Browsing by Subject "Animal experiment"

Now showing 1 - 20 of 29

Open Access
Accumulation of nonylphenol in gold fish and suckermouth catfish in the semi static aquarium system
(Indian Veterinary Association, 2004) Uguz, C.; Dagcan, A. T.; Iscan, M.; Togan, I.
[No abstract available]
Open Access
Angiogenic heparin-mimetic peptide nanofiber gel improves regenerative healing of acute wounds
(American Chemical Society, 2017) Uzunalli, G.; Mammadov R.; Yesildal, F.; Alhan, D.; Ozturk, S.; Ozgurtas, T.; Güler, Mustafa O.; Tekinay, A. B.
Wound repair in adult mammals typically ends with the formation of a scar, which prevents full restoration of the function of the healthy tissue, although most of the wounded skin heals. Rapid and functional recovery of major wound injuries requires therapeutic approaches that can enhance the healing process via overcoming mechanical and biochemical problems. In this study, we showed that self-assembled heparin-mimetic peptide nanofiber gel was an effective bioactive wound dressing for the rapid and functional repair of full-thickness excisional wounds in the rat model. The bioactive gel-treated wounds exhibited increased angiogenesis (p < 0.05), re-epithelization (p < 0.05), skin appendage formation, and granulation tissue organization (p < 0.05) compared to sucrose-treated samples. Increased blood vessel numbers in the gel-treated wounds on day 7 suggest that angiogenesis played a key role in improvement of tissue healing in bioactive gel-treated wounds. Overall, the angiogenic heparin-mimetic peptide nanofiber gel is a promising platform for enhancing the scar-free recovery of acute wounds.
Open Access
Angiogenic peptide nanofibers improve wound healing in STZ-induced diabetic rats
(American Chemical Society, 2016-06) Senturk, B.; Mercan, S.; Delibasi, T.; Güler, Mustafa O.; Tekinay, A. B.
Low expressions of angiogenic growth factors delay the healing of diabetic wounds by interfering with the process of blood vessel formation. Heparin mimetic peptide nanofibers can bind to and enhance production and activity of major angiogenic growth factors, including VEGF. In this study, we showed that heparin mimetic peptide nanofibers can serve as angiogenic scaffolds that allow slow release of growth factors and protect them from degradation, providing a new therapeutic way to accelerate healing of diabetic wounds. We treated wounds in STZ-induced diabetic rats with heparin mimetic peptide nanofibers and studied repair of full-thickness diabetic skin wounds. Wound recovery was quantified by analyses of re-epithelialization, granulation tissue formation and blood vessel density, as well as VEGF and inflammatory response measurements. Wound closure and granulation tissue formation were found to be significantly accelerated in heparin mimetic gel treated groups. In addition, blood vessel counts and the expressions of alpha smooth muscle actin and VEGF were significantly higher in bioactive gel treated animals. These results strongly suggest that angiogenic heparin mimetic nanofiber therapy can be used to support the impaired healing process in diabetic wounds.
Open Access
Angiogenic peptide nanofibers repair cardiac tissue defect after myocardial infarction
(Acta Materialia Inc, 2017) Rufaihah, A. J.; Yasa, I. C.; Ramanujam, V. S.; Arularasu, S. C.; Kofidis, T.; Güler, Mustafa O.; Tekinay, A. B.
Myocardial infarction remains one of the top leading causes of death in the world and the damage sustained in the heart eventually develops into heart failure. Limited conventional treatment options due to the inability of the myocardium to regenerate after injury and shortage of organ donors require the development of alternative therapies to repair the damaged myocardium. Current efforts in repairing damage after myocardial infarction concentrates on using biologically derived molecules such as growth factors or stem cells, which carry risks of serious side effects including the formation of teratomas. Here, we demonstrate that synthetic glycosaminoglycan (GAG) mimetic peptide nanofiber scaffolds induce neovascularization in cardiovascular tissue after myocardial infarction, without the addition of any biologically derived factors or stem cells. When the GAG mimetic nanofiber gels were injected in the infarct site of rodent myocardial infarct model, increased VEGF-A expression and recruitment of vascular cells was observed. This was accompanied with significant degree of neovascularization and better cardiac performance when compared to the control saline group. The results demonstrate the potential of future clinical applications of these bioactive peptide nanofibers as a promising strategy for cardiovascular repair. Statement of Significance We present a synthetic bioactive peptide nanofiber system can enhance cardiac function and enhance cardiovascular regeneration after myocardial infarction (MI) without the addition of growth factors, stem cells or other biologically derived molecules. Current state of the art in cardiac repair after MI utilize at least one of the above mentioned biologically derived molecules, thus our approach is ground-breaking for cardiovascular therapy after MI. In this work, we showed that synthetic glycosaminoglycan (GAG) mimetic peptide nanofiber scaffolds induce neovascularization and cardiomyocyte differentiation for the regeneration of cardiovascular tissue after myocardial infarction in a rat infarct model. When the peptide nanofiber gels were injected in infarct site at rodent myocardial infarct model, recruitment of vascular cells was observed, neovascularization was significantly induced and cardiac performance was improved. These results demonstrate the potential of future clinical applications of these bioactive peptide nanofibers as a promising strategy for cardiovascular repair.
