The corrosion behavior of 316H stainless steel(SS)in the impure and purified Na Cl–KCl–Mg Cl_(2) salt was investigated at700°C.Results indicate that the main deleterious impurity induced corrosion in the impure...The corrosion behavior of 316H stainless steel(SS)in the impure and purified Na Cl–KCl–Mg Cl_(2) salt was investigated at700°C.Results indicate that the main deleterious impurity induced corrosion in the impure salt was the absorbed moisture,present in the form of Mg Cl_(2)·6H_(2)O.316H SS occurred severe intergranular corrosion with a corrosion depth of 130μm for1000 h in the impure Na Cl–KCl–Mg Cl_(2) salt.In contrast,the purification treatment of molten chloride salt by the dissolved Mg metal can remove the absorbed moisture,and the corresponding reactions were also discussed.As a result,the corrosiveness of Na Cl–KCl–Mg Cl_(2) salt is reduced significantly.316H SS occurred slight uniform corrosion with a depth of less than 5μm for 3000 h in the purified Na Cl–KCl–Mg Cl_(2) salt.展开更多
The ultraviolet(UV)light stability of silicon heterojunction(SHJ)solar cells should be addressed before large-scale production and applications.Introducing downshifting(DS)nanophosphors on top of solar cells that can ...The ultraviolet(UV)light stability of silicon heterojunction(SHJ)solar cells should be addressed before large-scale production and applications.Introducing downshifting(DS)nanophosphors on top of solar cells that can convert UV light to visible light may reduce UV-induced degradation(UVID)without sacrificing the power conversion efficiency(PCE).Herein,a novel composite DS nanomaterial composed of YVO_(4):Eu^(3+),Bi^(3+)nanoparticles(NPs)and AgNPs was synthesized and introduced onto the incident light side of industrial SHJ solar cells to achieve UV shielding.The YVO_(4):Eu^(3+),Bi^(3+)NPs and Ag NPs were synthesized via a sol-gel method and a wet chemical reduction method,respectively.Then,a composite structure of the YVO_(4):Eu^(3+),Bi^(3+)NPs decorated with Ag NPs was synthesized by an ultrasonic method.The emission intensities of the YVO_(4):Eu^(3+),Bi^(3+)nanophosphors were significantly enhanced upon decoration with an appropriate amount of~20 nm Ag NPs due to the localized surface plasmon resonance(LSPR)effect.Upon the introduction of LSPR-enhanced downshifting,the SHJ solar cells exhibited an~0.54%relative decrease in PCE degradation under UV irradiation with a cumulative dose of 45 k W h compared to their counterparts,suggesting excellent potential for application in UV-light stability enhancement of solar cells or modules.展开更多
There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspect...There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspective of energy metabolism flux regulation.Metabolic flux analysis(MFA)was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol(ISO)-induced ischemia-like cardiomyocytes.It showed that[U-13 C]glucose derived m+2 isotopologues from the upstream tricarboxylic acid(TCA)cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes,but the opposite was seen for the downstream metabolites,while their total cellular concentrations were increased.This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources.A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction.It showed that bilobalide protected against impaired mitochondrial aerobic respiration.MFA also showed that bilobalide significantly modulated the TCA cycle flux,reduced abnormal metabolite accumulation,and balanced the demand of different carbon sources.Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells.Bilobalide’s efficacy was verified by in vivo experiments in rats.This is the first report to show that bilobalide,the active ingredient of GBE,protects against MI by rescuing impaired TCA cycle flux.This provides a new mechanism and potential drug treatment for MI.It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.展开更多
In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4＇-O-demethylepipodophyllotoxin derivatives were designed and syn...In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4＇-O-demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro, and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC50 value at 10^-7 mol/L level.展开更多
BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characte...BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characterize the microbiome in patients with IL10 RA mutations and to explore the association between gut dysbiosis and disease severity.METHODS Fecal samples were collected from patients who were diagnosed with loss-offunction mutations in the IL10 RA gene between January 2017 and July 2018 at the Children’s Hospital of Fudan University.Age-matched volunteer children were recruited as healthy controls.Patients with Crohn’s disease(CD) were used as disease controls to standardize the antibiotic exposure.Microbial DNA was extracted from the fecal samples.All analyses were based on the 16 S rRNA gene sequencing data.RESULTS Seventeen patients with IL10 RA mutations(IL10 RA group),17 patients with pediatric CD, and 26 healthy children were included.Both patients with IL10 RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability.The relative abundance of Firmicutes was substantially increased in the IL10 RA group(P=0.02).On further comparison of the relative abundance of taxa between patients with IL10 RA mutations and healthy children,13 taxa showed significant differences.The IL10 RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD.CONCLUSION In patients with IL10 RA mutations and early onset inflammatory bowel disease,gut dysbiosis shows a moderate association with disease severity.展开更多
