Jian Lu

Second Military Medical University, Shanghai, Shanghai, Shanghai Shi, China

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Publications (36)97.54 Total impact

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    ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) plays a key role in tissue remodeling and tumor development by suppression of plasminogen activator function. Glucocorticoids (GCs) and transforming growth factor beta (TGF-β) signal pathways cross-talk to regulate gene expression, but the mechanism is poorly understood. Here we investigated the mechanism and significance of co-regulation of PAI-1 by TGF-β and dexamethasone (DEX), a synthetic glucocorticoid in ovarian cancer cells. We found TGF-β and DEX showed rapidly synergistic induction of PAI-1 expression, which contributed to the early pro-adhesion effects. The synergistic induction effect was accomplished by several signal pathways, including GC receptor (GR) pathway and TGF-β-activated p38MAPK, ERK and Smad3 pathways. TGF-β-activated p38MAPK and ERK pathways cross-talked with GR pathway to augment the expression of PAI-1 through enhancing DEX-induced GR phosphorylation at Ser211 in ovarian cancer cells. These findings reveal possible novel mechanisms by which TGF-β pathways cooperatively cross-talk with GR pathway to regulate gene expression. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 03/2015; 407. DOI:10.1016/j.mce.2015.03.005 · 4.24 Impact Factor
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    ABSTRACT: Both leptin (LEP) and leptin receptor (LEPR) are important in the regulation of body weight. In this study, we evaluated the individual and combined effects of a polymorphic microsatellite marker in the LEP gene 3′ flanking region and two polymorphisms (Lys109Arg and Lys656Asn) of the LEPR gene on metabolic markers for obesity in a Chinese population. The genotypes of polymorphisms in LEP and LEPR gene were determined by PCR and SSCP assay in 230 simple obese subjects and 202 control subjects of Chinese population. Logistic regression analysis showed that polymorphism in LEP gene 3′ flanking region was associated with waist/hip ratio (WHR) (P = 0.042). Individually, Lys109Arg variant in LEPR gene was associated with systolic blood pressure (P = 0.031) in males, and Lys656Asn variant was associated with serum triglyceride level (P = 0.026). Interestingly, only subjects that simultaneously exhibit all three polymorphisms showed a significantly elevated BMI (29.30 ± 0.85 vs 26.91 ± 1.19, P = 0.037). Taken together, our data suggest that a combination of polymorphism in the LEP gene 3′ flanking region, and Lys109Arg, Lys656Asn variants in LEPR gene is associated with obesity in Chinese Han population.:
    Obesity Research & Clinical Practice 12/2013; 7(6):e431-500. DOI:10.1016/j.orcp.2012.06.007 · 0.70 Impact Factor
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    ABSTRACT: The study aims to evaluate the quality of life (QOL) in burn patients in China and find out principal influencing factors, so as to provide evidence for interventions. A total of 271 burn patients in three major burn units in China were asked to fill in the adapted Chinese version (ACV) of the Burn Specific Health Scale-Brief (ACV BSHS-B) in order to seek out the principal influencing factors in combination with a self-designed demographic and disease condition questionnaire. Multivariable linear regression was used to analyse the principal influencing factors. The findings showed that there were seven principal influencing factors for the overall ACV BSHS-B score. They were: percent total body surface area (TBSA) burned (with the standardised regression coefficient being -0.594), burn area of lower limber (0.241), itch level (-0.227), pain level (-0.220), gender (0.217), mechanical ventilation (0.216) and hand deformity (-0.141). QOL decreased in burn patients to different degrees depending on the intensity of burns. With a better understanding of influencing factors of burn patients' QOL, the medical and nursing staff can take specific countermeasures to help patients gain a higher QOL.
    Burns: journal of the International Society for Burn Injuries 11/2013; 40(4). DOI:10.1016/j.burns.2013.09.011 · 1.84 Impact Factor
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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; 17(7). DOI:10.1111/jcmm.12069 · 3.70 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.
    09/2012; 73(5). DOI:10.1097/TA.0b013e318265cbe9
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    ABSTRACT: Small GTPase RhoB has been well documented in regulating cell adhesion, motility, proliferation, and survival, but to date, there is little information about the relationship between RhoB and inflammation. In this study, the mRNA and protein levels of RhoB were induced by lipopolysaccharide (LPS) in RAW264.7 cells determined by real-time PCR and Western blot. The upregulation of RhoB by LPS was also observed in mouse peritoneal macrophages and in mouse lung, liver, and kidney. RhoB overexpression by transfecting with wild RhoB plasmid increased the secretion of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) in RAW264.7 cells, while RhoB knockdown by RNA interference decreased the secretion of TNF-α and NO in RAW264.7 cells. TNF-α and NO synthase are the target genes of nuclear factor-kappaB (NF-κB), and overexpression of RhoB increased, whereas inhibition of RhoB decreased the basal and LPS-activated transcriptional activity of NF-κB in the cells. These results demonstrated that LPS induced RhoB expression in mouse in vivo and in vitro and in RAW264.7 cells, and the role of RhoB on LPS-induced secretion of TNF-α and NO was at least partly mediated via NF-κB. These results indicated that RhoB was involved in LPS-induced inflammation in mouse in vivo and in vitro.
