Aim： To identify the serum biomarkers of prostate cancer （PCa） by protein chip and bioinformatics. Methods： Serum samples from 83 PCa patients and 95 healthy men were taken from a mass screening in Changchun, Chin...Aim： To identify the serum biomarkers of prostate cancer （PCa） by protein chip and bioinformatics. Methods： Serum samples from 83 PCa patients and 95 healthy men were taken from a mass screening in Changchun, China. Protein profiling was carried out using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry （SELDI-TOF MS）. The data of spectra were analyzed using two bioinformatics tools. Results： Eighteen serum differential proteins were identified in the PCa group compared with the control group （P 〈 0.01）. There were four proteins at the higher serum level and 14 proteins at the lower serum level in the PCa group. A decision tree classification algorithm that used an eight-protein mass pattern was developed to correctly classify the samples. A sensitivity of 92.0 % and a specificity of 96.7 % for the study group were obtained by comparing the PCa and control groups. Conclusion： We identified new serum biomarkers of PCa. SELDI-TOF MS coupled with a decision tree classification algorithm will provide a highly accurate and innovative approach for the early diagnosis of PCa. （Asian J Androl 2006 Jan; 8： 45-51）展开更多
The aim of this study was to determine and examine the possible reasons for the difference in prostate cancer incidence between Asian men and North American men by literature review. Data regarding cancer incidence an...The aim of this study was to determine and examine the possible reasons for the difference in prostate cancer incidence between Asian men and North American men by literature review. Data regarding cancer incidence and mortality were obtained from the database of the International Agency for Research on Cancer （IARC）. A literature review was conducted by studying related articles published in peer-reviewed journals such as the The New England Journal of Medicine, Journal of Clinical Oncology, A Cancer Journal for Clinicians and Asian Journal of Andrology. To evaluate the early diagnosis and survival rates, the mortality.to-incidence rate ratio （MR/IR） was calculated from the IARC data. By comparing prostate cancer data between Asian men and North American men, we found that differences in the incidence rate and MR/IR could be attributed largely to a lack of annual prostate cancer screening with serum prostate-specific antigen （PSA） in most Asian countries. It is likely that PSA screening also contributes significantly to the differences in prostate cancer mortality rates. Prostate cancer has the highest incidence rate among five common malignancies in Asian Americans. However, the MR/IR ratio of prostate cancer is the lowest among cancers. These data seem to further support the usefulness of PSA screening, even though the percentage of low risk cancers is greater in prostate cancer than in other cancers. The low incidence rate of prostate cancer does not reflect the actual statistics of this disease in Asia. The data from limited institutions in many Asian countries seem to bias the true incidence and mortality rates. To improve this situation, incorporating PSA screening for prostate cancer, as well as constructing a nationwide cancer registration system, will be helpful.展开更多
AIM： To clone and characterize the porcine aquaporins （AQPs） in the gastrointestinal system.METHODS： A PCR-based cloning strategy and RACE were used to clone full-length AQP coding sequence from reversely transcri...AIM： To clone and characterize the porcine aquaporins （AQPs） in the gastrointestinal system.METHODS： A PCR-based cloning strategy and RACE were used to clone full-length AQP coding sequence from reversely transcribed pig liver cDNA. Stopped-flow light scattering and a YFP-based fluorescence method were used to measure the osmotic water permeability of erythrocytes and the stably transfected CHO cells. RT-PCR, Northern blot, and immunohistochemistry were used to determine the gastrointestinal expression and localization of cloned AQPs. Protein expression in transfected cells and red blood cells was analyzed by Western blot.RESULTS： An 813 bp cDNA encoding a 271 amino acid porcine aquaporin （designated pAQP1） was cloned from liver mRNA （pAQP1 has a 93% identity with human AQP1 and contains two NPA motifs conserved in AQP family, one consensus sequence for N-linked glycosylation, and one mercury-sensitive site at cysteine 191）. RT-PCR analysis revealed extensive expression of pAQP1 mRNA in porcine digestive glands and gut. Northern blot showed a single 3.0 kb transcript in selected digestive organs, pAQP1 protein was localized at central lacteals of the small intestine, microvessles of salivary glands, as well as epithelium of intrahepatic bile ducts by immunoperoxydase. High osmotic water permeability that is inhibitable by HgCI2 was detected in porcine erythrocytes and CHO cells stably transfected with pAQP1 cDNA. Immunoblot analysis of porcine erythrocytes and pAQP-transfected CHO cells revealed an unglycosylated 28 ku band and larger glycosylated proteins.CONCLUSION： pAQP1 is the first porcine aquaporin that can be molecularly identified so far. The broad distribution of pAQP1 in epithelium and endothelium of porcine digestive organs may suggest an important role of channel-mediated water transport in fluid secretion/absorption as well as in digestive function and pathophysiology of the gastrointestinal system.展开更多