Open Access
Biocompatibility studies on lanthanum oxide nanoparticles
(Royal Society of Chemistry, 2015) Brabu, B.; Haribabu, S.; Revathy, M.; Anitha, S.; Thangapandiyan, M.; Navaneethakrishnan, K. R.; Gopalakrishnan, C.; Murugan, S. S.; Kumaravel, T. S.
Lanthanum oxide nanoparticles (LONP), a rare earth metal oxide, have unique properties that make them a suitable candidate for several biomedical applications. We investigated certain key in vitro and in vivo biocompatibility endpoints on LONP. LONP were cytotoxic in in vitro assays and predominantly exerted their action via release of reactive oxygen species. These nanoparticles were neither irritants nor sensitizers in a rabbit model. LONP extracts did not exert any acute systemic toxicity effects in mice. On the other hand LONP exerted toxicity to the liver following oral administration, suggesting that these particles are absorbed from the gastrointestinal (GI) tract and deposited in the hepatobiliary system. LONP did not induce any mutation in the Ames test both in the presence or absence of S-9. These observations provide a base line biocompatibility and toxicity data on LONP. The current findings will also be useful in defining standards for nanoparticle containing devices. © The Royal Society of Chemistry.
Open Access
Chondrogenic differentiation of mesenchymal stem cells on glycosaminoglycan-mimetic peptide nanofibers
(American Chemical Society, 2016) Yaylaci, S .U.; Sen, M.; Bulut, O.; Arslan, E.; Güler, Mustafa O.; Tekinay, A. B.
Glycosaminoglycans (GAGs) are important extracellular matrix components of cartilage tissue and provide biological signals to stem cells and chondrocytes for development and functional regeneration of cartilage. Among their many functions, particularly sulfated glycosaminoglycans bind to growth factors and enhance their functionality through enabling growth factor-receptor interactions. Growth factor binding ability of the native sulfated glycosaminoglycans can be incorporated into the synthetic scaffold matrix through functionalization with specific chemical moieties. In this study, we used peptide amphiphile nanofibers functionalized with the chemical groups of native glycosaminoglycan molecules such as sulfonate, carboxylate and hydroxyl to induce the chondrogenic differentiation of rat mesenchymal stem cells (MSCs). The MSCs cultured on GAG-mimetic peptide nanofibers formed cartilage-like nodules and deposited cartilage-specific matrix components by day 7, suggesting that the GAG-mimetic peptide nanofibers effectively facilitated their commitment into the chondrogenic lineage. Interestingly, the chondrogenic differentiation degree was manipulated with the sulfonation degree of the nanofiber system. The GAG-mimetic peptide nanofibers network presented here serve as a tailorable bioactive and bioinductive platform for stem-cell-based cartilage regeneration studies.
Open Access
Design of a novel MRI compatible manipulator for image guided prostate interventions
(IEEE, 2005-02) Krieger, A.; Susil, R. C.; Ménard, C.; Coleman, J. A.; Fichtinger, G.; Atalar, Ergin; Whitcomb, L. L.
This paper reports a novel remotely actuated manipulator for access to prostate tissue under magnetic resonance imaging guidance (APT-MRI) device, designed for use in a standard high-field MRI scanner. The device provides three-dimensional MRI guided needle placement with millimeter accuracy under physician control. Procedures enabled by this device include MRI guided needle biopsy, fiducial marker placements, and therapy delivery. Its compact size allows for use in both standard cylindrical and open configuration MRI scanners. Preliminary in vivo canine experiments and first clinical trials are reported.
