Construction and validation of prognostic model based on autophagy-related lncRNAs in gastric cancer

Gastric cancer(GC)is one of the most common cancer worldwide.Although emerging evidence indicates that autophagy-related long non-coding RNA(lncRNA)plays an important role in the progression of GC,the prognosis of GC based on autophagy is still deficient.The Cancer Genome of Atlas stomach adenocarcinoma(TCGA-STAD)dataset was downloaded and separated into a training set and a testing set randomly.Then,24 autophagy-related lncRNAs were found strongly associated with the survival of the TCGA-STAD dataset.11 lncRNAs were selected to build the risk score model through the least absolute shrinkage and selection operator(LASSO)regression.Every patient got a risk score(RS),and patients were separated into a high-risk group and a low-risk group due to the median RS.The multivariate Cox analysis showed that the RS could be an independent prognosis predictor.The Kaplan-Meier survival analysis and the Receiver Operating Characteristic(ROC)curve indicated the model had an excellent prediction effect.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed that the mRNAs in the prognostic network were mainly involved in the autophagy and ubiquitin-like protein ligase binding.Gene Set Enrichment Analysis(GSEA)analysis uncovered that the differentially expressed genes(DEGs)in the high-risk group partially participated in the ECM receptor interaction and other signaling pathways.Our results indicated that the risk score model based on the autophagy-related lncRNAs performed well in the prediction of prognosis for patients with GC.

Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants

SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination.The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences.Molecular markers for evaluating the pathogenicity of new variants are therefore needed.By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels,six key molecules on the polyamine biosynthesis pathway including putrescine,SAM,dc-SAM,ODC1,SAMS,and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants.To validate our discovery,human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients.Using ODC1 as a proof-ofconcept,differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system(RAS)and positively associated with ACE2 activity.Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern(VOCs)and was found to be correlated with each VOCs’pathogenic properties.Particularly,the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models.Our work,therefore,presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.

Mesothelin targeted nano-system enhanced chemodynamic therapy and tirapazamine chemotherapy via lactate depletion

The enhanced permeability and retention(EPR)effect alone is not enough for nanoparticles to reach the target.Combination of active and passive targeting may be an effective drug delivery route.Hollow ferric-tannic acid complex nanocapsules(HFe-TA)may effectively degrade and release Fe^(2+) ions,Fe^(2+)ions induce the production of·OH,however,the fenton reaction needs amount of H_(2)O_(2)to enhance chemodynamic therapy.Due to their deficiencies,such nanoparticles cannot realize intravenous drug delivery.Here,the mesothelin-targeted membrane(MTM)was constructed to realize accurate delivery nano-system,mesothelin antibody was expressed on the 293T cell membrane to prepare a MTM.Lactate oxidase(Lox)was loaded on HFe-TA to obtain Lox@HFe-TA.Lox@HFe-TA was coated with MTM to develop the MTM nanosystem.Tirapazamine(TPZ)therapy also requires hypoxia circumstance.The MTM nanosystem combined with TPZ can significantly kill tumour cells and inhibit metastasis in vivo and in vitro.We also tested the biological safety of the treatment.In this study,we overcame the EPR defects via the MTM nanosystem,which can realize acute targeted delivery to the tumour site,lactate depletion,promoted reactive oxygen species(ROS)induction,enhanced the effect of TPZ,demonstrating a potential synergistic combination of cancer therapy with better efficacy and biosafety.

Adverse effects of triclosan on kidney in mice: Implication of lipid metabolism disorders

Triclosan(TCS)is a ubiquitous antimicrobial used in daily consumer products.Previous reports have shown that TCS could induce hepatotoxicity,endocrine disruption,disturbance on immune function and impaired thyroid function.Kidney is critical in the elimination of toxins,while the effects of TCS on kidney have not yet been well-characterized.The aim of the present study was to investigate the effects of TCS exposure on kidney function and the possible underlying mechanisms in mice.Male C57BL/6 mice were orally exposed to TCS with the doses of 10 and 100 mg/(kg•day)for 13 weeks.TCS was dissolved in dimethyl sulfoxide(DMSO)and diluted by corn oil for exposure.Corn oil containing DMSO was used as vehicle control.Serum and kidney tissues were collected for study.Biomarkers associated with kidney function,oxidative stress,inflammation and fibrosis were assessed.Our results showed that TCS could cause renal injury as was revealed by increased levels of renal function markers including serum creatinine,urea nitrogen and uric acid,as well as increased oxidative stress,pro-inflammatory cytokines and fibroticmarkers in a dose dependent manner,whichweremore significantly in 100 mg/(kg•day)group.Mass spectrometry-based analysis of metabolites relatedwith lipid metabolism demonstrated the occurrence of lipid accumulation and defective fatty acid oxidation in 100 mg/(kg•day)TCS-exposed mouse kidney.These processes might lead to lipotoxicity and energy depletion,thus resulting in kidney fibrosis and functional decline.Taken together,the present study demonstrated that TCS could induce lipid accumulation and fatty acid metabolism disturbance in mouse kidney,whichmight contribute to renal function impairment.The present study further widens our insights into the adverse effects of TCS.

