INTRODUCTION Gliomas are the most common brain and central nervous system (CNS) tumors. According to cancer statistics, gliomas account for approximately 80% of all malignant primary brain tumors and 57.3% of gliomas was glioblastoma (GBM) [1, 2]. Hideo Nakamura et al. reported that the incidence rate for glioma was 6•6 per www.aging-us.com
Liver cancer is the leading cause of cancer-related mortality worldwide and its incidence is increasing. Considerable effort has been made in recent decades to improve the diagnosis and treatment of liver cancer. Advanced liver cancer often exhibits a poor response to chemotherapy and poor prognosis due to acquired chemoresistance and tumor recurrence. Understanding the precise molecular mechanisms that are responsible for chemotherapeutic drug-induced cell death could potentially identify novel therapeutic targets and improve liver cancer treatment. In the present study, it was demonstrated that in response to doxorubicin, the most frequently used chemical compound for liver cancer treatment, histone deacetylase sirtuin 6 (SIRT6) is specifically downregulated. This enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme-inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin-induced cell death. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. Finally, it was identified that the effect of SIRT6 in preventing doxorubicin-induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin-induced cell death in FOXO3-knockdown cells. Therefore, it was concluded that SIRT6 plays a central role in determining doxorubicin-induced cell death via modulation of FOXO3 activity. Therapeutic targeting of SIRT6 and/or FOXO3 may offer novel strategies for treatment of liver cancer.
Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) mimic the immunostimulatory activity of microbial DNA by interacting with Toll-like receptor 9 (TLR9) to activate both the innate and adaptive immune responses in different species. However, few studies have been published to compare the effects of CpG ODN on different pig breeds. Therefore, in this study, whole blood gene expression profiles of DPL and Landrace pigs treated with CpG ODN were studied using RNA-seq technology. Five Hundred differentially expressed genes (DEGs) were identified between the two breeds. DPL pigs had significantly higher number of immune-relevant DEGs than the Landrace pigs after CpG ODN treatment. Pathway analysis showed that cytokine-cytokine receptor interaction and chemokine signaling pathway were the major enriched pathways of the immune-relevant DEGs. Further in vitro experiments showed that PBMCs of the DPL pigs had significantly higher levels of TLR9 mRNA than those of the Landrace pigs, both before and after CpG ODN stimulation. Cytokine and chemokine induction in the PBMCs of both breeds were also measured after CpG ODN stimulation. Our data showed that mRNA levels of cytokines (IFNα, IL8, IL12 p40) and chemokines (CXCL9, CXCL13) were significantly higher in the PBMCs of the DPL pigs than those of the Landrace pigs. Taken together, our data provide new information regarding the pig breed difference in response to CpG ODN stimulation and that higher levels of TLR9 mRNA in DPL pigs may be a major contributor for disease resistance.
Objective: To study the role of the receptor for advanced glycation end products (RAGE) in endothelial barrier dysfunction induced by heat stress, to further explore the signal pathway by which RAGE contributes to heat-induced endothelia response, and thereby find a novel target for the clinical treatment of ALI (acute lung injury) induced by heatstroke. Methods: This study established the animal model of heatstroke using RAGE knockout mice. We observed the role of RAGE in acute lung injury induced by heatstroke in mice by evaluating the leukocytes, neutrophils, and protein concentration in BALF (Bronchoalveolar lavage fluids), lung wet/dry ratio, histopathological changes, and the morphological ultrastructure of lung tissue and arterial blood gas analysis. To further study the mechanism, we established a heat stress model of HUVEC and concentrated on the role of RAGE and its signal pathway in the endothelial barrier dysfunction induced by heat stress, measuring Transendothelial electrical resistance (TEER) and western blot. Results: RAGE played a key role in acute lung injury induced by heatstroke in mice. The mechanism C-Jun is located in the promoter region of the RAGE gene. C-Jun increased the RAGE protein expression while HSF1 suppressed RAGE protein expression. The overexpressed RAGE protein then increased HUVEC monolayer permeability by activating ERK and P38 MAPK under heat stress. Conclusion: This study indicates the critical role of RAGE in heat stress-induced endothelial hyperpermeability in acute lung injury and suggests that RAGE could be a potential therapeutic target in protecting patients against acute lung injury induced by heatstroke.
Myocardin-related transcription factor-A (MRTF-A) can transduce biomechanical and humoral signals, which can positively modulate cardiac damage induced by acute myocardial infarction (AMI). In the clinic, bone marrow stem cell (BMSC) therapy is being increasingly utilized for AMI; however, the effects of BMSC transplantation remain to be optimized. Therefore, a novel strategy to enhance BMSC‑directed myocardial repair is particularly important. The present study was performed to assess the efficacy of MRTF‑A-overexpressing BMSCs in a rat model of AMI. Primary cardiomyocytes were prepared from neonatal Sprague-Dawley rats and BMSCs were isolated from male Sprague-Dawley rats (aged 8-12 weeks). Annexin V-phycoerythrin/7-actinomycin D staining was used to evaluate BMSC and cardiomyocyte survival after exposure to hydrogen peroxide in vitro. B-cell lymphoma 2 (Bcl-2) protein expression was measured by flow cytometric and western blot analyses. The effects of MRTF-A‑overexpressing BMSCs in a rat model of AMI were investigated by hematoxylin and eosin staining and western blot analysis of Bcl-2 expression in myocardial tissue sections. MRTF-A enhanced the migration of BMSCs, and overexpression of MRTF-A in BMSCs prevented hydrogen peroxide-induced apoptosis in primary cardiomyocytes ex vivo. In addition, co-culture of cardiomyocytes with MRTF‑A-overexpressing BMSCs inhibited hydrogen peroxide-induced apoptosis and the enhanced expression of Bcl-2. Furthermore, in vivo, enhanced cell survival was observed in the MRTF-A-modified BMSC group compared with that in the control group. These observations indicated that MRTF-A-overexpressing BMSCs have the potential to exert cardioprotective effects against hydrogen peroxide-induced injury and that treatment with MRTF‑A‑modified BMSCs is able to reverse cardiac dysfunction after AMI.
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