AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female S...AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female Sprague-Dawley rats were ovariectomized(OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin(HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction(q RT-PCR). Collagengel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance(IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of Rho A and ROCK Ⅱ, and even suppressed ROCK Ⅱ activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase(e NOS) and phosphorylated e NOS, and promoted the activities of protein kinase G(PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK Ⅱ activity in activated HSCs. Finally, in vivo /in vitro experiments demonstrated that MLC activity was inhibited by DPN.CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver Rho A/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.展开更多
Climate change and human activities have changed a number of characteristics of river flow in the Taihu Basin.Based on long-term time series of hydrological data from 1986 to 2015,we analyzed variability in precipitat...Climate change and human activities have changed a number of characteristics of river flow in the Taihu Basin.Based on long-term time series of hydrological data from 1986 to 2015,we analyzed variability in precipitation,water stage,water diversion from the Yangtze River,and net inflow into Taihu Lake with the Mann-Kendall test.The non-stationary relationship between precipitation and water stage was first analyzed for the Taihu Basin and the Wuchengxiyu(WCXY)sub-region.The optimized regional and urban regulation schemes were explored to tackle high water stage problems through the hydrodynamic model.The results showed the following:(1)The highest,lowest,and average Taihu Lake water stages of all months had increasing trends.The total net inflow into Taihu Lake from the Huxi(HX)sub-region and the Wangting Sluice increased significantly.(2)The Taihu Lake water stage decreased much more slowly after 2002;it was steadier and higher after 2002.After the construction of Wuxi urban flood control projects,the average water stage of the inner city was 0.16e0.40 m lower than that of suburbs in the flood season,leading to the transfer of flooding in inner cities to suburbs and increasing inflow from HX into Taihu Lake.(3)The regional optimized schemes were more satisfactory in not increasing the inner city flood control burden,thereby decreasing the average water stage by 0.04e0.13 m,and the highest water stage by 0.04e0.09 m for Taihu Lake and the sub-region in the flood season.Future flood control research should set the basin as the basic unit.Decreasing diversion and drainage lines along the Yangtze River can take an active role in flood control.展开更多
AIM: To evaluate the significance of γ-catenin in clinical pathology, cellular function and signaling mechanism in esophageal squamous cell carcinoma (ESCC).
AIM:To explore the role of S-phase kinase-associated protein-2(Skp2)in gallbladder carcinoma and to identify whether depletion of Skp2 by Skp2-RNAi could attenuate proliferation and migration of gallbladder carcinoma....AIM:To explore the role of S-phase kinase-associated protein-2(Skp2)in gallbladder carcinoma and to identify whether depletion of Skp2 by Skp2-RNAi could attenuate proliferation and migration of gallbladder carcinoma.METHODS:Skp2-RNAi was transduced into cells of the gallbladder carcinoma cell line GBC-SD,using a lentiviral vector.The effect of Skp2-RNAi on the proliferation,migration,invasion and cell cycle of GBC-SD cells was studied using in vitro assays for cell proliferation,colony formation,wound healing and cell cycle.The expression of Skp2 and p27 was detected by real-time polymerase chain reaction and Western immunoblotting.The effect of Skp2-RNAi on the proliferation of GBC-SD cells in vivo was investigated by tumorigenicity experiments in nude mice.RESULTS:Lentivirus-mediated RNAi reduced the expression of Skp2 in cultured cells.The expression of the p27 protein increased along with the down-regulation of Skp2,although no significant difference was found in p27 mRNA expression.Flow cytometry revealed that Skp2-RNAi transfection significantly increased the proportion of cells in the S phase and significantly decreased the proportion of cells in the G 2 /M phase.No significant difference in the frequency of cells in the G0/G1 phase was observed.The results from the cell proliferation,colony formation and wound healing assays revealed that Skp2-RNAi transfection markedly inhibited the proliferation and migration of GBC-SD cells in vitro.Additionally,tumorigenicity experiments showed that suppression of Skp2 significantly decreased the weights of the tumors(0.56 ± 0.11 and 0.55 ± 0.07 g in the control and Scr-RNAi groups vs 0.37 ± 0.09 and 0.35 ± 0.08 g in the Skp2-RNAi-L and Skp2-RNAi-H groups).CONCLUSION:The expression of Skp2 in GBC-SD cells was inhibited following Skp2-RNAi transfection.Silencing of the Skp2 gene inhibited proliferation,migration and invasiveness of GBC-SD cells by mechanisms dependent on enhanced expression of the p27 protein.展开更多
