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ABSTRACT: Stomatin is an important lipid raft-associated protein which interacts with membrane proteins and plays a role in the membrane organization. However, it is unknown whether it is involved in the response to hypoxia and glucocorticoid (GC) in alveolar epithelial cells (AEC). In this study we found that hypoxia and dexamethasone (dex), a synthetic GC not only up-regulated the expression of stomatin alone, but also imposed additive effect on the expression of stomatin in A549 cells, primary AEC and lung of rats. Then we investigated whether hypoxia and dex transcriptionally up-regulated the expression of stomatin by reporter gene assay, and found that dex, but not hypoxia could increase the activity of a stomatin promoter-driven reporter gene. Further deletion and mutational studies demonstrated that a GC response element (GRE) within the promoter region mainly contributed to the induction of stomatin by dex. Moreover, we found that hypoxia exposure did not affect membrane-associated actin, but decreased actin in cytoplasm in A549 cells. Inhibiting stomatin expression by stomatin siRNA significantly decreased dense of peripheral actin ring in hypoxia or dex treated A549 cells. Taken all together, these data indicated that dex and/or hypoxia significantly up-regulated the expression of stomatin in vivo and in vitro, which could stabilize membrane-associated actin in AEC. We suppose that the up-regulation of stomatin by hypoxia and dex may enhance the barrier function of alveolar epithelia and mediate the adaptive role of GC to hypoxia.
Journal of Cellular and Molecular Medicine 05/2013; · 4.13 Impact Factor
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ABSTRACT: BACKGROUND: Pulmonary surfactant (PS) administration has been attempted for the treatment of adults with acute lung injury (ALI)/adult respiratory distress syndrome. Aerosolized surfactants inhaled by spontaneous breathing may be an effective method of surfactant-based therapies. Using a noninvasive apparatus, we evaluated the therapeutic effects of aerosolized PS alone or together with dexamethasone (Dex) on a rat model of ALI. METHODS: Severe ALI was induced by intravenous injection of 20% oleic acid (0.2 mL/kg) into adult Sprague-Dawley rats. Animals were divided into eight groups: sham (n = 10); model (injury only, n = 10); normal saline (NS) aerosol driven by compressed air (air-NS, n = 13); PS aerosol driven by compressed air (air-PS, n = 13); NS aerosol driven by O2 (O2-NS, n = 13); PS aerosol driven by O2 (O2-PS, n = 13); Dex aerosol driven by O2 (O2-Dex, n = 13); and PS and Dex aerosol driven by O2 (O2-PS-Dex, n = 13). Blood gases, breathing rate, lung index, total protein, and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1β, interleukin 6) in the bronchoalveolar lavage fluid (BALF), and lung histology were examined. RESULTS: Animals treated with air-PS for 20 minutes had significantly improved lung function, reduced pulmonary edema, decreased concentration of total protein and proinflammatory cytokines in BALF, ameliorated lung injury, and improved animal survival. In the O2-PS group, the breathing rates and lung injury scores were significantly lower than that of the air-PS group. In the O2-PS-Dex group, lung edema, total protein, and inflammatory cytokines in BALF were significantly reduced in comparison with the O2-PS group. CONCLUSION: Inhalation of aerosolized PS generated by the noninvasive apparatus could significantly reduce lung injury, while using oxygen line available in the clinical wards to generate PS aerosol is more convenient and adds further benefits. This method can also be used to deliver Dex and other therapeutic agents to ameliorate lung injury.
The journal of trauma and acute care surgery. 09/2012;
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ABSTRACT: Aim: Hypoxia, a characteristic of almost all types of solid tumors, has been associated with poor outcome in a number of human malignancies. The aim of this study was to investigate the molecular mechanisms involved in hypoxia-induced activation of the human survivin gene promoter in cervical HeLa cells. Material and Methods: Immunohistochemical staining was used to detect the expression of HIF-1α and survivin in cervical cancer samples and normal cervical samples. Under normoxic and hypoxic conditions, the expression of hypoxia inducible factor (HIF)-1α and survivin in cervical cancer HeLa cells was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. Luciferase reporter assays was used to investigate the molecular mechanisms in hypoxia-induced survivin activation. We also studied the effect of HIF-1α overexpression on the expression of survivin in cervical cancer HeLa cells. Results: Significant HIF-1α and survivin overexpression is associated with cervical cancer, and HIF-1α protein expression is strongly correlated with survivin protein expression. In cervical cancer cell line (HeLa), hypoxia upregulated both HIF-1α and survivin expression. Moreover, luciferase reporter assays using survivin core promoter demonstrated that survivin transcription was activated under hypoxia conditions and was associated with HIF-1α overexpression. The transcriptional activation of reporter genes in response to hypoxia is independent of potential HIF-1α-responsive element, located between -86 and -82 regions. HIF-1α overexpression significantly activated survivin expression. Conclusion: Our results demonstrate that survivin expression is upregulated following the induction of HIF-1α by hypoxia resulting from tumor formation, possibly leading to tumor progression. These findings have potential implication in developing novel cancer therapy targeting HIF-1.
