International Journal of Molecular Medicine (INT J MOL MED )

Publisher: Panepistēmio tēs Krētēs

Description

  • Impact factor
    1.96
    Show impact factor history
     
    Impact factor
  • 5-year impact
    2.05
  • Cited half-life
    5.80
  • Immediacy index
    0.31
  • Eigenfactor
    0.01
  • Article influence
    0.49
  • Website
    International Journal of Molecular Medicine website
  • Other titles
    International journal of molecular medicine (Online)
  • ISSN
    1107-3756
  • OCLC
    53915595
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Taurine (Tau), the most abundant free amino acid in humans has numerous potential health benefits through its antioxidant and anti‑inflammatory properties. However, limited studies have assessed its effect on tumors and the antitumor mechanism remains unknown. The present study investigated the cellular and molecular changes induced by Tau, leading to the induction of apoptosis in human breast cancer cell lines MCF‑7 and MDA‑MB‑231. MCF‑7 is p53 proficient (p53+/+) and MDA‑MB‑231 is a p53 null mutant (p53-/-). Cell proliferation and viability were assessed by MTT. Flow cytometry and hoechst33342 fluorescent staining were employed to detect apoptosis. Spectrophotometry was used to detect caspase‑3 activity. Reverse transcription‑polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53‑upregulated modulator of apoptosis (PUMA), Bax and Bcl‑2. Finally, the affect of Tau on the growth of MDA‑MB‑231‑cell‑nude mice xenografts was examined. In the study, Tau inhibited growth and induced apoptosis of the two cell lines in a concentration‑ and time‑dependent manner. Notably, the inhibitory effect of Tau on p53-/- cancer cells was clearly significant compared to the p53+/+ cancer cells. Further studies showed that Tau promoted apoptosis in human breast cancer cells and inhibited the growth of tumor in nude mice by inducing the expression of PUMA, which further up‑ and downregulated the expression of Bax and Bcl‑2 protein, giving rise to increased activation of caspase‑3. Collectively, these results indicate that Tau is a potent candidate for the chemotherapy of breast cancer through increasing the PUMA expression independent of p53 status.
    International Journal of Molecular Medicine 11/2014;
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    ABSTRACT: Interleukin-34 (IL-34) is a novel cytokine, which is composed of 222 amino acids and forms homodimers. It binds to the macrophage colony-stimulating factor (M-CSF) receptor and plays an important role in innate immunity and inflammatory processes. In the present study, we identified the completed IL-34 gene in 25 various mammalian genomes and found that IL-34 existed in all types of vertebrates, including fish, amphibians, birds and mammals. These species have a similar 7 exon/6 intron gene organization. The phylogenetic tree indicated that the IL-34 gene from the primate lineage, rodent lineage and teleost lineage form a species-specific cluster. It was found mammalian that IL-34 was under positive selection pressure with the identified positively selected site, 196Val. Fifty-five functionally relevant single nucleotide polymorphisms (SNPs), including 32 SNPs causing missense mutations, 3 exonic splicing enhancer SNPs and 20 SNPs causing nonsense mutations were identified from 2,141 available SNPs in the human IL-34 gene. IL-34 was expressed in various types of cancer, including blood, brain, breast, colorectal, eye, head and neck, lung, ovarian and skin cancer. A total of 5 out of 40 tests (1 blood cancer, 1 brain cancer, 1 colorectal cancer and 2 lung cancer) revealed an association between IL-34 gene expression and cancer prognosis. It was found that the association between the expression of IL-34 and cancer prognosis varied in different types of cancer, even in the same types of cancer from different databases. This suggests that the function of IL-34 in these tumors may be multidimensional. The upstream transcription factor 1 (USF1), regulatory factor X-1 (RFX1), the Sp1 transcription factor 1 , POU class 3 homeobox 2 (POU3F2) and forkhead box L1 (FOXL1) regulatory transcription factor binding sites were identified in the IL-34 gene upstream (promoter) region, which may be involved in the effects of IL-34 in tumors.
    International Journal of Molecular Medicine 11/2014;
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    ABSTRACT: The use of peptide‑based vaccines as therapeutics aims to elicit immune responses through antigenic epitopes derived from tumor antigens. Peptide‑based vaccines are easily synthesized and chemically stable entities, and of note, they are absent of oncogenic potential. However, their application is more complicated as the success of an effective peptide‑based vaccine is determined by numerous parameters. The success thus far has been limited by the choice of tumor antigenic peptides, poor immunogenicity and incorporation of strategies to reverse cancer‑mediated immune suppression. In the present review, an overview of the mechanisms of peptide‑based vaccines is provided and antigenic peptides are categorized with respect to their tissue distribution in order to determine their usefulness as targets. Furthermore, certain approaches are proposed that induce and maintain T cells for immunotherapy. The recent progress indicates that peptide‑based vaccines are preferential for targeted therapy in cancer patients.