AIM:To evaluate the effects of estrogen(E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.METHODS:Fifty castrated female Sprague-Dawley rats were divided into five groups:sham operati...AIM:To evaluate the effects of estrogen(E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.METHODS:Fifty castrated female Sprague-Dawley rats were divided into five groups:sham operation(SO),partial portal vein ligation(PPVL) + placebo(PLAC),PPVL + E2,PPVL + ICI and PPVL + E2 + ICI. Hemodynamic measurements were performed using ultrasonography. Mesenteric arteriole contractility in response to norepinephrine was determined using a vessel perfusion system. Oxidative stress in the mesenteric artery was investigated by in situ detection of the superoxide anion(O2) and hydrogen peroxide(H2O2) concentrations.RESULTS:Treatment with E2 resulted in a significant decrease of portal pressure(P < 0.01) and portal venous inflow(P < 0.05),and higher systemic vascular resistance(P < 0.05) and splanchnic arteriolar resistance(P < 0.01) in PPVL + E2 rats compared to PPVL+ PLAC rats. In the mesenteric arterioles of PPVL +E2 rats,the dose-response curve was shifted left,and the EC50was decreased(P < 0.01). E2 reduced O2 production and H2O2concentration in the mesenteric artery. However,ICI182,780 reversed the beneficial effects of E2,therefore,the systemic and splanchnic hyperdynamic circulation were more deteriorated in ICI182,780-treated rats.CONCLUSION:Treatment with estrogen improved the systemic and splanchnic hyperdynamic circulation in PPVL rats,in part due to the alleviation of oxidative stress.展开更多
Anomalous characteristics of the atmospheric water cycle structure are highly significant to the mechanisms of seasonal-scale meteorological droughts.They also play an important role in the identification of indicativ...Anomalous characteristics of the atmospheric water cycle structure are highly significant to the mechanisms of seasonal-scale meteorological droughts.They also play an important role in the identification of indicative predictors of droughts.To better understand the causes of seasonal meteorological droughts in the middle and lower reaches of the Yangtze River(MLRYR),characteristics of the atmospheric water cycle structure at different drought stages were determined using standardized anomalies.The results showed that the total column water vapor(TCWV)was anomalously low during drought occurrence periods.In contrast,there were no anomalous signals at the drought persistence and recovery stages in the MLRYR.Moreover,there was no significant temporal correlation between the TCWV anomaly and seasonal-scale drought index(the 3-month standardized precipitation index(SPI_(3))).During drought events,water vapor that mainly originated from the Bay of Bengal was transported southwest of the MLRYR.Meanwhile,the anomalous signal of water vapor transport was negative at the drought appearance stage.At the drought persistence stage,the negative anomalous signal was the most significant.Water vapor flux divergence in the MLRYR showed significant positive anomalous signals during drought events,and the signal intensity shifted from an increasing to a decreasing trend at different drought stages.In addition,a significant positive correlation existed between the anomaly of water vapor flux divergence and regional SPI_(3).Overall,water vapor flux divergence is more predictive of droughts in the MLRYR.展开更多
BACKGROUND Portal hypertension(PHT)is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow.Vascular hyporeactivity both in systemic circulation and in...BACKGROUND Portal hypertension(PHT)is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow.Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.AIM To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.METHODS Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride(CCl4)in both male and female integral and castrated rats(ovariectomized[OVX]in female rats,orchiectomy[ORX]in male rats).The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.RESULTS No significant difference in portal pressure was observed between integral and castrated male PHT rats(15.2±2.1 mmHg vs 16.7±2.7 mmHg,P>0.05).The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats(12.7±2.7 mmHg vs 16.5±2.4 mmHg,P<0.05).In PHT rats,the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right,and the maximal responses(Emax)values were decreased and effective concentrations causing half maximum responses(EC50)values were increased,compared to those of non-PHT rats,both in male and female rats.Compared to non-PHT integral male rats,the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased(P>0.05).However,there was no difference between integral and ORX male rats with PHT.In integral female PHT rats,the concentration response curves were shifted to the left(P<0.05),and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats.CONCLUSION Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats.Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.展开更多
BACKGROUND: The increased β-arrestin-2 and its combination with G-protein-coupled receptors (GPCRs) lead to GPCRs desensitization. The latter may be responsible for decreased contractile reactivity in the mesenteric ...BACKGROUND: The increased β-arrestin-2 and its combination with G-protein-coupled receptors (GPCRs) lead to GPCRs desensitization. The latter may be responsible for decreased contractile reactivity in the mesenteric arteries of cirrhotic patients and rats. The present study is to investigate the machinery changes of α-adrenergic receptors and G proteins and their roles in the contractility of mesenteric arteries of cirrhotic patients and animal models. METHODS: Patients with cirrhosis due to hepatitis B and cirrhotic rats induced by CCl 4 were studied. Mesenteric artery contractility in response to norepinephrine was determined by a vessel perfusion system. The contractile effect