Open Access
Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG
(Wiley - V C H Verlag GmbH & Co. KGaA, 2015) Yildiz, S.; Alpdundar, E.; Gungor, B.; Kahraman, T.; Bayyurt, B.; Gursel, I.; Gursel, M.
Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrate that a simple complex of cylic-di-GMP with a cell-penetrating peptide enhances both cellular delivery and biological activity of the cyclic-di-GMP in murine splenocytes. Furthermore, our findings establish that activation of the TLR-dependent and TLR-independent DNA recognition pathways through combined use of CpG oligonucleotide (ODN) and CDN results in synergistic activity, augmenting cytokine production (IFN-α/β, IL-6, TNF-α, IP-10), costimulatory molecule upregulation (MHC class II, CD86), and antigen-specific humoral and cellular immunity. Results presented herein indicate that 3′3′-cGAMP, a recently identified bacterial CDN, is a superior stimulator of IFN genes ligand than cyclic-di-GMP in human PBMCs. Collectively, these findings suggest that the immune-stimulatory properties of CDNs can be augmented through peptide complexation or synergistic use with CpG oligonucleotide and may be of interest for the development of CDN-based immunotherapeutic agents.
Open Access
Functionally conserved effects of rapamycin exposure on zebrafish
(Spandidos Publications, 2016-03) Sucularli, C.; Shehwana, H.; Kuscu, C.; Dungul, D. C.; Ozdag, H.; Konu, O.
Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase important in cell proliferation, growth and protein translation. Rapamycin, a well-known anti-cancer agent and immunosuppressant drug, inhibits mTOR activity in different taxa including zebrafish. In the present study, the effect of rapamycin exposure on the transcriptome of a zebrafish fibroblast cell line, ZF4, was investigated. Microarray analysis demonstrated that rapamycin treatment modulated a large set of genes with varying functions including protein synthesis, assembly of mitochondrial and proteasomal machinery, cell cycle, metabolism and oxidative phosphorylation in ZF4 cells. A mild however, coordinated reduction in the expression of proteasomal and mitochondrial ribosomal subunits was detected, while the expression of numerous ribosomal subunits increased. Meta-analysis of heterogeneous mouse rapamycin microarray datasets enabled the comparison of zebrafish and mouse pathways modulated by rapamycin, using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analysis. The analyses demonstrated a high degree of functional conservation between zebrafish and mice in response to rapamycin. In addition, rapamycin treatment resulted in a marked dose-dependent reduction in body size and pigmentation in zebrafish embryos. The present study is the first, to the best of our knowledge, to evaluate the conservation of rapamycin-modulated functional pathways between zebrafish and mice, in addition to the dose-dependent growth curves of zebrafish embryos upon rapamycin exposure.
Open Access
A glycosaminoglycan mimetic peptide nanofiber gel as an osteoinductive scaffold
(Royal Society of Chemistry, 2016) Tansik, G.; Kilic, E.; Beter, M.; Demiralp, B.; K.Sendur, G.; Can, N.; Ozkan, H.; Ergul, E.; Güler, Mustafa O.; Tekinay, A. B.
Biomineralization of the extracellular matrix (ECM) plays a crucial role in bone formation. Functional and structural biomimetic native bone ECM components can therefore be used to change the fate of stem cells and induce bone regeneration and mineralization. Glycosaminoglycan (GAG) mimetic peptide nanofibers can interact with several growth factors. These nanostructures are capable of enhancing the osteogenic activity and mineral deposition of osteoblastic cells, which is indicative of their potential application in bone tissue regeneration. In this study, we investigated the potential of GAG-mimetic peptide nanofibers to promote the osteogenic differentiation of rat mesenchymal stem cells (rMSCs) in vitro and enhance the bone regeneration and biomineralization process in vivo in a rabbit tibial bone defect model. Alkaline phosphatase (ALP) activity and Alizarin red staining results suggested that osteogenic differentiation is enhanced when rMSCs are cultured on GAG-mimetic peptide nanofibers. Moreover, osteogenic marker genes were shown to be upregulated in the presence of the peptide nanofiber system. Histological and micro-computed tomography (Micro-CT) observations of regenerated bone defects in rabbit tibia bone also suggested that the injection of a GAG-mimetic nanofiber gel supports cortical bone deposition by enhancing the secretion of an inorganic mineral matrix. The volume of the repaired cortical bone was higher in GAG-PA gel injected animals. The overall results indicate that GAG-mimetic peptide nanofibers can be utilized effectively as a new bioactive platform for bone regeneration. © 2016 The Royal Society of Chemistry.