The spatial distribution characteristics of six heavy metals and metalloid in soil of Zhuji Lipu copper mining area, Zhejiang Province, was studied by using geostatistics approaches combined with GIS. These elements i...The spatial distribution characteristics of six heavy metals and metalloid in soil of Zhuji Lipu copper mining area, Zhejiang Province, was studied by using geostatistics approaches combined with GIS. These elements included Pb, As, Cr, Cu, Zn and Ni. The statistical analyses showed that concentrations of these elements were lognormal distribution. Concentrations of Pb, As, Cu, Zn and Ni were strongly correlated with each other indicating that these elements in soils may be from the same pollution source. However, accumulation of Cr was unique with its geometric mean being close to that in the control soil. This indicates that Cr content was mainly influenced by soil factors. The Kriging method was applied to estimate the unobserved points. The Kriging interpolation maps reflected significant spatial distribution of these elements as influenced by both pollution and geological factors. The present study indicated that GIS based geostatistics method could accurately analyze the spatial variation of heavy metals and metalloid in the mining area. Overall, higher concentrations of heavy metals and metalloid were found in the center of both the north and south sides. The content of copper in the south was significantly higher than that in the north due to paddy field land uses. In addition, the terrain of four terraces tilted to the center and the broad irrigation accident occurred in the 4th trench in the south of sampling area were also contributed to the higher concentrations of these elements.展开更多
Background:The mental health of left-behind rural children of China has become a prominent social problem.At the same time,psychological capital has become a positive psychological resource to promote personal growth....Background:The mental health of left-behind rural children of China has become a prominent social problem.At the same time,psychological capital has become a positive psychological resource to promote personal growth.However,the relationship between psychological capital and mental health of left-behind rural children has not been explored.Method:A total of 332 left-behind rural children were investigated using a questionnaire of psychological capital and mental health scale.The psychological capital status of left-behind rural children and its impact on mental health were analyzed.Results:(1)Left-behind rural children were found to have a psychological capital score of was 3.16±0.56;Gender,age,grade,and school style had no significant effect on psychological capital.(2)Left-behind rural children obtained a mental health score of 2.21±0.5 G and gender,age,grade,and school style had no significant effect on mental health.(3)A significant negative correlation is found between psychological capital and mental health scores of left-behind rural children.Regression analysis shows that psychological capital is negatively correlated with mental health scores.Conclusion:The psychological capital of left-behind rural children can positively predict their mental health,and thus developing the former can promote the latter.展开更多
The manufacturing industry is an important pillar of the national economy.It is of vital importance to develop statistical modellings in order to quantify the relationship between potential internal drivers and the tr...The manufacturing industry is an important pillar of the national economy.It is of vital importance to develop statistical modellings in order to quantify the relationship between potential internal drivers and the trend of output values in the manufacturing industry.However,only a few statistical modellings have been established to investigate such associations.This study developed the correlation coefficient model and generalized linear model(GLM)to measure the single and interactive effects of the internal drivers on the changes of the output values.For the GLM,different predictive variables were developed to fit into the dataset,and the performance of the models were compared using fitness parameters.Furthermore,an industry survey dataset for 1,180 manufacturing enterprises in 2020 was used to validate the models.The use of the GLM combining land area,number of employees,scientific research input,and labor productivity may have a great potential to bolster capacity in monitoring and predicting the trend of output values in the manufacture industry.展开更多
Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Previous studies showed tha...Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Previous studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein adducts.The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes.In the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers.Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,respectively.Mechanistically,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against AILI.We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists.Among these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in mice.In conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.展开更多
