Jozef Dulak

Jagiellonian University, Cracovia, Lesser Poland Voivodeship, Poland

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Publications (175)776.97 Total impact

  • Toxicology 12/2014; · 3.75 Impact Factor
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    ABSTRACT: Background Peroxisome proliferator-activated receptor-¿ (PPAR¿) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPAR¿ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs).MethodsPACs were isolated from bone marrow of 10¿12 weeks old, wild type, db/db and PPAR¿ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 ¿mol/L) or GW9662 (10 ¿mol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model.ResultsECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPAR¿ activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells.Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPAR¿ and changed expression of PPAR¿-regulated genes. Using normoglycemic PPAR¿+/¿ mice we demonstrated that reduced expression of PPAR¿ does not influence neovascularization either in wound healing or in hind limb ischemia models.Conclusions In summary, activation of PPAR¿ by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPAR¿ in diabetes does not impair angiogenesis.
    Cardiovascular Diabetology 11/2014; 13(1):150. · 3.71 Impact Factor
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    ABSTRACT: Sarcoidosis is a granulomatous disease of unknown etiology. The disease has an important inflammatory and immune component; however, its immunopathogenesis is not completely understood. Recently, the role of microRNAs (miRNAs), the small non-coding RNAs, has attracted attention as both being involved in pathogenesis and serving as disease markers. Accordingly, changes in the expression of some miRNAs have been also associated with different autoimmune pathologies. However, not much is known about the role of miRNAs in sarcoidosis. Therefore, the aim of this study was to compare the level of expression of selected miRNAs in healthy individuals and patients with sarcoidosis. We detected significantly increased level of miR-34a in peripheral blood mononuclear cells isolated from sarcoidosis patients. Moreover, significantly up-regulated levels of interferon (IFN)-γ, IFN-γ inducible protein (IP-10) and vascular endothelial growth factor were detected in sera of patients when compared to healthy subjects. Our results add to a known inflammatory component in sarcoidosis. Changes in the levels of miR-34a may suggest its involvement in the pathology of this disease.
    Archivum Immunologiae et Therapiae Experimentalis 11/2014; · 2.38 Impact Factor
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    ABSTRACT: Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.
    PLoS ONE 05/2014; 9(5):e97070. · 3.53 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children. Two main subtypes of rhabdomyosarcoma with different molecular pattern and distinct clinical behaviour may be identified-embryonal and alveolar rhabdomyosarcoma. All types of rhabdomyosarcoma are believed to be of myogenic origin as they express high levels of myogenesis-related factors. They all, however, fail to undergo a terminal differentiation which results in tumour formation. In the aberrant regulation of myogenesis in rhabdomyosarcoma, microRNAs and epigenetic factors are particularly involved. Indeed, these mediators seem to be even more significant for the development of rhabdomyosarcoma than canonical myogenic transcription factors like MyoD, a master regulatory switch for myogenesis. Therefore, in this review we focus on the regulation of rhabdomyosarcoma progression by microRNAs, and especially on microRNAs of the myo-miRNAs family (miR-1, -133a/b and -206), other well-known myogenic regulators like miR-29, and on microRNAs recently recognized to play a role in the differentiation of rhabdomyosarcoma, such as miR-450b-5p or miR-203. We also review changes in epigenetic modifiers associated with rhabdomyosarcoma, namely histone deacetylases and methyltransferases, especially from the Polycomp Group, like Yin Yang1 and Enhancer of Zeste Homolog2. Finally, we summarize how the functioning of these molecules can be affected by oxidative stress and how antioxidative enzymes can influence the development of this tumour.
    The international journal of biochemistry & cell biology 05/2014; · 4.89 Impact Factor
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    ABSTRACT: In their recent paper published in Stem Cells and Development Suszynska et al. (Stem Cells Dev 2013 Dec 3. [Epub ahead of print]) discussed the strategies of analysing the so called very small embryonic-like cells (VSELs), defined as Lin<sup>-</sup>Sca-1<sup>+</sup>CD45<sup>-</sup>FSC<sup>low</sup>, which were claimed to be the pluripotent stem cells present in the bone marrow. In their text Suszynska et al. have cited our recent study published in PLoS One (Szade et al. PloS One 2013: 8: e63329), in which we undermined the stem cells characteristics of VSELs. The analysis performed by Suszynska et al. contains several statements we believe are misleading and we comment on them here.
