemcitabine are limited due to its short biological half-life. The aim of this study was to obtain an effective, less toxic targeted delivery system for Gemcitabine. Half generations, between G4.5 and G7.5, of PAMAM dendrimer coated magnetic nanoparticles (DcMNPs) were synthesized and conjugated with Gemcitabine. TEM images showed nanoscale size (12-14nm) of the nanoparticles. The zeta-potential analysis indicated a decreased negativity of surface charge in drug bound dendrimer compared to the empty nanoparticles. Gemcitabine was effectively conjugated successfully onto the surface of half-generations of PAMAM DcMNPs. It was observed Gemcitabine did not effectively bind to Generations G4 and G5. The highest drug loading was obtained for DcMNPs with Generation 5.5. Empty nanoparticles showed no significant cytotoxicity on SKBR-3 and MCF-7 cells. On the other hand, Gemcitabine loaded nanoparticles were 6.0 fold more toxic on SKBR-3 and 3.0 fold more toxic on MCF-7 cells compared to free Gemcitabine. Gemcitabine loaded on Generation 5.5 DcMNPs showed a higher stability than free Gemcitabine. About 94% of the drug was retained over 6 weeks period, at pH 7.2. Due to their targetability under magnetic field, stability, size distribution, cellular uptake and toxicity characteristics the dendrimeric nanoparticles obtained in this study can be useful a delivery system for Gemcitabine in cancer therapy.
Analysis of hematopathology and alteration of JAK1/STAT3/STAT5 signaling axis in experimental myelodysplastic syndrome.Tuesday, October 11, 2016
Daw S, Chatterjee R, Law A, Law S,
Chemico-biological interactions. 8-Oct-2016
Hematological disorders like myelodysplastic syndrome (MDS) may arise due to cumulative dysregulation of various signalling pathways controlling proliferation, differentiation, maturation and apoptosis of bone marrow cells. This devastating bone marrow condition can be due to consequential abnormalities in haematopoiesis as well as its supportive microenvironment. Although mutations related to JAK/STAT pathway are common in myeloproliferative neoplasms, further studies are required to fully explore the myelodysplastic scenario regarding the concerned pathway. In this study, we have investigated the JAK-STAT signalling pathway which inevitably plays a crucial role in haematopoiesis. MDS was mimicked in a mouse model with an induction of ENU in adult mice. The bone marrow of the control and MDS groups of animals were subjected to a variety of tests, including cell morphology study in peripheral blood and bone marrow, cytochemistry and histochemistry of bone marrow smears, karyotyping and flowcytometric expression analysis of the phosphorylated forms of proteins like JAK1, STAT3 and STAT5 (denoted as pJAK1, pSTAT3 and pSTAT5) and the phenotypic expression of proteins like CD45 and CD71. The results revealed that the morphology of the blood and bone marrow cells were dysplastic compared to the affected blast populations of different lineages. The expression of common leucocyte antigen CD45 was less in comparison to the expression of transferrin receptor CD71 which was increased in the ENU induced MDS mouse model. Moreover, we have observed an upregulated expression of JAK1 followed by STAT5. Therefore, we can conclude that downregulation of CD45 may have helped in the upregulation of JAK-STAT signaling and CD71 expression. This aberrant signaling may be among one of the activated signaling axes that lead to affected hematopoietic lineages in Myelodysplastic syndrome.
KATapulting toward Pluripotency and Cancer.Monday, October 10, 2016
Hirsch CL, Wrana JL, Dent SY,
Journal of molecular biology. 6-Oct-2016
Development is generally regarded as a unidirectional process that results in the acquisition of specialized cell fates. During this process, cellular identity is precisely defined by signaling cues that tailor the chromatin landscape for cell-specific gene expression programs. Once established, these pathways and cell states are typically resistant to disruption. However, loss of cell identity occurs during tumor initiation and upon injury response. Moreover, terminally differentiated cells can be experimentally provoked to become pluripotent. Chromatin reorganization is key to the establishment of new gene expression signatures and thus new cell identity. Here, we explore an emerging concept that lysine acetyltransferase (KAT) enzymes drive cellular plasticity in the context of somatic cell reprogramming and tumorigenesis.
Mechanisms of cellular uptake and endosomal escape of calcium-siRNA nanocomplexes.Monday, October 10, 2016
Goldshtein M, Forti E, Ruvinov E, Cohen S,
International journal of pharmaceutics. 5-Oct-2016
Ca(2+)-siRNA nanocomplexes represent a simple yet an effective platform for siRNA delivery into the cell cytoplasm, with subsequent successful siRNA-induced target gene silencing. Herein, we aimed to elucidate the roles played by calcium ions in siRNA nanocomplex formation, cell uptake, and endosomal escape. We investigated whether the replacement of Ca(2+)in the nanocomplex by other bivalent cations would affect their cell entry and subsequent gene silencing. Our results indicate that Mg(2+) and Ba(2+) lead to the formation of nanocomplexes of similar physical features (size=100nm, surface charge ζ=-8mV) as the Ca(2+)-siRNA nanocomplexes. Yet, these nanocomplexes were not uptaken by the cells to the same extent as those prepared with Ca(2+), and siRNA-induced target gene silencing was not obtained. Cell internalization of Ca(2+-)-siRNA nanocomplexes, examined by employing chemical inhibitors to clathrin-, caveolin- and dynamin-mediated endocytosis pathways, indicated the involvement of all mechanisms in the process. Inhibition of endosome acidification by bafilomycin completely abolished the siRNA-mediated silencing by Ca(2+)-siRNA nanocomplexes. Collectively, our results indicate that Ca(2+) promotes cell internalization and rapid endosomal escape, thus leading to the efficient siRNA-induced target gene silencing elicited by the Ca(2+)-siRNA nanocomplexes.
