Publications by authors named "Jun-Wei Liu"

31 Publications

The inactivation of the non-enveloped enterovirus 71 (EV71) by a novel disinfectant gel formulation for topical use.

Drug Dev Ind Pharm 2019 Mar 15;45(3):506-513. Epub 2019 Jan 15.

a Tianjin International Joint Academy of Biomedicine, The Tianjin Economic-Technological Development Area (TEDA) , Tianjin , China.

Background: Hand-foot-mouth disease may cause severe central nervous system complications and even death, that is induced mainly by enterovirus 71 (EV71), which is a non-enveloped virus. Inactivation of the EV71 on hands could effectively inhibit the transmission. However, the inactivations of the EV71 by conventional disinfectants including the alcohols are poor, due to the high stability of the EV71. A novel pyridyl imidazolidinone compound (TJAB1099) was designed to specifically inhibit EV71 replication in vitro. It may potentially be developed as formulations applied on hands for EV71 transmission control.

Methods: The stress stability of TJAB1099 was first evaluated after storing in high temperature (60 °C, RH 10%), high humidity (25 °C, RH90%), and the high-intensity photolysis (4500 Lx ± 500 Lx) for 15 days, respectively. A wash-free antimicrobial gel containing the TJAB1099 was developed using the copolymer carrier. The antiviral activity, the acute oral toxicity, and the local irritation of the antimicrobial gel were evaluated accordingly.

Results: The results indicated that the TJAB1099 was stable during the storage in high temperature and humidity. However, a significant change (p < .0001) was detected when TJAB1099 stored in the high-intensity photolysis. The antimicrobial gel containing 1 μM TJAB1099 could inhibit EV71 significantly higher than the ethanol (75%) (p < .0001) and commercialized disinfectant products (p < .0001). The results of acute oral toxicity and the local irritation suggest that the TJAB1099 containing antimicrobial gel was not causing skin irritations and acute oral toxicity symptoms.

Conclusions: The results suggest that the antimicrobial gel containing TJAB1099 was safe and could effectively inhibit EV71 transmission in vitro.
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http://dx.doi.org/10.1080/03639045.2018.1562464DOI Listing
March 2019

Role of TGF-β1 Signaling in Heart Valve Calcification Induced by Abnormal Mechanical Stimulation in a Tissue Engineering Model.

Curr Med Sci 2018 Oct 20;38(5):765-775. Epub 2018 Oct 20.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

A tissue engineering model of heart valve calcification induced in a bioreactor was established to evaluate the calcification induced by abnormal mechanical stimulation and explore the underlying molecular mechanisms. Polyethylene glycol (PEG)-modified decellularized porcine aortic leaflets seeded with human valve interstitial cells (huVICs) were mounted on a Ti-Ni alloy frame to fabricate two-leaflet and threeleaflet tissue engineered valves. The two-leaflet model valves were exposed to abnormal pulsatile flow stimulation with null (group A), low (1000 mL/min, group B), medium (2000 mL/min, group C), and high velocity (3000 mL/min, group D) for 14 days. Morphology and calcification were assessed by von Kossa staining, alkaline phosphatase (ALP) content, and Runx2 immunostaining. Leaflet calcification and mRNA and protein expression of transforming growth factor (TGF)-β1, bone morphogenetic protein 2 (BMP2), Smad1, and MSX2 were measured at different time points. ALP content was examined in two-leaflet valves seeded with BMP2 shRNA plasmid-infected huVICs and exposed to the same stimulation conditions. The results showed that during 14 days of flow stimulation, huVICs on the leaflet surface proliferated to generate normal monolayer coverage in groups A, B, and C. Under mechanical stimulation, huVICs showed a parallel growth pattern in the direction of the fluid flow, but huVICs exhibited disordered growth in the high-velocity flow environment. von Kossa staining, ALP measurement, and immunohistochemical staining for Runx2 confirmed the lack of obvious calcification in group A and significant calcification in group D. Expression levels of TGF-β1, BMP2, and MSX2 mRNA and protein were increased under fluid stimulation. ALP production by BMP2 shRNA plasmid-infected huVICs on model leaflets was significantly reduced. In conclusion, abnormal mechanical stimulation in a bioreactor induced calcification in the tissue engineering valve model. The extent of calcification correlated positively with the flow velocity, as did the mRNA and protein levels of TGF-β1, BMP2, and MSX2. These findings indicate that TGF-β1/BMP2 signaling is involved in valve calcification induced by abnormal mechanical stimulation.
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http://dx.doi.org/10.1007/s11596-018-1943-9DOI Listing
October 2018

Characterization of the complete mitochondrial genome of three-spined stickleback, .

Mitochondrial DNA B Resour 2018 Sep 27;3(2):1133-1134. Epub 2018 Sep 27.

College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China.

In this study, the complete mitochondrial genome of three-spined stickleback, was determined through sequencing of PCR fragments. The complete mitochondrial genome of was 16,543 bp in length and encoded 13 protein-coding genes, 22 transfer RNA (tRNA) genes, and two ribosomal RNA genes. The overall nucleotide composition is: 27.0% A, 28.4% T, 27.4% C, and 17.2% G, with a total G + C content of 44.6%. By phylogenetic analysis using ML method, showed the closest relationship with the blackspotted stickleback ().
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http://dx.doi.org/10.1080/23802359.2018.1473732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800355PMC
September 2018

Application of Endoscopic Vein Harvesting in Obese Patients Undergoing Coronary Artery Bypass Grafting.