    Stem cells and development 03/2014; · 4.15 Impact Factor
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    ABSTRACT: Type 2 diabetes is often complicated by diabetic foot syndrome (DFS). We analyzed the circulating stem cells, growth factor and anti-oxidant gene expression profiles in type 2 diabetes patients without or with different forms of DFS.
    Journal of Diabetes Investigstion 02/2014; 5(1):99-107. · 1.50 Impact Factor
  • Jozef Dulak, Alicja Jozkowicz
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    ABSTRACT: Not only double, Janus face, but numerous appearances characterize heme oxygenase-1 (HO-1), an inducible enzyme which main role is to degrade heme. Recently, the non-canonical functions of HO-1 have particularly attracted researchers' attention. Indeed, understanding the enzyme-independent activities of HO-1 can provide additional chances for translational application of research on HO-1. In this Forum Issue eight reviews and two original papers describe a plethora of mechanisms in which this pleiotropic protein is involved. Further understanding of HO-1 functions is of particular significance for elucidating the pathology of various human diseases and providing rationale for novel therapies.
    Antioxidants & Redox Signaling 12/2013; · 8.20 Impact Factor
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    ABSTRACT: Purpose. Retinal degenerative diseases targeting the retinal pigment epithelium (RPE) and adjacent photoreceptors affect millions of people worldwide. The field of stem cell- and gene-based therapy holds great potential for the treatment of such diseases. The present study sought to graft genetically engineered mesenchymal stem cells (MSCs) that continuously produce neurotrophin-4 (NT-4) into the murine eye after the onset of acute retinal injury. Methods. C57BL/6 mice were subjected to acute retinal damage using a low dose of sodium iodate (20 mg/kg of body weight), followed by intravitreal injection of lentivirally modified MSCs-NT-4 into the right eye. At 3 months after the MSC transplantation grafted cell survival, retinal function and gene expression were analyzed. Results. Immunofluorescence analysis confirmed that transplanted MSCs survived for at least 3 months after intravitreal injection and preferentially migrated towards sites of injury within the retina. MSC-NT-4 actively produced NT-4 in the injured retina and significantly protected damaged retinal cells, as evaluated by electroretinography (ERG) and optical coherence tomography (OCT). Importantly, the long-term therapy with MSCs-NT-4 was also associated with induction of prosurvival signaling, considerable overexpression of some subsets of transcripts, including several members of the crystallin β-γ superfamily (Cryba4, Crybb3, Cryba2, Crybb1, Crybb2, Cryba1, Crygc) and significant upregulation of biological processes associated with visual perception, sensory perception of light stimulus, eye development, sensory organ development, and system development. Conclusions. Transplantation of genetically modified MSCs that produce neurotrophic growth factors may represent a useful strategy for treatment of different forms of retinopathies in the future.
    Investigative ophthalmology & visual science 11/2013; · 3.43 Impact Factor
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    ABSTRACT: Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, which can be downregulated in diabetes. Its importance for mature endothelium has been described, but a role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin-CD45-cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1-/- BMDCs revealed the attenuated upregulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/- diabetic mice subjected to hind limb ischemia showed the reduced local expression of VEGF, PlGF, SDF-1, VEGFR-1, VEGFR-2, CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. Low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, what can be rescued by local injection of conditioned media from cultured BMDCs.
    Antioxidants & Redox Signaling 11/2013; · 8.20 Impact Factor
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    ABSTRACT: Vascular endothelial growth factors (VEGFs) are found at high levels in hypoxic tumors. As major components directing pathologic neo-vascularisation, they regulate stromal reactions. Consequently, novel strategies, targeting and inhibiting VEGF over-production upon hypoxia offer considerable potential for modern anti-cancer therapies controlling rather than destroying tumor angiogenesis. Here we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE-promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on the control of angiogenesis. A concomitant increase of intra-tumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel-controlled normalization and the novel design of adjuvants for combined cancer therapies.
    Molecular Cancer Therapeutics 10/2013; · 5.60 Impact Factor
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    ABSTRACT: Aim: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, IL-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PAC). Here we investigated angiogenic properties of Nrf2 in PAC, endothelial cells and inflammation-related revascularization. Results: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration and angiogenic potential of murine PAC and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2-/- in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2-/- mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, anti-inflammatory agent, etodolac, tended to diminish blood flow in the Nrf2-/- mice. Innovation: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PAC. Conclusion: Nrf2 contributes to angiogenic potential of both endothelial cells and PAC, however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PAC in such conditions.