Journal of Obstetrics and Gynaecology Research 08/2012; · 0.94 Impact Factor
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ABSTRACT: In our previous study, an intronic MAR sequence in human PI3Kγ gene (PIMAR) was identified using bioinformatics and biochemical methods. We used MatInspector® software to identify potential binding sites for MAR-binding proteins in PIMAR. In this study, a tissue-specific MAR-binding protein (SATB1) was used to characterize the potential binding sites. Southwestern
blot analysis indicates that recombinant SATB1 directly binds PIMAR sequence in vitro. Reporter gene assay showed that overexpression of SATB1 downregulates the luciferase reporter linked with
reversed PIMAR by approximately threefold in the NIH-3T3 cell line. These results indicate that SATB1 may play antagonistic roles in PI3Kγ transcriptional regulation.
Molecular Biology Reports 04/2012; 37(3):1461-1465. · 2.93 Impact Factor
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ABSTRACT: Hypoxia and inflammation often develop concurrently in numerous diseases, and the influence of hypoxia on natural evolution of inflammatory responses is widely accepted. Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory cytokines IL-1β, IL-6, and TNF-α under normoxic and hypoxic conditions. We found that hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ small interfering RNA led to a significant increase in mRNA production and protein secretion of IL-1β and IL-6 in hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and IL-6 in hypoxia. We also found that adrenal hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.
The Journal of Immunology 11/2011; 188(1):222-9. · 5.79 Impact Factor
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ABSTRACT: It has been reported by us and other groups that the expression of small GTP binding protein RhoB can be induced by genotoxic stressors and glucocorticoid (GC), a stress hormone that plays a key role in stress response. Until now stress-induced genes that confer cytoprotection under stressed conditions are largely unknown. In this study, we investigated the effects and mechanism of non-genotoxic stressors, including scalding in vivo and heat stress in vitro on the expression of RhoB. We found for the first time that both scalding, which could induce typical neuroendocrine responses of acute stress and cellular heat stress significantly increased the expression of RhoB at mRNA and protein levels. Moreover, in vitro experiments in human lung epithelial cells (A549) showed that induction of RhoB by heat stress was in a glucocorticoid receptor (GR)-independent manner and through multiple pathways including stabilization of RhoB mRNA and activation of p38 MAPK. Further experiments demonstrated that up-regulation of RhoB significantly inhibited heat stress-induced apoptosis and elevated transcriptional activity of NF-κB, but did not affect the expression of Hsp70 in A549 cells. In conclusion, we showed for the first time that RhoB was up-regulated by scalding in vivo and heat stress in vitro and played an important cytoprotective role during heat stress-induced apoptotic cell death.
Journal of Cellular Physiology 03/2011; 226(3):729-38. · 3.87 Impact Factor
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ABSTRACT: Stomatin is an important membrane raft protein which can combine skeleton protein, some ion channel, and transporter to regulate their functions. However, until now no data on its expression and function in CNS are available. In this study, we examined distribution of stomatin in CNS of rat, and investigated the effects of hypoxia exposure and glucocorticoid on stomatin expression in cerebral cortex of rat. Immunofluorescence staining revealed a broad expression of stomatin protein in many areas of adult rat brain and spinal cord, including the ventral horn of spinal cord, causal magnocellular nucleus of hypothalamus, the V layer of the cerebral cortex, solitary nucleus, 10 and 12 nuclei, and so on. Hypoxia or ischemic hypoxia significantly up-regulated stomatin expression in cerebral cortex, and the up-regulation was independent on adrenocortical steroids since it also occurred in adrenalectomized (ADX) rats. Moreover, treatment of ADX or sham-operated rats with dexamethasone, a synthetic glucocorticoid alone could significantly stimulate expression of stomatin in lung and heart, but not in cerebral cortex. However, dexamethasone could enhance the hypoxia-stimulated expression of stomatin in cerebral cortex of ADX rats. These findings suggested that stomatin might be involved in various physiological functions and cellular events of neurons in CNS under physiological conditions and play a potential protective role under hypoxic conditions.
