Chongqing, China
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Chen Z.,Institute of Combined Injury | Wang X.,Institute of Combined Injury | Jin T.,Institute of Combined Injury | Wang Y.,Institute of Combined Injury | And 6 more authors.
Cell Death and Disease | Year: 2017

The timing of radiation after mechanical injury such as in the case of surgery is considered a clinical challenge because radiation is assumed to impair wound healing. However, the physiological responses and underlying mechanisms of this healing impairment are still unclear. Here, we show that mechanical injury occurring before ionizing radiation decreases radiation-induced cell damage and increases cell repair in normal fibroblasts but not tumor cells in vitro and in vivo. At the molecular level, mechanical injury interrupts focal adhesion complexes and cell-cell cadherin interactions, transducing mechanical signals into intracellular chemical signals via activation of the phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 beta (GSK-3β) pathways. We show that subsequent nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and β-catenin strengthen the stemness, antioxidant capabilities, and DNA double-strand break repair abilities of fibroblasts, ultimately contributing to increased radioresistance. Our findings demonstrate that mechanical injury to normal fibroblasts enhances radioresistance and may therefore question conventional wisdom surrounding the timing of radiation after surgery. © The Author(s) 2017.


Guo L.,General Hospital of Guangzhou Military Command | Xu K.,General Hospital of Guangzhou Military Command | Yan H.,General Hospital of Guangzhou Military Command | Feng H.,General Hospital of Guangzhou Military Command | And 3 more authors.
Molecular Medicine Reports | Year: 2017

Hypertrophic scars (HS) area fibroproliferative disorder of the skin, which causes aesthetic and functional impairment. However, the molecular pathogenesis of this disease remains largely unknown and currently no efficient treatment exists. MicroRNAs (miRNAs) are involved in a variety of pathophysiological processes, however the role of miRNAs in HS development remains unclear. To investigate the miRNA expression signature of HS, microarray analysis was performed and 152 miRNAs were observed to be differentially expressed in HS tissue compared with normal skin tissues. Of the miRNAs identified, miRNA-21 (miR-21) was significantly increased in HS tissues and hypertrophic scar fibroblasts (HSFBs) as determined by reverse transcription-quantitative polymerase chain reaction analysis. It was also observed that, when MIR-21 in HSFBs was blocked through use of an antagomir, the phenotype of fibrotic fibroblasts in vitro was reversed, as demonstrated by growth inhibition, induction of apoptosis and suppressed expression of fibrosis-associated genes collagen type I α 1 chain (COL1A1), COL1A2 and fibronectin. Furthermore, MIR-21 antagomir administration significantly reduced the severity of HS formation and decreased collagen deposition in a rabbit ear HS model. The total scar area and scar elevation index were calculated and were demonstrated to be significantly decreased in the treatment group compared with control rabbits. These results indicated that the MIR-21 antagomir has a therapeutic effect on HS and suggests that targeting miRNAs may be a successful and novel therapeutic strategy in the treatment of fibrotic diseases that are difficult to treat with existing methods.


Wu K.,Nanjing Medical University | Huang R.,Nanjing Medical University | Liu Y.,Nanjing Medical University | Yang C.,Nanjing Medical University | And 5 more authors.
Molecular Medicine Reports | Year: 2016

Vascular endothelial growth factor (VEGF) serves an important role in promoting angiogenesis and tissue regeneration. However, the lack of an effective delivery system that can target this growth factor to the injured site reduces its therapeutic efficacy. Therefore, in the current study, collagen-binding VEGF was constructed by fusing a collagen-binding domain (CBD) to the N-terminal of native VEGF. The CBD-VEGF can specifically bind to collagen which is the major component of the extracellular matrix in fibrotic liver. The anti-fibrotic effects of this novel material were investigated by the carbon tetrachloride (CCl4)-induced liver fibrotic mouse model. Mice were injected with CCl4 intraperitoneally to induce liver fibrosis. CBD-VEGF was injected directly into the liver tissue of mice. The liver tissues were stained with hematoxylin and eosin for general observation or with Masson's trichrome staining for detection of collagen deposition. The hepatic stellate cell activation, blood vessel formation and hepatocyte proliferation were measured by immunohistochemical staining for smooth muscle actin, CD31 and Ki67 in the liver tissue. The fluorescent TUNEL assay was performed to evaluate the hepatocyte apoptosis. The present study identified that the CBD-VEGF injection could significantly promote vascularization of the liver tissue of fibrotic mice and attenuate liver fibrosis. Furthermore, hepatocyte apoptosis and hepatic stellate cell activation were attenuated by CBD-VEGF treatment. CBD-VEGF treatment could additionally promote hepatocyte regeneration in the liver tissue of fibrotic mice. Thus, it was suggested that CBD-VEGF may be used as a novel therapeutic intervention for liver fibrosis.


