Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis

Rheumatoid arthritis(RA)is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability,thus adversely affecting locomotion ability and life quality.Consequently,good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA.Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging.Herein,we review the fluorescent probes developed for the detection and imaging of RA biomarkers,namely reactive oxygen/nitrogen species(hypochlorous acid,peroxynitrite,hydroxyl radical,nitroxyl),pH,and cysteine,and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.

广义线性模型在Python中的实现

目的探索广义线性模型(generalized linear model,GLM)在Python软件中的实现方法,并比较其与其他常用统计软件在算法过程和结果方面的异同。方法分别利用Python软件statsmodles库中的GLM函数、Logit和Poisson函数,R软件GLM函数,SAS的PROC GENMOD过程步,对二项分布和泊松分布的数据集进行分析,比较三种软件的算法过程和分析结果。结果三种软件构建GLM的逻辑相似,但在代码实现和模型拟合方法等方面稍有区别,各软件的结果基本相同。结论Python软件可采用不同的算法构建广义线性模型,并且能提供与其他主流统计软件相同的统计分析结论。

环境流行病学研究中广义可加模型在Python中的实现

目的探索环境流行病学领域中常见的时间序列资料,利用Python以及其他常用统计软件实现广义可加模型(generalized additive models,GAM)的建模,比较各软件建模过程和结果的异同。方法以研究某地PM_(2.5)暴露与呼吸系统疾病入院人次之间的关系作为实例,分别利用Python软件statsmodles库、R软件mgcv库和SAS软件的proc gam语法,构建GAM模型,比较各软件命令代码、参数设置以及参数估计的差异。结果三种软件构建GAM模型的建模逻辑相似,但在内置函数拟合过程、命令代码以及可调用的样条函数等方面有所差别,各软件输出结果基本一致。结论Python软件利用第三方库可实现广义可加模型的构建,为进一步拓展其在流行病学领域的应用提供了参考。

病例交叉研究中条件Logistic回归在Python中的实现

目的 探索病例交叉研究中条件Logistic回归在Python软件中的实现。方法以研究某地空气污染物NO2暴露与因肺部感染住院的关系作为实例,利用Python构建条件Logistic回归模型,比较其与常用统计软件R和SAS的建模过程以及统计分析结果的异同。结果 Python、R和SAS三种软件建模逻辑相似,Python的建模语言与其他统计软件相比稍显繁琐,与SAS在参数检验方法上也略有差异,但三种软件的参数估计结果完全相同。结论 Python软件可实现条件Logistic回归分析,进一步拓展了Python在统计分析的应用场景。

Dihydromyricetin inhibits migration and invasion of hepatoma cells through regulation of MMP-9 expression

AIM: To investigate the effects of dihydromyricetin (DHM) on the migration and invasion of human hepatic cancer cells.

Hepatoprotective effects of baicalein against CCl 4-induced acute liver injury in mice

AIM:To investigate the hepatoprotective effect of baicalein against carbon tetrachloride(CCl 4)-induced liver damage in mice.METHODS:Mice were orally administered with baicalein after CCl 4 injection,and therapeutic baicalein was given twice a day for 4 d.The anti-inflammation effects of baicalein were assessed directly by hepatic histology and serum alanine aminotranferease and aspartate aminotransferase measurement.Proliferating cell nuclear antigen was used to evaluate the effect of baicalein in promoting hepatocyte proliferation.Serum interleukin(IL)-6,IL-1β and tumor necrosis factor-α(TNF-α) levels were measured by enzyme-linked immunosorbent assay and liver IL-6,TNF-α,transforming growth factor-α(TGF-α),hepatocyte growth factor(HGF) and epidermal growth factor(EGF) genes expression were determined by quantitative real-time polymerase chain reaction.RESULTS:CCl4-induced acute liver failure model offers a survival benefit in baicalein-treated mice.The data indicated that the mRNA levels of IL-6 and TNF-α significantly increased within 12 h after CCl 4 treatment in baicalein administration groups,but at 24,48 and 72 h,the expression of IL-6 and TNF-α was kept at lower levels compared with the control.The expression of TGF-α,HGF and EGF was enhanced dramatically in baicalein administration group at 12,24,48 and 72 h.Furthermore,we found that baicalein significantly elevated the serum level of TNF-α and IL-6 at the early phase,which indicated that baicalein could facilitate the initiating events in liver regeneration.CONCLUSION:Baicalein may be a therapeutic candidate for acute liver injury.Baicalein accelerates liver regeneration by regulating TNF-α and IL-6 mediated pathways.

