Objective:To explore the mechanisms of fulminant hepatitis(FH) in the early stages,and to determine the critical pathways in its initiation and progression.Methods:Twelve BALB/c mice were divided into four groups:one ...Objective:To explore the mechanisms of fulminant hepatitis(FH) in the early stages,and to determine the critical pathways in its initiation and progression.Methods:Twelve BALB/c mice were divided into four groups:one group left as negative control and sacrificed immediately after injection of phosphate-buffered saline(PBS),and another three groups with concanavalin A(Con A) administration sacrificed at 1,3,and 6 h after injection.Affymetrix GeneChip Mouse 430 2.0 Array was employed to evaluate the expression profile of each of the 12 samples.Further analysis was done on the microarray data to extract the genes that were differentially expressed.Enrichment analysis was carried out to determine relevant pathways within which regulated genes were significantly enriched.Results:A total of 393,8354 and 11 344 differentially expressed genes were found,respectively,at three time points.During 0-1 h and 1-3 h,most of the pathways enriched with regulated genes were related to immune response and inflammation,among which Toll-like receptor(TLR) signaling and mitogen-activated protein kinase(MAPK) signaling appeared during both phases,while cytokine-cytokine receptor interaction,apoptosis,T cell receptor signaling,and natural killer(NK) cell-mediated cytotoxicity pathways emerged during the second phase.Pathways found to be significant during 3-6 h were mostly related to metabolic processes.Conclusion:The TLR signaling pathway dominates the early responses of Con A-induced FH in mice.It stimulates the production of type I cytokines,therefore recruiting and activating T/NK cells.Activated T/NK cells exert their cytotoxicity on hepatocytes through inducing death receptorintermediated apoptosis,resulting in liver injury.展开更多
BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role i...BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.展开更多
4-Nitrophenol(4-NP),as a toxic and refractory pollutant,has generated significant concern due to its adverse effects.However,the potential toxic effects andmechanism remained unclear.In this study,the reproduction,dev...4-Nitrophenol(4-NP),as a toxic and refractory pollutant,has generated significant concern due to its adverse effects.However,the potential toxic effects andmechanism remained unclear.In this study,the reproduction,development,locomotion and reactive oxygen species(ROS)production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity.We used metabolomics to assess the potential damage mechanisms.The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis.4-NP(8 ng/L and 8μg/L)caused significant reduction of brood size,ovulation rate,total germ cells numbers,head thrashes and body bends,and an increase in ROS.However,the oosperm numbers in uterus,body length and body width were decreased in 8μg/L.Moreover,36 differential metabolites were enriched in the significant metabolic pathways,including lysine biosynthesis,β-alanine metabolism,tryptophan metabolism,pentose phosphate pathway,pentose and glucuronate interconversions,amino sugar and nucleotide sugar metabolism,starch and sucrose metabolism,galactose metabolism,propanoate metabolism,glycerolipid metabolism,and estrogen signaling pathway.The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid,which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism,and finally affected the estrogen signaling pathway to exert toxic effects.Moreover,correlation and mediation analysis showed glycerol-3P,glucosamine-6P,glucosamine-1P,UDP-galactose,L-aspartic acid,and uracilwere potential markers for the reproduction and glucose-1,6P2 for developmental toxicity.The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.展开更多
Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is h...Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages(acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs(miR-21, let-7, miR-223, miR-10 b, miR-132, miR-15 b, miR-127, miR-29 a, miR-29 b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29 a, and miR-29 b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs(i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China(approval No. 20190303-18) on March 3, 2019.展开更多
The neural regeneration process is driven by a wide range of molecules and pathways. Adherens junctions are critical cellular junctions for the integrity of peripheral nerves. However, few studies have systematically ...The neural regeneration process is driven by a wide range of molecules and pathways. Adherens junctions are critical cellular junctions for the integrity of peripheral nerves. However, few studies have systematically characterized the transcript changes in the adherens junction pathway following injury. In this study, a rat model of sciatic nerve crush injury was established by forceps. Deep sequencing data were analyzed using comprehensive transcriptome analysis at 0, 1, 4, 7, and 14 days after injury. Results showed that most individual molecules in the adherens junctions were either upregulated or downregulated after nerve injury. The m RNA expression of ARPC1 B, ARPC3, TUBA8, TUBA1 C, CTNNA2, ACTN3, MET, HGF, NME1 and ARF6, which are involved in the adherens junction pathway and in remodeling of adherens junctions, was analyzed using quantitative real-time polymerase chain reaction. Most of these genes were upregulated in the sciatic nerve stump following peripheral nerve injury, except for CTNNA2, which was downregulated. Our findings reveal the dynamic changes of key molecules in adherens junctions and in remodeling of adherens junctions. These key genes provide a reference for the selection of clinical therapeutic targets for peripheral nerve injury.展开更多
Objective: To identify mutually regulated proteins in PC-3 and DU145 androgen-independent prostate cancer cell lines treated with 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one(MS17), and to study the molecular pathway...Objective: To identify mutually regulated proteins in PC-3 and DU145 androgen-independent prostate cancer cell lines treated with 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one(MS17), and to study the molecular pathways that contributed to the anticancer activity of MS17.Methods: PC-3 and DU145 cells were treated with 3 × EC_(50)(15 μM) concentration of MS17 for 24 h and were subjected to protein expression profiling using two-dimensional gel electrophoresis and protein identification by mass spectrometry.Selected differentially expressed proteins with significant P-value of P<0.05 and fold change over 1.5-folds were filtered through and ontologically classified.Mutually regulated proteins were ranked by fold change and identified as common protein targets of MS17.Results: Profiling data revealed that, the mutually down-regulated proteins included ACTB and ACTG associated with structural molecule activity, ACTN1 with cell cycle, ACTN4 with cell migration, HNRPK with apoptosis, PLST with morphogenesis and TERA with proteolysis.However, the expressions of CH60 and HS71 A respectively associated with response to unfolded protein demonstrated opposing regulation in PC-3 and DU145 cells.Pathway analysis of the differentially expressed proteins in PC-3 cells demonstrated the modulation of top pathways associated with cell-cell adhesion and cytoskeletal organization while in DU145 cells the pathways were associated with proteosomal degradation, regulation of electrolytes and water, regulation control of germ cells and organization of filament assembly/disassembly.Conclusions: The findings of the present study provide an understanding on the anti-tumorigenic activity of MS17 at the proteome level and warrant further research for its potential application for the management and treatment of androgen-independent prostate cancer.展开更多
