Comprehensive analysis reveals an arachidonic acid metabolism-related gene signature in patients with pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)is highly heterogeneous,making its prognosis prediction difficult.The arachidonic acid(AA)cascade is involved in carcinogenesis.Therefore,the metabolic enzymes of the AA cascade consist of lipoxygenases(LOXs),phospholipase A2s(PLA2s),and cyclooxygenases(COXs)along with their metabolic products,including leukotrienes.Nevertheless,the prognostic potential of AA metabolism-associated PDAC has not been explored.Herein,the mRNA expression patterns and the matching clinical information of individuals with PDAC were abstracted from online data resources.We employed the LASSO Cox regression model to develop a multigene clinical signature in the TCGA queue.The GEO queue and the ICGC queue were employed as the validation queue.There was differential expression of a significant number of AA metabolism-associated genes(56.8%)between PDAC and neighboring nonmalignant tissues in the TCGA queue.Univariate Cox regression demonstrated that 13 of the differentially expressed genes(DEGs)were linked to overall survival(OS)(p<0.05).A 6-gene clinical signature was developed for stratifying the PDAC patients into two risk groups,with the high-risk group patients exhibiting remarkably lower OS than the low-risk group patients(p<0.001 in the TCGA data set and the ICGC queue,and p=0.001 in the GEO data set).The multivariate Cox data revealed the risk score as an independent OS predictor(HR>1,p<0.01).The receiver operating characteristic(ROC)curve verified the predictive potential of our signature.The expression and alteration of the six genes in PDAC were also validated using online databases.Functional analyses demonstrated that immune-linked cascades were enriched,and the immune status was remarkably different between the high-and low-risk groups.In summary,an AA metabolism-associated clinical gene signature can be applied for prognostic estimation in PDAC.

New insights into the interactions between the gut microbiota and the inflammatory response to ulcerative colitis in a mouse model of dextran sodium sulfate and possible mechanisms of action for treatment with PE&AFWE

Background:Inflammatory bowel disease(IBD),comprising Crohn's disease(CD)and ulcerative colitis(UC),is a heterogeneous state of chronic intestinal inflammation.Intestinal innate immunity,including innate immune cells,defends against pathogens and excessive entry of gut microbiota,while preserving immune tolerance to resident intestinal microbiota,and may be characterized by its capacity to produce a rapid and nonspecific reaction.The association between microbiota dysbiosis and the pathogenesis of IBD is complex and dynamic.When the intestinal ecosystem is in dysbiosis,the reduced abundance and diversity of intestinal gut microbiota make the host more vulnerable to the attack of exogenous and endogenous pathogenic gut microbiota.The aim of our study was to comprehensively assess the relationship between microbial populations within UC,the signaling pathways of pathogenic gut microbe therein and the inflammatory response,as well as to understand the effects of using PE&AFWE(poppy extract[Papaver nudicaule L.]and Artemisia frigida Willd.extract)on UC modulation.Methods:A UC mouse model was established by inducing SPF-grade C57BL/6 mice using dextrose sodium sulfate(DSS).Based on metagenomic sequencing to characterize the gut microbiome,the relationship between gut microbiota dysbiosis and gut microbiota was further studied using random forest and Bayesian network analysis methods,as well as histopathological analysis.Results:(1)We found that the 5 gut microbiota with the highest relative abundance of inflammatory bowel disease UC model gut microbiota were consistent with the top 5 ranked natural bacteria.There were three types of abundance changes in the model groups:increases(Chlamydiae/Proteobacteria and Deferribacteres),decreases(Firmicutes),and no significant changes(Bacteroidetes).The UC model group was significantly different from the control group,with 1308 differentially expressed species with abundance changes greater than or equal to 2-fold.(2)The proportion of the fecal flora in the UC group decreased by 37.5%in the Firmicutes and increased by 14.29%in the proportion of Proteobacteria compared to the control group before treatment.(3)The significantly enriched and increased signaling pathways screened were the'arachidonic acid metabolic pathway'and the'phagosomal pathway',which both showed a decreasing trend after drug administration.(4)Based on the causal relationship between different OTUs and the UC model/PE&AFWE administration,screening for directly relevant OTU networks,the UC group was found to directly affect OTU69,followed by a cascade of effects on OTU12,OTU121,OTU93,and OTU7,which may be the pathway of action that initiated the pathological changes in normal mice.(5)We identified a causal relationship between common differentially expressed OTUs and PE&AFWE and UC in the pre-and post-PE&AFWE-treated groups.Thereby,we learned that PE&AFWE can directly affect OTU90,after which it inhibits UC,inhibiting the activity of arachidonic acid metabolic pathway by affecting OTU118,which in turn inhibits the colonization of gut microbiota by OTU93 and OTU7.(6)Histopathological observation and scoring(HS)of the colon showed that there was a significant difference between the model group and the control group(p<0.001),and that there was a significant recovery in both the sulfasalazine(SASP)and the PE&AFWE groups after the administration of the drug(p<0.0001).Conclusion:We demonstrated causal effects and inflammatory metabolic pathways in gut microbiota dysbiosis and IBD,with five opportunistic pathogens directly contributing to IBD.PE&AFWE reduced the abundance of proteobacteria in the gut microbiota,and histopathology showed significant improvement.