of G protein-coupled receptor kinase-2 (GRK-2) inhibitor on the mesenteric artery was evaluated. The protein expression of the α 1 adrenergic receptor, G proteins, β-arrestin-2, GRK-2 as well as the activity of Rho associated coiled-coil forming protein kinase-1 (ROCK-1) were measured by Western blot. In addition, the interaction of α 1 adrenergic receptor with β-arrestin-2 was assessed by co-immunoprecipitation. RESULTS: The portal vein pressure of cirrhotic patients and rats was significantly higher than that of controls. The doseresponse curve to norepinephrine in mesenteric arteriole was shifted to the right, and EC 50 was significantly increased in cirrhotic patients and rats. There were no significant differences in the expressions of the α 1 adrenergic receptor and G proteins in the cirrhotic group compared with the controls. However, the protein expressions of GRK-2 and β-arrestin-2 were significantly elevated in cirrhotic patients and rats compared with those of the controls. The interaction of the α 1 adrenergic receptor and β-arrestin-2 was significantly aggravated. This interaction was significantly reversed by GRK-2 inhibitor. Both the protein expression and activity of ROCK-1 were significantly decreased in the mesenteric artery in patients with cirrhosis compared with those of the controls, and this phenomenon was not shown in the cirrhotic rats. Norepinephrine significantly increased the activity of ROCK-1 in normal rats but not in cirrhotic ones. Norepinephrine significantly increased ROCK-1 activity in cirrhotic rats when GRK-2 inhibitor was used. CONCLUSIONS: β-arrestin-2 expression and its interaction with GPCRs are significantly upregulated in the mesenteric arteries in patients and rats with cirrhosis. These upregulations result in GPCR desensitization, G-protein dysfunction and ROCK inhibition. These may explain the decreased contractility of the mesenteric artery in response to vasoconstrictors.展开更多
BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate t...BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODS This multicenter,open-label,pilot randomized controlled trial enrolled 68 EGFRmutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy+icotinib groups.RESULTS The median progression-free survival in the icotinib alone and chemotherapy+icotinib groups was 8.0 mo(95%CI:3.84-11.63)and 13.4 mo(95%CI:10.18-16.33),respectively(P=0.0249).No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen(all P>0.05).CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.展开更多
A simply synthesized 4-aminonaphthalimide derivative 1 expresses both polarity and viscosity sensitive fluorescence spectra,indicating its potential usage as an environmentally sensitive fluorescence probe. By compari...A simply synthesized 4-aminonaphthalimide derivative 1 expresses both polarity and viscosity sensitive fluorescence spectra,indicating its potential usage as an environmentally sensitive fluorescence probe. By comparing the fluorescence behavior of 1 with that of a known 4-aminonaphthalimide derivative 2,it was found that the substitution of the 4-amino group has profound influence on the environmentally sensitive fluorescence properties of 4-aminonaphthalimide.展开更多
Background:Esophageal squamous cell carcinoma(ESCC)is the predominant subtype of esophageal carcinoma in China.This study was to develop a staging model to predict outcomes of patients with ESCC.Methods:Using Cox regr...Background:Esophageal squamous cell carcinoma(ESCC)is the predominant subtype of esophageal carcinoma in China.This study was to develop a staging model to predict outcomes of patients with ESCC.Methods:Using Cox regression analysis,principal component analysis(PCA),partitioning clustering,Kaplan-Meier analysis,receiver operating characteristic(ROC)curve analysis,and classification and regression tree(CART)analysis,we mined the Gene Expression Omnibus database to determine the expression profiles of genes in 179 patients with ESCC from GSE63624 and GSE63622 dataset.Results:Univariate cox regression analysis of the GSE63624 dataset revealed that 2404 protein-coding genes(PCGs)and 635 long non-coding RNAs(lncRNAs)were associated with the survival of patients with ESCC.PCA categorized these PCGs and lncRNAs into three principal components(PCs),which were used to cluster the patients into three groups.ROC analysis demonstrated that the predictive ability of PCG-lncRNA PCs when applied to new patients was better than that of the tumor-node-metastasis staging(area under ROC curve[AUC]:0.69 vs.0.65,P<0.05).Accord-ingly,we constructed a molecular disaggregated model comprising one lncRNA and two PCGs,which we desig-nated as the LSB staging model using CART analysis in the GSE63624 dataset.This LSB staging model classified the GSE63622 dataset of patients into three different groups,and its effectiveness was validated by analysis of another cohort of 105 patients.Conclusions:The LSB staging model has clinical significance for the prognosis prediction of patients with ESCC and may serve as a three-gene staging microarray.展开更多