Broiler chicks are fast-growing and susceptible to dietary selenium(Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male c...Broiler chicks are fast-growing and susceptible to dietary selenium(Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male chicks(n=6 cages/diet, 6 chicks/cage) were fed with a Se-deficient diet(Se-Def, 0.047 mg Se/kg) or the Se-Def+0.3 mg Se/kg(Control, 0.345 mg Se/kg) for 6weeks. The serum, liver, pancreas, spleen, heart, and pectoral muscle of the broilers were collected at week 6 to assay for Se concentration, histopathology, serum metabolome, and tissue transcriptome. Compared with the Control group, Se deficiency induced growth retardation and histopathological lesions and reduced Se concentration in the five organs. Integrated transcriptomics and metabolomics analysis revealed that dysregulation of immune and redox homeostasis related biological processes and pathways contributed to Se deficiency-induced multiple tissue damage in the broilers. Meanwhile, four metabolites in the serum, daidzein, epinephrine, L-aspartic acid and 5-hydroxyindoleacetic acid, interacted with differentially expressed genes with antioxidative effects and immunity among all the five organs, which contributed to the metabolic diseases induced by Se deficiency. Overall, this study systematically elucidated the underlying molecular mechanisms in the pathogenesis of Se deficiency-related diseases, which provides a better understanding of the significance of Se-mediated heath in animals.展开更多
Objective:To isolate the phenolic compounds obtained from the dried roots ofPolygonum multiflorum and investigate their pharmacological activities.Methods:The chemical constituents were isolated and purified by combin...Objective:To isolate the phenolic compounds obtained from the dried roots ofPolygonum multiflorum and investigate their pharmacological activities.Methods:The chemical constituents were isolated and purified by combining them with a macroporous resin(DM-8),MCI gel,and Sephadex LH-20 and by performing ODS column chromatography.Their structures were elucidated by 1D and 2D NMR analyses,as well as mass spectrometry.The isolated compounds were evaluated to determine their hepatoprotective andα-glucosidase inhibitory activities in vitro.Results:Two phenolic compounds,namely,polygonimitin E(1)and polygonimitin F(2),were isolated from the dried roots of P.multiflorum.Compound 2(10μmol/L)only showed moderate hepatoprotective activity against N-acetyl-p-aminophenol(APAP)-induced HepG2 cell damage.Unfortunately,these two compounds exhibited noα-glucosidase inhibitory activity.Conclusion:Compounds 1 and 2 were new compounds.Compound 2 could be one of the potential hepatoprotective constituents of P.multiflorum.展开更多
Type Ⅱ Epstein-Barr virus （EBV） associated malignancies such as nasopharyngeal carcinoma and non-Hodgkin＇s lymphomas consistently express latent membrane 2A （LMP2A） proteins, which have been suggested to be an i...Type Ⅱ Epstein-Barr virus （EBV） associated malignancies such as nasopharyngeal carcinoma and non-Hodgkin＇s lymphomas consistently express latent membrane 2A （LMP2A） proteins, which have been suggested to be an ideal target for immunotherapy. In previous studies we have demonstrated that using LMP2A protein loaded dendritic cells, the most powerful antigen processing cells in the body can elicit specific and robust anti-tumor cellular immune response in vitro. In this paper, we further investigated the T cell profile of the anti-tumor immune response. We found that LMP2A specific CD4＋ and CD8＋ T cells could be stimulated by LMP2A protein loaded dendritic cells （DCs）. The Thl type immune response is dominant in the immune response mediated by LMP2A specific CD4^＋ T cells. The CD8^＋ cytotoxic T cells can lyse LMP2A bearing cells effectively and specifically. The CD8^＋ cytotoxic T cells can also secrete high level of intracellular IFN-γ, which indicates these cells are EBV-LMP2A specific cytotoxic T cells. Altogether, our studies proved that LMP2A protein loaded DCs can elicit anti-tumor cellular immune responses efficiently. This study provides a rationale for the DC-based immunotherapy against EBV-LMP2A expressing malignancies.展开更多
To establish an animal model of acute-on-chronic liver failure(ACLF) that would replicate the pathological process of ACLF in humans, rats were administered porcine serum(PS) for 11 weeks. Liver fibrosis was determine...To establish an animal model of acute-on-chronic liver failure(ACLF) that would replicate the pathological process of ACLF in humans, rats were administered porcine serum(PS) for 11 weeks. Liver fibrosis was determined by pathological and biochemical assessments. The animals then were injected with D-galactosamine(D-gal) and lipopolysaccharide(LPS). The survival times of animals with cirrhosis and ACLF were determined over 48 h. Other animals were killed at 0, 4, 8 and 12 h after administration of D-gal/LPS. Liver injury was assessed by histopathological analysis and biochemical indices, and apoptosis was detected by Western blot and TUNEL analysis. After PS administration for 11 weeks the serum levels of hyaluronic acid and N-procollagen type III peptide increased significantly, and serious fibrosis and cirrhosis was observed at weeks 10 and 11. Cirrhotic rats were injected with D-gal/LPS to induced ACLF; the rate of mortality over 48 h was 80%. ALT and AST levels increased markedly at 4 h, but decreased significantly at8 and 12 h post-treatment. The total bilirubin, direct bilirubin, and total bile acids levels increased markedly at 8 and 12 h. Clotting times, TNF-α and IL-6 levels increased significantly, except for 12 h post-treatment.Apoptosis, inflammation and necrosis were elevated as determined by hematoxylin-eosin staining and TUNEL assays. BCL-2 levels decreased significantly, While BAX levels increased significantly.Cytochrome c expression peaked at 8 h postD-gal/LPS treatment. In conclusion, an ACLF model induced by PS and D-gal/LPS was established and the underlying mechanisms of ACLF development were explored.展开更多
Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/2...Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/24:0)in the progression of ACLF to validate the biomarker using ACLF rat model.Methods:ACLF rats were sacrificed at 4 and 8 h post-D-galactosamine(D-gal)/lipopolysaccharide(LPS)administration to investigate the liver biochemical markers,prothrombin time and liver histopathology.Change in dhCer and other sphingolipids levels were investigated by high-performance liquid chromatography coupled to tandem mass spectrometry(HPLC-MS/MS).Rats were treated with N-(4-hydroxyphenyl)retinamide(4-HPR)to examine the mortality rate and its role in improving ACLF.Results:LPS/D-gal administration resulted in significant elevation in alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Prothrombin time was prolonged and histopathological examination showed abnormality.HPLC-MS/MS results showed total dhCer levels in ACLF group(64.10±8.90 pmol/100 mL,64.22±6.78 pmol/100 mL for 4 and 8 h,respectively)were decreased significantly compared with control group(121.61±23.09 pmol/100 mL)(P<0.05).In particular,dhCer(d18:0/24:0),dhCer(d18:0/20:0),and dhCer(d18:0/22:0)levels were decreased.Treatment with 4-HPR significantly increased the levels of dhCers,including dhCer(d18:0/24:0)compared with ACLF group,for the level of dhCer(d18:0/24:0)in 4-HPR group was 20.10±8.60 pmol/100 mL and the level of dhCer(d18:0/24:0)in ACLF group was 9.74±2.99 pmol/100 mL(P<0.05).This was associated with reduced mortality rate and prolonged survival time.The ALT and AST in 4-HPR group were significantly decreased compared with ACLF group.The prothrombin time of 4-HPR group(41.49 s)was significantly lower than the prothrombin time of ACLF group(57.96 s)(P<0.05).4-HPR also decreased plasma ammonia levels slightly,as the plasma ammonia levels in 4-HPR group and ACLF group were 207.37±60.43,209.15±60.43 mmol/L,respectively.Further,4-HPR treatment improved histopathological parameters.Conclusions:DhCer,especially dhCer(d18:0/24:0),is involved in the progression of ACLF.Increasing the levels of dhCer can reduce the mortality rate of ACLF rats and alleviate liver injury.展开更多
Background:Acetaminophen(APAP)overdose can cause liver injury and liver failure,which is one of the most common causes of drug-induced liver injury in the United States.Pharmacological activation of autophagy by inhib...Background:Acetaminophen(APAP)overdose can cause liver injury and liver failure,which is one of the most common causes of drug-induced liver injury in the United States.Pharmacological activation of autophagy by inhibiting mechanistic target of rapamycin(mTOR)protects against APAP-induced liver injury likely via autophagic removal of APAP-adducts and damaged mitochondria.In the present study,we aimed to investigate the role of genetic ablation of mTOR pathways in mouse liver in APAP-induced liver injury and liver repair/regeneration.Methods:Albumin-Cre(Alb-Cre)mice,mTOR^(f/f) and Raptor^(f/f) mice(C57BL/6J background)were crossbred to produce liver-specific mTOR knockout(L-mTOR KO,Alb Cret/-,mTOR^(f/f))and liver-specific Raptor KO(L-Raptor,Alb Cret/-,Raptor^(f/f))mice.Alb-Cre littermates were used as wild-type(WT)mice.These mice were treated with APAP for various time points for up to 48 h.Liver injury,cell proliferation,autophagy and mTOR activation were determined.Results:We found that genetic deletion of neither Raptor,an important adaptor protein in mTOR complex 1,nor mTOR,in the mouse liver significantly protected against APAP-induced liver injury despite increased hepatic autophagic flux.Genetic deletion of Raptor or mTOR in mouse livers did not affect APAP metabolism and APAP-induced c-Jun N-terminal kinase(JNK)activation,but slightly improved mouse survival likely due to increased hepatocyte proliferation.Conclusions:Our results indicate that genetic ablation of mTOR in mouse livers does not protect against APAP-induced liver injury but may slightly improve liver regeneration and mouse survival after APAP overdose.展开更多
基金supported by the National Science Foundation of Shanghai(No.22ZR1474600)the National Natural Science Foundation of China(No.12175302)+1 种基金the“Thorium Molten Salt Reactor Nuclear Energy System”Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA 02040000)the“Transformational Technologies for Clean Energy and Demonstration,”Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA 21000000)。
文摘The corrosion behavior of 316H stainless steel(SS)in the impure and purified Na Cl–KCl–Mg Cl_(2) salt was investigated at700°C.Results indicate that the main deleterious impurity induced corrosion in the impure salt was the absorbed moisture,present in the form of Mg Cl_(2)·6H_(2)O.316H SS occurred severe intergranular corrosion with a corrosion depth of 130μm for1000 h in the impure Na Cl–KCl–Mg Cl_(2) salt.In contrast,the purification treatment of molten chloride salt by the dissolved Mg metal can remove the absorbed moisture,and the corresponding reactions were also discussed.As a result,the corrosiveness of Na Cl–KCl–Mg Cl_(2) salt is reduced significantly.316H SS occurred slight uniform corrosion with a depth of less than 5μm for 3000 h in the purified Na Cl–KCl–Mg Cl_(2) salt.