Protective effect of Radix Acanthopanacis Senticosi capsule on colon of rat depression model

AIM: To investigate the abnormity of rat colon caused by depression and the ameliorative effects of Radix Acanthopanacis Senticosi (RAS) capsule on colon and their mechanisms in rat depression model. METHODS: Chronic stress-induced model of depression of Wistar rats was produced. The experimental animals were randomly divided into model control, 5-aminosalicylic acid (5-ASA) therapy group and three RAS capsule therapy groups. These five groups were intracolonically treated daily (8:00 a.m.) for 2 wk with normal saline, 5-ASA (100 mg/kg) and RAS capsule at the doses of 300, 600 and 900 mg/kg, respectively. A normal control group of rats was also included in the study. Colonic activities of nitric oxide (NO) and superoxide dismutase (SOD), levels of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) were determined by ultraviolet spectrophotometry. The expression of cyclooxygenase-2 (COX-2) in colonic tissue was detected by immunohistochemistry. RESULTS: Enhanced colon inflammatory response and oxidative stress were observed in the chronic stress-induced rat depression model, which manifested as the significant increase of MDA, iNOS and NO levels, as well as the expressions of COX-2 in the colon tissue, but the colonic SOD activity was significantly decreased compared with the normal control (MDA: 10.34±2.77 vs2.55±0.70; iNOS: 1.11±0.44 vs 0.25±0.16; COX-2: 53.26±8.16 vs 4.87±1.65; NO: 11.28±5.66 vs 4.76±1.55; SOD: 53.39±11.15 vs 84.45±22.31; P<0.01). However, these parameters were significantly ameliorated in rats treated locally with RAS capsule at the doses of 300, 600 and 900 mg/kg (iNOS: 0.65±0.31,0.58±0.22 and 0.64±0.33; NO: 5.99±2.73, 6.87±1.96 and 6.50±1.58; MDA: 2.92±0.75, 3.19±1.08 and 3.26±1.24; SOD: 70.81±12.36, 73.30±15.30 and 69.09±11.03, respectively). The expressions of COX-2 in the colon were significantly ameliorated (28.83±9.48 and 27.04±9.56, respectively) when RAS capsule was administered at the doses of 600 and 900 mg/kg. CONCLUSION: Administration of RAS capsule intracolonically may have significant therapeutic effects on the colon of rat depression model, which are probably due to its antioxidative action and inhibition of arachidonic acid metabolism.

Inhibitory effects and mechanisms of high molecular-weight phlorotannins from Sargassum thunbergii on ADP-induced platelet aggregation

We evaluated the effects of high molecular-weight phlorotannins from Sargassum thunbergii(STP) on ADP-induced platelet aggregation and arachidonic acid(AA) metabolism in New Zealand white rabbits and Wistar rats.The inhibition of STP on platelet aggregation was investigated using a turbidimetric method,and the levels of the terminal products of AA metabolism were measured using the corresponding kits for maleic dialdehyde(MDA),thromboxane B2(TXB2) and 6-keto-prostaglandin F1α(6-keto-PGF1α) by colorimetry and radioimmunoassay,as appropriate.We found that STP could inhibit ADP-induced platelet aggregation,and the inhibitory ratio was 91.50% at the STP concentration of 4.0 mg/mL.Furthermore,STP markedly affected AA metabolism by decreasing the synthesis of MDA(P<0.01) and increasing the synthesis of 6-keto-PGF1α,thus changing the plasma TXB2/6-keto-PGF1α balance when the platelets were activated(P<0.01).Therefore,STP altered AA metabolism and these findings partly revealed the molecular mechanism by which STP inhibits ADP-induced platelet aggregation.