Curr Med Sci 2018 Aug 20;38(4):691-696. Epub 2018 Aug 20.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

This study aims to evaluate the clinical outcomes of endoscopic vein harvesting (EVH) for coronary artery bypass grafting (CABG) in obese patients. Totally, 153 obese patients who underwent EVH (n=81) or standard bridging technique (SBT, n=12) in CABG surgery from May 2012 to October 2014 in our hospital were enrolled in this retrospective non-randomized controlled study. The general situation of operation, postoperative complications and short medium-term outcomes were analyzed. The baseline characteristics were similar between these two groups (P>0.05). There were no statistical differences in total operation time (226±28 min vs. 224±30 min, P>0.05), number of damaged vessels (0.12±0.05 vs. 0.16±0.06,P>0.05) and short medium-term outcomes including revascularization rate (1.25% vs. 2.78%, i 0.05), vessel dysfunction rate (11.25% vs. 11.11%,P>0.05) and mortality (0.00% v . 0.00%, P>0.05). Use of EVH was associated with significant reduction of total harvesting time (41 ±6 min vs. 63± 11 min, P<0.05), incision length (4.4±1.1 cm 18.2±4.5 cm, P<0.05) and postoperative lower extremity complications (P<0.05). EVH can reduce the risk of wound complications, whereas does not influence short- and medium-term outcomes in obese patients. It can be considered a reliable procedure of harvesting vessel conduits for obese patients undergoing CABG.
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http://dx.doi.org/10.1007/s11596-018-1932-zDOI Listing
August 2018

MiR-200a inhibits cell proliferation and EMT by down-regulating the ASPH expression levels and affecting ERK and PI3K/Akt pathways in human hepatoma cells.

Am J Transl Res 2018 15;10(4):1117-1130. Epub 2018 Apr 15.

Department of Hepato-Biliary-Pancreatic Surgery, People's Hospital of Hangzhou Medical College Hangzhou 310014, P.R. China.

The primary objective of this study was to investigate the role of miR-200a in cell proliferation and epithelial-mesenchymal transition (EMT) through regulating targeting aspartate-β-hydroxylase (ASPH), which may further affect the activation of ERK/PI3K/Akt pathway. Liver cancer and adjacent tissues were collected from 72 cases of liver cancer patients with surgery in our hospital. In this study, the mRNA expression level of miR-200a was significantly decreased by real-time PCR (RT-PCR) detection. ASPH expressions, however, had an opposite tendency compared to that of miR-200a. We found a significantly negative correlation between miR-200a expressions and ASPH expressions. The survival rate of liver cancer patients with the low expressed ASPH was significantly higher than those with the high expressed ASPH. RT-PCR and Western blot results showed that low expressed miR-200a and highexpressed ASPH were found in liver cancer cell lines. Further research discovered that miR-200a transfection could significantly decrease the relative luciferase activity when it was integrated with ASPH 3'-untranslated region (3'-UTR) in HepG2 cells. Cell Counting Kit (CCK-8) detection showed that treatment with miR-200a mimics reduced cell viability, while the over-expressed ASPH increased cell viability by regulating the c-mycmrna (c-Myc) and Cyclin-D1 expressions. The EMT-related genes including E-Cadherin, N-Cadherin and Vimentin expressions were significantly increased, whereas the over-expressed ASPH exerted the opposite effects. In addition, extracellular signal regulated kinase (ERK), phosphoinositide-3-kinase (PI3K) and serine threonine kinase (AKT) were suppressed by miR-200a mimics. In conclusion, miR-200a inhibits cell proliferation and EMT in human hepatoma cells by targeting ASPH and affecting ERK and PI3K/Akt signaling pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934571PMC
April 2018

[Depression and anxiety caused by pegylated interferon treatment in patients with chronic hepatitis B and the therapeutic effects of escitalopram and alprazolam].

Nan Fang Yi Ke Da Xue Xue Bao 2017 Sep;37(9):1201-1205

Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.E-mail:

Objective: To evaluate the incidence of depression and anxiety caused by pegylated interferon α (PegIFN-α) treatment for chronic hepatitis B (CHB) and assess the efficacy of intervention with escitalopram and alprazolam.

Methods: A total of 165 CHB patients receiving PegIFN-α-based treatment for 12 weeks were assessed for moderate to severe depression and anxiety using Patient Health Questionnaire (PHQ-9) and 7-item Generalized Anxiety Disorder Scale (GAD-7)]. The patients identified to have moderate to severe depression and anxiety treated with escitalopram or alprazolam and the psychological condition of the patients was assessed at the 2nd, 4th and 8th weeks of the treatments.

Results: In the 165 patients receiving PegIFN-α treatment, 51 patients developed moderate to severe psychiatric symptoms, incuding 37 (22.4%) with depression, 31 (18.8%) with anxiety, and 17 (10.3%) with both. The symptoms of depression and anxiety was both significantly improved by intervention with escitalopram (P=0.000); alprazolam was effective for anxiety (P=0.001) but did not produce obvious effects on depression (P=0.904). Nevertheless, alprazolam had a much better therapeutic effect than escitalopram on anxiety in these patients (t=-3.198, P=0.010).

Conclusion: Psychological symptoms are common in CHB patients receiving PegIFN-α treatment. The symptoms of depression and anxiety can be ameliorated by intervention with escitalopram and alprazolam, respectively.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765486PMC
September 2017

[Responses of soil microbial community structure and function to simulated warming in alpine forest.]

Ying Yong Sheng Tai Xue Bao 2016 Sep;27(9):2855-2863

Long-term Research Station of Alpine Forest Ecosystems/Key Laboratory of Forestry Ecological Engineering in the Upper Reaches of Yangtze River/Institute of Ecology & Forestry, Sichuan Agricultural University, Chengdu 611130, China.