基金supported by the National Natural Science Foundation of China (Grant Nos.52202276 and 51821002)the China Postdoctoral Science Foundation (Grant No.2022M712300)+1 种基金the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No.22KJB480010)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)。
文摘The ultraviolet(UV)light stability of silicon heterojunction(SHJ)solar cells should be addressed before large-scale production and applications.Introducing downshifting(DS)nanophosphors on top of solar cells that can convert UV light to visible light may reduce UV-induced degradation(UVID)without sacrificing the power conversion efficiency(PCE).Herein,a novel composite DS nanomaterial composed of YVO_(4):Eu^(3+),Bi^(3+)nanoparticles(NPs)and AgNPs was synthesized and introduced onto the incident light side of industrial SHJ solar cells to achieve UV shielding.The YVO_(4):Eu^(3+),Bi^(3+)NPs and Ag NPs were synthesized via a sol-gel method and a wet chemical reduction method,respectively.Then,a composite structure of the YVO_(4):Eu^(3+),Bi^(3+)NPs decorated with Ag NPs was synthesized by an ultrasonic method.The emission intensities of the YVO_(4):Eu^(3+),Bi^(3+)nanophosphors were significantly enhanced upon decoration with an appropriate amount of~20 nm Ag NPs due to the localized surface plasmon resonance(LSPR)effect.Upon the introduction of LSPR-enhanced downshifting,the SHJ solar cells exhibited an~0.54%relative decrease in PCE degradation under UV irradiation with a cumulative dose of 45 k W h compared to their counterparts,suggesting excellent potential for application in UV-light stability enhancement of solar cells or modules.
基金supported by grants from the National Natural Science Foundation of China(Grant No.:81803496)the CAMS Innovation Fund for Medical Sciences(Grant No.:2016-I2M-3-016)the Applications and Core Technology University Research(ACT-UR,Grant No.:4084)。
文摘There is an urgent need to elucidate the pathogenesis of myocardial ischemia(MI)and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract(GBE)were studied from the perspective of energy metabolism flux regulation.Metabolic flux analysis(MFA)was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol(ISO)-induced ischemia-like cardiomyocytes.It showed that[U-13 C]glucose derived m+2 isotopologues from the upstream tricarboxylic acid(TCA)cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes,but the opposite was seen for the downstream metabolites,while their total cellular concentrations were increased.This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources.A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction.It showed that bilobalide protected against impaired mitochondrial aerobic respiration.MFA also showed that bilobalide significantly modulated the TCA cycle flux,reduced abnormal metabolite accumulation,and balanced the demand of different carbon sources.Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells.Bilobalide’s efficacy was verified by in vivo experiments in rats.This is the first report to show that bilobalide,the active ingredient of GBE,protects against MI by rescuing impaired TCA cycle flux.This provides a new mechanism and potential drug treatment for MI.It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.
文摘In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4＇-O-demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro, and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC50 value at 10^-7 mol/L level.
基金Supported by the Jiujiu Charitable Trust-PIBD China.
文摘BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characterize the microbiome in patients with IL10 RA mutations and to explore the association between gut dysbiosis and disease severity.METHODS Fecal samples were collected from patients who were diagnosed with loss-offunction mutations in the IL10 RA gene between January 2017 and July 2018 at the Children’s Hospital of Fudan University.Age-matched volunteer children were recruited as healthy controls.Patients with Crohn’s disease(CD) were used as disease controls to standardize the antibiotic exposure.Microbial DNA was extracted from the fecal samples.All analyses were based on the 16 S rRNA gene sequencing data.RESULTS Seventeen patients with IL10 RA mutations(IL10 RA group),17 patients with pediatric CD, and 26 healthy children were included.Both patients with IL10 RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability.The relative abundance of Firmicutes was substantially increased in the IL10 RA group(P=0.02).On further comparison of the relative abundance of taxa between patients with IL10 RA mutations and healthy children,13 taxa showed significant differences.The IL10 RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD.CONCLUSION In patients with IL10 RA mutations and early onset inflammatory bowel disease,gut dysbiosis shows a moderate association with disease severity.