Open Access
Heparin mimetic peptide nanofiber gel promotes regeneration of full thickness burn injury
(Elsevier Ltd, 2017) Yergoz, F.; Hastar, N.; Cimenci, C. E.; Ozkan, A. D.; Güler, Mustafa O.; Tekinay, A. B.; Tekinay, T.; Güler, Mustafa O.
Burn injuries are one of the most common types of trauma worldwide, and their unique physiology requires the development of specialized therapeutic materials for their treatment. Here, we report the use of synthetic, functional and biodegradable peptide nanofiber gels for the improved healing of burn wounds to alleviate the progressive loss of tissue function at the post-burn wound site. These bioactive nanofiber gels form scaffolds that recapitulate the structure and function of the native extracellular matrix through signaling peptide epitopes, which can trigger angiogenesis through their affinity to basic growth factors. In this study, the angiogenesis-promoting properties of the bioactive scaffolds were utilized for the treatment of a thermal burn model. Following the excision of necrotic tissue, bioactive gels and control solutions were applied topically onto the wound area. The wound healing process was evaluated at 7, 14 and 21 days following injury through histological observations, immunostaining and marker RNA/protein analysis. Bioactive peptide nanofiber-treated burn wounds formed well-organized and collagen-rich granulation tissue layers, produced a greater density of newly formed blood vessels, and exhibited increased re-epithelialization and skin appendage development with minimal crust formation, while non-bioactive peptide nanofibers and the commercial wound dressing 3M™ Tegaderm™ did not exhibit significant efficiency over sucrose controls. Overall, the heparin-mimetic peptide nanofiber gels increased the rate of repair of burn injuries and can be used as an effective means of facilitating wound healing.
Open Access
Implantable microelectromechanical sensors for diagnostic monitoring and post-surgical prediction of bone fracture healing
(John Wiley and Sons Inc., 2015) McGilvray, K. C.; Ünal, E.; Troyer, K. L.; Santoni, B. G.; Palmer, R. H.; Easley, J. T.; Demir, Hilmi Volkan; Puttlitz, C. M.
The relationship between modern clinical diagnostic data, such as from radiographs or computed tomography, and the temporal biomechanical integrity of bone fracture healing has not been well-established. A diagnostic tool that could quantitatively describe the biomechanical stability of the fracture site in order to predict the course of healing would represent a paradigm shift in the way fracture healing is evaluated. This paper describes the development and evaluation of a wireless, biocompatible, implantable, microelectromechanical system (bioMEMS) sensor, and its implementation in a large animal (ovine) model, that utilized both normal and delayed healing variants. The in vivo data indicated that the bioMEMS sensor was capable of detecting statistically significant differences (p-value <0.04) between the two fracture healing groups as early as 21 days post-fracture. In addition, post-sacrifice micro-computed tomography, and histology data demonstrated that the two model variants represented significantly different fracture healing outcomes, providing explicit supporting evidence that the sensor has the ability to predict differential healing cascades. These data verify that the bioMEMS sensor can be used as a diagnostic tool for detecting the in vivo course of fracture healing in the acute post-treatment period. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
Open Access
In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction
(Lippincott Williams & Wilkins, 2003) Kraitchman, D. L.; Heldman, A. W.; Atalar, Ergin; Amado, L. C.; Martin, B. J.; Pittenger, M. F.; Hare, J. M.; Bulte, J. W. M.
Background - We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. Methods and Results - Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16×107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. Conclusion - MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.