The plasmon-enhanced second-harmonic generation(SHG)of Au nanorods(NRs),Au-Ag NRs,and asymmetric Au@CdSe heterorods are comparatively investigated.The Au@CdSe tip-and side-heterorods are synthesized by precisely contr...The plasmon-enhanced second-harmonic generation(SHG)of Au nanorods(NRs),Au-Ag NRs,and asymmetric Au@CdSe heterorods are comparatively investigated.The Au@CdSe tip-and side-heterorods are synthesized by precisely controlling the concentration of Cd2+precursor,and the plasmon resonances can be well tuned simultaneously.The SHG of asymmetric Au@CdSe heterorods has been greatly enhanced with up to 617.7-fold enhancement compared with the Au NRs because of the asymmetric morphology and local field enhancement.Moreover,the harmonic energy transfer induced by the local interband transition of Au has also been demonstrated by the excitation-wavelengthdependent SHG in the Au NRs and Au@CdSe side-heterorods,while it is negligible in the Au-Ag NRs and Au@CdSe tipheterorods because of the presence of Ag.The plasmon-enhanced SHG of asymmetric Au@CdSe heterorods enables potential applications ranging from sensing to biological spectroscopy.展开更多
Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remai...Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remains unclear.This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.Methods:Immunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor(PCAF),and immunofluorescence was used to investigate their colocalization.An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry.A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma(ESCC)cells using Western blotting by overexpressing and knocking down PCAF expression.An in vitro cell migration assay was performed,and a xenograft model was established to study in vivo tumor metastasis.Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation.The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.Results:Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471(K471)by PCAF.Using the specific antiAcK471-Fascin antibody,Fascin was found to be acetylated in ESCC cells,and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown.Functionally,Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis,whereas Fascin-K471 deacetylation exhibited a potent oncogenic function.Moreover,Fascin-K471 acetylation reduced filopodial length and density,and lifespan of ESCC cells,while its deacetylation produced the opposite effect.In the filipodium shaft,K471-acetylated Fascin displayed rapid dynamic exchange,suggesting that it remained in its monomeric form owing to its weakened actinbundling activity.Clinically,high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients.Conclusions:Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells.Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.展开更多
Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism...Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties;however, limited information is available regarding its therapeutic potential in PCOS.Methods::Female C57BL/6 mice were randomly assigned into four groups ( n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed. Results::Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone ( P < 0.001) and dehydroepiandrosterone sulfate ( P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly ( P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS. Conclusion::Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.展开更多
Invasive neural probes are one of the most critical components in the intracortical neural signal recording system.However,they can cause brain damage and tissue response during and after implantation.Thus,neural prob...Invasive neural probes are one of the most critical components in the intracortical neural signal recording system.However,they can cause brain damage and tissue response during and after implantation.Thus,neural probes with high flexibility,biocompatibility,and simple implantation methods are required in brain research.Here we present a novel approach to fabricating a multilayer flexible tassel-type neural probe using low-cost maskless laser direct-write lithog-raphy,combined with straightforward release and assembly methods to prepare a whole implantation system.The probe has 32 recording electrodes with an area of 8×8μm^(2),arranged into two rows of different depths and 16 separated shanks,aiming at the neural signal recording in an extensive range.Polyimide and gold are used as the insulating and conductive layers,respectively.With the help of a polyethylene glycol(PEG)coating,the tassel structure was mechanically enhanced for successful implantation,and our morphology characterization showed that the diameter of the coated probe was less than 50μm.Mechanical property tests also proved that it had the necessary stiffness for brain implantation.Afterwards,electrochemical tests were carried out,which showed that the probe had a rather low impedance after a simple gold electroplating.Finally,in vivo experiments demonstrated our probe can be successfully used in neural recording.展开更多
基金Supported by the National Natural Science Foundation for the Youth of China,No.81400630
文摘AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female Sprague-Dawley rats were ovariectomized(OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin(HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction(q RT-PCR). Collagengel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance(IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of Rho A and ROCK Ⅱ, and even suppressed ROCK Ⅱ activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase(e NOS) and phosphorylated e NOS, and promoted the activities of protein kinase G(PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK Ⅱ activity in activated HSCs. Finally, in vivo /in vitro experiments demonstrated that MLC activity was inhibited by DPN.CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver Rho A/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.