Soil samples were collected from an alpine coniferous forest. Soil cores with soil organic layer above and mineral soil layer below were incubated in plant growth chambers during 10 weeks. Taking the annual average soil temperature in the alpine forest as the control, and other two levels of temperature were increased 2 and 4 ℃, respectively, to investigate the responses of soil microbial community and soil enzyme activity to warming. The results showed that warming significantly reduced PLFAs content of bacteria in soil organic layer and PLFAs content of G in the mineral soil layer, whereas soil fungi was slightly influenced by warming. Warming caused the G/G increasing and changed the microbial community structure, but had no significant effect on soil enzymes activity, i.e., laccase (Lac), β-1,4-glucoside (BG), acid phosphate (AP), β-1,4-N-acetylglucosaminidase (NAG). There were significantly positive correlations between fungi, bacteria, G and G, showing the coordinated growth trend between soil microbial communities. There was significantly negative correlation between BG and bacteria, showing the BG competing for carbon source utilization with soil microbial community. In consequence, the soil microbe types responded differently to warming. Bacteria were more sensitive to temperature than fungi, and fungi had stronger ability to tolerate warming in the alpine forest.
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http://dx.doi.org/10.13287/j.1001-9332.201609.026DOI Listing
September 2016

Phthalide Derivatives with Anticoagulation Activities from Angelica sinensis.

J Nat Prod 2016 07 11;79(7):1857-61. Epub 2016 Jul 11.

School of Pharmacy, Xinxiang Medical University , Xinxiang 453003, People's Republic of China.

Two new phthalide derivatives, angesinenolides A and B (1 and 2), were isolated from the roots of Angelica sinensis. Their structures were elucidated using HRMS, NMR, and X-ray crystallographic data. Compound 1 is the first example of a phthalide trimer presumably formed through two [2+2] cycloaddition reactions. Compound 2 is a unique dimeric phthalide with a peroxy bridge between C-3a and C-6. Both phthalides were evaluated for in vitro anticoagulation activities. Compound 1 reduced the level of fibrinogen (FIB). Compound 2 significantly extended thrombin time and activated partial thromboplastin time, as well as markedly reduced the content of FIB.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00080DOI Listing
July 2016

[Entecavir combined with Fufang Biejia Ruangan tablet in treatment of chronic hepatitis B patients with liver fibrosis: 96-week efficacy analyses].

Nan Fang Yi Ke Da Xue Xue Bao 2016 Jun;36(6):775-9

uangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. E-mail:

Objective: To evaluate the effect of long-term therapy with entecavir and Fufang Biejia Ruangan tablet in patients with chronic hepatitis B (CHB)-associated fibrosis and explore the synergistic therapy that accelerates the reversion of liver fibrosis.

Methods: A total of 197 patients with CHB-associated fibrosis were recruited from Nanfang Hospital between June, 2010 and June, 2015. The patients were divided into two groups after matching for age, gender and liver stiffness measurement (LSM), namely group A (n=98) treated with Fufang Biejia Ruangan Tablet plus entecavir, and group B (n=99) to receive entecavir only. HBV DNA quantification, HBV serological indicators, blood biochemical indexes, and results of abdominal ultrasound and FibroScan were recorded every 12 weeks. FibroScan values were converted to Metavir staging.

Results: Both groups showed significant decreases in serum levels of HBV DNA, alanine aminotransferase (ALT), and LSM value from baseline (all P<0.05). The median time to achieve Metavir fibrosis staging improvement were 72 weeks in group A and 96 weeks in group B (P<0.05), and the median time to achieve ALT and AST normalization were 12 and 24 weeks in Group A, respectively, significantly shorter than the time in group B (P<0.05). No significant difference was found between the two groups in HBV DNA undetectable rate and HBeAg seroconversion rate.

Conclusion: The combination therapy with Fufang Biejia Ruangan tablet and entecavir produces a stronger efficacy than entecavir alone in the treatment of chronic hepatitis B patients with liver fibrosis, and Fufang Biejia Ruangan tablet shows an obvious hepatoprotective effect in these patients.
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June 2016

[Research progress of structures and pharmacological activities of phthalides from Angelica sinensis].

Zhongguo Zhong Yao Za Zhi 2016 Jan;41(2):167-176

School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China.

Angelica sinensis(Umbelliferae)is a worldwide-known medicinal plant and also a famous traditional Chinese medicinal herb. It is recorded to possess the efficacy of enriching the blood and invigorating the circulation of blood of the individual.Danggui was extensively applied to the treatment of gynecological disorders. Modern researches indicate that phthalides are main chemical components related to the bioactivities of A.sinensis, such as anti-tumor, analgesic and neuroprotective effect.The advances in studies on the structures and pharmacological activities of phthalides from A.sinensis are reviewed to provide references for further researches and utilization of their medicinal value.
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http://dx.doi.org/10.4268/cjcmm20160203DOI Listing
January 2016

Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection.

World J Gastroenterol 2014 Apr;20(14):4071-5

Kai-Li Wang, Han-Qian Xing, Hong Zhao, Jun-Wei Liu, Deng-Lian Gao, Xue-Hua Zhang, Hong-Yu Yao, Li Yan, Jun Zhao, Department of Blood Purification, 302 Hospital of the People's Liberation Army, Beijing 100039, China.

Aim: To evaluate the efficacy and tolerability of low-dose standard or pegylated interferon (PEG-IFN) in hepatitis C virus (HCV)-positive hemodialysis patients.

Methods: In total, 19 patients were enrolled in this study, of which 12 received PEG-IFNα-2a 67.5 μg 1 time/wk (Group 1) and 7 received standard interferon α-2b subcutaneously 1.5 × 10⁶ U 3 times/wk (Group 2). The treatment durations were 48 wk for patients infected with HCV genotype 1 and 24 wk for patients infected with HCV genotype 2/3. All patients were prospectively followed after the completion of therapy. The efficacy and tolerability of the treatment were evaluated based on the sustained virological response (SVR) and treatment-related drop-out rate.

Results: In Group 1, 11 of the 12 patients completed the treatment. Early virological response (EVR) and sustained virological response (SVR) rates were 83.3% and 91.7%, respectively. One patient withdrew from treatment due to an adverse event (leukopenia). The drop-out rate was 8.3% in this group. In Group 2, 5 of the 7 patients completed the treatment with an EVR and SVR of 85.7% and 71.4%, respectively. Two patients withdrew due to treatment-related adverse events (nausea and depression). In this group, the drop-out rate was 28.6%. In total, 16 of the patients attained EVR, and 15 of them completed the treatment. The SVR rate for the patients who attained EVR was 93.7%. Anemia was the most frequent side effect and was observed in 10/19 patients (55.5%), but could be effectively managed with erythropoietin.