Open Access
Intravascular MR-monitored balloon angioplasty: An in vivo feasibility study
(Elsevier Inc., 1998) Yang, Xiaoming; Bolster Jr., B. D.; Kraitchman, D. L.; Atalar, Ergin
PURPOSE: To develop a new method for monitoring balloon angioplasty by using an intravascular magnetic resonance (MR) imaging technique. MATERIALS AND METHODS: Nine New Zealand White rabbits were used: seven for technique refinement, including surgery, device insertion, stenosis creation, and MR protocol development; and two for the final MR imaging of the balloon angioplasty. The in vivo experimental method involved insertion of a catheter antenna and a balloon catheter, via femoral arteriotomies bilaterally, into the target site of the upper abdominal aorta, where a stenosis was artificially created by binding a plastic cable tie. Then, the entire process of the dilation of the stenosis with balloon inflation was monitored under MR fluoroscopy. RESULTS: Catheter insertions were successful, and a 5-mm-long stenosis of the aorta was produced in all nine rabbits. Eight complete balloon angioplasty procedures were satisfactorily monitored and recorded, showing clearly the stenosis of the aorta at the beginning of the procedure, the dilation of the stenosis during the balloon inflation, and the complete opening of the stenosis after balloon dilation. CONCLUSION: Preliminary results of in vivo balloon angioplasty monitored with intravascular MR imaging are presented. MR fluoroscopy, based on the intravascular MR imaging technique, may represent a potential alternative to x-ray fluoroscopy for guiding interventional treatment of cardiovascular diseases.
Open Access
Jnk1 deficiency in hematopoietic cells suppresses macrophage apoptosis and increases atherosclerosis in low-density lipoprotein receptor null mice
(Lippincott Williams and Wilkins, 2016) Babaev, V. R.; Yeung, M.; Erbay, E.; Ding, L.; Zhang, Y.; May, J. M.; Fazio, S.; Hotamisligil, G. S.; Linton, M. F.
Objective - The c-Jun NH 2 -terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis. Approach and Results - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr-/- mice were reconstituted with wild-type, Jnk1-/-, and Jnk2-/- hematopoietic cells and fed a high cholesterol diet. Jnk1-/- →Ldlr-/- mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2-/- cells. Moreover, genetic ablation of JNK to a single allele (Jnk1+/- /Jnk2-/- or Jnk1-/- /Jnk2+/-) in marrow of Ldlr-/- recipients further increased atherosclerosis compared with Jnk1-/- →Ldlr-/- and wild-type→Ldlr-/- mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1-/- macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways. Conclusions - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.
Open Access
Laminin mimetic peptide nanofibers regenerate acute muscle defect
(Acta Materialia Inc, 2017) Cimenci, C. E.; Uzunalli, G.; Uysal, O.; Yergoz, F.; Umay, E. K.; Güler, Mustafa O.; Tekinay, A. B.
Skeletal muscle cells are terminally differentiated and require the activation of muscle progenitor (satellite) cells for their regeneration. There is a clinical need for faster and more efficient treatment methods for acute muscle injuries, and the stimulation of satellite cell proliferation is promising in this context. In this study, we designed and synthesized a laminin-mimetic bioactive peptide (LM/E-PA) system that is capable of accelerating satellite cell activation by emulating the structure and function of laminin, a major protein of the basal membrane of the skeletal muscle. The LM/E-PA nanofibers enhance myogenic differentiation in vitro and the clinical relevance of the laminin-mimetic bioactive scaffold system was demonstrated further by assessing its effect on the regeneration of acute muscle injury in a rat model. Laminin mimetic peptide nanofibers significantly promoted satellite cell activation in skeletal muscle and accelerated myofibrillar regeneration following acute muscle injury. In addition, the LM/E-PA scaffold treatment significantly reduced the time required for the structural and functional repair of skeletal muscle. This study represents one of the first examples of molecular- and tissue-level regeneration of skeletal muscle facilitated by bioactive peptide nanofibers following acute muscle injury. Significance Statement Sports, heavy lifting and other strength-intensive tasks are ubiquitous in modern life and likely to cause acute skeletal muscle injury. Speeding up regeneration of skeletal muscle injuries would not only shorten the duration of recovery for the patient, but also support the general health and functionality of the repaired muscle tissue. In this work, we designed and synthesized a laminin-mimetic nanosystem to enhance muscle regeneration. We tested its activity in a rat tibialis anterior muscle by injecting the bioactive nanosystem. The evaluation of the regeneration and differentiation capacity of skeletal muscle suggested that the laminin-mimetic nanosystem enhances skeletal muscle regeneration and provides a suitable platform that is highly promising for the regeneration of acute muscle injuries. This work demonstrates for the first time that laminin-mimetic self-assembled peptide nanosystems facilitate myogenic differentiation in vivo without the need for additional treatment.