DNA vector-based Stat3-specific RNA interference （si-Stat3） blocks Stat3 signalling and inhibits prostate tumour growth. However, the antitumour activity depends on the efficient delivery of si-Stat3. The effects on...DNA vector-based Stat3-specific RNA interference （si-Stat3） blocks Stat3 signalling and inhibits prostate tumour growth. However, the antitumour activity depends on the efficient delivery of si-Stat3. The effects on the growth of mouse prostate cancer cells of si-Stat3 delivered by hydroxyapatite were determined in this study. RM-1 tumour blocks were transplanted into C57BIJ6 mice. CaCl2-modified hydroxyapatite carrying si-Stat3 plasmids were injected into tumours, and tumour growth and histology were determined. The expression levels of Star3, pTyr-Stat3, Bcl-2, Bax, Caspase3, VEGFand cyclin D1 were measured by western blot analysis. Amounts of apoptosis in cancer cells were analysed with immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling （TUNEL） assay. The results showed that hydroxyapatite-delivered si-Stat3 significantly suppressed tumour growth up to 74% （P〈0.01）. Stat3 expression was dramatically downregulated in the tumours. The immunohistochemistry and TUNEL results showed that si-Stat3-induced apoptosis （up to 42%, P〈0.01）. The Stat3 downstream genes Bcl-2, VEGFand cyclin DI were also strongly downregulated in the tumour tissues that also displayed significant increases in Bax expression and Caspase3 activity. These results suggest that hydroxyapatite can be used for the in vivo delivery of plasmid-based siRNAs into tumours.展开更多
OBJECTIVE Non-alcoholic fatty liver disease(NAFLD) encompasses a series of patho.logic changes ranging from steatosis to steatohepatitis,which may progress to cirrhosis and hepatocel.lular carcinoma.The purpose of thi...OBJECTIVE Non-alcoholic fatty liver disease(NAFLD) encompasses a series of patho.logic changes ranging from steatosis to steatohepatitis,which may progress to cirrhosis and hepatocel.lular carcinoma.The purpose of this study was to determine whether Ganoderma lucidum polysaccha.ride peptide(GLPP) has therapeutic effect on NAFLD.METHODS ob/ob mouse model and ApoC3 transgenic mouse model were used for exploring the effect of GLPP on NAFLD.Key metabolic path.ways and enzymes were identified by metabolomics combining with KEGG and PIUmet analyses and key enzymes were detected by Western blotting.Hepatosteatosis models of HepG2 cells and primary hepatocytes were used to further confirm the therapeutic effect of GLPP on NAFLD.RESULTS GLPP administrated for a month alleviated hepatosteatosis,dyslipidemia,liver dysfunction and liver insulin resistance.Pathways of glycerophospholipid metabolism,fatty acid metabolism and primary bile acid biosynthesis were involved in the therapeutic effect of GLPP on NAFLD.Detection of key enzymes revealed that GLPP reversed low expression of CYP7 A1,CYP8 B1,FXR,SHP and high expression of FGFR4 in ob/ob mice and ApoC3 mice.Besides,GLPP inhibited fatty acid synthesis by reducing the expression of SREBP1 c,FAS and ACC via a FXR-SHP dependent mechanism.Additionally,GLPP reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepato.cytes induced by oleic acid and palmitic acid.CONCLUSION GLPP significantly improves NAFLD via regulating bile acid synthesis dependent on FXR-SHP/FGF pathway,which finally inhibits fatty acid synthesis,indicating that GLPP might be developed as a therapeutic drug for NAFLD.展开更多
OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD) is a common.monogenetic disease characterized by progressive development of renal cysts.Thereis still further need for effective therapy.Based on our preci...OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD) is a common.monogenetic disease characterized by progressive development of renal cysts.Thereis still further need for effective therapy.Based on our precious study that Ganoderma triterpenes(GT),which is the major secondary metabolites of Ganoderma lucidum,is able to attenuate renal cyst development.The aim of this study was to investigate the effect of a monomer,Ganoderic acid A(GA-A) that was purified from the GT,which has been reported to exhibit antinociceptive,antioxidative,hepatoproctive and anti.cancer