Journal of Neurochemistry 02/2011; 116(3):374-84. · 4.06 Impact Factor
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ABSTRACT: Although more than 40 beta-defensins have been identified in rat epididymis, little is known about their regulation or their relation to male infertility caused by inflammation. Using a rat model of epididymitis induced by lipopolysaccharide (LPS), we examined expression of SPAG11E (also known as Bin1b), a caput epididymis-specific beta-defensin in rat. Unlike the expression of other beta-defensins in various epithelial cells with upregulated expression after LPS stimulation, expression of SPAG11E was significantly decreased by LPS at the mRNA and protein levels. LPS treatment also significantly decreased both sperm binding to SPAG11E and sperm motility, and supplementation of the spermatozoa with recombinant SPAG11E in vitro remarkably increased both SPAG11E binding and motility of sperm. To clarify whether decreased expression is a common pattern of epididymal beta-defensins after LPS stimulation, we examined the expression of another 12 epididymal beta-defensins expressed in the caput epididymis. For nine of these beta-defensins, expression was decreased, but for the other three, expression remained unaffected. These findings demonstrate that LPS-induced epididymitis can decrease the expression of epididymal beta-defensins and that disruption of SPAG11E expression is involved in the impairment of sperm motility.
Biology of Reproduction 12/2010; 83(6):1064-70. · 4.01 Impact Factor
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ABSTRACT: ATRA (all-trans retinoic acid) regulates gene expression by binding as a ligand to its specific receptors like C/EBPε which is directly induced. In the U937 cell line, PI3Kγ is selectively induced over other PI3Ks by ATRA, although the mechanism is still unclear. Here, we show that C/EBPε and PI3Kγ are induced in U937 cells by ATRA both in levels of mRNA and protein. Reporter gene assay revealed that C/EBPε is able to interact with a previously identified 2 kb MAR (matrix attachment region) sequence in the last intron of PI3Kγ gene, and increases its linked heterogeneous reporter gene expression. ChIP assay showed that induction of endogenous PI3Kγ is at least partially caused by enhanced, direct C/EBPε binding to a 15 bp sequence at nucleotides 1428-1442 within this MAR sequence, and EMSA analysis confirmed this binding in vitro. The results above collectively show that C/EBPε participates in ATRA induction of PI3Kγ.
Molecular Biology Reports 12/2010; 37(8):3795-800. · 2.93 Impact Factor
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ABSTRACT: Glucocorticoid (GC) insensitivity/GC resistance is an important etiological and prognostic factor in multiple diseases and pathophysiological processes such as scald, shock and asthma. The function of GC was mediated by glucocorticoid receptor (GR). Scald not only decreased the expression of GR but also reduced the affinity of GR, which played an important role in GC resistance in scalded rats. Whereas the molecular mechanism responsible for the decrease of GR affinity resulted from scald remains unclear. Recent studies showed that the changes of heat shock proteins (hsp) especially hsp90 and hsp70 of GR heterocomplex were associated with GR low affinity in vitro.
The affinity of GR in hepatic cytosols and in the cytosols of SMMC-7721 cells were determined by radioligand binding assay and scatchard plot. GR heterocomplex in cytosols were captured by coimmunoprecipation and the levels of hsp90 and hsp70 of GR complex were detected by quantitative Western blotting.
Similar with that of hepatic cytosol of scalded rats, a remarkable decrease of GR affinity was also found in the cytosol of heat stressed SMMC-7721 cells. The level of hsp70 of GR complex in hepatic cytosol of scalded rats (30% total body surface area immersion scald) and in cytosol of heat stressed human hepatocarcinoma cell line SMMC-7721 were both increased by 1.5 fold, whereas no change of hsp90 in GR heterocomplex was found. According to the correlation analysis, there may be a positive relationship between increased hsp70 of GR complex and decreased GR affinity in the cytosols.
The primary results indicated that the level of hsp70 of GR heterocomplex was increased in the hepatic cytosol of scalded rats and the cytosol of heat stressed SMMC-7721 cells. The increase of hsp70 of GR complex might be associated with the decrease of GR affinity.