Ovarian cancer is a major health problem for women in the United States. Despite evidence of considerable heterogeneity, most cases of ovarian cancer are treated in a similar fashion. The molecular basis for the clini...Ovarian cancer is a major health problem for women in the United States. Despite evidence of considerable heterogeneity, most cases of ovarian cancer are treated in a similar fashion. The molecular basis for the clinicopathologic characteristics of these tumors remains poorly defined. Whole genome expression profiling is a genomic tool, which can identify dysregulated genes and uncover unique sub-classes of tumors. The application of this technology to ovarian cancer has provided a solid molecular basis for differences in histology and grade of ovarian tumors. Differentially expressed genes identified pathways implicated in cell proliferation, invasion, motility, chromosomal instability, and gene silencing and provided new insights into the origin and potential treatment of these cancers. The added knowledge provided by global gene expression profiling should allow for a more rational treatment of ovarian cancers. These techniques are leading to a paradigm shift from empirical treatment to an individually tailored approach. This review summarizes the new genomic data on epithelial ovarian cancers of different histology and grade and the impact it will have on our understanding and treatment of this disease.展开更多
Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally dev...Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally developed for the studies of gene expression data,it has become a powerful analytic procedure for indepth mining of genome-wide genetic variation data.Astonishing discoveries were made in the past years,uncovering genes and biological mechanisms underlying common and complex disorders.However,as massive amounts of diverse functional genomics data accrue,there is a pressing need for newer generations of pathway analysis methods that can utilize multiple layers of high-throughput genomics data.In this review,we provide an intellectual foundation of this powerful analytic strategy,as well as an update of the state-of-the-art in recent method developments.The goal of this review is threefold:(1)introduce the motivation and basic steps of pathway analysis for genome-wide genetic variation data;(2)review the merits and the shortcomings of classic and newly emerging integrative pathway analysis tools;and(3)discuss remaining challenges and future directions for further method developments.展开更多
OBJECTIVE To explore the hypolipidemic mechanisms of the total phenylpropanoid glycosides fromLigustrum robustum(Roxb.) Blume(LRTPG) in hamsters using proteomics technique.METHODS The hamsters were fed with a high fat...OBJECTIVE To explore the hypolipidemic mechanisms of the total phenylpropanoid glycosides fromLigustrum robustum(Roxb.) Blume(LRTPG) in hamsters using proteomics technique.METHODS The hamsters were fed with a high fat diet to induce hyperlipidemia.Then LRTPG of high(1.2 g·kg^(-1)),medium(0.6 g·kg^(-1)) and low(0.3 g·kg^(-1)) doses were administrated daily for 4 weeks.Then the concentrations of plasma and hepatic lipids were determined using enzymic methods.The total protein was extracted from livers of the model group and the group treated with the high dose of LRTPG for label-free quantitative proteomics.RESULTS LRTPG significantly reduced the concentrations of plasma and hepatic lipids in hamsters fed a high fat diet.The proteomics data showed that a total of 2231 proteins were identified,and 549 proteins were found to be differentially expressed between the model group and the group treated with LRTPG.Among the 549 proteins,93 proteins were up-regulated and 59 proteins were down-regulated,and 397 proteins were absent or not.And some of these proteins were much related to the lipid metabolism.Further,gene ontology(GO) analysis indicated metabolic process,transport,oxidation-reduction process,phosphorylation,signal transduction,lipid metabolic process were the main biological processes that those differentially expressed proteins participated.KEGG pathway analysis showed that those proteins were involved in several metabolic pathways including oxidative phosphorylation,non-alcoholic fatty liver disease(NAFLD),PI3K-Akt signaling pathway,cAMP signaling pathway,cGMP-PKG signaling pathway.CONCLUSION The proteomics study could provide valuable clues to help us to understand the hypolipidemic mechanisms of LRTPG much better.展开更多
Cotton(Gossypium hirsutum L.) is the leading fiber crop and one of the mainstays of the economy in the world.Cotton fibers,as the main product of cotton plants,are unicellular,linear
Ammonia is gaining increasing attention as a green alternative fuel for achieving large-scale carbon emission reduction. Despite its potential technical prospects, the harsh ignition conditions and slow flame propagat...Ammonia is gaining increasing attention as a green alternative fuel for achieving large-scale carbon emission reduction. Despite its potential technical prospects, the harsh ignition conditions and slow flame propagation speed of ammonia pose significant challenges to its application in engines. Non-equilibrium plasma has been identified as a promising method, but current research on plasma-enhanced ammonia combustion is limited and primarily focuses on ignition characteristics revealed by kinetic models. In this study, low-temperature and low-pressure chemistry in plasma-assisted ammonia oxidative pyrolysis is investigated by integrated studies of steady-state GC measurements and mathematical simulation. The detailed kinetic mechanism of NH_(3) decomposition in plasma-driven Ar/NH_(3) and Ar/NH_(3)/O_(2) mixtures has been developed. The numerical model has good agreements with the experimental measurements in NH_(3)/O_(2) consumption and N_(2)/H_(2) generation, which demonstrates the rationality of modelling. Based on the modelling results, species density profiles, path flux and sensitivity analysis for the key plasmaproduced species such as NH_(2), NH, H_(2), OH, H, O, O(^(1)D), O_(2)(a^(1)△_(g)), O_(2)(b^(1)∑_(g)^(+)), Ar^(*), H^(-), Ar^(+), NH_(3)^(+), O_(2)^(-) in the discharge and afterglow are analyzed in detail to illustrate the effectiveness of the active species on NH_(3) excitation and decomposition at low temperature and relatively higher E/N values. The results revealed that NH_(2), NH, H as well as H_(2) are primarily generated through the electron collision reactions e + NH_(3)→ e + NH_(2)+ H, e + NH_(3)→ e + NH + H_(2) and the excited-argon collision reaction Ar^(*) + NH_(3)+ H → Ar + NH_(2)+ 2H, which will then react with highly reactive oxidative species such as O_(2)^(*), O^(*), O, OH, and O_(2) to produce stable products of NOx and H_(2)O. NH_(3)→ NH is found a specific pathway for NH_(3) consumption with plasma assistance, which further highlights the enhanced kinetic effects.展开更多
