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Lu W.,Tianjin Medical University | Zhao M.,Tianjin Medical University | Rajbhandary S.,Tianjin Medical University | Xie F.,Tianjin Medical University | And 7 more authors.
European Journal of Haematology | Year: 2013

Objectives: Transfusional iron overload is of major concern in hematological disease. Iron-overload-related dyserythropoiesis and reactive oxygen species (ROS)-related damage to hematopoietic stem cell (HSC) function are major setbacks in treatment for such disorders. We therefore aim to investigate the effect of iron overload on hematopoiesis in the patients and explore the role of ROS in iron-induced oxidative damage in hematopoietic cells and microenvironment in vitro. Patients and methods: The hematopoietic colony-forming capacity and ROS level of bone marrow cells were tested before and after iron chelation therapy. In vitro, we first established an iron overload model of bone marrow mononuclear cells (BMMNC) and umbilical cord-derived mesenchymal stem cells (UC-MSC). ROS level, cell cycle, and apoptosis were measured by FACS. Function of cells was individually studied by Colony-forming cell (CFC) assay and co-culture system. Finally, ROS-related signaling pathway was also detected by Western blot. Results: After administering deferoxamine (DFO), reduced blood transfusion, increased neutrophil, increased platelet, and improved pancytopenia were observed in 76.9%, 46.2%, 26.9%, and 15.4% of the patients, respectively. Furthermore, the colony-forming capacity of BMMNC from iron overload patient was deficient, and ROS level was higher, which were partially recovered following iron chelation therapy. In vitro, exposure of BMMNC to ferric ammonium citrate (FAC) for 24 h decreased the ratio of CD34+ cell from 0.91 ± 0.12% to 0.39 ± 0.07%. Excessive iron could also induce apoptosis, arrest cell cycle, and decrease function of BMMNC and UC-MSC, which was accompanied by increased ROS level and stimulated p38MAPK, p53 signaling pathway. More importantly, N-acetyl-L-cysteine (NAC) or DFO could partially attenuate cell injury and inhibit the signaling pathway induced by excessive iron. Conclusions: Our study shows that iron overload injures the hematopoiesis by damaging hematopoietic cell and hematopoietic microenvironment, which is mediated by ROS-related signaling proteins. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

Yu W.,Tianjin First Center Hospital | Sheng M.,Tianjin First Center Hospital | Xu R.,Tianjin First Center Hospital | Yu J.,Tianjin Chest Hospital | And 6 more authors.
Journal of Translational Medicine | Year: 2013

Background: Ischemia/reperfusion injury plays a crucial role in renal transplantation, and represents a significant risk factor for acute renal failure and delayed graft function. The pathophysiological contribution of endoplasmic reticulum and mitochondria stress to ischemia/reperfusion injury has also been highlighted. Berberine (BBR) has been showed to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The study was carried out to investigate whether the pretreatment of BBR could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting mitochondria stress and endoplasmic reticulum stress pathways. Methods: The cultured human renal proximal tubular cell line HK-2 cells were exposed to 24 h hypoxia (5% CO2, 1% O2, 94% N2) followed by 3 h reoxygenation (5% CO2, 21% O2, 74% N2). And BBR was added to the culture medium 2h prior to the treatment. Then the cell viability, oxidative stress level, morphological change of apoptosis and apoptotic rate were determined. In addition, Western blot analysis was performed to identify the expression of apoptotic pathway parameters, including Bcl-2, Bax and cytochrome C involved in mitochondrial-dependent pathway and ER stress hallmarks such as glucose-regulated protein 78 and CCAAT/enhancer binding protein homologous protein. Results: H/R produced dramatic injuries in HK-2 cells. The cell viability and the oxidative stress level in group H/R was significantly decreased. The classical morphological change of apoptosis was found, while the apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased (p<0.05). Administration of BBR significantly inhibited these H/R induced changes (p<0.05). Conclusion: This study revealed that BBR pretreatment serves a protective role against H/R induced apoptosis of human renal proximal tubular cells, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress pathways. © 2013 Yu et al; licensee BioMed Central Ltd. Source

Liu T.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Liu T.,Organ Transplant Center | Zu C.-H.,Tianjin Medical University | Wang S.-S.,Key Laboratory for Critical Care Medicine of the Ministry of Health | And 9 more authors.
Oncotarget | Year: 2016