PubMed | Institute of Combined Injury and Chongqing Medical University
Type: Journal Article | Journal: Blood | Year: 2016

The effect of sympathetic stimulation on thrombopoiesis is not well understood. Here, we demonstrate that both continual noise and exhaustive exercise elevate peripheral platelet levels in normal and splenectomized mice, but not in dopamine -hydroxylase-deficient (Dbh(-/-)) mice that lack norepinephrine (NE) and epinephrine (EPI). Further investigation demonstrates that sympathetic stimulation via NE or EPI injection markedly promotes platelet recovery in mice with thrombocytopenia induced by 6.0 Gy of total-body irradiation and in mice that received bone marrow transplants after 10.0 Gy of lethal irradiation. Unfavorably, sympathetic stress-stimulated thrombopoiesis may also contribute to the pathogenesis of atherosclerosis by increasing both the amount and activity of platelets in apolipoprotein E-deficient (ApoE(-/-)) mice. In vitro studies reveal that both NE and EPI promote megakaryocyte adhesion, migration, and proplatelet formation (PPF) in addition to the expansion of CD34(+) cells, thereby facilitating platelet production. It is found that 2-adrenoceptor-mediated extracellular signal-regulated kinase 1/2 (ERK1/2) activation is involved in NE- and EPI-induced megakaryocyte adhesion and migration, and PPF is regulated by ERK1/2 activation-mediated RhoA GTPase signaling. Our data deeply characterize the role of sympathetic stimulation in the regulation of thrombopoiesis and reevaluate its physiopathological implications.


PubMed | Peking University, The Texas Institute, Institute of Combined Injury, Chongqing Medical University and Xinqiao Hospital
Type: Journal Article | Journal: Journal of the American Society of Nephrology : JASN | Year: 2015

Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=-0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.


Li X.,Urologic | Li X.,Chongqing Medical University | Song B.,Urologic | Song B.,Chongqing Medical University | And 8 more authors.
Pakistan Journal of Medical Sciences | Year: 2012

Objectives: Upper urinary tract damage secondary to voiding dysfunction is an important reason for the end stage of renal diseases. We evaluated clinical manifestations and outcomes of various treatments, and analyzed underlying mechanism in order to improve guidance for their therapy. Methodology: Two hundred seventy one patients suffering from upper urinary tract damage caused by voiding dysfunction diseases from Jan. 1999 to Oct. 2009 were enrolled and data of urodynamics, urinary imaging and renal functions before and after treatments were retrospectively analyzed. Results: Bladder pressure was over 40 cmH 2O in 78.2% of the patients, and among them, the average pressures for the first voiding desire was 42.3±6.0 cmH 2O with the maximum bladder pressure of 67.3±5.8cmH 2O in 271 patients. In 157 patients the residual urine bladder volume was 100ml, but smaller and moderate residual urine volume was occurring in 37.9% of the upper urinary tract damage patients, which implied that residual urine is not an appropriate indicator. 89.3% of the patients exhibited bladder outlet obstruction and 95.2% of those suffered moderate to severe LUTS. After the relief of obstruction treatment and resulting intravesical pressure reduction, 264 patients showed a good recovery and in 202 of them hydronephrosis have disappeared and their renal function returned to normal, due to reduced bladder pressure. Conclusions: We found that high bladder pressure is the main reason of upper urinary tract damage caused by voiding dysfunction. Thus, attention should be paid in order to achieve and maintain reduced bladder pressure below the safety line.