Human adipose-derived stem cells ameliorate repetitive behavior, social deficit and anxiety in a VPA-induced autism mouse model.Saturday, October 08, 2016
Ha S, Park H, Mahmood U, Ra JC, Suh YH, Chang KA,
Behavioural brain research. 4-Oct-2016
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication, and patients often display co-occurring repetitive behaviors. Although the global prevalence of ASD has increased over time, the etiology and treatments for ASD are poorly understood. Recently, some researchers have suggested that stem cells have therapeutic potential for ASD. Thus, in the present study, we investigated the therapeutic effects of human adipose-derived stem cells (hASCs), a kind of autologous mesenchymal stem cells (MSCs) isolated from adipose tissue, on valproic acid (VPA)-induced autism model mice. Human ASCs were injected into the neonatal pups (P2 or P3) intraventricularly and then we evaluated major behavior symptoms of ASD. VPA-treated mice showed increased repetitive behaviors, decreased social interactions and increased anxiety but these autistic behaviors were ameliorated through transplantation of hASCs. In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice. The decreased level of vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10) by VPA were rescued in the brains of the hASC-injected VPA mice. With these results, we experimentally found hASCs' therapeutic effects on autistic phenotypes in a ASD model mice for the first time. This animal model system can be used to elucidate further mechanisms of therapeutic effects of hASCs in ASD.
Neural stem cells from mouse strain Thy1 YFP-16 are a valuable tool to monitor and evaluate neuronal differentiation and morphology.Friday, October 07, 2016
Alić I, Kosi N, Kapuralin K, Gorup D, Gajović S, Pochet R, Mitrečić D,
Neuroscience letters. 3-Oct-2016
To analyse events following transplantation of stem cells in the brain robust tools for tracing stem cells are required. Here we took advantage of the mouse strain B6.Cg-Tg(Thy1-YFP)16Jrs/J (Thy1 YFP-16), where yellow fluorescent protein (YFP) is under control of the promoter of Thy1 gene. This allows visualising whole neurons, i.e. their cell body, axons and dendrites. In this work fluorescent cells were followed during embryonic development, in vitro differentiation, and after transplantation in the healthy and stroke-affected mouse brain. During embryonic development Thy1-YFP positive cells were first observed on E12.5 and subsequently located in the prosencephalon, rhombencephalon, spinal cord and peripheral nerves. Quantitative analysis by RT-PCR and immunocytochemistry revealed that Thy1-YFP positive cells during embryo development and in vitro differentiation were expressing nestin and SOX2 then MAP2, β3-tubulin and NeuN. Thy1-YFP positive cells isolated from E14.5 represented 21.88±053% (SD) of the cultivated neurons and this remained constant along in vitro differentiation. On the other hand, proportion of Thy1-YFP positive cells reached 50% of neurons in perinatal and one month old mouse brain. Neural stem cells isolated from Thy1 YFP-16 mouse strain transplanted near hippocampus of the healthy and stroke-affected brain were distinguishable by YFP fluorescence. They differentiated into mature neurons and were detectable even 14 weeks after transplantation, the end point of our experiment. In conclusion, stem cells originating from Thy1 YFP-16 mice represent an outstanding tool to monitor neurogenesis enabling morphological analyses of new neurons and their projections, in particular after transplantation in the brain.
A stabilized peptide ligand for multifunctional glioma targeted drug delivery.Monday, October 03, 2016
Ying M, Shen Q, Zhan C, Wei X, Gao J, Xie C, Yao B, Lu W,
Journal of controlled release : official journal of the Controlled Release Society. 29-Sep-2016
Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of (L)A7R to receptors. It is very interesting that cA7R adopting a different structure from (L)A7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or (L)A7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or (L)A7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to (L)A7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did (L)A7R conjugation, which in turn, cA7R-LS/DOX could substantially suppress subcutaneous tumor growth when compared with other DOX formulations (free DOX, LS/DOX and (L)A7R-LS/DOX). The designed cyclic A7R exhibited the capability of targeting glioma cells, neovasculature and VM simultaneously in vivo. Considering the ease of synthesis, high binding affinity to receptors and increased stability of cA7R peptide in the present study, the design of head-to-tail cyclized peptides by the formation of amide bond based on computer-aided peptide design presents an alternative method to identify proteolytically stable peptide ligands.
Significance of optineurin mutations in glaucoma and other diseases.Monday, October 03, 2016
Minegishi Y, Nakayama M, Iejima D, Kawase K, Iwata T,
Progress in retinal and eye research. 29-Sep-2016
Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport. Recently, OPTN mutations were found to cause amyotrophic lateral sclerosis (ALS). Surprisingly, a mutation in the OPTN interacting protein, i.e., the duplication of TANK binding protein 1 (TBK1) gene, also can cause both NTG and ALS. These phenotypically distinct neuronal diseases are now merging into one common pathological mechanism by these two genes. TBK1 inhibition has emerged as a potential therapy for NTG. In this manuscript, we focus on the OPTN E50K mutation, the most common mutation for NTG, to describe the molecular mechanism of NTG by expressing a mutant Optn gene in cells and genetically modified mice. Patient iPS cells were developed and differentiated into neural cells to observe abnormal behavior and the impact of the E50K mutation. These in vitro studies were further extended to identify the inhibitors BX795 and amlexanox, which have the potential to reverse the disease-causing phenomenon in patient's neural cells. Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice.
Perturbation of redox balance after thioredoxin reductase deficiency interrupts autophagy-lysosomal degradation pathway and enhances cell death in nutritionally stressed SH-SY5Y cells.Monday, October 03, 2016
Nagakannan P, Iqbal MA, Yeung A, Thliveris JA, Rastegar M, Ghavami S, Eftekharpour E,
Free radical biology & medicine. 28-Sep-2016
Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases.
RhoA regulates Activin B-induced stress fiber formation and migration of bone marrow-derived mesenchymal stromal cell through distinct signaling.Monday, October 03, 2016
Wang X, Tang P, Guo F, Zhang M, Chen Y, Yan Y, Tian Z, Xu P, Zhang L, Zhang L, Zhang L,
Biochimica et biophysica acta. 28-Sep-2016
Better understanding of the molecular mechanisms of BMSCs migration will help optimize therapeutic strategy to target BMSCs at injured tissues.
