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Gan G.,Hunan Province Geriatric Hospital | Gan G.,University of South China | Hu R.,Hunan Province Geriatric Hospital | Dai A.,Hunan Province Geriatric Hospital | And 4 more authors.
Cellular Physiology and Biochemistry | Year: 2011

Apoptosis is of considerable importance in the pathogenesis of emphysema, and recent studies show that endoplasmic reticulum (ER) stress is involved in emphysema. In our research, we investigated the role of protein kinase RNA (PKR)-like ER kinase (PERK)/ eukaryotic initiation factor 2 alpha (eIF2α) pathway, the CCAAT enhancer-binding protein-homologous protein (CHOP) expression, caspase-12 activation and apoptosis in emphysema results from cigarette smoke (CS) exposure. Expression of phosphorylated-PERK (p-PERK), phospholated-eIF2α (p-eIF2α),CHOP and caspase-12 as well as the apoptosis rate are remarkably increased in rats after exposure to 2 months CS compared with control rats, significantly elevated in rats exposed to 4 months CS over rats exposed only to 2 months CS, and slightly decreased in ex-smoking rats in contrast to rats exposed to 4 months CS. Taken together, our results show that CS induces ER stress in lung epithelial cells, which may subsequently lead to lung injury in rats, and this might be a novel target for protection of pulmonary epithelial cells from ER stress injury in emphysema. Copyright © 2011 S. Karger AG, Basel.

PubMed | University of South China, Central South University, Sun Yat Sen University, Hunan Province Geriatric Hospital and Eighth Hospital of Changsha
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Although the great progress has been made in diagnosis and therapeutic in lung cancer, it induces the most cancer death worldwide in both males and females. Chemokines, which have chemotactic abilities, contain up to 50 family members. By binding to G protein-coupled receptors (GPCR), holding seven-transmembrane domain, they function in immune cell trafficking and regulation of cell proliferation, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. In addition to human tissues of the bone marrow, liver, adrenal glands, and brain, the CXC chemokine SDF-1 or CXCL12 is also highly expressed in lung cancer tissues and is associated with lung metastasis. Lung cancer cells have the capabilities to utilize and manipulate the CXCL12/CXCR system to benefit growth and distant spread. CXCL12/CXCR4 axis is a major culprit for lung cancer and has a crucial role in lung cancer initiation and progression by activating cancer stem cell. This review provides an evaluation of CXCL12/CXCR4 as the potential therapeutic target for lung cancers; it also focuses on the synergistic effects of inhibition of CXCL12/CXCR4 axis and immunotherapy as well as chemotherapy. Together, CXCL12/CXCR4 axis can be a potential therapeutic target for lung cancers and has additive effects with immunotherapy.

PubMed | University of South China and Hunan Province Geriatric Hospital
Type: Journal Article | Journal: Molecular medicine reports | Year: 2016

Hypoxic pulmonary vascular remodeling (HPSR) has an important role in the development of hypoxic pulmonary hypertension. HPSR is predominantly mediated by the proliferation of pulmonary artery smooth muscle cells (PASMCs). Our previous study demonstrated that hypoxiainducible factor (HIF)1 was able to promote the proliferation of PASMCs. Small ubiquitinlike modifier (SUMO)ylation is a posttranslational modification that is important in various cellular processes. It has previously been demonstrated that HIF1 may be SUMOylated by SUMO. Conversely, SUMOspecific protease 1 (SENP1) was able to increase the stability of HIF1 by decreasing SUMOylation of HIF1. In order to investigate whether SUMOylation of HIF1 has a role in the proliferation of PASMCs, the present study cultured PASMCs in hypoxic and normoxic chambers in vitro. The proliferation ability of PASMCs was measured using the Cell Counting kit8 and 5ethynyl2deoxyuridine cell proliferation assays. In addition, short hairpin RNA lentiviral particles were used to knockdown the expression of SENP1, and the expression levels of HIF1, SENP1 and vascular endothelial growth factor (VEGF) were detected at the mRNA and protein levels using semiquantitative polymerase chain reaction and western blotting, respectively. The present study demonstrated that SENP1 was able to enhance the proliferative ability of PASMCs by initiating deSUMOylation of HIF1 and increasing the expression of its downstream responsive gene, VEGF.