BACKGROUND The emergency department(ED)plays a critical role in establishing artificial airways and implementing mechanical ventilation.Managing airbags in the ED presents a prime opportunity to mitigate the risk of v...BACKGROUND The emergency department(ED)plays a critical role in establishing artificial airways and implementing mechanical ventilation.Managing airbags in the ED presents a prime opportunity to mitigate the risk of ventilator-associated pneumonia.Nonetheless,existing research has largely overlooked the understanding,beliefs,and practical dimensions of airway airbag management among ED nurses,with a predominant focus on intensive care unit nurses.AIM To investigate the current status of ED nurses'knowledge,beliefs,and practical behaviors in airway airbag management and their influencing factors.METHODS A survey was conducted from July 10th to August 10th,2023,using convenience sampling on 520 ED nurses from 15 tertiary hospitals and 5 sary hospitals in Shanghai.Pathway analysis was utilized to analyze the influencing factors.RESULTS The scores for ED nurses'airway airbag management knowledge were 60.26±23.00,belief was 88.65±13.36,and behavior was 75.10±19.84.The main influencing factors of airbag management knowledge included participation in specialized nurse or mechanical ventilation training,department,and work experience in the department.Influencing factors of airbag management belief comprised knowledge,department,and participation in specialized nurse or mechanical ventilation training.Primary influencing factors of airbag management behavior included knowledge,belief,department,participation in specialized nurse or mechanical ventilation training,and professional title.The belief in airbag management among ED nurses acted as a partial mediator between knowledge and behavior,with a total effect value of 0.513,and an indirect effect of 0.085,constituting 16.6%of the total effect.CONCLUSION ED nurses exhibit a positive attitude toward airbag management with relatively standardized practices,yet there remains room for improvement in their knowledge levels.Nursing managers should implement interventions tailored to the characteristics of ED nurses'airbag management knowledge,beliefs,and practices to enhance their airbag management proficiency.展开更多
Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility ...Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved.Materials and methods:In this 2-stage functional genomics study,we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics,followed by a meta-analysis of gene-level significance p values,to obtain a consensus gene ranking in terms of association with BCa.Subsequently,we performed preranked gene-set enrich-ment analysis to identify the functional pathways involved in BCa genetic susceptibility.Joint analysis with gene-set enrichment analysis,based on somatic alteration frequency,was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa.Results:Other than the well-known BCa genes(such as FGFR3,MYC,TERT,CCNE1,and TP63),we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development,including SETD2,a possible tumor suppressor gene involved in chromatin remodeling.We further demonstrated convergence between genetic associations and somatic alterations at both the gene(eg,FGFR3 and TERT)and pathway levels(eg,cell cycle and chromatin modification),as well as functional ontologies specifically impli-cated in germline predisposition to BCa(eg,CD8/TCR signaling,immune checkpoints,and cytokine signaling).Conclusions:We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the devel-opment of BCa by affecting antitumor immunity,response to toxic exposure,and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.展开更多
OBJECTIVE:To investigating the molecular mechanism of herbal pairs in three types of Chinese medicinals:Qi-tonifying,blood activation,blood-stasis breaking in treatment of coronary heart disease(CHD).METHODS:The compo...OBJECTIVE:To investigating the molecular mechanism of herbal pairs in three types of Chinese medicinals:Qi-tonifying,blood activation,blood-stasis breaking in treatment of coronary heart disease(CHD).METHODS:The components of six herbs were searched in Chinese medicine dictionary and their target proteins were found in PubChem.CHD genes were obtained from PubMed gene database.Ingenuity Pathways Analysis was used to build the pharmacological network of three herbal pairs and CHD molecular network.The canonical pathways between each herbal pair network and CHD network was compared to decipher the molecular mechanism on three herbal pairs in treating CHD.RESULTS:The network analysis showed that there were the common signal pathways of three herbal pairs in treating CHD including hypoxia signaling in the cardiovascular system,Hypoxia-inducible factor 1-alpha signaling,glucocorticoid receptor signaling,G-Protein coupled receptor signaling and pregnane X receptor/retinoid X receptor(PXR/RXR)activation.Further to analyze cardiovascular signaling,cytokine signaling and cytokine signaling,the effective molecules for three herbal pairs in treating CHD included HIF1α and estrogen receptor 1,Qi-tonifying herbal pair included albumin and matrix metallopeptidase 2,and blood-activation herbal pair included estrogen receptor 2 and peroxisome proliferator-activated receptor-γ.CONCLUSION:Each herbal pair can affect some respective CHD-related functions and pathways,meanwhile three herbal pairs exert some mutual effects on CHD-related functions and pathways.Mutual effects of three herbal pairs may be the key components of their total molecular mechanisms and respective effects of each herbal pair may be the characteristic components of their respective molecular mechanism.展开更多
The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regen...The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regeneration.Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing.Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3,9 hours,1,4,or 7 days after nerve crush,compared with the 0 hour control.Thirty-six rat models of sciatic nerve crush injury were prepared as described previously.Then,they were divided into six groups to measure the expression changes of representative genes at 0,3,9 hours,1,4 or 7 days post crush.Our current study measured the expression levels of representative upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin genes,and explored critical signaling pathways and biological process through bioinformatic analysis.Our data revealed that many of these dysregulated upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin,participated in tissue remodeling and axon growth-related biological processes Therefore,the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury.Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves.All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals,China(approval No.20170302-017)on March 2,2017.展开更多
Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identi...Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis （2D-DIGE） and isotope labelling tags for relative and absolute quantification （iTRAQ）. Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins （P〈0.01） were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins （〉 1.3 fold; P〈0.05）. The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure （i.e., 23 overexpressed and 42 underexpressed）. Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT （P=0.006） and HSPB1 （P=0.046）.展开更多
[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases wer...[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases were first searched for genes and proteins known to be associated with CRC,as well as those predicted to be targets of triptolide,and then Ingenuity Pathway Analysis(IPA)was applied to identify enriched gene pathways and networks.Networks and pathways that overlapped between CRC-associated proteins and triptolide target proteins were then used to predict candidate protein targets of triptolide in CRC.[Results]The following proteins were found to be expressed in both CRC-associated networks and triptolide target networks:JUN,FOS,CASP3,BCL2,IFNG,and VEGFA.Docking studies suggested that triptolide can fit in the binding pocket of the four top candidate triptolide target proteins(CASP3,BCL2,VEGFA and IFNG).The overlapping pathways were activation of neuroinflammation signaling,glucocorticoid receptor signaling,T helper(Th)cell differentiation,Th1/Th2 activation,and colorectal cancer metastasis signaling.[Conclusions]These results show that network pharmacology can be used to generate hypotheses about how triptolide exerts therapeutic effects in CRC.Network pharmacology may be a useful method for characterizing multi-target drugs in complex diseases.展开更多
[Objectives]To elucidate the mechanism of action of apigenin against lung cancer.[Methods]First,drug-target pathways and networks were constructed to predict potential protein targets of apigenin and their main intera...[Objectives]To elucidate the mechanism of action of apigenin against lung cancer.[Methods]First,drug-target pathways and networks were constructed to predict potential protein targets of apigenin and their main interactions with the drug.Then,the ingenuity pathway analysis(IPA)was carried out to identify enriched gene pathways and networks,and the candidate protein targets of apigenin were predicted using networks and pathways that overlapped between proteins associated with lung cancer and proteins targeted by apigenin.[Results]Docking studies with apigenin indicated that BCL-2,CASP9,CDK2,CYCLIND1,PI3K,NF-κB,Rb1,p53,and AKT are the top candidate targets of apigenin,suggesting that the drug acts against lung cancer by regulating proteins involved in molecular mechanisms of cancer,as well as small cell lung cancer,pancreatic adenocarcinoma,glucocorticoid receptor,and p53 signaling.It was also found that apigenin affects networks mainly involved in the cell cycle,cell-to-cell signaling and interactions,hematological system development and function,cell death and survival,and organismal injury and abnormalities.[Conclusions]This study shows that network pharmacology is useful in generating hypotheses about how apigenin exerts therapeutic effects in lung cancer,as well as in discovering new multitarget drugs against other complex diseases.展开更多
The differential expression of genes in HepG2 cells caused by UC001 kfo RNAi was investigated using RNA-seq. HepG2 cells were infected by Lenti-sh UC001 kfo lentivirus particles. The expression of UC001 kfo m RNA in t...The differential expression of genes in HepG2 cells caused by UC001 kfo RNAi was investigated using RNA-seq. HepG2 cells were infected by Lenti-sh UC001 kfo lentivirus particles. The expression of UC001 kfo m RNA in the HepG2-sh UC001 kfo cell line was detected by real-time PCR. RNA-seq technology was used to identify the difference in the expression of genes regulated by lnc RNA UC001 kfo in the HepG2 cell line. Gene ontology and signaling pathway analysis were performed to reveal the biological functions of the genes encoding of significantly different m RNAs. The results showed that m RNAs were differentially expressed between the HepG2-sh UC001 kfo cell line and the HepG2 cell line. The UC001 kfo m RNA was significantly down-regulated in the stable cell line HepG2-sh UC001kfo（P〈0.001）. Additionally, we found 19 signaling pathways or functional classifications encompassing 30 genes that played a role in cancer characteristics, cell adhesion, invasion and migration. The results also showed that the expression of many genes associated with cancer cell invasion and metastasis was decreased with the down-regulation of the lnc RNA UC001 kfo. Lnc RNA UC001 kfo may play a role in regulating cancer cell invasion and metastasis. It was suggested that m RNAs were differentially expressed in the HepG2 cell line after the down-regulation of lnc RNA-UC001 kfo. Some took part in the extracellular matrix, cell adhesion, motility, growth, and localization. The genes encoding of differentially expressed m RNAs may participate in cell invasion and metastasis.展开更多
The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level i...The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.展开更多
基金Project supported by the National Natural Science Foundation of China (No 30771918)the National Basic Research Program (973) of China (No 2007CB512905)the State S & T Projects (11th Five Year) (No 2008ZX10002-007) of China
文摘Objective:To explore the mechanisms of fulminant hepatitis(FH) in the early stages,and to determine the critical pathways in its initiation and progression.Methods:Twelve BALB/c mice were divided into four groups:one group left as negative control and sacrificed immediately after injection of phosphate-buffered saline(PBS),and another three groups with concanavalin A(Con A) administration sacrificed at 1,3,and 6 h after injection.Affymetrix GeneChip Mouse 430 2.0 Array was employed to evaluate the expression profile of each of the 12 samples.Further analysis was done on the microarray data to extract the genes that were differentially expressed.Enrichment analysis was carried out to determine relevant pathways within which regulated genes were significantly enriched.Results:A total of 393,8354 and 11 344 differentially expressed genes were found,respectively,at three time points.During 0-1 h and 1-3 h,most of the pathways enriched with regulated genes were related to immune response and inflammation,among which Toll-like receptor(TLR) signaling and mitogen-activated protein kinase(MAPK) signaling appeared during both phases,while cytokine-cytokine receptor interaction,apoptosis,T cell receptor signaling,and natural killer(NK) cell-mediated cytotoxicity pathways emerged during the second phase.Pathways found to be significant during 3-6 h were mostly related to metabolic processes.Conclusion:The TLR signaling pathway dominates the early responses of Con A-induced FH in mice.It stimulates the production of type I cytokines,therefore recruiting and activating T/NK cells.Activated T/NK cells exert their cytotoxicity on hepatocytes through inducing death receptorintermediated apoptosis,resulting in liver injury.