    Antioxidants & Redox Signaling 09/2013; · 8.20 Impact Factor
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    ABSTRACT: Heme oxygenease-1 (HO-1) converts heme to biliverdin, carbon monoxide and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and pro-angiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. Recently, body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. In this review we discuss a role of HO-1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells.
    Antioxidants & Redox Signaling 09/2013; · 8.20 Impact Factor
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    ABSTRACT: Gene therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. Here we aimed to achieve angiogenic synergism between vascular endothelial growth factor-A (VEGF-A, VEGF) and fibroblast growth factor 4 (FGF4) in murine normoperfused and ischemic limb muscles. Adeno-associated viral vectors (AAVs) carrying beta-galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A) or two angiogenic genes (AAV-FGF4-IRES-VEGF-A) were injected into the normo-perfused adductor muscles of C57Bl/6 mice. Moreover, in a different experiment, mice were subjected to unilateral hindlimb ischemia by femoral artery ligation followed by intramuscular injections of AAV-LacZ, AAV-VEGF-A or AAV-FGF4-IRES-VEGF-A below the site of ligation. Post-ischemic blood flow recovery was assessed sequentially by color laser Doppler. Mice were monitored for 28 days. VEGF-A delivered alone (AAV-VEGF-A) or in combination with FGF4 (AAV-FGF4-IRES-VEGF-A) increased the number of capillaries in normo-perfused hindlimbs when compared to AAV-LacZ. Simultaneous overexpression of both agents (VEGF-A and FGF4) stimulated the capillary wall remodeling in the non-ischemic model. Moreover, AAV-FGF4-IRES-VEGF-A faster restored the post-ischemic foot blood flow and decreased the incidence of toe necrosis in comparison to AAV-LacZ. Synergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy.
    Vascular cell. 07/2013; 5(1):13.
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    ABSTRACT: Murine very small embryonic-like (VSEL) cells, defined by the Lin(-)Sca-1(+)CD45(-) phenotype and small size, were described as pluripotent cells and proposed to be the most primitive hematopoietic precursors in adult bone marrow. Although their isolation and potential application rely entirely on flow cytometry, the immunophenotype of VSELs has not been extensively characterized. Our aim was to analyze the possible heterogeneity of Lin(-)Sca(+)CD45(-) population and investigate the extent to which VSELs characteristics may overlap with that of hematopoietic stem cells (HSCs) or endothelial progenitor cells (EPCs). The study evidenced that murine Lin(-)Sca-1(+)CD45(-) population was heterogeneous in terms of c-Kit and KDR expression. Accordingly, the c-Kit(+)KDR(-), c-Kit(-)KDR(+), and c-Kit(-)KDR(-) subpopulations could be distinguished, while c-Kit(+)KDR(+) events were very rare. The c-Kit(+)KDR(-) subset contained almost solely small cells, meeting the size criterion of VSELs, in contrast to relatively bigger c-Kit(-)KDR(+) cells. The c-Kit(-)KDR(-)FSC(low) subset was highly enriched in Annexin V-positive, apoptotic cells, hence omitted from further analysis. Importantly, using qRT-PCR, we evidenced lack of Oct-4A and Oct-4B mRNA expression either in whole adult murine bone marrow or in the sorted of Lin(-)Sca-1(+)CD45(-)FSC(low) population, even by single-cell qRT-PCR. We also found that the Lin(-)Sca-1(+)CD45(-)c-Kit(+) subset did not exhibit hematopoietic potential in a single cell-derived colony in vitro assay, although it comprised the Sca-1(+)c-Kit(+)Lin(-) (SKL) CD34(-)CD45(-)CD105(+) cells, expressing particular HSC markers. Co-culture of Lin(-)Sca-1(+)CD45(-)FSC(low) with OP9 cells did not induce hematopoietic potential. Further investigation revealed that SKL CD45(-)CD105(+) subset consisted of early apoptotic cells with fragmented chromatin, and could be contaminated with nuclei expelled from erythroblasts. Concluding, murine bone marrow Lin(-)Sca-1(+)CD45(-)FSC(low) cells are heterogeneous population, which do not express the pluripotency marker Oct-4A. Despite expression of some hematopoietic markers by a Lin(-)Sca-1(+)CD45(-)c-Kit(+)KDR(-) subset of VSELs, they do not display hematopoietic potential in a clonogenic assay and are enriched in early apoptotic cells.