activities,to have a potent anti-cyst effect in ADPKD.METHODS We first evaluated the potential cytotoxicity of GA-A on MDCK cells using a CCK-8 assay.Then we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer cells.MDCK cells were co-incu.bated with 10 μmol·L^(-1) FSK with or without GA-A(25 μg·mL-1) and equal concentration GT as positive control from day 0 to day 6 to investigate the inhibitory effect of GA-A on cyst formation.And to further investigate the inhibitory effect of GA-A on cyst enlargement,MDCK cysts were treated with different concentration of GA-A(6.25,25 and 100 μg·mL-1) from day 5 to day 12.Next we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-cAMP to prove the renal cyst inhibition at organ level.Meanwhile,we explored the possible mechanisms underlying GA-A inhibition on renal cyst development using MDCK cells treated with 10 μmol·L^(-1) FSK co-incubated with GA-A(25 μg·mL-1) and equal concentration GT.Several key components of Ras/MAPK pathway was evaluated by Western blot,the protein expression of H-ras,B-raf,p-ERK,Egr-1 and c-fos was evaluated.RESULTS MDCK cell viability was not affected by GA-A that were used ofincreasing concentrations up to 200 μg·mL^(-1).GA-A had no significant influence on cyst formation,but inhibited cyst enlargement dose-dependently and the inhibitory effect is significantly better than that of the same concentration of GT which proved that GA-A may be an effective monomer from GT.And after washing out GA-A on day 8,MDCK cysts regrew to a large size,suggesting that the inhibitory effect of GA-A on MDCK cyst enlargement was reversible.GA-A inhibited embryonic kidney cyst development significantly in a dose-dependent and reversible manner proving GA-A cyst inhibition at organ level,which is also more effective than equal concentration GT.Treatment of MDCK cells with FSK caused a significant elevation of H-ras,B-raf,p-ERK,Egr-1 and c-fos signaling molecules,while treatment with GA-A reduced the level of H-ras,B-raf,p-ERK,Egr-1 and c-fos expression.GA-A downregulated Ras/MAPK signaling pathway could contribute to its inhibitory effect on cyst development.CONCLUSION Ganoderic acid A from Ganoderma lucidum retard ADPKD renal cyst development via down-regulating Ras/MAPK signaling pathway.展开更多
OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD)is a common inherited disease with a high morbidity around 1/1000-1/400,characterized by progressive enlargement of fluid-fil ed cysts derived from renal tu...OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD)is a common inherited disease with a high morbidity around 1/1000-1/400,characterized by progressive enlargement of fluid-fil ed cysts derived from renal tubular epithelial cells.Massive cysts gradually compress renal parenchyma destroying normal renal structures and compromising renal functions.Unfortunately,it will cause end-stage renal disease in most of the patients but without effective therapy now,who have to live on hemodialysis or kidney transplantation.Based on this present situation,it is of great significance to find early intervention to inhibit renal cyst development.The projective of this study was to investigate whether Ganoderma triterpenes(GT)can inhibit renal cyst development and study the related mechanism.METHODS and RESULTS First,we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer cells.GT inhibited MDCK cyst formation significantly,and inhibited cyst enlargement dose-dependently proving GT cyst inhibition in vitro.Then we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-c AMP.GT inhibited embryonic kidney cyst development significantly in a dosedependent and reversible manner proving GT cyst inhibition at organ level.Furthermore,we used two ADPKD mouse models with severe cystic kidney disease phenotypes.GT dramatically inhibited renal cyst development,decreased ADPKD mouse kidney volume and the cyst index inside proving GT cyst inhibition in vivo.By Western blot,we proved GT down-regulated Ras/MAPK signal pathway without detectable effect on m TOR signal pathway both in MDCK cells and two ADPKD mouse kidneys.CONCLUSION GT retard renal cyst development both in vitro and in vivo significantly.The related mechanisms were involved in GT promoting renal tubular epithelial cell differentiation,down-regulating intracellular c AMP level and Ras/MAPK signal pathway.展开更多