Conclusion: Low-dose interferon monotherapy, either with PEG-IFNα-2a or standard interferon α-2b, is an effective treatment option for hemodialysis patients with chronic hepatitis C.
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http://dx.doi.org/10.3748/wjg.v20.i14.4071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983465PMC
April 2014

[Effect of ginsenoside Rb1 on cerebral infarction volume and IL-1 beta in the brain tissue and sera of focal cerebral ischemia/reperfusion injury model rats].

Zhongguo Zhong Xi Yi Jie He Za Zhi 2013 Dec;33(12):1696-700

Department of Anesthesiology, First Affiliated Hospital, Wenzhou Medical College, Zhejiang 325000, China.

Objective: To investigate the effect of ginsenoside Rb1 on cerebral infarction volume as well as IL-1 beta in the brain tissue and sera of focal cerebral ischemia/reperfusion (I/R) injury model rats.

Methods: The I/R rat model was established by using thread according to Zea-Longa. SD rats were randomly divided into five groups, i.e., the sham-operation group, the model group, the low dose ginsenoside Rb1 (20 mg/kg) group, the medium dose ginsenoside Rb1 group (40 mg/kg), and the high dose ginsenoside Rb1 group (80 mg/kg), 12 in each group. Rats in the sham-operation group only received middle cerebral artery occlusion (MCAO) but without thread insertion. The MCAO model was prepared in the rest 4 groups, followed by MCAO2 h later. Ginsenoside Rb1 at each dose was peritoneally administrated to rats in corresponding groups immediately after cerebral ischemia. Equal volume of normal saline was administered to rats in the sham-operation group. Rats' cerebral infarction volume, integrals of neurologic defect degree, expression of IL-1 beta content in the brain tissue and sera were observed 24 h after 2-h cerebral I/R.

Results: In the model group, integrals of neurologic defect degree were improved (P < 0.01), IL-1 beta positive cells in the brain tissue increased and serum IL-1 beta content elevated (P < 0.05), when compared with the sham-operation group. In comparison of the model group, integrals of neurologic defect degree were lowered in the medium dose and high dose ginsenoside Rb1 groups (P < 0.05, P < 0.01). The cerebral infarction volume was all shrunken in each ginsenoside Rb1 group, IL-1 beta positive cells in the brain tissue decreased, and IL-1 beta content in serum reduced (P < 0.01, P < 0.05). Compared with the low dose ginsenoside Rb1 group, integrals of neurologic defect degree decreased, the cerebral infarction volume shrunken, and IL-1 beta content in serum reduced in the high dose ginsenoside Rb1 group (P < 0.01, P < 0.05).

Conclusion: Ginsenoside Rb1 (20, 40, 80 mg/kg) might effectively release local cerebral ischemia by down-regulating the IL-1 beta expression.
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December 2013

Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress.

Cancer Sci 2014 Apr 17;105(4):445-54. Epub 2014 Mar 17.

Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Chemotherapy drugs themselves may act as stressors to induce adaptive responses to promote the chemoresistance of cancer cells. Our previous research showed that sirtuin 1 (SIRT1) was overexpressed in pancreatic cancer patients and deregulation of SIRT1 with RNAi could enhance chemosensitivity. Thus, we hypothesized that SIRT1 might facilitate chemoresistance in pancreatic cancer cells through regulating the adaptive response to chemotherapy-induced stress. In the present study, SIRT1 in PANC-1, BXPC-3, and ASPC-1 cells was upregulated after treatment with gemcitabine. Moreover, the decrease in SIRT1 activity with special inhibitor EX527 had a synergic effect on chemotherapy with gemcitabine in PANC-1 and ASPC-1 cell lines, which significantly promoted apoptosis, senescence, and G0 /G1 cycle arrest. Western blot results also showed that SIRT1, acetylated-p53, FOXO3a, and p21 were upregulated after combined treatment, whereas no obvious change was evident in total p53 protein. To further confirm the role of SIRT1 in clinical chemotherapy, SIRT1 was detected in eight pancreatic cancer tissues acquired by endoscopy ultrasonography guided fine needle aspiration biopsy before and after chemotherapy. Compared to before chemotherapy, SIRT1 was significantly increased after treatment with gemcitabine in six cases. Thus, our results indicated a special role for SIRT1 in the regulation of adaptive response to chemotherapy-induced stress, which is involved in chemoresistance. Moreover, it indicates that blocking SIRT1 activity with targeting drugs might be a novel strategy to reverse the chemoresistance of pancreatic cancer.
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http://dx.doi.org/10.1111/cas.12364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317803PMC
April 2014

[Effects of ginsenoside Rb1 on the mRNA expression of tyrosine kinase B in the hippocampus of acute immobilization stress rats].

Zhongguo Zhong Xi Yi Jie He Za Zhi 2013 Mar;33(3):376-9

Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical College, Zhejiang (325000, China.

Objective: To observe the effects of acute immobilization stress on the mRNA expression of tyrosine kinase B (TrkB) in rats' hippocampus.

Methods: Eighteen SD rats were randomly divided into three groups, i.e., the normal control group, the model group, and the medication group, 6 in each group. The acute immobilization stress model was prepared in the model group using acute immobilization for 2 h. Ginsenoside Rb1 (40 mg/kg) was peritoneally injected to rats in the medication group 30 min before modeling, with the same procedure as those for rats in the model group. No treatment was performed to rats in the normal control group. The plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) contents were detected using ELISA. The mRNA expression of TrkB in the rats' hippocampus was detected using real-time fluorescence quantitative RT-PCR.