Jiang Y.,Guangzhou University | Jiang Y.,Hunan Province Geriatric Hospital | Dai A.,Hunan Province Geriatric Hospital | Zhou Y.,Guangzhou University | And 5 more authors.
Cellular Physiology and Biochemistry | Year: 2014

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling with airway smooth muscle (ASM) hypertrophy and hyperplasia. Since tobacco use is the key risk factor for the development of COPD and intracellular Ca2+ concentration ([Ca2+] i) plays a major role in both cell proliferation and differentiation, we hypothesized that nicotinic acetylcholine receptor (nAChR) activation plays a role in the elevation of [Ca2+]i in airway smooth muscle cells (ASMCs). Methods: We examined the expression of nAChR and characterized the functions of α7-nAChR in ASMCs. Results: RT-PCR analysis showed that α2-7, β2, and β3-nAChR subunits are expressed in rat ASMCs, with α7 being one of the most abundantly expressed subtypes. Chronic nicotine exposure increased α7-nAChR mRNA and protein expression, and elevated resting [Ca2+]i in cultured rat ASMCs. Acute application of nicotine evoked a rapid increase in [Ca2+]i in a concentration-dependent manner, and the response was significantly enhanced in ASMCs cultured with 1 μM nicotine for 48 hours. Nicotine-induced Ca 2+ response was reversibly blocked by the α7-nAChR nicotinic antagonists, methyllycaconitine and α-bungarotoxin. Small interfering RNA suppression of α7-nAChR also substantially blunted the Ca2+ responses induced by nicotine. Conclusion: These observations suggest that nicotine elevates [Ca2+]i in ASMCs through α7-nAChR-mediated signals pathways, and highlight the possibility that α7-nAChR can be considered as a potential target for the treatment of airway remodeling.that nicotine elevates [Ca2+]i in ASMCs through α7-nAChR-mediated signals pathways, and highlight the possibility that α7-nAChR can be considered as a potential target for the treatment of airway remodeling. Copyright © 2014 S. Karger AG, Basel.

Chen Y.R.,Hunan Province Geriatric Hospital
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology | Year: 2012

To observe the expression of hypoxia-inducible factor-lalpha subunit (HIF-1alpha), HIF prolyl hydroxylase domain-containing protein(PHDs) and factor inhibiting HIF-1(FIH) in pulmonary arteries of patient with chronic obstructive pulmonary disease (COPD). Pulmonary specimens were obtained from patients undergoing lobectomy for lung cancer, 12 had concurrent COPD (COPD group) and 14 without COPD (control group). The ratio of vascular wall area to total vascular area (WA%) and pulmonary artery media thickness (PAMT) was observed, and HIF-1alpha and its hydroxylases(PHD1, PHD2, PHD3, FIH) mRNA and protein were detected by in situ hybridization and immunohistochemistry respectively. WA% and PAMT of COPD patients(50 microm +/- 9 microm, 40% +/- 5%, were statistically different from those of the control subjects (39 microm +/- 6 microm, 31% +/- 4%, P < 0.01). Relative quantification of mRNA and protein levels (absorbance, A) showed that HIF-lalpha mRNA and protein levels in COPD group (0.230 +/- 0.036,0.275 +/- 0.039) were statistically higher than those of the control subjects (0.174 +/- 0.029, 0.102 +/- 0.015, P < 0.01 ), and that the protein level increased more markedly. PHD1 mRNA in COPD subjects (0.180 +/- 0.030) was comparable to that in control group (0.191 +/- 0.029, P > 0.05); PHD2 and PHD3 mRNA levels in COPD (0.245 +/- 0.044, 0.252 +/- 0.023) were significantly higher than those in control group(0.182 +/- 0.028, 0.127 +/- 0.017, P < 0.01). On the other hand, in COPD subjects PHD1 protein (0.104 +/- 0.015) was significantly lower(P < 0.01), whereas PHD2 protein (0.274 +/- 0.044) was significantly higher(P < 0.01) than those in control group(0.209 +/- 0.023, 0.219+/- 0.043). As for PHD3 protein, no significant changes were observed between the two groups (0.161+/- 0.023 in COPD, 0.146 +/- 0.021 in control, P > 0.05). FIH mRNA and protein both showed no differences between the two groups. Linear correlation analysis showed that HIF1alpha protein was positively correlated with WA%, PAMT, PHD2 mRNA and protein, PHD3 mRNA, and that HIF1alpha protein was negatively correlated with PHD1 protein. PHDs may be involved in the process of hypoxic pulmonary vascular remodeling in COPD via regulation of HIF-1alpha gene expression