文摘Aim： To identify the serum biomarkers of prostate cancer （PCa） by protein chip and bioinformatics. Methods： Serum samples from 83 PCa patients and 95 healthy men were taken from a mass screening in Changchun, China. Protein profiling was carried out using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry （SELDI-TOF MS）. The data of spectra were analyzed using two bioinformatics tools. Results： Eighteen serum differential proteins were identified in the PCa group compared with the control group （P 〈 0.01）. There were four proteins at the higher serum level and 14 proteins at the lower serum level in the PCa group. A decision tree classification algorithm that used an eight-protein mass pattern was developed to correctly classify the samples. A sensitivity of 92.0 % and a specificity of 96.7 % for the study group were obtained by comparing the PCa and control groups. Conclusion： We identified new serum biomarkers of PCa. SELDI-TOF MS coupled with a decision tree classification algorithm will provide a highly accurate and innovative approach for the early diagnosis of PCa. （Asian J Androl 2006 Jan; 8： 45-51）
基金ACKNOWLEDGM ENTS The authors are grateful to Professor Masaaki Kuwahara for his critical reading and revising of our manuscript. This work was funded by the National Natural Science Foundation of China （Nos. 30801354 and 30970791） and lilin Provincial Science ＆ Technology Department China （No. 20080154）.
文摘The aim of this study was to determine and examine the possible reasons for the difference in prostate cancer incidence between Asian men and North American men by literature review. Data regarding cancer incidence and mortality were obtained from the database of the International Agency for Research on Cancer （IARC）. A literature review was conducted by studying related articles published in peer-reviewed journals such as the The New England Journal of Medicine, Journal of Clinical Oncology, A Cancer Journal for Clinicians and Asian Journal of Andrology. To evaluate the early diagnosis and survival rates, the mortality.to-incidence rate ratio （MR/IR） was calculated from the IARC data. By comparing prostate cancer data between Asian men and North American men, we found that differences in the incidence rate and MR/IR could be attributed largely to a lack of annual prostate cancer screening with serum prostate-specific antigen （PSA） in most Asian countries. It is likely that PSA screening also contributes significantly to the differences in prostate cancer mortality rates. Prostate cancer has the highest incidence rate among five common malignancies in Asian Americans. However, the MR/IR ratio of prostate cancer is the lowest among cancers. These data seem to further support the usefulness of PSA screening, even though the percentage of low risk cancers is greater in prostate cancer than in other cancers. The low incidence rate of prostate cancer does not reflect the actual statistics of this disease in Asia. The data from limited institutions in many Asian countries seem to bias the true incidence and mortality rates. To improve this situation, incorporating PSA screening for prostate cancer, as well as constructing a nationwide cancer registration system, will be helpful.
基金Supported by National Natural Science Foundation for Distinguished Young Scholars,No.30325011National Natural Science Foundation of China,No.30470405Distinguished Young Scholar Foundation of Jilin Province,No.20030112.
文摘AIM： To clone and characterize the porcine aquaporins （AQPs） in the gastrointestinal system.METHODS： A PCR-based cloning strategy and RACE were used to clone full-length AQP coding sequence from reversely transcribed pig liver cDNA. Stopped-flow light scattering and a YFP-based fluorescence method were used to measure the osmotic water permeability of erythrocytes and the stably transfected CHO cells. RT-PCR, Northern blot, and immunohistochemistry were used to determine the gastrointestinal expression and localization of cloned AQPs. Protein expression in transfected cells and red blood cells was analyzed by Western blot.RESULTS： An 813 bp cDNA encoding a 271 amino acid porcine aquaporin （designated pAQP1） was cloned from liver mRNA （pAQP1 has a 93% identity with human AQP1 and contains two NPA motifs conserved in AQP family, one consensus sequence for N-linked glycosylation, and one mercury-sensitive site at cysteine 191）. RT-PCR analysis revealed extensive expression of pAQP1 mRNA in porcine digestive glands and gut. Northern blot showed a single 3.0 kb transcript in selected digestive organs, pAQP1 protein was localized at central lacteals of the small intestine, microvessles of salivary glands, as well as epithelium of intrahepatic bile ducts by immunoperoxydase. High osmotic water permeability that is inhibitable by HgCI2 was detected in porcine erythrocytes and CHO cells stably transfected with pAQP1 cDNA. Immunoblot analysis of porcine erythrocytes and pAQP-transfected CHO cells revealed an unglycosylated 28 ku band and larger glycosylated proteins.CONCLUSION： pAQP1 is the first porcine aquaporin that can be molecularly identified so far. The broad distribution of pAQP1 in epithelium and endothelium of porcine digestive organs may suggest an important role of channel-mediated water transport in fluid secretion/absorption as well as in digestive function and pathophysiology of the gastrointestinal system.