Reactive oxygen species-mediated cardiac-reperfusion injury: Mechanisms and therapies.Monday, September 26, 2016
Bagheri F, Khori V, Alizadeh AM, Khalighfard S, Khodayari S, Khodayari H,
Life sciences. 15-Nov-2016
Reperfusion injury is an inherent response to the restoration of blood flow after ischemia. It is a complex process involving numerous mechanisms occurring in the intracellular and extracellular environments, and it is mediated in part by reactive oxygen species (ROS). The imbalance between the cellular formation of free radicals and cells' capacity to defend against them can cause cardiac tissue injuries. In this context, ROS play an essential role in both the organ injury and repair processes. After reperfusion, infiltration into the myocardium of inflammatory leucocytes, such as macrophages and neutrophils, causes further ROS production beyond the initiation of the inflammatory cascade. In this case, ROS overproduction is crucial in cardiac injury, and it can increase the complications related to cardiac reperfusion. In myocardial tissue, ROS can be produced from several sources, such as xanthine oxidase, cytochrome oxidase, cyclooxygenase, mediated unsaturated fatty acid oxidation, oxidation of catecholamines, mitochondrial oxidation, activation of leukocyte nicotinamide adenine dinucleotide phosphate oxidase, iron release, and reduction-oxidation reaction cycling; all of these sources reduce molecular oxygen in the reperfused myocardium. This review discusses about the molecular and therapeutic aspects of cardiac-reperfusion injuries generated by ROS. Experimental and clinical evidence with respect to the use of ischemic preconditioning, Ca(2+), nitric oxide, and conventional antioxidants in cardiac-reperfusion injury are summarized, and causal therapy approaches with various antioxidants are discussed.
Biocompatibility of three new calcium silicate-based endodontic sealers on human periodontal ligament stem cells.Monday, September 26, 2016
Collado-González M, García-Bernal D, Oñate-Sánchez RE, Ortolani-Seltenerich PS, Lozano A, Forner L, Llena C, Rodríguez-Lozano FJ,
International endodontic journal. 26-Sep-2016
BR and NCS were associated with better cytocompatibility than ES. Further in vitro and in vivo investigations are required to confirm the suitability of these calcium silicate-based endodontic sealers for clinical application.
Adverse early life environment increases hippocampal microglia abundance in conjunction with decreased neural stem cells in juvenile mice.Thursday, September 29, 2016
Cohen S, Ke X, Liu Q, Fu Q, Majnik A, Lane R,
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 22-Sep-2016
AELE increased the neuro-inflammatory cellular response in the juvenile HP. We speculate that increased neuro-inflammatory responses may contribute to impaired neurogenesis seen in this model.
Dentin remineralization in acid challenge environment via PAMAM and calcium phosphate composite.Monday, September 26, 2016
Liang K, Weir MD, Xie X, Wang L, Reynolds MA, Li J, Xu HH,
Dental materials : official publication of the Academy of Dental Materials. Nov-2016
The superior remineralization efficacy of PAMAM+NACP was demonstrated for the first time. PAMAM+NACP induced remineralization in demineralized dentin in an acid challenge environment, when conventional remineralization methods such as PAMAM did not work well. The novel PAMAM+NACP composite approach is promising for a wide range of dental applications to inhibit caries and protect tooth structures.
Distribution of the obligate endosymbiont Blochmannia floridanus and expression analysis of putative immune genes in ovaries of the carpenter ant Camponotus floridanus.Saturday, September 24, 2016
Kupper M, Stigloher C, Feldhaar H, Gross R,
Arthropod structure & development. Sep-2016
The bacterial endosymbiont Blochmannia floridanus of the carpenter ant Camponotus floridanus contributes to its hosts' ontogeny via nutritional upgrading during metamorphosis. This primary endosymbiosis is essential for both partners and vertical transmission of the endosymbionts is guaranteed by bacterial infestation of oocytes. Here we present a detailed analysis of the presence and localisation of B. floridanus in the ants' ovaries obtained by FISH and TEM analyses. The most apical part of the germarium harbouring germ-line stem cells (GSCs) is not infected by the bacteria. The bacteria are detectable for the first time in lower parts of the germarium when cystocytes undergo the 4th and 5th division and B. floridanus infects somatic cells lying under the basal lamina surrounding the ovarioles. With the beginning of cystocyte differentiation, the endosymbionts are exclusively transported from follicle cells into the growing oocytes. This infestation of the oocytes by bacteria very likely involves exocytosis-endocytosis processes between follicle cells and the oocytes. Nurse cells were never found to harbour the endosymbionts. Furthermore we present first gene expression data in C. floridanus ovaries. These data indicate a modulation of immune gene expression which may facilitate tolerance towards the endosymbionts and thus may contribute to their transovarial transmission.
Azithromycin modulates immune response of human monocyte-derived dendritic cells and CD4(+) T cells.Thursday, September 29, 2016
Lin SJ, Kuo ML, Hsiao HS, Lee PT,
International immunopharmacology. 21-Sep-2016
Azithromycin (AZM) is a macrolide antibiotic that exhibits anti-inflammatory activity aside from its antimicrobial effect, a feature that may ameliorate certain inflammatory disorders and prevent graft-versus-host disease in patients receiving stem cell transplantation. In the present study, we investigated the ability of AZM to influence the function of human monocyte-derived dendritic cells (DCs) and CD4(+) T cells. We found that AZM down-regulated CD80, CD86, and HLA-DR expression in lipopolysaccharide (LPS)-stimulated DCs and suppressed interleukin (IL)-6, IL-10, IL-12, and tumor necrosis factor-alpha production in these cells. In addition, AZM increased endocytosis and/or expression of Toll-like receptor (TLR)2, TLR4, and TLR9 in DCs and suppressed anti-CD3/CD28-induced CD4(+) T cell proliferation and interferon-gamma production, an effect that was synergistic with dexamethasone. Finally, AZM suppressed DC-induced allogeneic T cell proliferation and cytokine production. Our study demonstrates that AZM modulates DC and CD4(+) T cell function and may be of therapeutic benefit in various inflammatory disorders.