    International Journal of Molecular Medicine 11/2014;
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    ABSTRACT: Peroxisome proliferator‑activated receptor γ (PPARγ) expression and activity are increased in brain ischemic injury and its agonists have shown potential for brain injury protection. The influence of 12/15‑lipoxygenase (12/15‑LOX) on the activity of PPARγ in oxygen‑glucose deprivation (OGD) and ischemia‑reperfusion (I/R) was investigated. A middle cerebral artery occlusion/reperfusion model with Sprague Dawley (SD) rats was established. For I/R intervention, the rats were treated with the 12/15‑LOX‑derived product 12‑hydroxyeicosatetraenoic acid (12‑HETE) for 30 min before cerebral artery occlusion. Primary cortical neurons from SD rats were used to establish an OGD cell model. 12‑HETE or a 12/15‑LOX antisense oligonucleotide (asON‑12/15‑LOX) was added to OGD‑treated neurons. Western blots, immunofluorescence and enzyme‑linked immunosorbent assays detected protein. Reverse transcription‑polymerase chain reaction analyzed the expression of the PPARγ target genes. PPARγ‑DNA binding activity was determined by peroxisome proliferator responsive element luciferase reporter vectors. 12/15‑LOX total protein increased significantly with I/R, and expression of 12‑HETE was also upregulated. 12‑HETE treatment increased PPARγ protein expression and inhibited inducible nitric oxide synthase protein expression, which was upregulated with I/R. PPARγ nuclear protein and 12/15‑LOX total protein expression in OGD‑treated neurons increased significantly. 12‑HETE treatment increased the expression of PPARγ nuclear protein, upregulated the mRNA levels of PPARγ target genes (lipoprotein lipase and acyl‑CoA oxidase) and enhanced PPARγ‑DNA binding activity. asON‑12/15‑LOX treatment inhibited 12/15‑LOX and PPARγ protein expression and lipoprotein lipase mRNA. Cerebral I/R injury in rats and OGD treatment in neurons promoted 12/15‑LOX expression, and 12‑HETE activated PPARγ. Therefore, PPARγ can be activated by the 12/15‑LOX pathway during cerebral I/R injury.
    International Journal of Molecular Medicine 11/2014;
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    ABSTRACT: Ageing is a major cause of illness, disease and mortality, mainly due to the shortening of telomeres, resulting in cells undergoing senescence and apoptosis. Increasing autophagy and the levels of antioxidants removes oxidants that cause DNA and telomere damage, thus reducing the rate at which telomeres shorten, resulting in a longer cellular lifespan. Phosphatase and tensin homolog (PTEN) has been shown to increase the lifespan of organisms by upregulating pathways involved in DNA damage repair, autophagy/antioxidants. The aim of this study was to investigate the effects of the overexpression of PTEN on the longevity of human cell cultures by examining the increase in antioxidant potential. Human umbilical vein endothelial cell (HUVEC) cultures were transfected with PTEN plasmids using lipofectamine. An assay was performed to quantify the protein levels of PTEN and the antioxidant potential of the cell cultures. The cell cultures were maintained until senescence occurred in order to determine longevity. The results of each assay were then compared and correlated with each other and with the longevity of the cells. The transfected cultures showed a significant increase in PTEN protein levels, total antioxidant potential and longevity (all P-values <0.001) compared with the non-transfected cell cultures. The correlation coefficient between cell longevity and PTEN levels was 0.8727; and the correlation coefficient between cell longevity and antioxidant potential was 0.6564. The successful transfection of PTEN led to an increase in PTEN levels, antioxidant potential and an increased cellular longevity. This study demonstrates that there is a potential for PTEN to be used to extend human longevity. This can lay the foundation for further studies to be carried out on humans involving PTEN and longevity.
    International Journal of Molecular Medicine 11/2014;
  • International Journal of Molecular Medicine; 11/2014
  • International Journal of Molecular Medicine 10/2014; 34(1):S34.