基金The authors would thank Mr Qiang-Lin Duan for English usage and paper revision.This work was funded by the National Natural Science Foundation of China （No. 30801354, No. 30970791 and No. 30870921）, the Fundamental Research Funds for the Central Universities of China （No. 200810012） and the Jilin Provincial Science ＆ Technology Department, China （No. 20080154）.
文摘DNA vector-based Stat3-specific RNA interference （si-Stat3） blocks Stat3 signalling and inhibits prostate tumour growth. However, the antitumour activity depends on the efficient delivery of si-Stat3. The effects on the growth of mouse prostate cancer cells of si-Stat3 delivered by hydroxyapatite were determined in this study. RM-1 tumour blocks were transplanted into C57BIJ6 mice. CaCl2-modified hydroxyapatite carrying si-Stat3 plasmids were injected into tumours, and tumour growth and histology were determined. The expression levels of Star3, pTyr-Stat3, Bcl-2, Bax, Caspase3, VEGFand cyclin D1 were measured by western blot analysis. Amounts of apoptosis in cancer cells were analysed with immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling （TUNEL） assay. The results showed that hydroxyapatite-delivered si-Stat3 significantly suppressed tumour growth up to 74% （P〈0.01）. Stat3 expression was dramatically downregulated in the tumours. The immunohistochemistry and TUNEL results showed that si-Stat3-induced apoptosis （up to 42%, P〈0.01）. The Stat3 downstream genes Bcl-2, VEGFand cyclin DI were also strongly downregulated in the tumour tissues that also displayed significant increases in Bax expression and Caspase3 activity. These results suggest that hydroxyapatite can be used for the in vivo delivery of plasmid-based siRNAs into tumours.
基金supported by National Natural Science Foundation of China(8133007481620108029+1 种基金81261160507) Beijing Natural Science Foundation(7172113)
文摘OBJECTIVE Non-alcoholic fatty liver disease(NAFLD) encompasses a series of patho.logic changes ranging from steatosis to steatohepatitis,which may progress to cirrhosis and hepatocel.lular carcinoma.The purpose of this study was to determine whether Ganoderma lucidum polysaccha.ride peptide(GLPP) has therapeutic effect on NAFLD.METHODS ob/ob mouse model and ApoC3 transgenic mouse model were used for exploring the effect of GLPP on NAFLD.Key metabolic path.ways and enzymes were identified by metabolomics combining with KEGG and PIUmet analyses and key enzymes were detected by Western blotting.Hepatosteatosis models of HepG2 cells and primary hepatocytes were used to further confirm the therapeutic effect of GLPP on NAFLD.RESULTS GLPP administrated for a month alleviated hepatosteatosis,dyslipidemia,liver dysfunction and liver insulin resistance.Pathways of glycerophospholipid metabolism,fatty acid metabolism and primary bile acid biosynthesis were involved in the therapeutic effect of GLPP on NAFLD.Detection of key enzymes revealed that GLPP reversed low expression of CYP7 A1,CYP8 B1,FXR,SHP and high expression of FGFR4 in ob/ob mice and ApoC3 mice.Besides,GLPP inhibited fatty acid synthesis by reducing the expression of SREBP1 c,FAS and ACC via a FXR-SHP dependent mechanism.Additionally,GLPP reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepato.cytes induced by oleic acid and palmitic acid.CONCLUSION GLPP significantly improves NAFLD via regulating bile acid synthesis dependent on FXR-SHP/FGF pathway,which finally inhibits fatty acid synthesis,indicating that GLPP might be developed as a therapeutic drug for NAFLD.