Effect of D609 on the expression of GADD45β protein: Potential inhibitory role in the growth of glioblastoma cancer stem like cells.Friday, September 30, 2016
Kalluri HS, Kuo JS, Dempsey RJ,
European journal of pharmacology. 20-Sep-2016
GADD45β (Growth Arrest and DNA Damage inducible protein) is a stress activated protein which plays an important role in regulating apoptosis, proliferation, DNA repair and potentially may have a role in cancer. In this study we examined the role of anti-oxidative stress on the expression of GADD45β in glioma stem-like cells (GSC). We show that patient derived GSCs have high survival in the absence of exogenous growth factors. Addition of D609 (Tricyclodecan-9-yl-xanthogenate), a known anti-oxidative compound, to GSCs reduced the cellular ATP content with significant effects observed when GSCs were cultured in growth factor free medium. D609 exposure also resulted in a decrease in the protein and an increase in mRNA of GADD45β with a concomitant decline in the survival of cells. However, under similar conditions the phosphorylation of p38 MAP kinase (stress activated MAP kinase), a downstream target of GADD45β, was significantly enhanced in response to D609. Therefore it appears that GADD45β might play a role in glioma stem cell survival and that p38 MAP kinase may not be directly activated by GADD45β. Together these observations suggest that anti-oxidative compounds like D609 can target GADD45β which may be one strategy to curtail the growth of glioma stem like cells.
Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.Tuesday, September 20, 2016
Takasuna K, Asakura K, Araki S, Ando H, Kazusa K, Kitaguchi T, Kunimatsu T, Suzuki S, Miyamoto N,
Journal of pharmacological and toxicological methods. 17-Sep-2016
Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi;, based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each. Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.
Hyaluronic acid-laminin hydrogels increase neural stem cell transplant retention and migratory response to SDF-1α.Tuesday, September 20, 2016
Addington CP, Dharmawaj S, Heffernan JM, Sirianni RW, Stabenfeldt SE,
Matrix biology : journal of the International Society for Matrix Biology. 17-Sep-2016
The chemokine SDF-1α plays a critical role in mediating stem cell response to injury and disease and has specifically been shown to mobilize neural progenitor/stem cells (NPSCs) towards sites of neural injury. Current neural transplant paradigms within the brain suffer from low rates of retention and engraftment after injury. Therefore, increasing transplant sensitivity to injury-induced SDF-1α represents a method for increasing neural transplant efficacy. Previously, we have reported on a hyaluronic acid-laminin based hydrogel (HA-Lm gel) that increases NPSC expression of SDF-1α receptor, CXCR4, and subsequently, NPSC chemotactic migration towards a source of SDF-1α in vitro. The study presented here investigates the capacity of the HA-Lm gel to promote NPSC response to exogenous SDF-1α in vivo. We observed the HA-Lm gel to significantly increase NPSC transplant retention and migration in response to SDF-1α in a manner critically dependent on signaling via the SDF-1α-CXCR4 axis. This work lays the foundation for development of a more effective cell therapy for neural injury, but also has broader implications in the fields of tissue engineering and regenerative medicine given the essential roles of SDF-1α across injury and disease states.
Oleanolic acid-loaded PLGA-TPGS nanoparticles combined with heparin sodium-loaded PLGA-TPGS nanoparticles for enhancing chemotherapy to liver cancer.Monday, September 19, 2016
Gao M, Xu H, Bao X, Zhang C, Guan X, Liu H, Lv L, Deng S, Gao D, Wang C, Tian Y,
Life sciences. 15-Nov-2016
This research suggests that the combined therapy system of OPTNs and HPTNs could be a new means of hepatoma therapy.
Metabolic profiling and in vitro assessment of anthelmintic fractions of Picria fel-terrae Lour.Sunday, September 18, 2016
Kumarasingha R, Karpe AV, Preston S, Yeo TC, Lim DS, Tu CL, Luu J, Simpson KJ, Shaw JM, Gasser RB, Beale DJ, Morrison PD, Palombo EA, Boag PR,
International journal for parasitology. Drugs and drug resistance. 26-Aug-2016
Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented.
Magnetic nanofiber scaffold-induced stimulation of odontogenesis and pro-angiogenesis of human dental pulp cells through Wnt/MAPK/NF-κB pathways.Friday, September 16, 2016
Yun HM, Kang SK, Singh RK, Lee JH, Lee HH, Park KR, Yi JK, Lee DW, Kim HW, Kim EC,
Dental materials : official publication of the Academy of Dental Materials. Nov-2016
This study is the first to demonstrate that magnetic nanofiber scaffolds stimulate HDPCs in the events of growth, odontogenic differentiation, and pro-angiogenesis, and the findings imply the novel scaffolds can be potentially useful as dentin-pulp regenerative matrices.
Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease.Friday, September 30, 2016
Vallejo A, Monge-Maillo B, Gutiérrez C, Norman FF, López-Vélez R, Pérez-Molina JA,
Acta tropica. 9-Sep-2016
Symptomatic chronic Chagas disease affects up to 40% of patients infected with Trypanosoma cruzi. The lack of reliable early markers of cure after therapy hinders disease management and clinical trials with new drugs. We performed a study with 18 months of follow-up to compare changes in immune parameters and T. cruzi-specific immune responses as surrogate markers of response to therapy between patients treated with benznidazole and untreated patients. This was a pilot, open-label, randomised clinical trial of treatment with benznidazole versus no treatment in patients with indeterminate chronic T. cruzi infection. In both groups we investigated changes in T-cell activation, T-cell subpopulations, regulatory T-cell counts, IL6, and sCD14 levels, and T. cruzi-specific immune responses (Th1, Th2, and Th17 responses). Fourteen patients were included in the study (seven in each group). Median age was 35 years (P25-75 31-43), 57% were female, and 93% were Bolivian. Benznidazole was administered at 5mg/kg/day for 60days. Three patients discontinued benznidazole owing to adverse reactions and were not evaluated. At the end of the follow-up period, treated patients showed significantly less immune activation and lower regulatory T-cell counts, with an increased Th17 and Th1 response. This randomised pilot clinical trial administering benznidazole to patients with indeterminate chronic Chagas disease brings about changes in the adaptive immunity, leading to a general decrease in inflammatory status. This apparently beneficial response could act as the basis for monitoring new antiparasitic drugs.
Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue.Monday, September 12, 2016
Gautieri A, Passini FS, Silván U, Guizar-Sicairos M, Carimati G, Volpi P, Moretti M, Schoenhuber H, Redaelli A, Berli M, Snedeker JG,
Matrix biology : journal of the International Society for Matrix Biology. 9-Sep-2016
Concurrent with a progressive loss of regenerative capacity, connective tissue aging is characterized by a progressive accumulation of Advanced Glycation End-products (AGEs). Besides being part of the typical aging process, type II diabetics are particularly affected by AGE accumulation due to abnormally high levels of systemic glucose that increases the glycation rate of long-lived proteins such as collagen. Although AGEs are associated with a wide range of clinical disorders, the mechanisms by which AGEs contribute to connective tissue disease in aging and diabetes are still poorly understood. The present study harnesses advanced multiscale imaging techniques to characterize a widely employed in vitro model of ribose induced collagen aging and further benchmarks these data against experiments on native human tissues from donors of different age. These efforts yield unprecedented insight into the mechanical changes in collagen tissues across hierarchical scales from molecular, to fiber, to tissue-levels. We observed a linear increase in molecular spacing (from 1.45nm to 1.5nm) and a decrease in the D-period length (from 67.5nm to 67.1nm) in aged tissues, both using the ribose model of in vitro glycation and in native human probes. Multiscale mechanical analysis of in vitro glycated tendons strongly suggests that AGEs reduce tissue viscoelasticity by severely limiting fiber-fiber and fibril-fibril sliding. This study lays an important foundation for interpreting the functional and biological effects of AGEs in collagen connective tissues, by exploiting experimental models of AGEs crosslinking and benchmarking them for the first time against endogenous AGEs in native tissue.
Small molecules exert anti-apoptotic effect and reduce oxidative stress augmenting insulin secretion in stem cells engineered islets against hypoxia.Friday, September 30, 2016
Chandravanshi B, Bhonde R,
European journal of pharmacology. 8-Sep-2016
Transplantation of pancreatic islets is the most reliable treatment for Type 1 diabetes. However cell death mediated by hypoxia is considered as one of the main difficulties hindering success in islet transplantation. The aim of our experiment was to investigate the role of small molecules in survival of Islet like cell aggregates (ICAs) engineered from umbilical cord matrix under oxygen deprived condition (<5% O2). ICAs were analyzed for cell death via fluoroscein diacetate/propidium iodide (FDA/PI) staining, estimation of Caspase 3 and free radical release in presence and absence of small molecules. The samples were also analyzed for the presence of hypoxia inducible factor 1α (HIF1α) at both transcriptional and translational level. The addition of small molecules showed profound defensive effect on ICAs under hypoxic environment as evidenced by their viability and insulin secretion compared to untreated ICAs. The combinations of Eicosapentaenoic acid (EPA), Docosahexaenoic acid(DHA) and metformin and EPA, DHAandγ amino butyric acid (GABA) acted as anti-apoptotic agents for human ICAs when exposed to 1% O2 for 48h. The combinations of the small molecules reduced the total reactive oxygen species and malonaldehyde (MDA) levels and enhanced the production of glutathione peroxidise (GPx) enzyme under hypoxic conditions. Finally the increase in HIF1α at both protein and gene level confirmed the defensive effect of the additives in hypoxia. These results suggest that the combination of small molecules maintained the viability and functionality of the ICAs in hypoxia by up-regulating HIF1α expression and down regulating the Caspase 3 activity.
Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells.Friday, September 30, 2016
Bayati S, Bashash D, Ahmadian S, Safaroghli-Azar A, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH,
European journal of pharmacology. 6-Sep-2016
Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK1 receptor (NK1R) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK1R expression as compared to normal lymphocytes, using NK1R antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of NK1R with aprepitant, a selective high-affinity antagonist of the human NK1R, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin. Our data showed that treatment of the cells with the inhibitor resulted in apoptotic cell death, at least partly, through abrogation of PI3K/Akt pathway, as revealed by the reduction of phospho/total Akt ratio. In agreement with the inhibitory effect on Akt, we also found that aprepitant increased the expression level of p21 and p27, which in turn leads to the induction of G1 cell cycle arrest. Overall, this study recommends mechanistic pathways by which inhibition of NK1R can augment apoptotic cell death through a plausible p53-dependent pathway rather than NF-κB-depended mechanism in pre-B ALL cells; however, further studies are needed to better characterize the application of NK1R inhibition in clinical cancer treatment.
3,3'-diindolylmethane mitigates total body irradiation-induced hematopoietic injury in mice.Tuesday, September 27, 2016
Lu L, Dong J, Li D, Zhang J, Fan S,
Free radical biology & medicine. 5-Sep-2016
We have reported that hematopoietic system injury induced by total body irradiation (TBI) leads to generation of intracellular reactive oxygen species (ROS) and DNA damage, which are ameliorated by antioxidant agents. In the present study, we reported that administration of DIM, a potent antioxidant agent, not only protected mice against TBI-induced lethality, also ameliorated TBI-induced hematopoietic injury. The latter effect was probably attributable to DIM's inhibition of TBI-induced increases in ROS production in hematopoietic stem cells (HSCs) and the phosphorylation of histone H2AX (γ-H2AX). In particular, DIM led to significant improvements in bone marrow (BM) HSC frequency, hematopoietic progenitor cell (HPC) clonogenic function, and multilineage engraftment after transplantation. A downregulation of NADPH oxidase 4 (NOX4) and an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression were observed following DIM treatment. Notably, the anti-apoptotic potential of DIM was correlated with increased expression of the anti-apoptotic protein Bcl-2 and decreased expression of the pro-apoptotic protein Bax. These findings suggest that DIM attenuates TBI-induced hematopoietic injury through the inhibition of both oxidative stress in HSCs and hematopoietic cell apoptosis. Furthermore, we demonstrated that DIM protected BM hematopoietic cells against ionizing radiation and led to increased clonogenicity in vitro. Therefore, DIM has the potential to be used as an effective radioprotectant to ameliorate TBI-induced hematopoietic injury.
The effect of ultrasound for increasing neural differentiation in hBM-MSCs and inducing neurogenesis in ischemic stroke model.Saturday, September 03, 2016
Cho SE, Kim YM, Jeong JS, Seo YK,
Life sciences. 15-Nov-2016
The present study showed that ultrasound promotes neural differentiation of hBM-MSC and neurogenesis in a mouse stroke model. This may be applicable as a therapeutic device with the aim of inducing neurogenesis following stroke.