Zhang C.,Institute of Combined Injury | Zhang C.,Chongqing Medical University | Peng Y.,Institute of Combined Injury | Wang F.,Institute of Combined Injury | And 13 more authors.
Biomaterials | Year: 2010

Failure to cure many cancers once they are disseminated has been attributed to the presence of resistant cancer stem cells. Cantharidin, a natural compound isolated from the beetles and other insects has been traditionally used as anticancer agent, but limited by its significant toxicity. It has shown that cantharidin can force cancer cells prematurely into cell cycle and subsequently induce apoptotic cell death through the inhibition of protein phosphatase 2A (PP2A). In this study, we showed that a synthesized analog of cantharidin, LB1, with significant PP2A inhibition activity but without apparent toxicity, greatly enhanced the effectiveness of the standard anti-sarcoma chemotherapeutic agent, doxorubicin (DOX), in the xenograft growth inhibition and lung metastases prevention of an aggressive sarcoma derived from transformed mesenchymal stem cells in syngeneic rats. We report here on the possibility of, pharmacologic inhibition of PP2A with low toxicity cantharidin derivatives may be a useful strategy to enhance the effectiveness of DNA-damaged chemotherapeutic drugs against stem cell-derived cancer. © 2010 Elsevier Ltd.


Zhang C.,Institute of Combined Injury | Zhang C.,Chongqing Medical University | Wang S.,Institute of Combined Injury | Xiao J.,Institute of Combined Injury | And 6 more authors.
Biomaterials | Year: 2010

We describe a near-infrared fluorescent heptamethine dye (IR-780 iodide) with unique properties for sentinel lymph node (SLN) mapping in both small and large animals. This dye has a significant photobrightening effect in serum and a long retention time in the lymphatic system which allows to acquire much higher signal-to-noise ratios. Injection of only 10 nmol of this dye permits SLNs to be imaged easily in pigs using excitation fluence rates of only 2 μW/cm2. In addition, this dye has a unique stability property after formalin fixation in tissues which raises the possibility of developing new and sensitive means of detecting lymph nodes in harvested surgical specimens. This dye can be completely cleared from the circulation in a couple of days and does not cause acute systemic toxicity. © 2009 Elsevier Ltd. All rights reserved.


PubMed | Institute of Combined Injury
Type: Journal Article | Journal: Biomaterials | Year: 2010

Failure to cure many cancers once they are disseminated has been attributed to the presence of resistant cancer stem cells. Cantharidin, a natural compound isolated from the beetles and other insects has been traditionally used as anticancer agent, but limited by its significant toxicity. It has shown that cantharidin can force cancer cells prematurely into cell cycle and subsequently induce apoptotic cell death through the inhibition of protein phosphatase 2A (PP2A). In this study, we showed that a synthesized analog of cantharidin, LB1, with significant PP2A inhibition activity but without apparent toxicity, greatly enhanced the effectiveness of the standard anti-sarcoma chemotherapeutic agent, doxorubicin (DOX), in the xenograft growth inhibition and lung metastases prevention of an aggressive sarcoma derived from transformed mesenchymal stem cells in syngeneic rats. We report here on the possibility of, pharmacologic inhibition of PP2A with low toxicity cantharidin derivatives may be a useful strategy to enhance the effectiveness of DNA-damaged chemotherapeutic drugs against stem cell-derived cancer.


PubMed | Institute of Combined Injury
Type: Journal Article | Journal: Blood | Year: 2014

Human growth hormone (hGH) is known to play a functional role in regulating hematopoiesis, although its direct effect on thrombopoiesis is unclear. In this study, we show for the first time that hGH has a distinct capacity to promote the differentiation of human primary megakaryocytes derived from umbilical cord blood CD34(+) cells. In particular, hGH is potent in facilitating proplatelet formation and platelet production from cultured megakaryocytes. The stage- and time-specific activations of extracellular signal-regulated kinase 1/2 and protein kinase B signaling pathways are involved in the action of hGH. Fusion with hGH enhances the effect of a tandem dimer of thrombopoietin mimetic peptide (dTMP) on thrombopoiesis, manifested by a significant acceleration and increase of platelet production, indicating that hGH may exert a complementary and synergistic effect with c-Mpl ligands on thrombopoiesis. Accordingly, the administration of dTMP-growth hormone fusion protein led to a rapid platelet recovery in mice with severe thrombocytopenia induced by 6.5 Gy total body irradiation, thereby markedly abridging the duration of thrombocytopenia crisis (platelets <150 10(9)/L), in comparison with high doses of dTMP. These findings demonstrate the functional role of growth hormone in promoting thrombopoiesis and provide a promising avenue for the treatment of severe thrombocytopenia.

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