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    ABSTRACT: Tumor invasion and metastasis are the main causes of mortality in patients with hepatocellular carcinoma (HCC). Thus, the effective inhibition of these tumorigenic processes is critical in order for HCC therapy to be effective. Previous studies have demonstrated that Notch1 is associated with metastasis in several human malignancies. However, the exact molecular mechanisms underlying the Notch1-mediated induction of the invasion of HCC cells remain poorly understood. In the present study, we demonstrate that, compared to the normal liver cell line, L02, Notch1 is highly expressed in the human HCC cell lines, HepG2 and MHCC97H. Using small interfering RNA (siRNA), we knocked down the expression of Notch1 in the cell lines. Notch1 expression in the HCC cell lines was also measured following transfection with siRNA using RT-PCR and western blot analysis. In addition, a migration and invasion assay was performed to determine the effects of Notch1 knockdown on cell migration and invasion. Our results demonstrated that the downregulation of Notch1 by small interfering RNA (siRNA) significantly inhibited the migration and invasion of both HCC cell lines. Additionally, we demonstrated that the knockdown of Notch1 in both HCC cell lines increased both the total expression of phosphatase and tensin homolog (PTEN) and its phosphorylated form. By contrast, focal adhesion kinase (FAK) and phospho-FAK expression was decreased following Notch1 depletion. Taken together, our data suggest that targeting Notch1 may be a useful therapeutic approach to inhibiting the metastasis of HCC cells.
    International Journal of Molecular Medicine 08/2014;
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    ABSTRACT: Sirtuins (Sirt) are a family of phylogenetically conserved nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylases, among which Sirt3 resides primarily in the mitochondria and serves as a stress responsive deacetylase, playing a role in protecting cells from damage under stress conditions. The present study aimed to investigate the role of Sirt3 in hydrogen peroxide (H2O2)-induced oxidative neuronal injury in HT22 mouse hippocampal cells. Treatment with H2O2 increased the expression of Sirt3 in a dose- and time-dependent manner, and the knockdown of Sirt3 using specific small interfering RNA (siRNA) exacerbated the H2O2-induced neuronal injury. The overexpression of Sirt3 induced by lentiviral transfection significantly reduced the generation of reactive oxygen species (ROS) and lipid peroxidation following injury, whereas the activities of endogenous antioxidant enzymes were not affected. Further experiments revealed that the H2O2-induced inhibition of mitochondrial complex activity and adenosine triphosphate (ATP) synthesis, the decrease in mitochondrial Ca2+ buffering capacity and mitochondrial swelling were all partly reversed by Sirt3. Furthermore, the overexpression of Sirt3 attenuated the release of cytochrome c, the increase in the Bax/Bcl-2 ratio, as well as caspase-9/caspase-3 activity induced by H2O2, and eventually inhibited apoptotic neuronal cell death. These results suggest that Sirt3 acts as a prosurvival factor, playing an essential role in protecting HT22 cells under H2O2-induced oxidative stress, possibly by inhibiting ROS accumulation and the activation of the mitochondrial apoptotic pathway.
    International Journal of Molecular Medicine 08/2014;
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    ABSTRACT: The human prion protein (PrP) fragment PrP(106‑126) possesses the majority of the pathogenic properties associated with the infectious scrapie isoform of PrP, known as PrPSc. The accumulation of PrPSc in the brain of humans and animals affects the central nervous system. Recent epidemiological studies have suggested that caffeine, one of the major components of coffee, exerts protective effects against the development of neurodegeneration. However, the protective effects of caffeine against prion disease have not been reported to date. In this study, we therefore investigated the effects of caffeine on PrP-mediated neurotoxicity. The protein expression of the autophagosomal marker, LC3-II, was increased by caffeine in a dose-dependent manner, and the autophagy induced by caffeine protected the neuronal cells against PrP(106‑126)‑induced cell death. On the contrary, the downregulation of LC3-II using the autophagy inhibitors, 3-methyladenine (3-ΜΑ) and wortmannin, prevented the caffeine-mediated neuroprotective effects. To the best of our knowledge, the present study provides the first evidence that treatment with caffeine protects human neuronal cells against prion‑mediated neurotoxicity and these neuroprotective effects are mediated by caffeine-induced autophagy signals. Our data suggest that treatment with caffeine may be a novel therapeutic strategy for prion peptide‑induced apoptosis.
    International Journal of Molecular Medicine 08/2014; 34(2):553-8.