Dihydromyricetin alleviates carbon tetrachloride-induced acute liver injury via JNK-dependent mechanism in mice

AIM: To assess the effects of dihydromyricetin(DHM) as a hepatoprotective candidate in reducing hepatic injury and accelerating hepatocyte proliferation after carbon tetrachloride(CCl4) treatment.METHODS: C57 BL/6 mice were used in this study. Mice were orally administered with DHM(150 mg/kg) for 4 d after CCl4 treatment. Serum and liver tissue samples were collected on days 1, 2, 3, 5 and 7 after CCl4 treatment. The anti-inflammatory effect of DHM was assessed directly by hepatic histology detection and indirectly by serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), albumin, and superoxide dismutase(SOD). Inflammatory cytokines, such as interleukin(IL)-1β, IL-6 and tumor necrosis factor-α(TNF-α), were detected using ELISA kits. Proliferating cell nuclear antigen(PCNA) staining was used to evaluate the role of DHM in promoting hepatocyte proliferation. Hepatocyte apoptosis wasmeasured by TUNEL assay.Furthermore,apoptosis proteins Caspases-3,6,8,and 9 were detected by Western blot.SP600125 were used to confirm whether DHM regulated liver regeneration through JNK/TNF-αpathways.RESULTS:DHM showed a strong anti-inflammatory effect on CCl4-induced liver injury in mice.DHM could significantly decrease serum ALT,AST,IL-1β,IL-6 and TNF-αand increase serum albumin,SOD and liver SOD compared to the control group after CCl4 treatment(P<0.05).PCNA results indicated that DHM could significantly increase the number of PCNA positive cells compared to the control(348.9±56.0 vs 107.1±31.4,P<0.01).TUNEL assay showed that DHM dramatically reduced the number of apoptotic cells after CCl4 treatment compared to the control(365.4±99.4 vs 90.5±13.8,P<0.01).Caspase activity detection showed that DHM could reduce the activities of Caspases-8,3,6 and 9 compared to the control(P<0.05).The results of Western blot showed that DHM increased the expression of JNK and decreased TNF-αexpression.However,DHM could not affect TNF-αexpression after SP600125 treatment.Furthermore,DHM could significantly improve the survival rate of acute liver failure(ALF)mice(73.3%vs 20.0%,P<0.0001),and SP600125 could inhibit the effect of DHM.CONCLUSION:These findings demonstrate that DHM alleviates CCl4-induced liver injury,suggesting that DHM is a promising candidate for reversing liver injury and ALF.

Interactive effects of porosity and microstructure on strength of 6063 aluminum alloy CMT MIX + Synchropulse welded joint

The porosity, pore size and softening of 6063 aluminum alloy CMT MIX + Synchropulse welded joint with different welding speeds were studied. The results show that with the increase of welding speed(from 55 to 65 cm/min), the porosity increases dramatically(from 0.1% to 3.9%) and large pores(341.1 μm) appear. The pore size distributions are mainly concentrated at 87.8 and 20.6 μm in the joints produced from weld speeds of 65 and 55 cm/min, respectively. The dissolution and transformation of the β′′ phase in the base metal(BM) result in a significant softening of both the fusion zone and heat-affected zone, and the latter was more serious. The effects of welding speed on the average tensile strength of the full penetration welded joints are minor, which was about 155 MPa(67.4% that of the BM).

Phycocyanobilin accelerates liver regeneration and reduces mortality rate in carbon tetrachloride-induced liver injury mice

AIM: To investigate the hepatoprotective effects of phycocyanobilin(PCB) in reducing hepatic injury and accelerating hepatocyte proliferation following carbon tetrachloride(CCl4) treatment.METHODS: C57BL/6 mice were orally administered PCB 100 mg/kg for 4 d after CCl4 injection, and then the serum and liver tissue of the mice were collected at days 1, 2, 3, 5 and 7 after CCl4 treatment. A series of evaluations were performed to identify the curative effects on liver injury and recovery. Aspartate aminotransferase(AST), alanine aminotransferase(ALT), albumin and superoxide dismutase(SOD) were detected to indirectly assess the anti-inflammatory effects of PCB. Meanwhile, we detected the expressions of hepatocyte growth factor, transforming growth factor alpha(TGF-α), TGF-β, tumor necrosis factor-alpha(TNF-α) and interleukin-6(IL-6), the factors which are associated with inflammation and liver regeneration. The protein expressions of proliferating cell nuclear antigen(PCNA), TNF-α and cytochrome C were detected by western blot. Furthermore, the survivalrates were analyzed of mice which were administered a lethal dose of CCl4(2.6 mg/kg)with or without PCB.RESULTS:In our research,PCB showed a strongly anti-inflammatory effect on CCl4-induced liver injury in mice.The ALT was significantly decreased after CCl4 treatment from day 1(P<0.01)and the AST was significantly decreased from day 2(P<0.001).Both albumin and liver SOD were increased from day2(P<0.001 and P<0.01),but serum SOD levels did not show a significant increase(P>0.05).PCB protected the structure of liver from the injury by CCl4.TUNEL assay showed that PCB dramatically reduced the number of apoptotic cells after CCl4 treatment compared to the control(101.0±25.4 vs 25.7±6.4,P<0.01).The result of western blotting showed that PCB could increase PCNA expression,decrease TNF-αand cytochrome C expression.Furthermore,data shows that PCB could improve the survival rate of acute liver failure(ALF)mice which were injected with a lethal dose of CCl4(60.0%vs 20.0%).CONCLUSION:Our study indicated that PCB could be an ideal candidate for reversing acute liver injury or ALF.