Evaluation of Angelicae sinensis radix as a promising treatmentoption for hyperlipidemia based on network pharmacology

Background: Angelicae sinensis radix has been widely applied in traditional Chinese medicine while little isexplored in its potential mechanism. This study aims to elucidate the effective components and defattingmechanism based on network pharmacology. Methods: Traditional Chinese Medicine Systems PharmacologyDatabase and Analysis Platform was screened to collect the possible active ingredients and their CAS and SMILESwas searched in Pubchem, which further used for reverse molecular docking in Swiss Target Prediction database toobtain potential targets. Hyperlipidemia-related molecules were obtained from GeneCards database, and thepredicted targets of Angelicae sinensis radix for hyperlipidemia treatment were selected by Wayne diagram. Formechanism analysis, the protein-protein interactions were constructed with String, the Gene Oncology enrichmentanalysis and Kyoto Encyclopedia of Genes and Genomes analysis were conducted in DAVID. Results: Usingnetwork-based systems biology analysis, we predicted that 5 active ingredients in Angelicae sinensis radix hasantilipemic effects with 71 potential targets. Through Gene Oncology and Kyoto Encyclopedia of Genes andGenomes analysis, we found that the related signaling pathways mainly involved in arachidonic acid metabolism,and regulation of lipolysis in adipocytes. The related genes are ALOX5, CYP2C19, EPHX2, PTGS1, PTGS2,ADRB1, and ADRB3. Conclusion: Angelicae sinensis radix may alleviate hyperlipidemia through arachidonic acidmetabolism, and regulation of lipolysis in adipocytes. ALOX5, CYP2C19, EPHX2, PTGS1, PTGS2, ADRB1, andADRB3 may be new targets for treatment.

Investigating mechanism of Jiang-zhi-dai-pao-cha for treatment of hyperlipidemia by network pharmacology

Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets of JZDPC were searched from ETCM databases,the targets related to hyperlipidemia were searched from DisGeNET and GeneCards databases,and then the intersection targets and corresponding key components were obtained.Cytoscape 3.8.2 software was used to construct and analyze networks,and then Metascape online database was applied for gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of core putative targets.Results:There were 99 overlapping targets between JZDPC and hyperlipidemia,among which NR3C1,ESR1,NR1I2,NFKB1,ESR2,ALOX5,PTGS1,PPARA,RXRA,LPL,PLA2G1B,PYGM,CYP2C9 were the core putative targets,and many members of nuclear receptor 1(NR1)subfamily were included.The core components of JZDPC,such as Ursolic Acid,β-Sitosterol,Resveratrol,Arirubic Acid,Alisol A,Oleanolic Acid,Rhein,Chrysophanol and Emodin,can regulate blood lipid by regulating a series of signaling pathways including the above core potential targets,such as non-alcoholic fatty liver disease(NAFLD)signaling pathway,pathways in cancer,arachidonic acid(AA)metabolism signaling pathway and peroxisome proliferator activated receptor(PPAR)signaling pathway,Starch and sucrose metabolism signaling pathway,etc.They play many roles in the treatment of hyperlipidemia by participating in lipid synthesis and metabolism,anti inflammation,anti oxidative stress,regulating hormone levels and carbohydrate metabolism.Conclusion:Network pharmacology provides a theoretical basis for investigating the mechanism of action of JZDPC,and the NAFLD signaling pathway is one of the most valuable pathways.

Clinical significance of EPHX2 deregulation in prostate cancer

The arachidonic acid(AA)metabolic pathway participates in various physiological processes as well as in the development of malignancies.We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas(TCGA)prostate cancer(PCa)dataset and found that the gene encoding soluble epoxide hydrolase(EPHX2)is frequently deleted in PCa.EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry.The expression data were analyzed in conjunction with clinicopathological variables.Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time.Furthermore,EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa,respectively.In addition,EPHX2 protein expression correlated negatively with Ki67 expression.In conclusion,EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.