文摘BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.
基金supported by the National Natural Science Foundation of China(Nos.82173479 and 81872579)Jiangsu Provincial Maternal and Child Health Scientific Research Project(No.F201907).
文摘4-Nitrophenol(4-NP),as a toxic and refractory pollutant,has generated significant concern due to its adverse effects.However,the potential toxic effects andmechanism remained unclear.In this study,the reproduction,development,locomotion and reactive oxygen species(ROS)production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity.We used metabolomics to assess the potential damage mechanisms.The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis.4-NP(8 ng/L and 8μg/L)caused significant reduction of brood size,ovulation rate,total germ cells numbers,head thrashes and body bends,and an increase in ROS.However,the oosperm numbers in uterus,body length and body width were decreased in 8μg/L.Moreover,36 differential metabolites were enriched in the significant metabolic pathways,including lysine biosynthesis,β-alanine metabolism,tryptophan metabolism,pentose phosphate pathway,pentose and glucuronate interconversions,amino sugar and nucleotide sugar metabolism,starch and sucrose metabolism,galactose metabolism,propanoate metabolism,glycerolipid metabolism,and estrogen signaling pathway.The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid,which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism,and finally affected the estrogen signaling pathway to exert toxic effects.Moreover,correlation and mediation analysis showed glycerol-3P,glucosamine-6P,glucosamine-1P,UDP-galactose,L-aspartic acid,and uracilwere potential markers for the reproduction and glucose-1,6P2 for developmental toxicity.The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
基金supported by the National Natural Science Foundation of China,No.31971276(to JHH)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.19KJA320005(to JHH)。
文摘Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages(acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs(miR-21, let-7, miR-223, miR-10 b, miR-132, miR-15 b, miR-127, miR-29 a, miR-29 b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29 a, and miR-29 b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs(i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China(approval No. 20190303-18) on March 3, 2019.
基金supported by the National Natural Science Foundation of China,No.31700926the Priority Academic Program Development of Jiangsu Higher Education Institutions of China
文摘The neural regeneration process is driven by a wide range of molecules and pathways. Adherens junctions are critical cellular junctions for the integrity of peripheral nerves. However, few studies have systematically characterized the transcript changes in the adherens junction pathway following injury. In this study, a rat model of sciatic nerve crush injury was established by forceps. Deep sequencing data were analyzed using comprehensive transcriptome analysis at 0, 1, 4, 7, and 14 days after injury. Results showed that most individual molecules in the adherens junctions were either upregulated or downregulated after nerve injury. The m RNA expression of ARPC1 B, ARPC3, TUBA8, TUBA1 C, CTNNA2, ACTN3, MET, HGF, NME1 and ARF6, which are involved in the adherens junction pathway and in remodeling of adherens junctions, was analyzed using quantitative real-time polymerase chain reaction. Most of these genes were upregulated in the sciatic nerve stump following peripheral nerve injury, except for CTNNA2, which was downregulated. Our findings reveal the dynamic changes of key molecules in adherens junctions and in remodeling of adherens junctions. These key genes provide a reference for the selection of clinical therapeutic targets for peripheral nerve injury.
基金financially supported by the Fundamental Research Grant Scheme,(FRGS/1/2016/SKK08/MUSM/02/1)under the Ministry of Higher Education,Malaysia
文摘Objective: To identify mutually regulated proteins in PC-3 and DU145 androgen-independent prostate cancer cell lines treated with 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one(MS17), and to study the molecular pathways that contributed to the anticancer activity of MS17.Methods: PC-3 and DU145 cells were treated with 3 × EC_(50)(15 μM) concentration of MS17 for 24 h and were subjected to protein expression profiling using two-dimensional gel electrophoresis and protein identification by mass spectrometry.Selected differentially expressed proteins with significant P-value of P<0.05 and fold change over 1.5-folds were filtered through and ontologically classified.Mutually regulated proteins were ranked by fold change and identified as common protein targets of MS17.Results: Profiling data revealed that, the mutually down-regulated proteins included ACTB and ACTG associated with structural molecule activity, ACTN1 with cell cycle, ACTN4 with cell migration, HNRPK with apoptosis, PLST with morphogenesis and TERA with proteolysis.However, the expressions of CH60 and HS71 A respectively associated with response to unfolded protein demonstrated opposing regulation in PC-3 and DU145 cells.Pathway analysis of the differentially expressed proteins in PC-3 cells demonstrated the modulation of top pathways associated with cell-cell adhesion and cytoskeletal organization while in DU145 cells the pathways were associated with proteosomal degradation, regulation of electrolytes and water, regulation control of germ cells and organization of filament assembly/disassembly.Conclusions: The findings of the present study provide an understanding on the anti-tumorigenic activity of MS17 at the proteome level and warrant further research for its potential application for the management and treatment of androgen-independent prostate cancer.