文摘The spatial distribution characteristics of six heavy metals and metalloid in soil of Zhuji Lipu copper mining area, Zhejiang Province, was studied by using geostatistics approaches combined with GIS. These elements included Pb, As, Cr, Cu, Zn and Ni. The statistical analyses showed that concentrations of these elements were lognormal distribution. Concentrations of Pb, As, Cu, Zn and Ni were strongly correlated with each other indicating that these elements in soils may be from the same pollution source. However, accumulation of Cr was unique with its geometric mean being close to that in the control soil. This indicates that Cr content was mainly influenced by soil factors. The Kriging method was applied to estimate the unobserved points. The Kriging interpolation maps reflected significant spatial distribution of these elements as influenced by both pollution and geological factors. The present study indicated that GIS based geostatistics method could accurately analyze the spatial variation of heavy metals and metalloid in the mining area. Overall, higher concentrations of heavy metals and metalloid were found in the center of both the north and south sides. The content of copper in the south was significantly higher than that in the north due to paddy field land uses. In addition, the terrain of four terraces tilted to the center and the broad irrigation accident occurred in the 4th trench in the south of sampling area were also contributed to the higher concentrations of these elements.
基金supported by the National Social Science Fund of China(17BTY043).
文摘Background:The mental health of left-behind rural children of China has become a prominent social problem.At the same time,psychological capital has become a positive psychological resource to promote personal growth.However,the relationship between psychological capital and mental health of left-behind rural children has not been explored.Method:A total of 332 left-behind rural children were investigated using a questionnaire of psychological capital and mental health scale.The psychological capital status of left-behind rural children and its impact on mental health were analyzed.Results:(1)Left-behind rural children were found to have a psychological capital score of was 3.16±0.56;Gender,age,grade,and school style had no significant effect on psychological capital.(2)Left-behind rural children obtained a mental health score of 2.21±0.5 G and gender,age,grade,and school style had no significant effect on mental health.(3)A significant negative correlation is found between psychological capital and mental health scores of left-behind rural children.Regression analysis shows that psychological capital is negatively correlated with mental health scores.Conclusion:The psychological capital of left-behind rural children can positively predict their mental health,and thus developing the former can promote the latter.
文摘The manufacturing industry is an important pillar of the national economy.It is of vital importance to develop statistical modellings in order to quantify the relationship between potential internal drivers and the trend of output values in the manufacturing industry.However,only a few statistical modellings have been established to investigate such associations.This study developed the correlation coefficient model and generalized linear model(GLM)to measure the single and interactive effects of the internal drivers on the changes of the output values.For the GLM,different predictive variables were developed to fit into the dataset,and the performance of the models were compared using fitness parameters.Furthermore,an industry survey dataset for 1,180 manufacturing enterprises in 2020 was used to validate the models.The use of the GLM combining land area,number of employees,scientific research input,and labor productivity may have a great potential to bolster capacity in monitoring and predicting the trend of output values in the manufacture industry.
基金We would like to thank Dr.Thomas Ru¨licke at Department of Biomedical Sciences,University of Veterinary Medicine Vienna,Vienna,Austria and Dr.Kurt Zatloukal at The Institute of Pathology,Medical University of Graz,A-8036 Graz,Austria for providing us whole body Sqstm1/p62 knockout mice for the hepatocyte isolation experiment.We also thank Larysa Stroganova at University of Kansas Medical Center for her excellent assistance for the EM studies.This study was supported in part by the National Institute of Health(NIH,USA)funds R01 DK102142,R01 AG072895,R37 AA020518(WXD)and in part by the Intramural Research Program of the National Center for Advancing Translational Sciences,NIH(USA).
文摘Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Previous studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein adducts.The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes.In the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers.Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,respectively.Mechanistically,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against AILI.We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists.Among these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in mice.In conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.
基金supported by the National Natural Science Foundation of China (32102588)the Top-notch Young Talent Supporting Program to LHSBeijing Deyuanshun Biological Technology Co.,Ltd。
文摘Broiler chicks are fast-growing and susceptible to dietary selenium(Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male chicks(n=6 cages/diet, 6 chicks/cage) were fed with a Se-deficient diet(Se-Def, 0.047 mg Se/kg) or the Se-Def+0.3 mg Se/kg(Control, 0.345 mg Se/kg) for 6weeks. The serum, liver, pancreas, spleen, heart, and pectoral muscle of the broilers were collected at week 6 to assay for Se concentration, histopathology, serum metabolome, and tissue transcriptome. Compared with the Control group, Se deficiency induced growth retardation and histopathological lesions and reduced Se concentration in the five organs. Integrated transcriptomics and metabolomics analysis revealed that dysregulation of immune and redox homeostasis related biological processes and pathways contributed to Se deficiency-induced multiple tissue damage in the broilers. Meanwhile, four metabolites in the serum, daidzein, epinephrine, L-aspartic acid and 5-hydroxyindoleacetic acid, interacted with differentially expressed genes with antioxidative effects and immunity among all the five organs, which contributed to the metabolic diseases induced by Se deficiency. Overall, this study systematically elucidated the underlying molecular mechanisms in the pathogenesis of Se deficiency-related diseases, which provides a better understanding of the significance of Se-mediated heath in animals.