Results: Before modeling there was no statistical difference of plasma CORT or ACTH concentrations among three groups (P >0.05). The plasma CORT and ACTH concentrations increased in the model group and the medication group more significantly after modeling than before modeling, showing statistical difference (P <0.05). Besides, they were obviously higher in the model group than in the normal control group (P <0.05). They were obviously higher in the medication group than in the model control group (P <0.05). Compared with the normal control group, the mRNA expression of TrkB significantly decreased in the model group (87.73 +/- 7.62 vs 50.65 +/- 5.19, P < 0.05), showing statistical difference. The mRNA expression of TrkB was significantly higher in the medication group (78.91 +/- 18.07) than in the model group, showing statistical difference (P <0.05).

Conclusion: Pretreatment by ginsenoside Rb1 could increase the plasma CORT and ACTH concentrations, maintain the mRNA expression of TrkB, thus relieving injury induced by acute immobilization stress.
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March 2013

Analysis of 19-nortestosterone residue in animal tissues by ion-trap gas chromatography-tandem mass spectrometry.

J Zhejiang Univ Sci B 2011 Jun;12(6):460-7

College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.

A rapid sample treatment procedure for the gas chromatography-tandem mass spectrometry (GC-MS) determination of 19-nortestosterone (19-NT) in animal tissues has been developed. In our optimized procedures, enzymatic hydrolysis with β-glucuronidase from Escherichia coli was performed in an acetate buffer (pH 5.2, 0.2 mol/L). Next, the homogenate was mixed with methanol and heated at 60 °C for 15 min, then placed in an ice-bath at -18 °C for 2 h. After liquid-liquid extraction with n-hexane, the analytes were subjected to a normal-phase solid phase extraction (SPE) C₁₈ cartridge for clean-up. The dried organic extracts were derivatized with heptafluorobutyric anhydride (HFBA), and then the products were injected into GC-MS. Using electron impact mass spectrometry (EI-MS) with positive chemical ionization (PCI), four diagnostic ions (m/z 666, 453, 318, and 306) were determined. A standard calibration curve over the concentration range of 1-20 ng/g was reached, with Y=467084X-68354 (R²=0.9997) for 19-NT, and the detection limit was 0.3 ng. When applied to spiked samples collected from bovine and ovine, the recoveries ranged from 63% to 101% with relative standard deviation (RSD) between 2.7% and 8.9%. The procedure is a highly efficient, sensitive, and more economical method which offers considerable potential to resolve cases of suspected nandrolone doping in husbandry animals.
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http://dx.doi.org/10.1631/jzus.B1000301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109148PMC
June 2011

Blockade of IGF-IR exerts anticancer effects in hepatocellular carcinoma.

Mol Med Rep 2011 Jul-Aug;4(4):719-22. Epub 2011 May 9.

Department of General Surgery, Xiasha Hospital, Hangzhou 310016, People's Republic of China.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is characterized by a high degree of malignancy and a low survival rate. Most HCCs express insulin-like growth factors and their receptors (IGF-IR), which mediate signaling, promote survival and invasion, and prevent apoptosis. Thus, they may be potential targets for the treatment of HCCs. In the present study, the potential therapeutic effect of Tyrphostin AG1024 in HCC was examined. After treatment with various concentrations of AG1024 (one selective inhibitor of IGF-IR), AG1024 not only dose-dependently inhibited the proliferation of HCC cells and induced apoptosis, but also markedly inhibited invasion ability. Expression of proteins detected by Western blot analysis revealed that AG1024 dose-dependently increased the expression of cytochrome C, while procaspase-3 and phospho-ERK were down-regulated. Thus, IGF-IR inhibition may be a promising novel approach to the treatment of HCC.
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http://dx.doi.org/10.3892/mmr.2011.486DOI Listing
September 2011

Unloading the infarcted heart affect MMPs-TIMPs axis in a rat cardiac heterotopic transplantation model.

Mol Biol Rep 2012 Jan 11;39(1):277-83. Epub 2011 May 11.

Department of Anesthesiology, First Affiliated Hospital of Wenzhou Medical College, Zhejiang, 325003, People's Republic of China.

Ventricular assist devices may function as a bridge to recovery or heart transplantation, however, little is known about its mechanisms. This study examined the role of matrix metalloproteinases (MMP)-tissue inhibitors of metalloproteinases (TIMP) axis in the process of recovery after unloading in a rat ischemic-induce heart failure (HF) model. Myocardial infarction model was created with the coronary artery ligation. The infarcted rats hearts were unloaded by heterotopic cardiac transplantation (n=14). 2 weeks later, the function of normal and infarcted hearts with or without loading was evaluated by Langendorff perfusion model. The hearts were then harvested and prepared for the study of expression of MMPs and TIMPs. Developed pressure in the unloading group was higher than the loading group (P=0.0074). Unloading increased the ratio of TIMP-1-MMP-1(1.38±0.11 vs. 0.76±0.09, P<0.05), TIMP-2-MMP-2 (1.06±0.10 vs. 0.33±0.07, P<0.01), TIMP-3-MMP-9(1.07±0.08 vs. 0.59±0.06, P<0.05). Although MMP-1, 2, 9 were downregulated (P<0.01, 0.01, 0.05, respectively), TIMP-2 and TIMP-3 upregulated (P<0.01, 0.05, respectively), MMP-7 and TIMP-1 was not affected significantly. The infarcted cardiac function could be improved by unloading. It was attributed to downregulation of MMP-1, 2 and 9, and upregulation of TIMP-2 and -3, and furthermore, the ratio of TIMPs to MMPs was increased, which might be more sensitive than sole MMPs or TIMPs for the judgment of myocardial matrix homeostasis.
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http://dx.doi.org/10.1007/s11033-011-0736-zDOI Listing
January 2012

Parthenolide induces proliferation inhibition and apoptosis of pancreatic cancer cells in vitro.

J Exp Clin Cancer Res 2010 Aug 10;29:108. Epub 2010 Aug 10.

Department of General Surgery, Sir Run Run Shaw Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.

Background: To explore the anti-tumor effects of parthenolide in human pancreatic cancer.