The impact of serotonergic system dysfunction on the regulation of P4501A isoforms during liver insufficiency and consequences for thyroid hormone homeostasis.Tuesday, September 27, 2016
Kot M, Daujat-Chavanieu M,
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 24-Aug-2016
This study aimed to evaluate the impact of serotonergic system dysfunction on the regulation of cytochrome P4501A (CYP1A) during liver insufficiency. A rat model of liver insufficiency with a dysfunctional serotonergic system was developed. To induce liver insufficiency, animals were treated with nitrosodiethylamine (DEN) at 50 mg/kg of body weight twice a week for 7 weeks. To induce serotonergic system dysfunction, the animals were fed a tryptophan-free diet for 3 days. Serotonergic system dysfunction during liver insufficiency generated the aryl hydrocarbon receptor (AhR) activation and the "superinduction" of the AhR target genes: CYP1A1, CYP1B1 and UGT1A, with a concomitant increase in CYP1A1 protein and activity. CYP1A2 gene expression was simultaneously down-regulated, with a concomitant decrease in CYP1A2 protein and activity. A significant reduction in TRβ receptor levels, together with a simultaneous increase of TRα receptor gene and protein level (mainly TRα2 isoform) after serotonergic system dysfunction, suggests that the serotoninergic system is involved in the regulation of CYP1A isoforms without influence from thyroid hormones during liver insufficiency. The interplay between the serotonergic system and the regulation of CYP1A isoforms, which are downstream targets of AhR activation, is dependent on hepatic function and can be observed without influence from thyroid hormones.
Characterization and anti-proliferative activity of curcumin loaded chitosan nanoparticles in cervical cancer.Friday, September 30, 2016
Khan MA, Zafaryab M, Mehdi SH, Ahmad I, Rizvi MM,
International journal of biological macromolecules. 24-Aug-2016
In the present study the chitosan nanoparticles (CsNPs) and curcumin loaded chitosan nanoparticles (CLCsNPs) were synthesized by tripolyphosphate (TPP) cross-linking method. The nanoparticles were prepared within a zone of appropriate chitosan and TPP concentrations. The average size of CsNPs and CLCsNPs were approximately 189±11.8nm and 197±16.8nm, exhibited a zeta potential of +76±5.6mV and +71±6.4mV respectively and drug entrapment efficiency was ≈85%. The CLCsNPs and CsNPs were further characterized by different physicochemical methods like transmission electron microscopy (TEM), dynamic light scattering (DLS), HPLC, MALDI-TOF, FT-IR, XRD and UV-vis Spectroscopy. In vitro studies revealed a fast release of ≈35% at pH 5 and ≈25% at pH 7.4 of the drug during the first 3h, followed by controlled release of curcumin over a period of 120h and sustained anti-proliferative activity of the drug in a dose and time dependent manner of CLCsNPs and combination with methyl jasmonate. The higher cytotoxicity effect of CLCsNPs may be due to their higher cellular uptake as compared to curcumin. Chitosan nanoparticles were not only stable but also a nontoxic. Our data suggested that curcumin loaded nanoformulations, therefore, might be promising candidates in cancer therapy.
Mesenchymal stem cells growth and proliferation enhancement using PLA vs PCL based nanofibrous scaffolds.Friday, September 30, 2016
Marei NH, El-Sherbiny IM, Lotfy A, El-Badawy A, El-Badri N,
International journal of biological macromolecules. 20-Aug-2016
Electrospinning of polymers is the most commonly used technique for nanofiber fabrication. polylactic acid (PLA) and polycaprolactone (PCL) have been shown to be ideal for nanofiber preparation in various biomedical applications, due to characteristics such as biodegradablity and their ability to promote the cell growth, similar to native tissues. The aim of this study was to develop biocompatible and biodegradable PLA and PCL-based nanofibrous scaffolds for enhancing stem cell growth and proliferation. The scaffolds were prepared by electrospinning, and their physicochemical properties were studied using Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and X-ray diffraction (XRD). The surface morphology of the developed scaffolds was determined using scanning electron microscopy (SEM). Mesenchymal stem cells (MSCs), derived from both adipose tissue and bone marrow, were seeded onto the prepared nanofibrous scaffolds. The effect of scaffold type, and structural characteristics on survival and proliferation of MSCs were evaluated. Our results show that after full physicochemical characterization of PCL and PLA nanofibrous scaffolds both were safe and non-toxic to the evaluated cells and both scaffolds supported cell attachment and proliferation of bone marrow and adipose tissue-derived MSCs.
Genomic changes detected after serial passages in cell culture of virulent human G1P[8] rotaviruses.Friday, September 30, 2016
Tsugawa T, Tsutsumi H,
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 16-Aug-2016
Serial passages of a virulent mouse rotavirus in cell cultures caused a loss of virulence in mice. To gain insight into the genomic mutations in human rotavirus during cell culture and its attenuation in humans, we serially passaged three wild type human G1P[8] rotavirus strains (Wa, DC3695, DC5685) derived from diarrheal stool samples up to 60 times in two different cell cultures (human colon adenocarcinoma cell line: HT29, and primary African green monkey kidney cells: primary AGMK). We sequenced the whole genomes of 60 times-passaged strains and compared them with those of the original viruses. Most substitutions were detected in VP4, followed by substitutions in VP7 and NSP4 genes. Substitution at amino acid 385 in the putative VP4 fusion domain and substitution T45M in NSP4 genes were detected in all AGMK-passaged strains, respectively. These genomic changes are likely to correlate with a loss of rotavirus virulence in humans.
Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality.Wednesday, July 27, 2016
Donahue TR, Dawson DW,
Trends in endocrinology and metabolism: TEM. Nov-2016
Pancreatic ductal adenocarcinoma (PDA) is a devastating malignancy with limited and modest clinical treatments. High-throughput technologies and accurate disease models now provide a comprehensive picture of the diverse molecular signaling pathways and cellular processes governing PDA tumorigenesis. Central among these is oncogenic KRAS, a mediator of cellular plasticity, metabolic reprogramming, and inflammatory and paracrine signaling required for tumor development and maintenance. Biological aggressiveness is further conferred by a highly fibrotic and immunosuppressive PDA microenvironment that also acts as a barrier to effective drug delivery. The regulation of these mechanisms and their implications for early cancer detection, chemoprevention and therapy are discussed.