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    ABSTRACT: Berberine (BBR) is a botanical alkaloid that has been reported to have effects in cardiovascular diseases; however, the mechanisms involved are not yet fully understood. In the present study, the protective effects of BBR were evaluated, and the underlying molecular mechanisms were investigated. The effects of a combination of atorvastatin and BBR on foam cell formation were also investigated. THP-1-derived macrophages were pre-treated with BBR (5, 10 and 20 mg/l) for 2 h prior to the addition of oxidized low density lipoprotein (ox-LDL; 50 mg/l). Small interfering RNA (siRNA) targeting sirtuin 1 (SIRT1) and the adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibitor, compound C, were used to investigate the mechanisms through which BBR exerts its effects. To determine the effect of a combination of atorvastatin and BBR, the macrophages were treated with atorvastatin and BBR separately or jointly for 2 h, and then treated with ox-LDL (50 mg/l) or lipopolysaccharide (LPS; 10 µM) for 12 h. Oil Red O staining was used to detect foam cell formation. Lipid amounts were assessed by high-performance liquid chromatography (HPLC). Gene and protein expression was evaluated by RT-qPCR, western blot analysis and enzyme-linked immunosorbent assay (ELISA) carried out separately or jointly. The results from Oil Red O staining and HPLC revealed that BBR effectively suppressed foam cell formation and lipid and cholesterol accumulation. Furthermore, BBR upregulated the expression of SIRT1 and AMPK and downregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Pre-treatment of the cells with SIRT1-siRNA or compound C attenuated the anti-atherosclerotic effects of BBR. The results obtained in the present study demonstrate that the combination of atorvastatin and BBR is more effective in inhibiting foam cell formation than using atorvastatin alone. These data suggest that BBR suppresses foam cell formation by activating the AMPK-SIRT1-PPAR-γ pathway and diminishing the uptake of ox-LDL. Combination therapy with BBR and atorvastatin was more effective in preventing atherosclerotic processes than atorvastatin alone.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage and levels of DNA repair are reduced during dietary lipid lowering. The tumor suppressor molecules play a pivotal role in regulating cell proliferation, DNA repair and cell death, which are important processes in regulating the composition of atherosclerotic plaque. Accordingly, in this review, we discuss the fundamental role of tumor suppressor molecules in regulating atherogenesis. In particular, we discuss how tumor suppressor molecules are activated in the complex environment of atherosclerotic plaque, and regulate growth arrest, cell senescence and the apoptosis of vascular smooth muscle cells, which may protect against the progression of atherosclerosis. In addition, we discuss promising alternatives to the use of medications (such as statin) against atherosclerosis, namely diet, with the use of plant-derived supplements to modulate the expression and/or activity of tumor suppressor molecules. We also summarize the progress of research made on herbs with a focus on the modulatory roles of tumor suppressors, and on the molecular mechanisms underlying the prevention if atherosclerosis, supporting designs for further research in this field.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Proliferative vitreoretinopathy (PVR) is a common cause of intraoperative failure following retinal reattachment surgery and is mediated in part through the migration, de-differentiation and proliferation of retinal pigment epithelial (RPE) cells. Given the cytotoxic effects of curcumin on epithelial and endothelial cells, in this study, we assessed the effects of curcumin on human RPE (hRPE) cell proliferation. WST-1 analysis revealed that curcumin significantly inhibited primary hRPE cell proliferation in a dose- and time-dependent manner (P<0.001) with the greatest inhibition observed at the dose of 15 µg/ml curcumin. Flow cytometric analysis indicated that the cytotoxic effects of curcumin on hRPE cell proliferation were mediated by cell cycle arrest at the G0/G1 phase and the induction of apoptosis (both P<0.001), which was confirmed by ultrastructural analysis using transmission electron microscopy. Furthermore, western blot analysis revealed that curcumin induced p53 and p21WAF1/CIP1 expression with a concomitant decrease in proliferating cell nuclear antigen protein levels (P<0.05). Curcumin effectively inhibited primary hRPE cell proliferation, which may be mediated by the p53 pathway. Further in vivo studies are required in order to fully explore the therapeutic potential of curcumin for PVR.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Previous studies have demonstrated that the aberrant expression of Wnt5a occurs in atherosclerotic lesions. However, the precise role of Wnt5a in the pathogenesis of atherosclerosis remains largely unknown. The present study was undertaken to determine whether the RNA interference of Wnt5a in vivo by adenovirus (Ad)-mediated small interfering RNA (siRNA) transfection is capable of inhibiting the progression of atherosclerosis. Recombinant adenovirus carrying siRNA targeting Wnt5a (Ad-Wnt5a siRNA) was designed. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat diet to induce the pathogenesis of atherosclerosis. Mice were randomly divided into 3 groups (n=15 in each group): the mock group, which received treatment with phosphate-buffered saline (PBS); the Ad-NC group, which received treatment with Ad-non-specific siRNA; and the Ad-Wnt5a siRNA group, which received treatment with Ad-Wnt5a siRNA. Treatment with Ad-Wnt5a siRNA markedly inhibited the mRNA and protein expression of Wnt5a in the aortic tissues. The knockdown of Wnt5a had no significant effect on blood lipid levels, but it suppressed atherosclerotic development and increased plaque stability, which was determined by hematoxylin and eosin staining, picrosirius red staining and Oil Red O staining. Furthermore, the mRNA and protein expression of inflammatory cytokines, including monocyte chemotactic protein-1 (MCP-1), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-2 and MMP-9 was significantly downregulated in the Ad-Wnt5a siRNA group. In addition, the knockdown of Wnt5a inhibited the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. These results demonstrate that Ad-mediated Wnt5a silencing in vivo attenuates the development of atherosclerotic disease by reducing inflammatory mediators involved in the MAPK/NF-κB pathways.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various cell types. The regucalcin gene, which is localized on the X chromosome, consists of 7 exons and 6 introns. Decreased liver regucalcin gene expression has been suggested to play a suppressive role in the development of hepatocellular carcinogenesis in animal models. This study was undertaken to determine the changes in regucalcin gene expression in various human normal and tumor tissues, including liver, kidney, brain and lung tissues. The full-length and alternatively spliced variants of regucalcin mRNA were found to be expressed in various human tissues. This expression was suppressed in tumor tissues of hepatocellular carcinoma, kidney transitional cell carcinoma, brain malignant meningioma and lung non-small cell carcinoma. The full-length regucalcin protein was found to be highly expressed in normal human liver and kidney tissues; its expression was suppressed, however, in the liver and kidney tumor tissues. The spliced variant proteins were found to be expressed in the normal liver and kidney tissues, and decreased in the tumor tissues. Such alternative variants were not observed in the liver and kidneys of rats and mice. The alternatively spliced variants of the regucalcin gene were found to be expressed in various human normal and tumor tissues.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Cumulative findings have demonstrated that the dysregulation of tumor suppressor genes may be implicated in cigarette smoke-induced carcinogenesis. Activating enhancer-binding protein 2 (AP-2) is a eukaryotic transcriptional factor that plays a significant role in embryonic development and tumorigenesis. The vertebrate AP-2 family consists of AP-2α, AP-2β, AP-2γ, AP-2δ and AP-2ε. Previous studies have suggested that cigarette smoking disrupts AP-2 regulation. In the present study, we investigated the effects of cigarette smoke condensate (CSC) on AP-2α expression in human lung cancer cell lines (NCI-H1299, NCI-H446 and A549), as well as the potential mechanisms involved. Using RT-qPCR, we found that CSC decreased AP-2α expression by suppressing its transcription in human lung cancer cell lines, particularly in p53-deficient NCI-H1299 cells. Western blotting and luciferase assays were implemented and we found that the restoration of p53 expression rescued the NCI-H1299 cells from CSC-induced AP-2α loss, while the silencing of p53 resulted in increased AP-2α loss induced by CSC, suggesting an antagonizing role of p53 in the regulation of AP-2α by CSC. Our results indicate that AP-2α downregulation may be involved in smoke-induced lung carcinogenesis.
    International Journal of Molecular Medicine 07/2014;
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    ABSTRACT: Sphingosine-1-phosphate (S1P) is a pluripotent lipid mediator that transmits signals through G-protein-coupled receptors to control diverse biological processes. The novel biological activity of S1P in the adipogenesis of 3T3-L1 preadipocytes was identified in the present study. S1P significantly decreased lipid accumulation in maturing preadipocytes in a dose‑dependent manner. In order to understand the anti‑adipogenic effects of S1P, preadipocytes were treated with S1P, and the change in the expression of several adipogenic transcription factors and enzymes was investigated using quantitative RT-PCR. S1P downregulated the transcriptional levels of the peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding proteins and adiponectin, which are markers of adipogenic differentiation. The effects of S1P on the levels of mitogen‑activated protein kinase (MAPK) signals in preadipocytes were also investigated. The activation of JNK and p38 were downregulated by S1P treatment in human preadipocytes. In conclusion, the results of this study suggest that S1P alters fat mass by directly affecting adipogenesis. This is mediated by the downregulation of adipogenic transcription factors and by inactivation of the JNK and p38 MAPK pathways. Thus, selective targeting of the S1P receptors and sphingosine kinases may have clinical applications for the treatment of obesity.
    International Journal of Molecular Medicine 07/2014;