Chinese medical journal 07/2010; 123(13):1780-5. · 0.86 Impact Factor
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ABSTRACT: An elevated level of hypoxia-inducible factor 1 (HIF-1) is common in solid tumors and correlates with poor prognosis. Therefore, targeting of HIF-1 presents an appealing approach for cancer therapy. In this study, we developed an adenoviral vector carrying a fusion of human WW domain-containing oxidoreductase (hWWOX) and the HIF-1alpha oxygen-dependent degradation domain (ODD) under the control of a synthetic human recombinant telomerase reverse transcriptase promoter (hrTRTP). Luciferase reporter assay showed elevated promoter activity of the synthetic hrTRTP in tested tumor cell lines, but not in WI-38, a nontransformed cell line. Furthermore, adenoviral hrTRTP-hWWOX-Linker-ODD (Ad-TWLH) expression induced apoptosis in a variety of human cancer cell lines under hypoxic conditions dose dependently. Importantly, Ad-TWLH injection into xenografts of A549 tumor cells dramatically reduced tumor size in vivo. Western blot and immunohistochemistry assays also confirmed that hWWOX-Linker-ODD fusion protein was expressed in the A549 xenografts. And the protein level in center part was much higher than that of the circumjacent area. In conclusion, our dual-regulated adenovirus specifically induced apoptosis in human cancer cell lines under hypoxic conditions in vitro and repressed ectopic xenograft tumor growth in vivo, thus providing a novel strategy for hypoxia-targeted cancer gene therapy.
Human gene therapy 10/2009; 21(1):27-39. · 4.20 Impact Factor
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Jianjun Zhang,
Shenglin Huang,
He Zhang,
Haibo Wang,
Haiyan Guo,
Guanxiang Qian,
Xianqun Fan, Jian Lu,
Andrew R Hoffman,
Ji-Fan Hu,
Shengfang Ge
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ABSTRACT: Targeting tumor-related overexpression of anti-apoptotic Bcl2 protein by RNAi has been suggested as a potential treatment for cancer. However, the stability of RNAi and its delivery are still major obstacles to the clinical testing of Bcl2 RNAi. Here, we explore a novel strategy of expressing a synthetic Bcl2 microRNA (smRNA) in the 3' untranslated region (UTR) of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an apoptosis-inducing protein without apparent toxic effects in normal cells. TRAIL was specifically expressed from the human telomerase reverse transcriptase promoter (pTRT) that is active in many human tumors. Using this approach, we demonstrated that pTRT drove the tumor-specific expression of Bcl2 smRNA, which was processed by the host RNAi machinery and silenced endogenous Bcl2 expression in tumor cells. Bcl2 smRNA induced tumor cell apoptosis by activating caspase-3 and led to significant sensitization of tumor cells to TRAIL-induced apoptosis, while normal cells were spared. We also showed that the combined therapy of TRAIL-induced apoptosis and Bcl2 downregulation was superior to the mono-therapy of TRAIL or Bcl2 smRNA alone. This study proves a general paradigm for cancer therapy by using 3' UTR microRNA technology.
International Journal of Cancer 09/2009; 126(9):2229-39. · 5.44 Impact Factor
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ABSTRACT: Glucocorticoids (GCs) are widely used as co-medication in the therapy of solid malignant tumors to relieve some of the side effects of chemotherapeutic drugs. However, recent studies have shown that GCs could render cancer cells more resistant to cytotoxic drug-induced apoptosis, but the mechanism is largely unknown. In the present study, we found that the treatment of human ovarian cancer cell lines HO-8910 and SKOV3 with synthetic GCs dexamethasone (Dex) significantly increased their adhesion to extracellular matrix (ECM) and their resistance to apoptosis induced by cytotoxic drugs cisplatin and paclitaxel. Dex also increased the protein levels of adhesion molecules integrins beta1, alpha 4, and alpha 5 in HO-8910 cells. The neutralizing antibody against integrin beta1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that transforming growth factor-beta1 (TGF-beta1) alone not only increased cell adhesion and cell survival of HO-8910 cells in the presence of cisplatin, but also had synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-beta1-neutralizing antibody that could block TGF-beta1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-beta1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-beta receptor type II and enhance the responsiveness of cells to TGF-beta1. In conclusion, our results indicate that increased adhesion to ECM through the enhancement of integrin beta1 signaling and TGF-beta1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells.
Endocrine Related Cancer 09/2009; 17(1):39-50. · 4.36 Impact Factor
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ABSTRACT: Several studies have investigated the influence of exogenous surfactants on inflammatory response in the lung, however results reported about effects of surfactants on the lung infiltration of leukocytes are controversial. Our previous study noticed that treatment of porcine surfactant (PS) significantly increased the lung infiltration of leukocytes in rats with acute lung injury (ALI). The objective of this study was to verify the effect of exogenous PS on the lung infiltration of leukocytes in vivo and investigate the possible mechanisms involved in vitro.