Impacts of sodium hydroxide and sodium hypochlorite aging on polyvinylidene fluoride membranes fabricated with different methods

This study compared the effects of chemical aging on the polyvinylidene fluoride（PVDF）membranes fabricated with the methods of non-solvent induced phase separation（NIPS）（named NIPS-PVDF） and thermally induced phase separation（TIPS）（named TIPS-PVDF）. The chemical solutions of sodium hypochlorite（NaClO） and sodium hydroxide（NaOH） were chosen at the concentration of 5000 mg/L. The equivalence of 5 and 10 years was respectively selected as the time of aging. The physicochemical evolutions of membrane aging are characterized on the base of morphology analysis, chemical components, permeation ability and mechanical properties. The aging of NIPS-PVDF membrane led to the elimination of surface hydrophilic additives, while NaO H focused on the dehydrofluorination process resulting in the formation of conjugated chains of polyene on the skeleton structure. The chemical components of the surface of TIPS-PVDF membrane were removed continuously during the aging processes of both NaClO and NaOH, which was caused by the saponification of surface additives and the chain scissions of skeleton structure, but without producing any obvious conjugated chains of polyene. All the aging processes led to the increase of contact angle and the decrease of mechanical properties, and the permeability was reduced first and increased later due to the enlargement of surface membrane pores and membrane block. With the influence of membrane aging, selectivity of membrane was decreased（except coliform bacteria）. At the beginning of filtration, the turbidity and particle count were at relatively high levels and declined with the filtration process.

Application of a real-ambient fine particulate matter exposure system on different animal models

Simulation of fine particulate matter(PM_(2.5))exposure is essential for evaluating adverse health effects.In this work,an ambient exposure system that mimicked real atmospheric conditions was installed in Taiyuan,China to study impacts of chronic PM_(2.5) exposure on adult and aged mice as well as Sirtuin3 knockout(Sirt3 KO)mice and wild-type(WT)mice.The real-ambient exposure system eliminated the possible artificial effects caused from exposure experiments and maintained the physiochemical characteristics of PM_(2.5).The case studies indicated that aged mice exhibited apparent heart dysfunction involving in-creased heart rate and decreased blood pressure after 17-week of real-ambient PM_(2.5) exposure.Meanwhile,15-week of real-ambient PM_(2.5) exposure decreased the heart rate and amounts of associated catecholamines to induce heart failure in Sirt3 KO mice.Additionally,the increased pro-inflammatory cytokines and decreased platelet related indices suggested that inflammation occurred.The changes of biomarkers detected by targeted metabolomics confirmed metabolic disorder in WT and Sirt3 KO mice after exposed to real-ambient PM_(2.5).These results indicated that the real-ambient PM_(2.5) exposure system could evaluate the risks of certain diseases associated with air pollution and have great potential for support-ing the investigations of PM_(2.5) effects on other types of rodent models.

Database-assisted global metabolomics profiling of pleural effusion induced by tuberculosis and malignancy

Database-assisted global metabolomics has received growing attention due to its capability for unbiased identification of metabolites in various biological samples.Herein,we established a mass spectrometry(MS)-based database-assisted global metabolomics method and investigated metabolic distance between pleural effusion induced by tuberculosis and malignancy,which are difficult to be distinguished due to their similar clinical symptoms.The present method utilized a liquid chromatography(LC) system coupled with high resolution mass spectrometry(MS) working on full scan and data dependent mode for data acquisition.Unbiased identification of metabolites was performed through mass spectral searching and then confirmed by using authentic standards.As a result,a total of 194 endogenous metabolites were identified and 33 metabolites were found to be differentiated between tuberculous and malignant pleural effusions.These metabolites involved in tryptophan catabolism,bile acid biosynthesis,and β-oxidation of fatty acids,provided non-invasive biomarkers for differentiation of the pleural effusion samples with high sensitivity and specificity.

ATP-responsive hollow nanocapsules for DOX/GOx delivery to enable tumor inhibition with suppressed P-glycoprotein

Multidrug resistance(MDR)restricts chemotherapy efficacy due to P-glycoprotein(P-gp)mediated drug efflux,whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges,such as low transfection,high toxicity and poor specificity.Here,hollow ferric-tannic acid complex nanocapsules(HFe-TA),which can be effectively degraded by the reaction with adenosine triphosphate(ATP),are synthesized for the delivery of glucose oxidase(GOx)and doxorubicin(DOX)for tumor treatment.The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption.Along with this ATP down-regulation,P-gp expression of tumor cells is suppressed remarkably,which in turn promotes the intracellular accumulation and anticancer efficacy of DOX.In addition,the production of•OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx.In consequence,HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions.This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.