Methods: BxPC-3 cell, a human pancreatic cancer, was treated with parthenolide at different concentrations. The MTT assay was used to analyze cell viability. Flow cytometry and DNA fragmentation analysis were applied to evaluate apoptosis after parthenolide treatment. The wound closure and cell invasion assay were also employed in the study. Western blotting was used to demonstrate Bad, Bcl-2, Bax, caspase-9 and pro-caspase-3 expression.

Results: The MTT assay indicated that the pancreatic cancer growth could be dose-dependently inhibited by parthenoolide. This phenomenon was confirmed by flow cytometry and DNA fragmentation analysis. The wound closure assay and cell invasion assay showed that BxPC-3 cell was significantly suppressed by parthenolide at 7.5 microM and 15 microM. Western Blotting demonstrated the Bcl-2 and pro-caspase-3 were down-regulated while the Bax and caspase-9 were up-regulated. No alteration in Bad expression was found after treatment.

Conclusions: The parthenolide can inhibit the cell growth, migration, and induce the apoptosis in human pancreatic cancer. These findings may provide a novel approach for pancreatic cancer treatment.
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http://dx.doi.org/10.1186/1756-9966-29-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924280PMC
August 2010

Cigarette smoke induces promoter methylation of single-stranded DNA-binding protein 2 in human esophageal squamous cell carcinoma.

Int J Cancer 2011 May;128(10):2261-73

Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Esophageal squamous cell carcinoma (ESCC) is the sixth most frequent cause of cancer death in the world, and cigarette smoke is a key factor in esophageal carcinogenesis. To identify molecular changes during cigarette smoke-induced ESCC, we examined the methylation status of 13 gene promoters in the human immortalized, nontumorigenic esophageal epithelial cell line (Het-1A) that were exposed to mainstream (MSE) or sidestream cigarette smoke extract (SSE) for 6 months in culture. The promoter of sequence-specific single-stranded DNA-binding protein 2 (SSBP2) was methylated in the Het-1A cells exposed to MSE (MSE-Het-1A). Promoter methylation (86%, 56/70) and downregulation of SSBP2 expression were frequently detected in tumor tissues from ESCC patients. In addition, reintroduction of SSBP2 in an ESCC cell line (TE1) that does not express SSBP2 and in the MSE-Het-1A cells inhibited expression of LRP6 and Dvl3, which are mediators of the Wnt signaling pathway. SSBP2 expression markedly decreased the colony-forming ability of ESCC cell lines and significantly inhibited cell growth of the MSE-Het-1A cells. Our results indicate that cigarette smoking is a cause of SSBP2 promoter methylation and that SSBP2 harbors a tumor suppressive role in ESCC through inhibition of the Wnt signaling pathway.
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http://dx.doi.org/10.1002/ijc.25569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206631PMC
May 2011

The Ras effector RASSF2 controls the PAR-4 tumor suppressor.

Mol Cell Biol 2010 Jun 5;30(11):2608-20. Epub 2010 Apr 5.

Department of Medicine, James Graham Brown Cancer Center, Molecular Targets Program, University of Louisville, 505 S. Hancock St., Louisville, KY 40202, USA.

RASSF2 is a novel proapoptotic effector of K-Ras. Inhibition of RASSF2 expression enhances the transforming effects of K-Ras, and epigenetic inactivation of RASSF2 is frequently detected in mutant Ras-containing primary tumors. Thus, RASSF2 is implicated as a tumor suppressor whose inactivation facilitates transformation by disconnecting apoptotic responses from Ras. The mechanism of action of RASSF2 is not known. Here we show that RASSF2 forms a direct and endogenous complex with the prostate apoptosis response protein 4 (PAR-4) tumor suppressor. This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 is primarily a nuclear protein, and shuttling of PAR-4 from the cytoplasm to the nucleus is essential for its function. We show that RASSF2 modulates the nuclear translocation of PAR-4 in prostate tumor cells, providing a mechanism for its biological effects. Thus, we identify the first tumor suppressor signaling pathway emanating from RASSF2, we identify a novel mode of action of a RASSF protein, and we provide an explanation for the extraordinarily high frequency of RASSF2 inactivation we have observed in primary prostate tumors.
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http://dx.doi.org/10.1128/MCB.00208-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876522PMC
June 2010

[Role of B7-H1 in pancreatic carcinoma immune evasion].

Zhonghua Wai Ke Za Zhi 2009 Feb;47(4):282-5

Key Laboratory of Biotherapy of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.

Objective: To investigate the role of B7-H1 expression in IL-10 production, the B7-H1 and IL-10 expression levels in pancreatic carcinoma tissues and to analyze the correlation between B7-H1 expression and IL-10 level.

Methods: The mRNA and protein levels expressions of B7-H1 and IL-10 in 35 cases of pancreatic cancer and corresponding paracarcinoma tissues and 5 cases of normal pancreas tissues were detected by RT-PCR, Western blot and immunohistochemistry respectively.

Results: The findings for the first time provided the evidences that there was a clear trend for B7-H1 and IL-10 expressions to be most highly expressed in carcinoma tissue, intermediately expressed in paracarcinoma tissue, and expressed at the lowest level in normal pancreatic tissue at mRNA and protein levels. Moreover, there were statistically significant differences in B7-H1 and IL-10 expression between pancreatic carcinoma tissues, corresponding paracarcinoma tissues and normal pancreatic tissues at mRNA and protein levels (P < 0.05). Furthermore, the immunohistochemistry indicated that there were high expression levels of B7-H1 (60.5% +/- 12.7%) and IL-10 (65.3% +/- 16.2%) in pancreatic carcinoma tissues while there were no significant expressions in normal pancreatic tissues. Meanwhile, correlation analysis revealed that B7-H1 expression was significant associated with IL-10 level in tumor tissues at mRNA (P = 0.008, r = 0.841) and protein levels (P = 0.007, r = 0.838).