The number of leukocytes in bronchoalveolar lavage fluid (BALF) of rats with or without lipopolysaccharide (LPS)-induced ALI was determined after treatment with different concentrations of PS, dexamethasone (Dex) or PS + Dex. The effect of PS and Curosurf, a commercially available porcine surfactant, on human peripheral neutrophil migration was determined by the Boyden Chamber Assay.
Instillation of PS significantly increased the number of leukocytes in BALF of normal rats and rats with LPS-induced ALI. Most of the increased leukocytes were neutrophils. Dex significantly decreased the number of leukocytes and TNF-alpha concentration in BALF caused by LPS, but did not significantly reduce the number of leukocytes increased by PS. In vitro experiments further demonstrated that both PS and Curosurf had direct chemotactic effects on neutrophils.
These results suggest that PS contain chemoattractant(s) which induce the infiltration of leukocytes, especially neutrophils, into lung.
Pulmonary Pharmacology & Therapeutics 07/2009; 22(3):253-9. · 2.80 Impact Factor
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ABSTRACT: In our previous study, an intronic MAR sequence in human PI3Kgamma gene (PIMAR) was identified using bioinformatics and biochemical methods. We used MatInspector software to identify potential binding sites for MAR-binding proteins in PIMAR. In this study, a tissue-specific MAR-binding protein (SATB1) was used to characterize the potential binding sites. Southwestern blot analysis indicates that recombinant SATB1 directly binds PIMAR sequence in vitro. Reporter gene assay showed that overexpression of SATB1 downregulates the luciferase reporter linked with reversed PIMAR by approximately threefold in the NIH-3T3 cell line. These results indicate that SATB1 may play antagonistic roles in PI3Kgamma transcriptional regulation.
Molecular Biology Reports 06/2009; 37(3):1461-5. · 2.93 Impact Factor
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ABSTRACT: Exogenous surfactant has been explored as a potential therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In the present study, a nebuliser driven by oxygen lines found in the hospital was developed to deliver aerosolised porcine pulmonary surfactant (PPS). We hypothesised that aerosolised surfactant inhaled through spontaneous breathing may effectively reduce severe lung injury.
Rats were intravenously injected with oleic acid (OA) to induce ALI and 30 minutes later they were divided into five groups: model (injury only), PPS aerosol (PPS-aer), saline aerosol (saline-aer), PPS instillation (PPS-inst), and saline instillation (Saline-Inst). Blood gases, lung histology, and protein and TNF-alpha concentrations in the bronchoalveolar lavage fluid (BALF) were examined.
The PPS aerosol particles were less than 2.0 mum in size as determined by a laser aerosol particle counter. Treatment of animals with a PPS aerosol significantly increased the phospholipid content in the BALF, improved lung function, reduced pulmonary oedema, decreased total protein and TNF-alpha concentrations in BALF, ameliorated lung injury and improved animal survival. These therapeutic effects are similar to those seen in the PPS-inst group.
This new method of PPS aerosolisation combines the therapeutic effects of a surfactant with partial oxygen inhalation under spontaneous breathing. It is an effective, simple and safe method of administering an exogenous surfactant.
Critical care (London, England) 04/2009; 13(2):R31. · 4.61 Impact Factor
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Jian Lu
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ABSTRACT: Glucocorticoid (GC) hormones exert an antiproliferative effect on various cells. The effect is mainly mediated by glucocorticoid receptor (GR) which acts as a transcription factor. Ligand-bound GR translocates from the cytoplasm into the nucleus to modulate gene expression in a variety of ways. Although the framework of transcriptional regulation by the GC/GR has been described, the molecular mechanism of antiproliferative effect of GC is still largely unclear. In this article, we reviewed GC-induced changes in gene expression that are involved in GC-antiproliferative effect, and mainly focused on our recently identified glucocorticoid-responsive genes, TGF-beta receptor type II (TbetaRII) and small GTP binding protein RhoB. We found that expressions of TbetaRII and RhoB were up-regulated by ligand-bound GR at mRNA and protein levels. Blocking the effect of TbetaRII by TbetaRII neutralizing antibody or reduction of RhoB mRNA expression by RNAi diminished dexamethasone-inhibitory effect on cell proliferation, thus confirming that these genes are involved in GC anti-proliferation effect. Collectively, GC up-regulating the expressions of RhoB and TbetaRII play an important role in GC anti-proliferation effect.