Competing endogenous RNAs (ceRNAs) are RNA transcripts that can crosstalk with each other by competing for shared microRNAs (miRNAs) through miRNA response elements (MREs). Involved in ceRNA networks, the RNA transcripts may be in a balance, disruption of which could lead to tumorigenesis. Here we reveal a ceRNA interaction between PIK3C2A and CD151 mRNAs in hepatocellular carcinoma (HCC) cells. PIK3C2A is a candidate ceRNA of CD151 because mRNA 3' untranslated regions (3'UTRs) of these two genes contain miR-124 binding sites. miR-124 is downregulated, while PIK3C2A and CD151 are upregulated in HCC cells compared with normal hepatocytes. Direct and negative regulation of PIK3C2A and CD151 by miR-124 was confirmed in HCC cells. miR-124 and the two potential ceRNAs are all recruited to the RNA-induced silencing complex (RISC). In HCC cell lines QGY- 7703 and SMMC-7721, and normal hepatic cell line HL-7702, miR-124 plays a tumor suppressor role by targeting PIK3C2A and CD151. The MREs within PIK3C2A 3'UTR can independently stimulate CD151 expression level by acting as miR-124 decoys. PIK3C2A MREs enhance HCC cell malignancy by absorbing endogenous miR-124 and activating CD151 in HCC cells. We conclude that PIK3C2A 3'UTR functions as a trans activator to stimulate CD151 by competing for miR-124 binding in HCC cells. The collaboration of PIK3C2A and CD151 through ceRNA mechanism may be implicated in HCC initiation and development. Source

Feng X.,First Central Hospital of Tianjin | Wang Y.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Xu X.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Wan C.,First Central Hospital of Tianjin | Wang J.,First Central Hospital of Tianjin
Transplantation Proceedings | Year: 2016

Background From the medical and ethical points of view, donation after brain death is a more acceptable organ source than that from a living donor because it has the advantage of providing multiple organs from a single donor source. Hence, it has become a more promising field of research which focuses on the protection of organs at brain death Here we investigated the role of transforming growth factor (TGF)-β1 in a porcine model of brain death. Methods A porcine model of brain death was established by increasing the intracranial pressure (ICP) after which TGF-β1 was monitored by immunofluorescence at the following time points: before ICP was performed (t1), at brain death (t2), and at 3 (t3), 6 (t4), 9 (t5), and 18 (t6) hours after brain death. The data were analyzed using the fixed effect regression method and the correlation between the results was determined by Pearson analysis. Results Our results showed that there was a significant increase in the levels of TGF-β1 (P <.05), urea (P <.01), creatinine (P <.01), and aspartate aminotransferase (AST; P <.01) during the 18-hour brain death process. There were negative correlations between TGF-β1 and urea, creatinine, alanine aminotransferase, AST, and total bilirubin. The negative correlations between TGF-β1 and creatinine and AST achieved statistical significance (P <.05). Conclusions These findings taken together confirm that significant damages are caused to the myocardial fiber cell and kidney glomerulus during brain death process, and that TGF-β1 is associated with the protection of these organs. © 2016 Elsevier Inc. Source

Liu T.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Shen Z.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Song Z.,Key Laboratory for Critical Care Medicine of the Ministry of Health | Chen X.,Union Stem and Gene Engineering Co. | Wang Y.,Key Laboratory for Critical Care Medicine of the Ministry of Health
Molecular Medicine Reports | Year: 2016

Adipose tissue-derived mesenchymal stem cells (ADSCs) have been considered to be attractive and readily available adult mesenchymal stem cells, and they are becoming increasingly popular for use in regenerative cell therapy, as they are readily accessible through minimally invasive techniques. The present study investigated whether autologous ADSC transplantation promoted liver regeneration following a repeat partial hepatectomy in rats. The rats were divided into three groups as follows: 70% partial hepatectomy (PH) group; repeat PH (R-PH) group and R-PH/ADSC group, subjected to R-PH and treated with autologous ADSCs via portal vein injection. In each group, the rats were sacrificed at different time points postoperatively in order to evaluate the changes in liver function and to estimate the liver regenerative response. The expression of proliferating cell nuclear antigen (PCNA) labeling index in the liver was measured using immunohistochemistry. The expression levels of hepatocyte growth factor (HGF) mRNA were measured using reverse transcription polymerase chain reaction. The results showed that regeneration of the remaining liver following R-PH was significantly promoted by ADSC transplantation, as shown by a significant increase in liver to body weight ratio and the PCNA labeling index at 24 h post-hepatectomy. Additionally, ADSC transplantation markedly inhibited the elevation of serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin, increased HGF content and also attenuated hepatic vacuolar degeneration 24 h postoperatively. Furthermore, the liver was found to almost fully recover from hepatocellular damage due to hepatectomy among the three groups at 168 h postoperatively. These results indicated that autologous ADSC transplantation enhanced the regenerative capacity of the remnant liver tissues in the early phase following R-PH. Source

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