Conclusions: Over-expression of B7-H1 may be responsible for the increasing IL-10 production in pancreatic cancer, which caused reduced immune response to tumor cells and contributed to pancreatic carcinoma escape from immune attack.
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February 2009

ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer.

Clin Cancer Res 2008 Jun;14(12):3754-60

Division of Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: Prostate cancer is a major cause of cancer death among men and the development of new biomarkers is important to augment current detection approaches.

Experimental Design: We identified hypermethylation of the ssDNA-binding protein 2 (SSBP2) promoter as a potential DNA marker for human prostate cancer based on previous bioinformatics results and pharmacologic unmasking microarray. We then did quantitative methylation-specific PCR in primary prostate cancer tissues to confirm hypermethylation of the SSBP2 promoter, and analyzed its correlation with clinicopathologic data. We further examined SSBP2 expression in primary prostate cancer and studied its role in cell growth.

Results: Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer. Reactivation of SSBP2 expression by the demethylating agent 5-aza-2'-deoxycytidine in prostate cancer cell lines confirmed epigenetic inactivation as one major mechanism of SSBP2 regulation. Moreover, forced expression of SSBP2 inhibited prostate cancer cell proliferation in the colony formation assay and caused cell cycle arrest.

Conclusion: SSBP2 inhibits prostate cancer cell proliferation and seems to represent a novel prostate cancer-specific DNA marker, especially in high stages of human prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082869PMC
June 2008

Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer.

Prostate 2008 Mar;68(4):418-26

Department of Otolaryngology, Division of Head and Neck Cancer Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: DNA methylation has emerged as a promising biomarker for prostate cancer detection. In this report, we screened 36 candidate genes generated by a bioinformatic analysis of the human genome, and found that the melanoma cell adhesion molecule (MCAM) was an excellent candidate for cancer-specific methylation in prostate cancer.

Methods: Direct sequencing of bisulfite-treated genomic DNA, conventional methylation-specific PCR (MSP), real-time quantitative methylation-specific PCR, immunohistochemistry, colony formation assay, and statistical analysis.

Results: We found that the melanoma cell adhesion molecule (MCAM) gene promoter was specifically methylated in prostate cancer cell lines and primary prostate cancer (PCa) but not in non-neoplastic prostate (BPH) tissues by direct sequencing of bisulfite-treated genomic DNA and conventional methylation-specific PCR (MSP). Further analysis with quantitative MSP showed greater hypermethylation of the MCAM promoter (80%, 70/88) in primary prostate cancer compared to 12.5% (3/24) in BPH. Prostatic intraepithelial neoplasias (PIN), potential precursors of prostate carcinoma, showed an intermediate methylation rate of 23% (7/30). We further observed that MCAM promoter methylation was directly correlated with tumor stage (pT3+pT4) (P = 0.001) and Gleason score (P = 0.018) in primary prostate carcinoma.

Conclusions: Our results suggest that MCAM promoter hypermethylation deserves further attention as a potential diagnostic prostatic DNA marker in human prostate cancer.
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http://dx.doi.org/10.1002/pros.20709DOI Listing
March 2008

Quantitative hypermethylation of NMDAR2B in human gastric cancer.

Int J Cancer 2007 Nov;121(9):1994-2000

Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

NMDA receptor Type 2B (NMDAR2B) is a candidate TSG first identified in esophageal squamous cell carcinoma (ESCC). To evaluate NMDAR2B methylation in gastric cancer progression, we performed quantitative methylation-specific PCR (MSP), RT-PCR and immnunohistochemistry (IHC) in primary gastric tissues and colony formation assays in gastric cancer cell lines. We found that the expression of NMDAR2B was reactivated by the demethylating agent, 5-aza-2'-deoxycytidine, with or without trichostatin A in gastric cancer cell lines. Moreover, inactivation of NMDAR2B was found to be closely correlated with promoter methylation status in gastric cell lines and primary gastric tumors. IHC data also showed that NMDAR2B was specifically expressed in gastric epithelial cells and its expression was diminished or absent in gastric cancer epithelium. Quantitative analysis of NMDAR2B promoter methylation showed 61% (17/28) hypermethylation in primary gastric tumors versus 5% (1/20) in normal gastric tissues from nongastric cancer patients. Forced over-expression of NMDAR2B in gastric cancer cell lines significantly inhibited cell colony formation. Taken together, the above results suggest that NMDAR2B methylation is a common and important biologically relevant event in gastric cancer progression.
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http://dx.doi.org/10.1002/ijc.22934DOI Listing
November 2007

A p53-type response element in the GDF15 promoter confers high specificity for p53 activation.

Biochem Biophys Res Commun 2007 Mar 25;354(4):913-8. Epub 2007 Jan 25.

Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

GDF15 is a transcriptional target gene for p53 and its family members, p63 and p73. Its promoter region contains two p53-type response elements, RE1 and RE2, and RE2 confers p53-specific transactivation. RE2 contains several mismatches from the canonical p53 response element (RRRCWWGYYY). Two mismatches in the RRR span and T base of the RE2 core sequence in the most 3' quarter-site are critical for inhibiting the binding affinity to p63 and p73 and corresponding promoter activity. Our results strongly suggest that differential DNA-binding affinities between p53 family member proteins act, at least in part, to confer specific target gene activation.
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http://dx.doi.org/10.1016/j.bbrc.2007.01.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975780PMC
March 2007

Cell survival signaling during apoptosis: implications in drug resistance and anti-cancer therapeutic development.

Prog Drug Res 2005 ;63:115-45

Department of Carcinogenesis, the University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.

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http://dx.doi.org/10.1007/3-7643-7414-4_6DOI Listing
November 2005

Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS.

Oncogene 2005 Mar;24(12):2020-31

Department of Carcinogenesis, the University of Texas MD Anderson Cancer Center, Science Park-Research Division 1C, Smithville, TX 78957, USA.

Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-X(L) and superoxide dismutase (SOD; including both MnSOD and Cu/ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e.g., MnSOD) and proapoptotic (e.g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.
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http://dx.doi.org/10.1038/sj.onc.1208385DOI Listing
March 2005

[A study of the psychological and social factors in patients with pulmonary tuberculosis].