基金The authors are grateful to the members of the analytical group of the State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences(CAMS)and Peking Union Medical College,Beijing,China for the spectroscopic data measurements and bioactivity tests.This project was financially supported by the National Natural Science Foundation of China(Nos.81703665,81773874,81973476 and 81903807)the National Major Scientific and Technological Special Project for"Significant New Drugs Development"(2018ZX09735006).
文摘Objective:To isolate the phenolic compounds obtained from the dried roots ofPolygonum multiflorum and investigate their pharmacological activities.Methods:The chemical constituents were isolated and purified by combining them with a macroporous resin(DM-8),MCI gel,and Sephadex LH-20 and by performing ODS column chromatography.Their structures were elucidated by 1D and 2D NMR analyses,as well as mass spectrometry.The isolated compounds were evaluated to determine their hepatoprotective andα-glucosidase inhibitory activities in vitro.Results:Two phenolic compounds,namely,polygonimitin E(1)and polygonimitin F(2),were isolated from the dried roots of P.multiflorum.Compound 2(10μmol/L)only showed moderate hepatoprotective activity against N-acetyl-p-aminophenol(APAP)-induced HepG2 cell damage.Unfortunately,these two compounds exhibited noα-glucosidase inhibitory activity.Conclusion:Compounds 1 and 2 were new compounds.Compound 2 could be one of the potential hepatoprotective constituents of P.multiflorum.
基金Acknowledgements We thank Professor Xueguang Zhang （Soochow University, Suzhou, China） for kindly providing plasmid pGEZ, pHIT456, pHIT60 and 293T cell lines. This work was supported by the National Natural Science Foundation of China （No. 30772003 and No. 30170880）, Jiangsu Province＇s Outstanding Medical Academic Leader programme （RC2007057） and Science Development Foundation of Nanjing Medical University （NMUZ009）.
文摘Type Ⅱ Epstein-Barr virus （EBV） associated malignancies such as nasopharyngeal carcinoma and non-Hodgkin＇s lymphomas consistently express latent membrane 2A （LMP2A） proteins, which have been suggested to be an ideal target for immunotherapy. In previous studies we have demonstrated that using LMP2A protein loaded dendritic cells, the most powerful antigen processing cells in the body can elicit specific and robust anti-tumor cellular immune response in vitro. In this paper, we further investigated the T cell profile of the anti-tumor immune response. We found that LMP2A specific CD4＋ and CD8＋ T cells could be stimulated by LMP2A protein loaded dendritic cells （DCs）. The Thl type immune response is dominant in the immune response mediated by LMP2A specific CD4^＋ T cells. The CD8^＋ cytotoxic T cells can lyse LMP2A bearing cells effectively and specifically. The CD8^＋ cytotoxic T cells can also secrete high level of intracellular IFN-γ, which indicates these cells are EBV-LMP2A specific cytotoxic T cells. Altogether, our studies proved that LMP2A protein loaded DCs can elicit anti-tumor cellular immune responses efficiently. This study provides a rationale for the DC-based immunotherapy against EBV-LMP2A expressing malignancies.
基金supported by 863 program(No.2014AA021101)from National High-tech R&D Program of Chinathe grants from National Sciences Foundation of China(Grant No.81573487)
文摘To establish an animal model of acute-on-chronic liver failure(ACLF) that would replicate the pathological process of ACLF in humans, rats were administered porcine serum(PS) for 11 weeks. Liver fibrosis was determined by pathological and biochemical assessments. The animals then were injected with D-galactosamine(D-gal) and lipopolysaccharide(LPS). The survival times of animals with cirrhosis and ACLF were determined over 48 h. Other animals were killed at 0, 4, 8 and 12 h after administration of D-gal/LPS. Liver injury was assessed by histopathological analysis and biochemical indices, and apoptosis was detected by Western blot and TUNEL analysis. After PS administration for 11 weeks the serum levels of hyaluronic acid and N-procollagen type III peptide increased significantly, and serious fibrosis and cirrhosis was observed at weeks 10 and 11. Cirrhotic rats were injected with D-gal/LPS to induced ACLF; the rate of mortality over 48 h was 80%. ALT and AST levels increased markedly at 4 h, but decreased significantly at8 and 12 h post-treatment. The total bilirubin, direct bilirubin, and total bile acids levels increased markedly at 8 and 12 h. Clotting times, TNF-α and IL-6 levels increased significantly, except for 12 h post-treatment.Apoptosis, inflammation and necrosis were elevated as determined by hematoxylin-eosin staining and TUNEL assays. BCL-2 levels decreased significantly, While BAX levels increased significantly.Cytochrome c expression peaked at 8 h postD-gal/LPS treatment. In conclusion, an ACLF model induced by PS and D-gal/LPS was established and the underlying mechanisms of ACLF development were explored.