文摘Ovarian cancer is a major health problem for women in the United States. Despite evidence of considerable heterogeneity, most cases of ovarian cancer are treated in a similar fashion. The molecular basis for the clinicopathologic characteristics of these tumors remains poorly defined. Whole genome expression profiling is a genomic tool, which can identify dysregulated genes and uncover unique sub-classes of tumors. The application of this technology to ovarian cancer has provided a solid molecular basis for differences in histology and grade of ovarian tumors. Differentially expressed genes identified pathways implicated in cell proliferation, invasion, motility, chromosomal instability, and gene silencing and provided new insights into the origin and potential treatment of these cancers. The added knowledge provided by global gene expression profiling should allow for a more rational treatment of ovarian cancers. These techniques are leading to a paradigm shift from empirical treatment to an individually tailored approach. This review summarizes the new genomic data on epithelial ovarian cancers of different histology and grade and the impact it will have on our understanding and treatment of this disease.
基金supported by National Institutes of Health R00 MH101367 and R01 MH119243(to P.H.Lee)。
文摘Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally developed for the studies of gene expression data,it has become a powerful analytic procedure for indepth mining of genome-wide genetic variation data.Astonishing discoveries were made in the past years,uncovering genes and biological mechanisms underlying common and complex disorders.However,as massive amounts of diverse functional genomics data accrue,there is a pressing need for newer generations of pathway analysis methods that can utilize multiple layers of high-throughput genomics data.In this review,we provide an intellectual foundation of this powerful analytic strategy,as well as an update of the state-of-the-art in recent method developments.The goal of this review is threefold:(1)introduce the motivation and basic steps of pathway analysis for genome-wide genetic variation data;(2)review the merits and the shortcomings of classic and newly emerging integrative pathway analysis tools;and(3)discuss remaining challenges and future directions for further method developments.
基金supported by the PUMC(Peking Union Medical College)Youth Fund(3332015142) National Natural Science Foundation of China(81703746)
文摘OBJECTIVE To explore the hypolipidemic mechanisms of the total phenylpropanoid glycosides fromLigustrum robustum(Roxb.) Blume(LRTPG) in hamsters using proteomics technique.METHODS The hamsters were fed with a high fat diet to induce hyperlipidemia.Then LRTPG of high(1.2 g·kg^(-1)),medium(0.6 g·kg^(-1)) and low(0.3 g·kg^(-1)) doses were administrated daily for 4 weeks.Then the concentrations of plasma and hepatic lipids were determined using enzymic methods.The total protein was extracted from livers of the model group and the group treated with the high dose of LRTPG for label-free quantitative proteomics.RESULTS LRTPG significantly reduced the concentrations of plasma and hepatic lipids in hamsters fed a high fat diet.The proteomics data showed that a total of 2231 proteins were identified,and 549 proteins were found to be differentially expressed between the model group and the group treated with LRTPG.Among the 549 proteins,93 proteins were up-regulated and 59 proteins were down-regulated,and 397 proteins were absent or not.And some of these proteins were much related to the lipid metabolism.Further,gene ontology(GO) analysis indicated metabolic process,transport,oxidation-reduction process,phosphorylation,signal transduction,lipid metabolic process were the main biological processes that those differentially expressed proteins participated.KEGG pathway analysis showed that those proteins were involved in several metabolic pathways including oxidative phosphorylation,non-alcoholic fatty liver disease(NAFLD),PI3K-Akt signaling pathway,cAMP signaling pathway,cGMP-PKG signaling pathway.CONCLUSION The proteomics study could provide valuable clues to help us to understand the hypolipidemic mechanisms of LRTPG much better.
基金This work was supported by the National Natural Science Foundation of China (No 30370904and No 30671258)the National High Technology Research and Development Program(863 project)of China (No 2006AA10Z121)the Program for New Century Excellent Talents in University(No NCET-07-0712)
文摘Cotton(Gossypium hirsutum L.) is the leading fiber crop and one of the mainstays of the economy in the world.Cotton fibers,as the main product of cotton plants,are unicellular,linear
基金the grant support from the National Natural Science Foundation of China (No. 21975018, 22278032)。
文摘Ammonia is gaining increasing attention as a green alternative fuel for achieving large-scale carbon emission reduction. Despite its potential technical prospects, the harsh ignition conditions and slow flame propagation speed of ammonia pose significant challenges to its application in engines. Non-equilibrium plasma has been identified as a promising method, but current research on plasma-enhanced ammonia combustion is limited and primarily focuses on ignition characteristics revealed by kinetic models. In this study, low-temperature and low-pressure chemistry in plasma-assisted ammonia oxidative pyrolysis is investigated by integrated studies of steady-state GC measurements and mathematical simulation. The detailed kinetic mechanism of NH_(3) decomposition in plasma-driven Ar/NH_(3) and Ar/NH_(3)/O_(2) mixtures has been developed. The numerical model has good agreements with the experimental measurements in NH_(3)/O_(2) consumption and N_(2)/H_(2) generation, which demonstrates the rationality of modelling. Based on the modelling results, species density profiles, path flux and sensitivity analysis for the key plasmaproduced species such as NH_(2), NH, H_(2), OH, H, O, O(^(1)D), O_(2)(a^(1)△_(g)), O_(2)(b^(1)∑_(g)^(+)), Ar^(*), H^(-), Ar^(+), NH_(3)^(+), O_(2)^(-) in the discharge and afterglow are analyzed in detail to illustrate the effectiveness of the active species on NH_(3) excitation and decomposition at low temperature and relatively higher E/N values. The results revealed that NH_(2), NH, H as well as H_(2) are primarily generated through the electron collision reactions e + NH_(3)→ e + NH_(2)+ H, e + NH_(3)→ e + NH + H_(2) and the excited-argon collision reaction Ar^(*) + NH_(3)+ H → Ar + NH_(2)+ 2H, which will then react with highly reactive oxidative species such as O_(2)^(*), O^(*), O, OH, and O_(2) to produce stable products of NOx and H_(2)O. NH_(3)→ NH is found a specific pathway for NH_(3) consumption with plasma assistance, which further highlights the enhanced kinetic effects.