基金supported by the National Key Research and Development Project(Grants No.2018YFC0407900 and 2017YFC1502403)the Special Public Sector Research Program of the Ministry of Water Resources of China(Grant No.201501014)the National Natural Science Foundation of China(Grants No.51779071 and 51579065).
文摘Climate change and human activities have changed a number of characteristics of river flow in the Taihu Basin.Based on long-term time series of hydrological data from 1986 to 2015,we analyzed variability in precipitation,water stage,water diversion from the Yangtze River,and net inflow into Taihu Lake with the Mann-Kendall test.The non-stationary relationship between precipitation and water stage was first analyzed for the Taihu Basin and the Wuchengxiyu(WCXY)sub-region.The optimized regional and urban regulation schemes were explored to tackle high water stage problems through the hydrodynamic model.The results showed the following:(1)The highest,lowest,and average Taihu Lake water stages of all months had increasing trends.The total net inflow into Taihu Lake from the Huxi(HX)sub-region and the Wangting Sluice increased significantly.(2)The Taihu Lake water stage decreased much more slowly after 2002;it was steadier and higher after 2002.After the construction of Wuxi urban flood control projects,the average water stage of the inner city was 0.16e0.40 m lower than that of suburbs in the flood season,leading to the transfer of flooding in inner cities to suburbs and increasing inflow from HX into Taihu Lake.(3)The regional optimized schemes were more satisfactory in not increasing the inner city flood control burden,thereby decreasing the average water stage by 0.04e0.13 m,and the highest water stage by 0.04e0.09 m for Taihu Lake and the sub-region in the flood season.Future flood control research should set the basin as the basic unit.Decreasing diversion and drainage lines along the Yangtze River can take an active role in flood control.
基金Supported by the National Natural Science Foundation of China,No.81101613the Guangdong Provincial Natural Science Foundation of China,No.S2011040004363+2 种基金the Specialized Research Fund for the Doctoral Program of Higher Education of China,No.20114402120005the National Basic Research Program of China,No.2012CB526600the Natural Science Foundation of China-Guangdong Joint Fund,No.U0932001
文摘AIM: To evaluate the significance of γ-catenin in clinical pathology, cellular function and signaling mechanism in esophageal squamous cell carcinoma (ESCC).
文摘AIM:To explore the role of S-phase kinase-associated protein-2(Skp2)in gallbladder carcinoma and to identify whether depletion of Skp2 by Skp2-RNAi could attenuate proliferation and migration of gallbladder carcinoma.METHODS:Skp2-RNAi was transduced into cells of the gallbladder carcinoma cell line GBC-SD,using a lentiviral vector.The effect of Skp2-RNAi on the proliferation,migration,invasion and cell cycle of GBC-SD cells was studied using in vitro assays for cell proliferation,colony formation,wound healing and cell cycle.The expression of Skp2 and p27 was detected by real-time polymerase chain reaction and Western immunoblotting.The effect of Skp2-RNAi on the proliferation of GBC-SD cells in vivo was investigated by tumorigenicity experiments in nude mice.RESULTS:Lentivirus-mediated RNAi reduced the expression of Skp2 in cultured cells.The expression of the p27 protein increased along with the down-regulation of Skp2,although no significant difference was found in p27 mRNA expression.Flow cytometry revealed that Skp2-RNAi transfection significantly increased the proportion of cells in the S phase and significantly decreased the proportion of cells in the G 2 /M phase.No significant difference in the frequency of cells in the G0/G1 phase was observed.The results from the cell proliferation,colony formation and wound healing assays revealed that Skp2-RNAi transfection markedly inhibited the proliferation and migration of GBC-SD cells in vitro.Additionally,tumorigenicity experiments showed that suppression of Skp2 significantly decreased the weights of the tumors(0.56 ± 0.11 and 0.55 ± 0.07 g in the control and Scr-RNAi groups vs 0.37 ± 0.09 and 0.35 ± 0.08 g in the Skp2-RNAi-L and Skp2-RNAi-H groups).CONCLUSION:The expression of Skp2 in GBC-SD cells was inhibited following Skp2-RNAi transfection.Silencing of the Skp2 gene inhibited proliferation,migration and invasiveness of GBC-SD cells by mechanisms dependent on enhanced expression of the p27 protein.