Zhonghua Jie He He Hu Xi Za Zhi 2003 Nov;26(11):704-7

Antituberculosis Institute of Zhuhai, Zhuhai 519001, China.

Objective: To investigate the mental health and social support in patients with tuberculosis.

Methods: Questionnaires were performed in 132 patients with tuberculosis and 71 healthy volunteers using Symptom Checklist 90 (SCL-90) and Social Support Rating Scale (SSRS). Statistical analyses were processed using Student's t test and ANOVA test.

Results: Somatization, obsessive-compulsiveness, anxiety, phobic anxiety and paranoid ideation, psychotism and the mean of positive factors of SCL-90 of the tuberculosis group (1.77 +/- 0.51, 1.63 +/- 0.50, 1.53 +/- 0.51, 1.33 +/- 0.41, 1.40 +/- 0.45, 1.41 +/- 0.40 and 36.07 +/- 20.84, respectively) were significantly higher than those of the control group (1.30 +/- 0.49, 1.43 +/- 0.49, 1.38 +/- 0.65, 1.24 +/- 0.48, 1.49 +/- 0.69, 1.30 +/- 0.44 and 24.92 +/- 18.22, respectively) (all P < 0.01). The result of symptom self-check differed among patients with different educational levels. The SSRS results of subjective and objective supports and total score of social supports of the tuberculosis group were 6.90 +/- 2.81, 19.25 +/- 5.62 and 32.96 +/- 7.86, respectively, much lower than those of the control group (7.92 +/- 2.57, 21.54 +/- 5.82 and 36.51 +/- 9.01, respectively) (all P < 0.01). Subjective support of patients with smear positive tuberculosis was much lower than that of patients with smear negative disease (18.15 +/- 5.72 vs. 20.75 +/- 5.78, P < 0.05); Subjective support, objective support and total score of social support of the unmarried patients (17.19 +/- 4.20, 6.17 +/- 2.18, 30.35 +/- 5.96, respectively) were lower than those of the married (20.72 +/- 5.96, 7.66 +/- 3.03, 35.19 +/- 8.74, respectively) (all P < 0.01). The results of SCL-90 and SSRS had no statistical relationship.

Conclusion: Our results suggest that the disordered mental conditions and lower social support in patients with tuberculosis need psychosocial interventions in addition to medical care.
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November 2003

Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration.

Oncogene 2003 Mar;22(10):1475-85

Department of Carcinogenesis, The Uniersity of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA.

While studying Bim, a BH3-only proapoptotic protein, we identified an approximately 36 kDa protein, which was abundantly expressed in all five strains of primary normal human prostate (NHP) epithelial cells but significantly reduced or lost in seven prostate cancer cell lines. The approximately 36 kDa protein was subsequently identified as annexin II by proteomic approach and confirmed by Western blotting using an annexin II-specific antibody. Conventional and 2D SDS-PAGE, together with Western blotting, also revealed reduced or lost expression of annexin I in prostate cancer cells. Subcellular localization studies revealed that in NHP cells, annexin II was distributed both in the cytosol and underneath the plasma membrane, but not on the cell surface. Prostate cancer cells showed reduced levels as well as altered expression patterns of annexin II. Since annexins play important roles in maintaining Ca(2+) homeostasis and regulating the cytoskeleton and cell motility, we hypothesized that the reduced or lost expression of annexin I/II might promote certain aggressive phenotypes of prostate cancer cells. In subsequent experiments, we indeed observed that restoration of annexin II expression inhibited the migration of the transfected prostate cancer cells without affecting cell proliferation or apoptosis. Hence, our results suggest that annexin II, and, likely, annexin I, may be endogenous suppressors of prostate cancer cell migration and their reduced or lost expression may contribute to prostate cancer development and progression.
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http://dx.doi.org/10.1038/sj.onc.1206196DOI Listing
March 2003

Early mitochondrial activation and cytochrome c up-regulation during apoptosis.

J Biol Chem 2002 Dec 28;277(52):50842-54. Epub 2002 Oct 28.

Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957, USA.

Apoptosis induced by many stimuli requires the mitochondrial respiratory chain (MRC) function. While studying the molecular mechanisms underlying this MRC-dependent apoptotic pathway, we find that apoptosis in multiple cell types induced by a variety of stimuli is preceded by an early induction of MRC proteins such as cytochrome c (which is encoded by a nuclear gene) and cytochrome c oxidase subunit II (COX II) (which is encoded by the mitochondrial genome). Several non-MRC proteins localized in the mitochondria, e.g. Smac, Bim, Bak, and Bcl-2, are also rapidly up-regulated. The up-regulation of many of these proteins (e.g. cytochrome c, COX II, and Bim) results from transcriptional activation of the respective genes. The up-regulated cytosolic cytochrome c rapidly translocates to the mitochondria, resulting in an accumulation of holocytochrome c in the mitochondria accompanied by increasing holocytochrome c release into the cytosol. The increased cytochrome c transport from cytosol to the mitochondria does not depend on the mitochondrial protein synthesis or MRC per se. In contrast, cytochrome c release from the mitochondria involves dynamic changes in Bcl-2 family proteins (e.g. up-regulation of Bak, Bcl-2, and Bcl-x(L)), opening of permeability transition pore, and loss of mitochondrial membrane potential. Overexpression of cytochrome c enhances caspase activation and promotes cell death in response to apoptotic stimulation, but simple up-regulation of cytochrome c using an ecdysone-inducible system is, by itself, insufficient to induce apoptosis. Taken together, these results suggest that apoptosis induced by many stimuli involves an early mitochondrial activation, which may be responsible for the subsequent disruption of MRC functions, loss of Deltapsi(m), cytochrome c release, and ultimately cell death.
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http://dx.doi.org/10.1074/jbc.M207622200DOI Listing
December 2002