文摘BACKGROUND The emergency department(ED)plays a critical role in establishing artificial airways and implementing mechanical ventilation.Managing airbags in the ED presents a prime opportunity to mitigate the risk of ventilator-associated pneumonia.Nonetheless,existing research has largely overlooked the understanding,beliefs,and practical dimensions of airway airbag management among ED nurses,with a predominant focus on intensive care unit nurses.AIM To investigate the current status of ED nurses'knowledge,beliefs,and practical behaviors in airway airbag management and their influencing factors.METHODS A survey was conducted from July 10th to August 10th,2023,using convenience sampling on 520 ED nurses from 15 tertiary hospitals and 5 sary hospitals in Shanghai.Pathway analysis was utilized to analyze the influencing factors.RESULTS The scores for ED nurses'airway airbag management knowledge were 60.26±23.00,belief was 88.65±13.36,and behavior was 75.10±19.84.The main influencing factors of airbag management knowledge included participation in specialized nurse or mechanical ventilation training,department,and work experience in the department.Influencing factors of airbag management belief comprised knowledge,department,and participation in specialized nurse or mechanical ventilation training.Primary influencing factors of airbag management behavior included knowledge,belief,department,participation in specialized nurse or mechanical ventilation training,and professional title.The belief in airbag management among ED nurses acted as a partial mediator between knowledge and behavior,with a total effect value of 0.513,and an indirect effect of 0.085,constituting 16.6%of the total effect.CONCLUSION ED nurses exhibit a positive attitude toward airbag management with relatively standardized practices,yet there remains room for improvement in their knowledge levels.Nursing managers should implement interventions tailored to the characteristics of ED nurses'airbag management knowledge,beliefs,and practices to enhance their airbag management proficiency.
基金XM is supported by National Natural Science Foundation of China(82303057)Natural Science Foundation of Hubei Province of China(2023AFB521)+2 种基金“Chutian Scholars Program”of Hubei Province of ChinaMS was supported by the National Natural Science Foundation of China(82373436)the Beijing Hospital Authority’s Youth Program(QML20230114).
文摘Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved.Materials and methods:In this 2-stage functional genomics study,we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics,followed by a meta-analysis of gene-level significance p values,to obtain a consensus gene ranking in terms of association with BCa.Subsequently,we performed preranked gene-set enrich-ment analysis to identify the functional pathways involved in BCa genetic susceptibility.Joint analysis with gene-set enrichment analysis,based on somatic alteration frequency,was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa.Results:Other than the well-known BCa genes(such as FGFR3,MYC,TERT,CCNE1,and TP63),we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development,including SETD2,a possible tumor suppressor gene involved in chromatin remodeling.We further demonstrated convergence between genetic associations and somatic alterations at both the gene(eg,FGFR3 and TERT)and pathway levels(eg,cell cycle and chromatin modification),as well as functional ontologies specifically impli-cated in germline predisposition to BCa(eg,CD8/TCR signaling,immune checkpoints,and cytokine signaling).Conclusions:We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the devel-opment of BCa by affecting antitumor immunity,response to toxic exposure,and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.
基金Supported by National Natural Science Foundation of China:The Molecular Mechanism Research of YiQi Huoxue Fang Postponing Vascular Endothelial Cell Senescence by SIRT1-autophagy Pathway(No.81503448)Self-Project Foundation from China Acadamy of Chinese Medical Sciences:the Mechanism Study of YiQi Huoxue Herbs Delaying the Vascular Aging(No.ZZ2013002)+1 种基金the Intervention Effects of the Extracts of Panax,Notoginseng and Rhizoma Ligustici Wallichii through Sirt1-autophagy pathway in endothelial cell senescence(No.ZZ2015011)Beijing Science and Technology Plan:Study on Traditional Chinese Herbal Medicine System Evaluation and Service(No.Z141102003414021)
文摘OBJECTIVE:To investigating the molecular mechanism of herbal pairs in three types of Chinese medicinals:Qi-tonifying,blood activation,blood-stasis breaking in treatment of coronary heart disease(CHD).METHODS:The components of six herbs were searched in Chinese medicine dictionary and their target proteins were found in PubChem.CHD genes were obtained from PubMed gene database.Ingenuity Pathways Analysis was used to build the pharmacological network of three herbal pairs and CHD molecular network.The canonical pathways between each herbal pair network and CHD network was compared to decipher the molecular mechanism on three herbal pairs in treating CHD.RESULTS:The network analysis showed that there were the common signal pathways of three herbal pairs in treating CHD including hypoxia signaling in the cardiovascular system,Hypoxia-inducible factor 1-alpha signaling,glucocorticoid receptor signaling,G-Protein coupled receptor signaling and pregnane X receptor/retinoid X receptor(PXR/RXR)activation.Further to analyze cardiovascular signaling,cytokine signaling and cytokine signaling,the effective molecules for three herbal pairs in treating CHD included HIF1α and estrogen receptor 1,Qi-tonifying herbal pair included albumin and matrix metallopeptidase 2,and blood-activation herbal pair included estrogen receptor 2 and peroxisome proliferator-activated receptor-γ.CONCLUSION:Each herbal pair can affect some respective CHD-related functions and pathways,meanwhile three herbal pairs exert some mutual effects on CHD-related functions and pathways.Mutual effects of three herbal pairs may be the key components of their total molecular mechanisms and respective effects of each herbal pair may be the characteristic components of their respective molecular mechanism.