    Journal of physiology and biochemistry 08/2012; DOI:10.1007/s13105-012-0201-z · 2.50 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. DOI:10.4049/jimmunol.1002958 · 5.36 Impact Factor
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    Genome Biology 09/2011; 12(1). DOI:10.1186/1465-6906-12-S1-P12 · 10.47 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. DOI:10.1002/jcp.22394 · 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. DOI:10.1111/j.1471-4159.2010.07117.x · 4.24 Impact Factor
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    ABSTRACT: Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from anandrogen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.
    Biochemical and Biophysical Research Communications 01/2011; 404(3):809-15. DOI:10.1016/j.bbrc.2010.12.065 · 2.28 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. DOI:10.1095/biolreprod.109.082180 · 3.45 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. · 1.02 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. DOI:10.1677/ERC-08-0296 · 4.91 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 &amp Therapeutics 07/2009; 22(3):253-9. DOI:10.1016/j.pupt.2009.01.001 · 2.57 Impact Factor
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    ABSTRACT: Serum HBeAg status and liver cirrhosis severity at the time of diagnosis of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-related cirrhosis remain inconclusive. The aim was to investigate the status of HBeAg and cirrhosis severity at the time of HCC development in the natural history of HBV-related cirrhosis in mainland China. In a retrospective cross-sectional hospital-based setting, HBeAg status and severity of underlying cirrhosis, estimated by MELD (model for end-stage liver disease) scores and aspartate aminotransferase (AST)--to-platelet ratio index (APRI), were comprehensively compared in 377 HBsAg-positive compensated and decompensated liver cirrhosis and 434 with HCC patients to clarify the independent and joint effects of the factors. The majority (80.6%) of the HCC patients was negative for serum HBeAg. More than two-thirds of the patients with HCC had MELD scores <10. Severity of underlying liver cirrhosis and loss of serum HBeAg independently correlated with the risk of HCC development. Compared with the contrast group of HBeAg-positive patients with MELD scores > or =20, the odds ratio of HCC development in the patients with HBeAg negativity and MELD score <10 was 26.51 (95%CI: 8.98-78.28). A large proportion of HBV-related cirrhotic patients had negative serum HBeAg and mild cirrhosis severity at the time of diagnosis of HCC.
    Medical science monitor: international medical journal of experimental and clinical research 06/2009; 15(6):CR274-9. · 1.22 Impact Factor
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    ABSTRACT: The relationship between serum viremia and the development of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-related cirrhosis remains unclear. We aimed at calculating odds ratios (OR) for the presence of HCC over a range of HBV DNA levels in these patients. Patients were identified retrospectively and 155 pairs of matched, treatment-naive HBV-related cirrhotic patients with and without HCC were recruited. Their serum HBV DNA levels were measured at HCC diagnosis, or at the equivalent age in non-HCC patients, and correlations between the presence of HCC and different DNA levels were calculated using conditional logistic regression. The median HBV DNA level was significantly higher in HCC patients than in non-HCC patients (5.15 vs 4.83 log(10) copies/mL, P = 0.024). The overall OR for HCC in patients with HBV DNA > or = 3 log(10) copies/mL was 2.13, compared with patients with levels <3 log(10) copies/mL. Compared with patients with <3 log(10) copies/mL, the OR for HCC were 2.39 and 2.61 for patients with 4 to <5 and 5 to <6 log(10) copies/mL, respectively, while the OR for DNA levels of > or = 6 log(10) copies/mL were not significantly different. In HBV-related cirrhosis, a detectable serum HBV DNA was associated with the presence of HCC, but the likelihood of having HCC did not successively increase with increasing serum HBV DNA levels: patients with serum HBV DNA levels between 4 and <6 log(10) copies/mL were most likely to present with HCC.
    Journal of Digestive Diseases 05/2009; 10(2):138-44. DOI:10.1111/j.1751-2980.2009.00376.x · 1.92 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. DOI:10.1186/cc7737
  • 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. DOI:10.1016/j.pathophys.2009.02.009
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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. DOI:10.1007/s10549-009-0323-3 · 4.20 Impact Factor