文摘AIM:To evaluate the effects of estrogen(E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.METHODS:Fifty castrated female Sprague-Dawley rats were divided into five groups:sham operation(SO),partial portal vein ligation(PPVL) + placebo(PLAC),PPVL + E2,PPVL + ICI and PPVL + E2 + ICI. Hemodynamic measurements were performed using ultrasonography. Mesenteric arteriole contractility in response to norepinephrine was determined using a vessel perfusion system. Oxidative stress in the mesenteric artery was investigated by in situ detection of the superoxide anion(O2) and hydrogen peroxide(H2O2) concentrations.RESULTS:Treatment with E2 resulted in a significant decrease of portal pressure(P < 0.01) and portal venous inflow(P < 0.05),and higher systemic vascular resistance(P < 0.05) and splanchnic arteriolar resistance(P < 0.01) in PPVL + E2 rats compared to PPVL+ PLAC rats. In the mesenteric arterioles of PPVL +E2 rats,the dose-response curve was shifted left,and the EC50was decreased(P < 0.01). E2 reduced O2 production and H2O2concentration in the mesenteric artery. However,ICI182,780 reversed the beneficial effects of E2,therefore,the systemic and splanchnic hyperdynamic circulation were more deteriorated in ICI182,780-treated rats.CONCLUSION:Treatment with estrogen improved the systemic and splanchnic hyperdynamic circulation in PPVL rats,in part due to the alleviation of oxidative stress.
基金supported by the National Key Research and Development Program of China(Grants No.2019YFC0409000,2017YFC1502403,and 2018YFC0407701)the Fundamental Research Funds for the Central Universities(Grant No.B200204045).
文摘Anomalous characteristics of the atmospheric water cycle structure are highly significant to the mechanisms of seasonal-scale meteorological droughts.They also play an important role in the identification of indicative predictors of droughts.To better understand the causes of seasonal meteorological droughts in the middle and lower reaches of the Yangtze River(MLRYR),characteristics of the atmospheric water cycle structure at different drought stages were determined using standardized anomalies.The results showed that the total column water vapor(TCWV)was anomalously low during drought occurrence periods.In contrast,there were no anomalous signals at the drought persistence and recovery stages in the MLRYR.Moreover,there was no significant temporal correlation between the TCWV anomaly and seasonal-scale drought index(the 3-month standardized precipitation index(SPI_(3))).During drought events,water vapor that mainly originated from the Bay of Bengal was transported southwest of the MLRYR.Meanwhile,the anomalous signal of water vapor transport was negative at the drought appearance stage.At the drought persistence stage,the negative anomalous signal was the most significant.Water vapor flux divergence in the MLRYR showed significant positive anomalous signals during drought events,and the signal intensity shifted from an increasing to a decreasing trend at different drought stages.In addition,a significant positive correlation existed between the anomaly of water vapor flux divergence and regional SPI_(3).Overall,water vapor flux divergence is more predictive of droughts in the MLRYR.
基金Supported by the National Natural Science Foundation for the Youth of China,No.81400630
文摘BACKGROUND Portal hypertension(PHT)is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow.Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.AIM To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.METHODS Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride(CCl4)in both male and female integral and castrated rats(ovariectomized[OVX]in female rats,orchiectomy[ORX]in male rats).The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.RESULTS No significant difference in portal pressure was observed between integral and castrated male PHT rats(15.2±2.1 mmHg vs 16.7±2.7 mmHg,P>0.05).The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats(12.7±2.7 mmHg vs 16.5±2.4 mmHg,P<0.05).In PHT rats,the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right,and the maximal responses(Emax)values were decreased and effective concentrations causing half maximum responses(EC50)values were increased,compared to those of non-PHT rats,both in male and female rats.Compared to non-PHT integral male rats,the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased(P>0.05).However,there was no difference between integral and ORX male rats with PHT.In integral female PHT rats,the concentration response curves were shifted to the left(P<0.05),and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats.CONCLUSION Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats.Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.