基金supported by the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.16KJA310005(to SYL)the Natural Science Foundation of Nantong City of China,No.JC2018058(to TMQ)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China
文摘The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regeneration.Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing.Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3,9 hours,1,4,or 7 days after nerve crush,compared with the 0 hour control.Thirty-six rat models of sciatic nerve crush injury were prepared as described previously.Then,they were divided into six groups to measure the expression changes of representative genes at 0,3,9 hours,1,4 or 7 days post crush.Our current study measured the expression levels of representative upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin genes,and explored critical signaling pathways and biological process through bioinformatic analysis.Our data revealed that many of these dysregulated upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin,participated in tissue remodeling and axon growth-related biological processes Therefore,the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury.Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves.All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals,China(approval No.20170302-017)on March 2,2017.
文摘Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis （2D-DIGE） and isotope labelling tags for relative and absolute quantification （iTRAQ）. Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins （P〈0.01） were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins （〉 1.3 fold; P〈0.05）. The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure （i.e., 23 overexpressed and 42 underexpressed）. Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT （P=0.006） and HSPB1 （P=0.046）.
基金National Natural Science Foundation of China(U1804179)Key Scientific and Technological Project in Henan Province(202102310190)+1 种基金Henan Science and Technology Innovation Team,Investigation on Plant Resources in Dabie Mountains and the Study and Utilization of Active Components of Special Plants(2017083)Nanhu Scholars Program for Young Scholars of Xinyang Normal University(2018001).
文摘[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases were first searched for genes and proteins known to be associated with CRC,as well as those predicted to be targets of triptolide,and then Ingenuity Pathway Analysis(IPA)was applied to identify enriched gene pathways and networks.Networks and pathways that overlapped between CRC-associated proteins and triptolide target proteins were then used to predict candidate protein targets of triptolide in CRC.[Results]The following proteins were found to be expressed in both CRC-associated networks and triptolide target networks:JUN,FOS,CASP3,BCL2,IFNG,and VEGFA.Docking studies suggested that triptolide can fit in the binding pocket of the four top candidate triptolide target proteins(CASP3,BCL2,VEGFA and IFNG).The overlapping pathways were activation of neuroinflammation signaling,glucocorticoid receptor signaling,T helper(Th)cell differentiation,Th1/Th2 activation,and colorectal cancer metastasis signaling.[Conclusions]These results show that network pharmacology can be used to generate hypotheses about how triptolide exerts therapeutic effects in CRC.Network pharmacology may be a useful method for characterizing multi-target drugs in complex diseases.
基金the National Natural Science Foundation of China(U1804179)the Henan Science and Technology Innovation Team for Investigation of Plant Resources in Dabie Mountains and the Study and Utilization of Active Components of Special Plants(2017083)the Nanhu Scholars Program for Young Scholars of Xinyang Normal University(2018001).
文摘[Objectives]To elucidate the mechanism of action of apigenin against lung cancer.[Methods]First,drug-target pathways and networks were constructed to predict potential protein targets of apigenin and their main interactions with the drug.Then,the ingenuity pathway analysis(IPA)was carried out to identify enriched gene pathways and networks,and the candidate protein targets of apigenin were predicted using networks and pathways that overlapped between proteins associated with lung cancer and proteins targeted by apigenin.[Results]Docking studies with apigenin indicated that BCL-2,CASP9,CDK2,CYCLIND1,PI3K,NF-κB,Rb1,p53,and AKT are the top candidate targets of apigenin,suggesting that the drug acts against lung cancer by regulating proteins involved in molecular mechanisms of cancer,as well as small cell lung cancer,pancreatic adenocarcinoma,glucocorticoid receptor,and p53 signaling.It was also found that apigenin affects networks mainly involved in the cell cycle,cell-to-cell signaling and interactions,hematological system development and function,cell death and survival,and organismal injury and abnormalities.[Conclusions]This study shows that network pharmacology is useful in generating hypotheses about how apigenin exerts therapeutic effects in lung cancer,as well as in discovering new multitarget drugs against other complex diseases.
基金supported by National Natural Science Foudation of China(No.U1404309)
文摘The differential expression of genes in HepG2 cells caused by UC001 kfo RNAi was investigated using RNA-seq. HepG2 cells were infected by Lenti-sh UC001 kfo lentivirus particles. The expression of UC001 kfo m RNA in the HepG2-sh UC001 kfo cell line was detected by real-time PCR. RNA-seq technology was used to identify the difference in the expression of genes regulated by lnc RNA UC001 kfo in the HepG2 cell line. Gene ontology and signaling pathway analysis were performed to reveal the biological functions of the genes encoding of significantly different m RNAs. The results showed that m RNAs were differentially expressed between the HepG2-sh UC001 kfo cell line and the HepG2 cell line. The UC001 kfo m RNA was significantly down-regulated in the stable cell line HepG2-sh UC001kfo（P〈0.001）. Additionally, we found 19 signaling pathways or functional classifications encompassing 30 genes that played a role in cancer characteristics, cell adhesion, invasion and migration. The results also showed that the expression of many genes associated with cancer cell invasion and metastasis was decreased with the down-regulation of the lnc RNA UC001 kfo. Lnc RNA UC001 kfo may play a role in regulating cancer cell invasion and metastasis. It was suggested that m RNAs were differentially expressed in the HepG2 cell line after the down-regulation of lnc RNA-UC001 kfo. Some took part in the extracellular matrix, cell adhesion, motility, growth, and localization. The genes encoding of differentially expressed m RNAs may participate in cell invasion and metastasis.
基金supported in part by a NIH grant,No.R01 DK106540(to WL).
文摘The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.