基金supported by National Natural Science Foundation of China
文摘OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD) is a common.monogenetic disease characterized by progressive development of renal cysts.Thereis still further need for effective therapy.Based on our precious study that Ganoderma triterpenes(GT),which is the major secondary metabolites of Ganoderma lucidum,is able to attenuate renal cyst development.The aim of this study was to investigate the effect of a monomer,Ganoderic acid A(GA-A) that was purified from the GT,which has been reported to exhibit antinociceptive,antioxidative,hepatoproctive and anti.cancer activities,to have a potent anti-cyst effect in ADPKD.METHODS We first evaluated the potential cytotoxicity of GA-A on MDCK cells using a CCK-8 assay.Then we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer cells.MDCK cells were co-incu.bated with 10 μmol·L^(-1) FSK with or without GA-A(25 μg·mL-1) and equal concentration GT as positive control from day 0 to day 6 to investigate the inhibitory effect of GA-A on cyst formation.And to further investigate the inhibitory effect of GA-A on cyst enlargement,MDCK cysts were treated with different concentration of GA-A(6.25,25 and 100 μg·mL-1) from day 5 to day 12.Next we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-cAMP to prove the renal cyst inhibition at organ level.Meanwhile,we explored the possible mechanisms underlying GA-A inhibition on renal cyst development using MDCK cells treated with 10 μmol·L^(-1) FSK co-incubated with GA-A(25 μg·mL-1) and equal concentration GT.Several key components of Ras/MAPK pathway was evaluated by Western blot,the protein expression of H-ras,B-raf,p-ERK,Egr-1 and c-fos was evaluated.RESULTS MDCK cell viability was not affected by GA-A that were used ofincreasing concentrations up to 200 μg·mL^(-1).GA-A had no significant influence on cyst formation,but inhibited cyst enlargement dose-dependently and the inhibitory effect is significantly better than that of the same concentration of GT which proved that GA-A may be an effective monomer from GT.And after washing out GA-A on day 8,MDCK cysts regrew to a large size,suggesting that the inhibitory effect of GA-A on MDCK cyst enlargement was reversible.GA-A inhibited embryonic kidney cyst development significantly in a dose-dependent and reversible manner proving GA-A cyst inhibition at organ level,which is also more effective than equal concentration GT.Treatment of MDCK cells with FSK caused a significant elevation of H-ras,B-raf,p-ERK,Egr-1 and c-fos signaling molecules,while treatment with GA-A reduced the level of H-ras,B-raf,p-ERK,Egr-1 and c-fos expression.GA-A downregulated Ras/MAPK signaling pathway could contribute to its inhibitory effect on cyst development.CONCLUSION Ganoderic acid A from Ganoderma lucidum retard ADPKD renal cyst development via down-regulating Ras/MAPK signaling pathway.
基金supported by National Natural Science Foundation of China(81261160507,81330074,81620108029 and 81170632)Beijing Natural Science Foundation(7172113)
文摘OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD)is a common inherited disease with a high morbidity around 1/1000-1/400,characterized by progressive enlargement of fluid-fil ed cysts derived from renal tubular epithelial cells.Massive cysts gradually compress renal parenchyma destroying normal renal structures and compromising renal functions.Unfortunately,it will cause end-stage renal disease in most of the patients but without effective therapy now,who have to live on hemodialysis or kidney transplantation.Based on this present situation,it is of great significance to find early intervention to inhibit renal cyst development.The projective of this study was to investigate whether Ganoderma triterpenes(GT)can inhibit renal cyst development and study the related mechanism.METHODS and RESULTS First,we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer cells.GT inhibited MDCK cyst formation significantly,and inhibited cyst enlargement dose-dependently proving GT cyst inhibition in vitro.Then we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-c AMP.GT inhibited embryonic kidney cyst development significantly in a dosedependent and reversible manner proving GT cyst inhibition at organ level.Furthermore,we used two ADPKD mouse models with severe cystic kidney disease phenotypes.GT dramatically inhibited renal cyst development,decreased ADPKD mouse kidney volume and the cyst index inside proving GT cyst inhibition in vivo.By Western blot,we proved GT down-regulated Ras/MAPK signal pathway without detectable effect on m TOR signal pathway both in MDCK cells and two ADPKD mouse kidneys.CONCLUSION GT retard renal cyst development both in vitro and in vivo significantly.The related mechanisms were involved in GT promoting renal tubular epithelial cell differentiation,down-regulating intracellular c AMP level and Ras/MAPK signal pathway.