Open Access
Local delivery of doxorubicin through supramolecular peptide amphiphile nanofiber gels
(Royal Society of Chemistry, 2017) Cinar, G.; Ozdemir, A.; Hamsici, S.; Gunay, G.; Dana, A.; Tekinay, A. B.; Güler, Mustafa O.
Peptide amphiphiles (PAs) self-assemble into supramolecular nanofiber gels that provide a suitable environment for encapsulation of both hydrophobic and hydrophilic molecules. The PA gels have significant advantages for controlled delivery applications due to their high capacity to retain water, biocompatibility, and biodegradability. In this study, we demonstrate injectable supramolecular PA nanofiber gels for drug delivery applications. Doxorubicin (Dox), as a widely used chemotherapeutic drug for breast cancer treatment, was encapsulated within the PA gels prepared at different concentrations. Physical and chemical properties of the gels were characterized, and slow release of the Dox molecules through the supramolecular PA nanofiber gels was studied. In addition, the diffusion constants of the drug molecules within the PA nanofiber gels were estimated using fluorescence recovery after the photobleaching (FRAP) method. The PA nanofiber gels did not show any cytotoxicity and the encapsulation strategy enhanced the activity of drug molecules on cellular viability through prolonged release compared to direct administration under in vitro conditions. Moreover, the local in vivo injection of the Dox encapsulated PA nanofiber gels (Dox/PA) to the tumor site demonstrated the lowest tumor growth rate compared to the direct Dox injection and increased the apoptotic cells within the tumor tissue for local drug release through the PA nanofiber gels under in vivo conditions.
Open Access
The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer
(Impact Journals LLC, 2016) Raza, U.; Saatci, O.; Uhlmann, S.; Ansari, S. A.; Eyüpoglu, E.; Yurdusev, E.; Mutlu, M.; Ersan, P. G.; Altundağ, M. K.; Zhang, J. D.; Dogan, H. T.; Güler, G.; Şahin, Ö.
Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.
Open Access
Nuclear exclusion of p33ING1b tumor suppressor protein: explored in HCC cells using a new highly specific antibody
(Mary Ann Liebert, Inc, 2009) Sayan, B.; Emre, N. C. T.; Irmak, M. B.; Ozturk, M.; Cetin Atalay, R.
Mouse monoclonal antibodies (MAb) were generated against p33ING1b tumor suppressor protein. 15B9 MAb was highly specific in recognizing a single protein band of ∼33 kDa endogenous p33ING1b protein from HCC cell lines and normal liver tissue by Western blot analysis and by immunoprecipitation. Although p33ING1b mutations are rarely observed in cancer, differential subcellular distribution and nuclear exclusion of p33ING1b were reported in different cancer types. Therefore we analyzed the expression and subcellular localization of p33ING1b in HCC cell lines using 15B9 MAb. So far, p33ING1b mutations or differential subcellular localization are not reported in HCC. In this study, by indirect immunofluorescence using MAb 15B9, we demonstrate that nuclear localization of p33ING1b was highly correlated with well-differentiated HCC cell lines whereas poorly differentiated HCC cells have nuclear exclusion of the protein. Moreover no association was observed between differential subcellular localization of p33ING1b and p53 mutation status of HCC cell lines. Hence our newly produced MAb 15B9 can be used for studying cellular activities of p33ING1b under normal and cancerous conditions. © Copyright 2009, Mary Ann Liebert, Inc.
Open Access
Patrolling monocytes control tumor metastasis to the lung
(American Association for the Advancement of Science, 2015) Hanna, R. N.; Cekic, C.; Sag, D.; Tacke, R.; Thomas, G. D.; Nowyhed, H.; Herrley, E.; Rasquinha, N.; McArdle, S.; Wu, R.; Peluso, E.; Metzger, D.; Ichinose, H.; Shaked, I.; Chodaczek, G.; Biswas, S. K.; Hedrick, C. C.
The immune system plays an important role in regulating tumor growth and metastasis. Classical monocytes promote tumorigenesis and cancer metastasis, but how nonclassical "patrolling" monocytes (PMo) interact with tumors is unknown. Here we show that PMo are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack PMo, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient PMo into Nr4a1-deficient mice prevented tumor invasion in the lung. PMo established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature, and promoted natural killer cell recruitment and activation. Thus, PMo contribute to cancer immunosurveillance and may be targets for cancer immunotherapy.