Nonadherent Spheres With Multiple Myeloma Surface Markers Contain Cells that Contribute to Sphere Formation and Are Capable of Internalizing Extracellular Double-Stranded DNA.Tuesday, July 19, 2016
Dolgova EV, Shevela EY, Tyrinova TV, Minkevich AM, Proskurina AS, Potter EA, Orishchenko KE, Zavjalov EL, Bayborodin SI, Nikolin VP, Popova NA, Pronkina NV, Ostanin AA, Chernykh ER, Bogachev SS,
Clinical lymphoma, myeloma & leukemia. Oct-2016
Nonadherent 3-D cell colonies (spheres) encompass B cells with CD73/CD20(+)/CD45(+)/CD19(dim) phenotype, as well as double-stranded DNA-internalizing cells. The latter cell type appears to function as a sphere-forming center. Different cells in the spheres communicate with each other by secreting specific sets of cytokines. For successful engraftment and tumor growth in mice, intact spheres containing ∼ 10(6) cells must be used.
Mesoscopic model of neuronal system deficits in Multiple Sclerosis.Saturday, July 16, 2016
Safarbali B, Hadaeghi F, Gharibzadeh S,
Journal of theoretical biology. 13-Jul-2016
Multiple Sclerosis (MS) is a devastating autoimmune disease which deteriorates the connections in central nervous system (CNS) through the attacks to oligodendrocytes. Studying its origin and progression, in addition to clinical developments such as MRI brain images, cerebrospinal fluid (CSF) variation and quantitative measures of disability (EDSS), which sought to early diagnosis and efficient therapy, there is an increasing interest in developing computational models using the experimental data obtained from MS patients. From the perspective of mathematical modelling, although the origin of systemic symptoms might be attributed to cellular phenomena in microscopic level such as axonal demyelination, symptoms mainly are observed in macroscopic levels. How to fill the gap between these two levels of system modelling, however, remains as a challenge in systems biology studies. Trying to provide a conceptual framework to bridge between these two levels of modelling in systems biology, we have suggested a mesoscopic model composed of interacting neuronal population, which successfully replicates the changes in neuronal population synchrony due to MS progression.
Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion.Friday, July 08, 2016
Cavallucci V, Fidaleo M, Pani G,
Trends in endocrinology and metabolism: TEM. Nov-2016
Adult neurogenesis initiated by neural stem cells (NSCs) contributes to brain homeostasis, damage repair, and cognition. Energy metabolism plays a pivotal role in neurogenic cell fate decisions regarding self-renewal, expansion and multilineage differentiation. NSCs need to fine-tune quiescence and proliferation/commitment to guarantee lifelong neurogenesis and avoid premature exhaustion. Accumulating evidence supports a model whereby calorie restriction or increased energy expenditure reinforce NSC quiescence and promote self-renewal. Conversely, growth/proliferation inputs and anabolic signals, although necessary for neurogenesis, deplete the NSCs pool in the long run. This framework incorporates the emerging neurogenic roles of nutrient-sensing signaling pathways, providing a rationale for the alarming connection between nutritional imbalances, metabolic disorders and accelerated brain aging.
Cancer Stem Cells, Epithelial to Mesenchymal Markers, and Circulating Tumor Cells in Small Cell Lung Cancer.Friday, July 01, 2016
Pore M, Meijer C, de Bock GH, Boersma-van Ek W, Terstappen LW, Groen HJ, Timens W, Kruyt FA, Hiltermann TJ,
Clinical lung cancer. Nov-2016
SCLC with a mesenchymal-like phenotype (c-MET(H)E-cad(L)) is associated with longer survival and showed a trend toward lower CTCs.
Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells.Friday, May 27, 2016
Corsaro A, Bajetto A, Thellung S, Begani G, Villa V, Nizzari M, Pattarozzi A, Solari A, Gatti M, Pagano A, Würth R, Daga A, Barbieri F, Florio T,
Oncotarget. 21-Jun-2016
Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.
High throughput chemical library screening identifies a novel p110-δ inhibitor that potentiates the anti-myeloma effect of bortezomib.Friday, May 27, 2016
Malek E, Driscoll JJ,
Oncotarget. 21-Jun-2016
Multiple myeloma (MM) remains an incurable plasma cell malignancy and drug resistance persists as the major cause of treatment failure leading to fatal outcomes. The phosphatidyl-inositol-3-kinase (PI3K) pathway is constitutively hyperactivated in MM to promote disease progression and drug resistance. While inhibiting PI3K induces apoptosis in MM and is predicted to increase tumor susceptibility to anticancer therapy, early-generation pan-PI3K inhibitors display poor clinical efficacy as well as intolerable side effects. Here, we found that PI3K activity is significantly upregulated in MM cell lines and patient tumor cells resistant to bortezomib and that the majority of PI3K activity in MM cells is dependent upon the p110-δ isoform. Genetic or pharmacologic inhibition of p110-δ substantially reduced myeloma viability and enhanced cellular sensitivity to bortezomib. Chemical library screens then identified a novel compound, DT97, that potently inhibited p110-δ kinase activity and induced apoptosis in MM cells. DT97 was evaluated in the NCI-60 panel of human cancer cell types and anticancer activity was greatest against MM, leukemia and lymphoma cells. Co-treatment with DT97 and bortezomib synergistically induced apoptosis in MM patient cells and overcame bortezomib-resistance. Although bone marrow stromal cells (BMSCs) promote MM growth, the pro-survival effects of BMSCs were significantly reduced by DT97 treatment. Co-treatment with bortezomib and DT97 reduced the growth of myeloma xenotransplants in murine models and prolonged host survival. Taken together, the results provide the basis for further clinical evaluation of p110-δ inhibitors, as monotherapy or in synergistic combinations, for the benefit of MM patients.
ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways.Wednesday, May 25, 2016
Zeng H, Gu H, Chen C, Li M, Xia F, Xie L, Liu X, Zhang F, Tong X, Wang J, Yu Z, Zheng J,
Oncotarget. 21-Jun-2016
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.
Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer.Wednesday, May 25, 2016
Lee KM, Lee M, Lee J, Kim SW, Moon HG, Noh DY, Han W,
Oncotarget. 21-Jun-2016
Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.
Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential.Wednesday, May 25, 2016
Sun R, Shen J, Gao Y, Zhou Y, Yu Z, Hornicek F, Kan Q, Duan Z,
Oncotarget. 21-Jun-2016
Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma.
The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.Wednesday, May 25, 2016
Wu Q, Madany P, Dobson JR, Schnabl JM, Sharma S, Smith TC, van Wijnen AJ, Stein JL, Lian JB, Stein GS, Muthuswami R, Imbalzano AN, Nickerson JA,
Oncotarget. 21-Jun-2016
Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.
Drug conjugated nanoparticles activated by cancer cell specific mRNA.Friday, May 20, 2016
Gossai NP, Naumann JA, Li NS, Zamora EA, Gordon DJ, Piccirilli JA, Gordon PM,
Oncotarget. 21-Jun-2016
We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated.
Nuclear delivery of recombinant OCT4 by chitosan nanoparticles for transgene-free generation of protein-induced pluripotent stem cells.Tuesday, May 17, 2016
Tammam S, Malak P, Correa D, Rothfuss O, Azzazy HM, Lamprecht A, Schulze-Osthoff K,
Oncotarget. 21-Jun-2016
Protein-based reprogramming of somatic cells is a non-genetic approach for the generation of induced pluripotent stem cells (iPSCs), whereby reprogramming factors, such as OCT4, SOX2, KLF4 and c-MYC, are delivered as functional proteins. The technique is considered safer than transgenic methods, but, unfortunately, most protein-based protocols provide very low reprogramming efficiencies. In this study, we developed exemplarily a nanoparticle (NP)-based delivery system for the reprogramming factor OCT4. To this end, we expressed human OCT4 in Sf9 insect cells using a baculoviral expression system. Recombinant OCT4 showed nuclear localization in Sf9 cells indicating proper protein folding. In comparison to soluble OCT4 protein, encapsulation of OCT4 in nuclear-targeted chitosan NPs strongly stabilized its DNA-binding activity even under cell culture conditions. OCT4-loaded NPs enabled cell treatment with high micromolar concentrations of OCT4 and successfully delivered active OCT4 into human fibroblasts. Chitosan NPs therefore provide a promising tool for the generation of transgene-free iPSCs.
MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis.Friday, April 15, 2016
Yang Z, Xu S, Jin P, Yang X, Li X, Wan D, Zhang T, Long S, Wei X, Chen G, Meng L, Liu D, Fang Y, Chen P, Ma D, Gao Q,
Oncotarget. 21-Jun-2016
The Cancer Genome Atlas network has revealed that the 'mesenchymal' epithelial ovarian cancer (EOC) subtype represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in disease progression. The cooperative role of CAFs in EOC metastasis has long been recognized, but the mechanisms of stromal CAFs activation are still obscure. Therefore, we carried out an integrative analysis to identify the regulator genes that are responsible for CAFs activation in microdissected tumor stroma profiles. Here, we determined that myristoylated alanine-rich C-kinase substrate (MARCKS) was highly expressed in ovarian stroma, and was required for the differentiation and tumor promoting function of CAFs. Suppression of MARCKS resulted in the loss of CAF features, and diminished role of CAFs in supporting tumor cell growth in 3D organotypic cultures and in murine xenograft model. Mechanistically, we found that MARCKS maintained CAF activation through suppression of cellular senescence and activation of the AKT/Twist1 signaling. Moreover, high MARCKS expression was associated with poor patient survival in EOC. Collectively, our findings identify the potential of MARCKS inhibition as a novel stroma-oriented therapy in EOC.
The deubiquitinase USP54 is overexpressed in colorectal cancer stem cells and promotes intestinal tumorigenesis.Friday, October 21, 2016
Fraile JM, Campos-Iglesias D, Rodríguez F, Español Y, Freije JM,
Oncotarget. 19-Oct-2016
Ubiquitin-Specific Proteases (USPs) are deubiquitinating enzymes frequently deregulated in human malignancies. Here, we show that USP54 is overexpressed in intestinal stem cells and demonstrate that its downregulation in colorectal carcinoma cells impedes tumorigenesis. We have generated mutant mice deficient for this deubiquitinase, which are viable and fertile, and protected against chemically-induced colorectal carcinoma. Furthermore, we show that USP54 is upregulated in human colon cancer and associates with poor prognosis. In agreement with these results, Usp54 downregulation in mouse melanoma cells inhibits lung metastasis formation. Collectively, this work has uncovered the pro-tumorigenic properties of USP54, highlighting the importance of deubiquitinating enzymes as promising targets for the development of specific anti-cancer therapies.
CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis.Friday, October 21, 2016
Tu Z, Chen Q, Zhang JT, Jiang X, Xia Y, Chan HC,
Oncotarget. 19-Oct-2016
While there is an increasing interest in the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) and cancer incidence, the role of CFTR in nasopharyngeal carcinoma (NPC) development remains unknown. In this study, we aimed to explore the prognostic value of CFTR in NPC patients. The expression of CFTR was determined in NPC cell lines and tissues. Statistical analysis was utilized to evaluate the correlation between CFTR expression levels and clinicopathological characteristics and prognosis in 225 cases of NPC patients. The results showed that CFTR was down-regulated in NPC tissues and cell lines. Low expression of CFTR was correlated with advanced stage (p = 0.026), distant metastasis (p < 0.001) and poor prognosis (p < 0.01). Multivariate analysis identified CFTR as an independent prognostic factor (p = 0.003). Additionally, wound healing and transwell assays revealed that overexpression of CFTR inhibited NPC cell migration and invasion, whereas knockdown of CFTR promoted cell migration and invasion. Thus, the current study indicates that CFTR, as demonstrated to play an important role in tumor migration and invasion, may be used as a potential prognostic indicator in NPC.
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