基金This work was supported by the National Natural Science Foundation of China(No.81573487)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2017-12M-1-013)the Drug Innovation Major Project(No.2018ZX09711001-003-011).
文摘Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/24:0)in the progression of ACLF to validate the biomarker using ACLF rat model.Methods:ACLF rats were sacrificed at 4 and 8 h post-D-galactosamine(D-gal)/lipopolysaccharide(LPS)administration to investigate the liver biochemical markers,prothrombin time and liver histopathology.Change in dhCer and other sphingolipids levels were investigated by high-performance liquid chromatography coupled to tandem mass spectrometry(HPLC-MS/MS).Rats were treated with N-(4-hydroxyphenyl)retinamide(4-HPR)to examine the mortality rate and its role in improving ACLF.Results:LPS/D-gal administration resulted in significant elevation in alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Prothrombin time was prolonged and histopathological examination showed abnormality.HPLC-MS/MS results showed total dhCer levels in ACLF group(64.10±8.90 pmol/100 mL,64.22±6.78 pmol/100 mL for 4 and 8 h,respectively)were decreased significantly compared with control group(121.61±23.09 pmol/100 mL)(P<0.05).In particular,dhCer(d18:0/24:0),dhCer(d18:0/20:0),and dhCer(d18:0/22:0)levels were decreased.Treatment with 4-HPR significantly increased the levels of dhCers,including dhCer(d18:0/24:0)compared with ACLF group,for the level of dhCer(d18:0/24:0)in 4-HPR group was 20.10±8.60 pmol/100 mL and the level of dhCer(d18:0/24:0)in ACLF group was 9.74±2.99 pmol/100 mL(P<0.05).This was associated with reduced mortality rate and prolonged survival time.The ALT and AST in 4-HPR group were significantly decreased compared with ACLF group.The prothrombin time of 4-HPR group(41.49 s)was significantly lower than the prothrombin time of ACLF group(57.96 s)(P<0.05).4-HPR also decreased plasma ammonia levels slightly,as the plasma ammonia levels in 4-HPR group and ACLF group were 207.37±60.43,209.15±60.43 mmol/L,respectively.Further,4-HPR treatment improved histopathological parameters.Conclusions:DhCer,especially dhCer(d18:0/24:0),is involved in the progression of ACLF.Increasing the levels of dhCer can reduce the mortality rate of ACLF rats and alleviate liver injury.
基金This work is partially funded by the USA National Institutes of Health R01 DK 102142(W.-X.Ding)We thank Margitta Lebofsky for technical assistance in the measurement of hepatic GSH.
文摘Background:Acetaminophen(APAP)overdose can cause liver injury and liver failure,which is one of the most common causes of drug-induced liver injury in the United States.Pharmacological activation of autophagy by inhibiting mechanistic target of rapamycin(mTOR)protects against APAP-induced liver injury likely via autophagic removal of APAP-adducts and damaged mitochondria.In the present study,we aimed to investigate the role of genetic ablation of mTOR pathways in mouse liver in APAP-induced liver injury and liver repair/regeneration.Methods:Albumin-Cre(Alb-Cre)mice,mTOR^(f/f) and Raptor^(f/f) mice(C57BL/6J background)were crossbred to produce liver-specific mTOR knockout(L-mTOR KO,Alb Cret/-,mTOR^(f/f))and liver-specific Raptor KO(L-Raptor,Alb Cret/-,Raptor^(f/f))mice.Alb-Cre littermates were used as wild-type(WT)mice.These mice were treated with APAP for various time points for up to 48 h.Liver injury,cell proliferation,autophagy and mTOR activation were determined.Results:We found that genetic deletion of neither Raptor,an important adaptor protein in mTOR complex 1,nor mTOR,in the mouse liver significantly protected against APAP-induced liver injury despite increased hepatic autophagic flux.Genetic deletion of Raptor or mTOR in mouse livers did not affect APAP metabolism and APAP-induced c-Jun N-terminal kinase(JNK)activation,but slightly improved mouse survival likely due to increased hepatocyte proliferation.Conclusions:Our results indicate that genetic ablation of mTOR in mouse livers does not protect against APAP-induced liver injury but may slightly improve liver regeneration and mouse survival after APAP overdose.