基金supported by a grant from the National Natural Science Foundation of China (30972920)
文摘BACKGROUND: The increased β-arrestin-2 and its combination with G-protein-coupled receptors (GPCRs) lead to GPCRs desensitization. The latter may be responsible for decreased contractile reactivity in the mesenteric arteries of cirrhotic patients and rats. The present study is to investigate the machinery changes of α-adrenergic receptors and G proteins and their roles in the contractility of mesenteric arteries of cirrhotic patients and animal models. METHODS: Patients with cirrhosis due to hepatitis B and cirrhotic rats induced by CCl 4 were studied. Mesenteric artery contractility in response to norepinephrine was determined by a vessel perfusion system. The contractile effect of G protein-coupled receptor kinase-2 (GRK-2) inhibitor on the mesenteric artery was evaluated. The protein expression of the α 1 adrenergic receptor, G proteins, β-arrestin-2, GRK-2 as well as the activity of Rho associated coiled-coil forming protein kinase-1 (ROCK-1) were measured by Western blot. In addition, the interaction of α 1 adrenergic receptor with β-arrestin-2 was assessed by co-immunoprecipitation. RESULTS: The portal vein pressure of cirrhotic patients and rats was significantly higher than that of controls. The doseresponse curve to norepinephrine in mesenteric arteriole was shifted to the right, and EC 50 was significantly increased in cirrhotic patients and rats. There were no significant differences in the expressions of the α 1 adrenergic receptor and G proteins in the cirrhotic group compared with the controls. However, the protein expressions of GRK-2 and β-arrestin-2 were significantly elevated in cirrhotic patients and rats compared with those of the controls. The interaction of the α 1 adrenergic receptor and β-arrestin-2 was significantly aggravated. This interaction was significantly reversed by GRK-2 inhibitor. Both the protein expression and activity of ROCK-1 were significantly decreased in the mesenteric artery in patients with cirrhosis compared with those of the controls, and this phenomenon was not shown in the cirrhotic rats. Norepinephrine significantly increased the activity of ROCK-1 in normal rats but not in cirrhotic ones. Norepinephrine significantly increased ROCK-1 activity in cirrhotic rats when GRK-2 inhibitor was used. CONCLUSIONS: β-arrestin-2 expression and its interaction with GPCRs are significantly upregulated in the mesenteric arteries in patients and rats with cirrhosis. These upregulations result in GPCR desensitization, G-protein dysfunction and ROCK inhibition. These may explain the decreased contractility of the mesenteric artery in response to vasoconstrictors.
文摘BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODS This multicenter,open-label,pilot randomized controlled trial enrolled 68 EGFRmutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy+icotinib groups.RESULTS The median progression-free survival in the icotinib alone and chemotherapy+icotinib groups was 8.0 mo(95%CI:3.84-11.63)and 13.4 mo(95%CI:10.18-16.33),respectively(P=0.0249).No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen(all P>0.05).CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
基金the National Science & Technology Pillar Program of China(No.2011BAE31B01)
文摘A simply synthesized 4-aminonaphthalimide derivative 1 expresses both polarity and viscosity sensitive fluorescence spectra,indicating its potential usage as an environmentally sensitive fluorescence probe. By comparing the fluorescence behavior of 1 with that of a known 4-aminonaphthalimide derivative 2,it was found that the substitution of the 4-amino group has profound influence on the environmentally sensitive fluorescence properties of 4-aminonaphthalimide.
基金supported by the Natural Science Foundation of China-Guangdong Joint Fund(Grant Numbers U1301227,U0932001)the National Natural Science Foundation of China(Grant Numbers 81360331,81472613,81572341)+1 种基金the Science&Technology Planning Project of Guangdong Province(Grant Number 2014A030304060)the Department of Education,Guangdong Government under the Top-tier University Development Scheme for Research and Control of Infectious Diseases.
文摘Background:Esophageal squamous cell carcinoma(ESCC)is the predominant subtype of esophageal carcinoma in China.This study was to develop a staging model to predict outcomes of patients with ESCC.Methods:Using Cox regression analysis,principal component analysis(PCA),partitioning clustering,Kaplan-Meier analysis,receiver operating characteristic(ROC)curve analysis,and classification and regression tree(CART)analysis,we mined the Gene Expression Omnibus database to determine the expression profiles of genes in 179 patients with ESCC from GSE63624 and GSE63622 dataset.Results:Univariate cox regression analysis of the GSE63624 dataset revealed that 2404 protein-coding genes(PCGs)and 635 long non-coding RNAs(lncRNAs)were associated with the survival of patients with ESCC.PCA categorized these PCGs and lncRNAs into three principal components(PCs),which were used to cluster the patients into three groups.ROC analysis demonstrated that the predictive ability of PCG-lncRNA PCs when applied to new patients was better than that of the tumor-node-metastasis staging(area under ROC curve[AUC]:0.69 vs.0.65,P<0.05).Accord-ingly,we constructed a molecular disaggregated model comprising one lncRNA and two PCGs,which we desig-nated as the LSB staging model using CART analysis in the GSE63624 dataset.This LSB staging model classified the GSE63622 dataset of patients into three different groups,and its effectiveness was validated by analysis of another cohort of 105 patients.Conclusions:The LSB staging model has clinical significance for the prognosis prediction of patients with ESCC and may serve as a three-gene staging microarray.