Li J.,Hunan Province Geriatric Hospital | Dai A.,Hunan Province Geriatric Hospital | Hu R.,Hunan Province Geriatric Hospital | Zhu L.,Hunan Province Geriatric Hospital | Tan S.,Hunan Province Geriatric Hospital
Acta Biochimica et Biophysica Sinica | Year: 2010

Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). γ-Glutamylcysteine synthetase (γ-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPARγ coactivator-1α (PGC-1α) is a PPARγ coactivator, which binds to PPARγ by induction of PPARγ ligands, co-activating PPARγ target genes. Growing evidence has suggested that PPARγ/PGC-1α can regulate multiple antioxidant genes. However, the effect of PPARγ/PGC- 1α on γ-GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPARγ, PGC-1α and γ-GCS, γ-GCS activity and reactive oxygen species (ROS) contents in lungs of rats treated by cigarette smoke (CS) + lipopolysaccharide (LPS) and CS + LPS + RGZ, as well as lungs of patients suffered from COPD. Compared with lungs from CS + LPS-treated rats, lungs of RGZ-treated rats demonstrated markedly lower ROS contents, and remarkable increase of -GCS activity and increase of the expression levels of PPARγ, PGC-1α, and γ-GCS. Furthermore, compared with controls, expression levels of PPARγ, PGC-1α, and γ-GCS significantly increased in the lungs of mild COPD patients, and progressively decreased in lungs of patients with moderate and severe COPD. γ-GCS protein was positively correlated with FEV 1%. PPARγ and PGC-1alpha; proteins were positively correlated with γ-GCS activity and mRNA level. In conclusion, γ-GCS showed compensatory upregulation in the early stage of COPD, which progressively decompensate with increasing COPD severity. The activation of the PPARγ/PGC-1α pathway may protect against COPD progression by upregulating γ-GCS and relieving oxidative stress. © The Author 2010.

Tian H.,Hunan Province Geriatric Hospital
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology | Year: 2012

To investigate the dynamic expression and role of SENP1 (SUMO-specific proteases-1) in the pulmonary vascular wall of rat during the development of hypoxic pulmonary hypertension (HPH). Forty adult male Wistar rats were randomly divided into 5 groups (n = 8), and exposed to normoxia (Control group) or exposed to hypoxia for 3, 7, 14 or 21 d, respectively. The HPH models were established by normobaric intermittent hypoxia. Mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), and vessel morphometry were measured. Reverse transcriptase-polymerase chain reaction(RT-PCR) and in situ hybridization were used to determine the mRNA expression of SENP1. Immunohistochemistry and Western blot were used to determine the protein expression of SENP1. The hypoxic rats developed pulmonary vascular remodeling in pulmonary arterioles after 7 d of hypoxia exposure. Pulmonary vascular remodeling in pulmonary arterioles significantly increased after 14 d of hypoxia. The level of mPAP in hypoxic rats increased significantly after 7 d of hypoxia, reached its peak after 14 d of hypoxic exposure. RVHI was markedly increased after 14 d of hypoxia. In situ hybridization and immunohistochemical analysis showed that SENP1 mRNA and protein were positively stained in control. SENP1 mRNA expression had little changes after exposure to hypoxia compared with the control, however, SENP1 protein expression was declined gradually after 7 d of hypoxia. The results of RT-PCR and Western blot showed that the same dynamic expression of SENP1 mRNA and protein in lung tissues of rats. Linear correlation analysis showed that SENP1 protein were negatively correlated with mPAP, pulmonary vascular remodeling index and RVHI. Under chronic hypoxia, SENP1 protein can be degradated. The dynamic expression of SENP1 protein may play a role in implicating in the development of HPH.