Pathophysiology 04/2009; 16(4):267-72.
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ABSTRACT: The failure of breast cancer treatment is largely due to the development of estrogen independence. Current data illustrate that Hedgehog (Hh) signaling may play an important role in breast cancer development. Here, we show that the expression of the Hh effector protein, Gli1 was significantly higher in estrogen-independent breast cancer cells than in estrogen-dependent cells. Our data showed for the first time that stable expression of Gli1 in ER positive breast cancer cell lines MCF-7 and T47D can induce estrogen-independent proliferation and promote G1/S phase transition, which associated with cyclin-Rb axi. Gli1 can also attenuate the response of proliferation to estrogenic stimulation, which was correlated with down-regulation of expression of ERalpha and PR, as well as down-regulation of transactivation of ERalpha. Our results suggest that up-regulation of Gli1 in breast cancer cells may be one of the mechanisms responsible for developing estrogen independence and this process may be regulated through down-regulation of expression and transactivation of ERalpha.
Breast Cancer Research and Treatment 03/2009; 119(1):39-51. · 4.43 Impact Factor
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ABSTRACT: Ever since the introduction of invasive hemodynamic monitoring to major burn care, its utility remains controversial. Besides complications, invasive monitoring as a guideline for burn shock resuscitation is often associated with significant excessive fluid burden. This study was to summarize the clinical experiences of noninvasive esophageal echo-Doppler (ED) monitoring in burn shock resuscitation and discuss the significance of hemodynamic variables in assessment of fluid therapeutic goal.
Twenty-one burn patients with an average total body surface area of 78.86% +/- 7.75% (62-92%) was enrolled in this retrospective study. Fluid therapy was guided according to Chinese general formula and adjusted with urinary output 1 mL/kg/hr as resuscitation goal. Hemodynamic parameters using ED was obtained, including cardiac output (CO), stroke volume (SV), myocardial contractility parameter--maximum acceleration at onset of systole (Acc), afterload parameter--total systemic vascular resistance (TSVR), preload parameter SV/Acc.
All patients were clinically diagnosed with a relatively stable condition during early shock stage. There existed inherent and dynamic tendency of hemodynamics during burn shock resuscitation with low CO, Acc, SV/Acc, and high TSVR at first followed by a continuous trend of increase in CO, Acc and SV/Acc and decrease in TSVR. Significant correlations could be seen between CO and Acc, CO and TSVR, CO and SV/Acc. The Standardized Regression Coefficients of Acc, TSVR, and SV/Acc with CO as dependent variable were 0.343, -0.670, and 0.053, respectively demonstrating that myocardial contractility and angiotasis played more important role than blood volume did in hemodynamic variation.
Hemodynamic variables cannot routinely substitute traditional variables as the burn shock resuscitation goal. Because of its noninvasiveness, ability to real-timely provide complete profile of hemodynamics, ED monitoring is a good adjunctive method for clinical judgment.
The Journal of trauma 01/2009; 65(6):1396-401. · 2.48 Impact Factor
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ABSTRACT: Targeting tumor-specific gene abnormalities has become an attractive approach in developing therapeutics to treat cancer. Overexpression of Bcl2 and mutations of p53 represent two of the most common molecular defects in tumors. In the nucleus, p53 induces cell cycle arrest, while it interacts with Bcl2 outside of the nucleus to regulate signal pathways involved in apoptosis. To potentiate antitumor activity, we tested a "double target" approach to antitumor therapy by combining H101, a recombinant oncolytic adenovirus that targets the inactive p53 in tumors, with a small interfering RNA (siBCL2) that targets Bcl2. In cell culture, the combined treatment significantly enhanced apoptosis and cytotoxicity as compared with treatment with either H101 or siBCL2 alone. In animals carrying tumor xenographs, combined H101 and siBCL2 treatment significantly inhibited tumor growth and prolonged survival. At the end of the study, all animals in the combined therapy group survived and two of the five animals showed complete eradication of their tumors. Interestingly, siBCL2 treatment increased H101 viral replication in both treated cells and tumor tissues. Simultaneously targeting two tumor-specific gene abnormalities using an oncolytic adenovirus and siRNA potentiates total antitumor activity.
Molecular Therapy 12/2008; 17(1):57-64. · 6.87 Impact Factor