    PLoS ONE 05/2013; 8(5):e63329. · 3.53 Impact Factor
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    ABSTRACT: Aims: Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation while in various tumors it has been demonstrated to promote growth, angiogenesis and metastasis. Here we investigated whether HMOX1 can modulate microRNAs and regulate human non-small cell lung cancer (NSCLC) development. Results: Stable HMOX1 overexpression in NSCLC NCI-H292 cells upregulated tumor suppressive microRNAs, whereas significantly diminished expression of oncomirs and angiomirs. The most potently downregulated was miR-378. HMOX1 also upregulated p53, downregulated Ang-1 and MUC5AC, reduced proliferation, migration and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53, while enhanced expression of MUC5AC, VEGF, IL-8 and Ang-1 and consequently increased proliferation, migration and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors. Innovation and Conclusion: In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antoxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason and Yasufumi Sato.
    Antioxidants & Redox Signaling 04/2013; · 8.20 Impact Factor
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    ABSTRACT: Stable vesicles for efficient curcumin encapsulation, delivery and controlled release have been obtained by coating of liposomes with thin layer of newly synthesized chitosan derivatives. Three different derivatives of chitosan were obtained and studied: the cationic (by introduction of the stable, quaternary ammonium groups), the hydrophobic (by attachment of N-dodecyl groups) and cationic-hydrophobic one (containing both quaternary ammonium and N-dodecyl groups). Zeta potential measurements confirmed effective coating of liposomes with all these chitosan derivatives. The liposomes coated with cationic-hydrophobic chitosan derivative are the most promising curcumin carriers; they can easily penetrate cell membrane and release curcumin in a controlled manner. Biological studies indicated that such systems are non-toxic for murine fibroblasts (NIH3T3) while toxic toward murine melanoma (B16F10) cell line.
    Colloids and surfaces B: Biointerfaces 04/2013; 109C:307-316. · 4.28 Impact Factor
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    ABSTRACT: Therapeutic angiogenesis for peripheral artery disease (PAD), achieved by gene and cell therapy, has recently raised a great deal of hope for patients who cannot undergo standard revascularizing treatment. Although pre-clinical studies gave very promising data, still clinical trials of gene therapy have not provided satisfactory results. On the other hand, cell therapy approach, despite several limitations, demonstrated more beneficial effects but constantly initial clinical studies must be validated by larger randomized, multi-centre, double-blinded, placebo-controlled trials. This review focuses on previous and recent gene and cell therapy studies for limb ischemia, including both experimental and clinical research, and summarizes some important papers published in this field. Moreover, it provides a short comment on combined gene and cell therapy approach on the example of heme oxygenase-1 overexpressing cells with therapeutic properties.
    Gene 04/2013; · 2.20 Impact Factor
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    ABSTRACT: Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise has been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, β-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registred in European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases.
    Gene 04/2013; · 2.20 Impact Factor

Publication Stats

4k Citations
776.97 Total Impact Points


  • 1998–2013
    • Jagiellonian University
      • • Department of Medical Biotechnology
      • • Department of Cell Biochemistry
      • • Chair of Clinical Biochemistry
      • • Department of Clinical Biochemistry
      Cracovia, Lesser Poland Voivodeship, Poland
  • 2011
    • Virginia Commonwealth University
      • Division of Cardiology
      Richmond, VA, United States
  • 2001–2010
    • University of Vienna
      • • Department of Surgery
      • • Department of Cardio-Thoracic Surgery
      Wien, Vienna, Austria
  • 2006
    • National Institutes of Health
      • Laboratory of Experimental Immunology
      Bethesda, MD, United States
    • Kyushu University
      Hukuoka, Fukuoka, Japan
  • 2001–2005
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2002
    • Collegium Medicum of the Jagiellonian University
      • Chair of Clinical Biochemistry
      Cracovia, Lesser Poland Voivodeship, Poland
  • 1999
    • Stanford University
      • Division of Cardiovascular Medicine
      Palo Alto, California, United States