基金supported by the National Key R&D Program of China(2017YFA0303402)the National Natural Science Foundation of China(11874293,91750113,11674254 and 11504105)。
文摘The plasmon-enhanced second-harmonic generation(SHG)of Au nanorods(NRs),Au-Ag NRs,and asymmetric Au@CdSe heterorods are comparatively investigated.The Au@CdSe tip-and side-heterorods are synthesized by precisely controlling the concentration of Cd2+precursor,and the plasmon resonances can be well tuned simultaneously.The SHG of asymmetric Au@CdSe heterorods has been greatly enhanced with up to 617.7-fold enhancement compared with the Au NRs because of the asymmetric morphology and local field enhancement.Moreover,the harmonic energy transfer induced by the local interband transition of Au has also been demonstrated by the excitation-wavelengthdependent SHG in the Au NRs and Au@CdSe side-heterorods,while it is negligible in the Au-Ag NRs and Au@CdSe tipheterorods because of the presence of Ag.The plasmon-enhanced SHG of asymmetric Au@CdSe heterorods enables potential applications ranging from sensing to biological spectroscopy.
基金National Natural Science Foundation of China,Grant/Award Numbers:81872372,81902469Natural Science Foundation of China-Guangdong Joint Fund,Grant/Award Number:U0932001+2 种基金National Cohort of Esophageal Cancer of China,Grant/Award Number:2016YFC0901400China Postdoctoral Science Foundation,Grant/Award Number:2018M6431342020 Li Ka Shing Foundation Cross-Disciplinary Research Grant,Grant/Award Number:2020LKSFG07B。
文摘Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remains unclear.This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.Methods:Immunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor(PCAF),and immunofluorescence was used to investigate their colocalization.An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry.A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma(ESCC)cells using Western blotting by overexpressing and knocking down PCAF expression.An in vitro cell migration assay was performed,and a xenograft model was established to study in vivo tumor metastasis.Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation.The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.Results:Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471(K471)by PCAF.Using the specific antiAcK471-Fascin antibody,Fascin was found to be acetylated in ESCC cells,and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown.Functionally,Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis,whereas Fascin-K471 deacetylation exhibited a potent oncogenic function.Moreover,Fascin-K471 acetylation reduced filopodial length and density,and lifespan of ESCC cells,while its deacetylation produced the opposite effect.In the filipodium shaft,K471-acetylated Fascin displayed rapid dynamic exchange,suggesting that it remained in its monomeric form owing to its weakened actinbundling activity.Clinically,high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients.Conclusions:Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells.Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.
基金This work was supported by the Shanghai Commission of Science and Technology Planning(22ZR1409100)to F.Zthe Shanghai Municipal Commission of Health and Family Planning(2017ZZ01016)to C.X.
文摘Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties;however, limited information is available regarding its therapeutic potential in PCOS.Methods::Female C57BL/6 mice were randomly assigned into four groups ( n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed. Results::Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone ( P < 0.001) and dehydroepiandrosterone sulfate ( P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly ( P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS. Conclusion::Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.
基金funded by the National Defense Science and Technology Innovation Special Zone–Spark Project(20-163-00-TS-009-152-01)the National Natural Science Foundation of China(U20A20227,61974030)+1 种基金the National Key R&D Program of China(2019YFA0709504)the National Natural Science Foundation of China(31900719).
文摘Invasive neural probes are one of the most critical components in the intracortical neural signal recording system.However,they can cause brain damage and tissue response during and after implantation.Thus,neural probes with high flexibility,biocompatibility,and simple implantation methods are required in brain research.Here we present a novel approach to fabricating a multilayer flexible tassel-type neural probe using low-cost maskless laser direct-write lithog-raphy,combined with straightforward release and assembly methods to prepare a whole implantation system.The probe has 32 recording electrodes with an area of 8×8μm^(2),arranged into two rows of different depths and 16 separated shanks,aiming at the neural signal recording in an extensive range.Polyimide and gold are used as the insulating and conductive layers,respectively.With the help of a polyethylene glycol(PEG)coating,the tassel structure was mechanically enhanced for successful implantation,and our morphology characterization showed that the diameter of the coated probe was less than 50μm.Mechanical property tests also proved that it had the necessary stiffness for brain implantation.Afterwards,electrochemical tests were carried out,which showed that the probe had a rather low impedance after a simple gold electroplating.Finally,in vivo experiments demonstrated our probe can be successfully used in neural recording.