Guo L.-J.,Central South University | Liao L.,Central South University | Yang L.,Hunan Province Geriatric Hospital | Li Y.,Central South University | Jiang T.-J.,Central South University
Experimental Cell Research | Year: 2014

MicroRNAs (miRNAs) play important roles in osteoclastogenesis and bone resorption. In the present study, we found that miR-125a was dramatically down-regulated during macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclastogenesis of circulating CD14+ peripheral blood mononuclear cells (PBMCs). Overexpression of miR-125a in CD14+ PBMCs inhibited osteoclastogenesis, while inhibition of miR-125a promoted osteoclastogenesis. TNF receptor-associated factor 6 (TRAF6), a transduction factor for RANKL/RANK/NFATc1 signal, was confirmed to be a target of miR-125a. EMSA and ChIP assays confirmed that NFATc1 bound to the promoter of the miR-125a. Overexpression of NFATc1 inhibited miR-125a transcription, and block of NFATc1 expression attenuated RANKL-regulated miR-125a transcription. Here, we reported that miR-125a played a biological function in osteoclastogenesis through a novel TRAF6/ NFATc1/miR-125a regulatory feedback loop. It suggests that regulation of miR-125a expression may be a potential strategy for ameliorating metabolic disease. © 2013 Elsevier Inc.

Hu R.,Hunan Province Geriatric Hospital | Ouyang Q.,Hunan Province Geriatric Hospital | Ouyang Q.,Central South University | Dai A.,Hunan Province Geriatric Hospital | And 3 more authors.
Respirology | Year: 2011

Background and objective: COPD is a global disease characterized by chronic bronchitis and obstructive emphysema. Its pathogenesis is not fully understood. This study aimed to use proteomics to provide new insights into the mechanisms of COPD. Methods: Protein lysates were prepared from lung tissue samples harvested from never-smokers, non-COPD smokers and COPD smokers, and were analysed using 2-dimensional gel electrophoresis. Differentially expressed proteins were identified using mass spectrometry. The differential expression of heat shock protein 27 (Hsp27) and cyclophilin A (CyPA) was validated by immunohistochemistry and western blotting. Results: Twenty-four proteins were identified by mass spectrometry as being differentially expressed among the three groups of subjects. The main functions of these proteins involve basic metabolism, oxidation/reduction, coagulation/fibrinolysis, protein degradation, signal transduction, inflammation and cell growth/differentiation/apoptosis. Proteomic analysis revealed that the expression of Hsp27 and CyPA was upregulated in smokers, and this upregulation was particularly marked in COPD smokers. The variation in expression of Hsp27 and CyPA between the groups was confirmed by immunohistochemistry and western blotting. Conclusions: Hsp27 and CyPA are associated with the pathogenesis of COPD, and smoking contributes to the overexpression of these proteins. Using differential proteomics analysis, immunohistochemistry and western blotting, on lung tissue from never-smokers, non-COPD smokers and COPD smokers, heat shock protein 27 and cyclophilin A are shown to be overexpressed in the lungs of non-COPD smokers and further upregulated in COPD smokers, as compared with never-smokers. © 2011 Asian Pacific Society of Respirology.

Tan S.-X.,Central South University | Hu R.-C.,Hunan Province Geriatric Hospital | Liu J.-J.,Hunan Province Geriatric Hospital | Tan Y.-L.,Hunan Province Geriatric Hospital | Liu W.-E.,Central South University
International Journal of Clinical and Experimental Pathology | Year: 2014

Aims: To investigate the changes of expression and methylation status of PRDM2, PRDM5, PRDM16 in lung cancer cells after treatment with demethylation agent. Methods: A549 (lung adenocarcinoma cell line), HTB-182 (lung squamous cell carcinoma cell line) and HBE (normal bronchial cell line) were treated with 5-aza-2dC. The methylation state of PRDM2, PRDM5, PRDM16 was detected by MSP. The expression of PRDM2, PRDM5, PRDM16 was detected by RT-PCR and Western blot analysis. Cell growth was detected by MTT assay. Results: 5-aza-2-dC reduced the methylation of PRDM2, PRDM5, PRDM16 gene in A549 and HTB-182 cells but not in HBE cells. Consistently, 5-aza-2dC increased mRNA and protein expression of PRDM2, PRDM5, PRDM16 in A549 and HTB-182 cells but not in HBE cells. Furthermore, 5-aza-2dC inhibited the growth of A549 and HTB-182 cells but not HBE cells. Conclusions: PRDM2, PRDM5, PRDM16 promoters are methylated and their expression is suppressed in lung cancer cells. Demethylation drug 5-aza-2dC could upregulate the expression of PRDM2, PRDM5, PRDM16 and suppress lung cancer cell growth. 5-aza-2dC has potential to be used for lung cancer therapy by epigenetic mechanism.

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