Chronic Toxicity of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group):four groups were treated with rhG-CSFa at 500,100,10,1 μg/kg,respectively,and one group was treated with vehicle only to serve as the control.The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks.During the course of the chronic toxicity study,the physical status,body weight,and food consumption were monitored.Half of the rats in each group (n=10) were sacrificed after the last rhG-CSFa administration,and the other half were sacrificed at five weeks after the last rhG-CSFa administration.Urinalyses,blood biochemistry,hematological analysis,histopathological examination,and immunological tests were performed for each of the rats.Results The hematological analyses revealed that the mean white blood cells count,neutrophils count,and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher,and these were related with the biological activity of rhG-CSFa.Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg,a dosage of 200 folds higher than the normal clinical dosage),but these abnormalities were recovered within 5-week recovery period.No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.

The different interactions of Colletotrichum gloeosporioides with two strawberry varieties and the involvement of salicylic acid

The disease symptoms recognized as‘Anthracnose’are caused by Colletotrichum spp.and lead to large-scale strawberry(Fragaria×ananassa Duchesne)losses worldwide in terms of both quality and production.Little is known regarding the mechanisms underlying the genetic variations in the strawberry–Colletotrichum spp.interaction.In this work,Colletotrichum gloeosporioides(C.gloeosporioides)infection was characterized in two varieties exhibiting different susceptibilities,and the involvement of salicylic acid(SA)was examined.Light microscopic observation showed that C.gloeosporioides conidia germinated earlier and faster on the leaf surface of the susceptible cultivar compared with the less-susceptible cultivar.Several PR genes were differentially expressed,with higher-amplitude changes observed in the less-susceptible cultivar.The less-susceptible cultivar contained a higher level of basal SA,and the SA levels increased rapidly upon infection,followed by a sharp decrease before the necrotrophic phase.External SA pretreatment reduced susceptibility and elevated the internal SA levels in both varieties,which were sharply reduced in the susceptible cultivar upon inoculation.The less-susceptible cultivar also displayed a more sensitive and marked increase in the transcripts of NB-LRR genes to C.gloeosporioides,and SA pretreatment differentially induced transcript accumulation in the two varieties during infection.Furthermore,SA directly inhibited the germination of C.gloeosporioides conidia;NB-LRR transcript accumulation in response to SA pretreatment was both dose-and cultivar-dependent.The results demonstrate that the less-susceptible cultivar showed reduced conidia germination.The contribution of SA might involve microbial isolate-specific sensitivity to SA,cultivar/tissue-specific SA homeostasis and signaling,and the sensitivity of R genes and the related defense network to SA and pathogens.

Continuous droplet rebound on heated surfaces and its effects on heat transfer property: A lattice Boltzmann study

A thermal multiphase lattice Boltzmann(LB) model is used to study the behavior of droplet impact on hot surface and the relevant heat transfer properties.After validating the correctness of the codes through the D^(2) law,the simulations of intrinsic contact angle and the temperature-dependent surface tension are performed.The LB model is then used to simulate the droplet impact on smooth and micro-hole heated surface.On the smooth surface,the impinging droplet is reluctant to rebound,unless the intrinsic wettability of the solid surface is fairly good.On the micro-hole surface,however,the micro-holes provide favorable sites for generating a high-pressure vapor cushion underneath the impinging droplet,which thereby facilitates the continuous droplet rebound.For the continuously rebounding droplet.The time evolution of volume and temperature display obvious oscillations.The achievable height of the rebounding droplet increases as the intrinsic wettability of the solid surface becomes better,and the maximum transient heat flux is found to be directly proportional to the droplet rebounding height.Within a certain time interval,the continuous rebounding behavior of the droplet is favorable for enhancing the total heat quantity/heat transfer efficiency,and the influence of intrinsic wettability on the total heat during droplet impingement is greater than that of the superheat.The LB simulations not only present different states of droplets on hot surfaces,but also guide the design of the micro-hole surface with desirable heat transfer properties.

Corticosteroid-induced Osteonecrosis of the Femoral Head:Detection,Diagnosis,and Treatment in Earlier Stages

Objective： This review aimed to provide a current recommendation to multidisciplinary physicians for early detection, diagnosis, and treatment of corticosteroid-induced osteonecrosis of the femoral head （ONFH） based on a comprehensive analysis of the clinical literature. Data Sources： For the purpose of collecting potentially eligible articles, we searched for articles in the PubMed, Cochrane Library, Embase, and CNKI databases up to February 2017, using the following key words： ＆quot;corticosteroid＆quot;, ＆quot;osteonecrosis of the femoral head＆quot;,＆quot;risk factors＆quot;, ＆quot;diagnosis＆quot;, ＆quot;prognosis＆quot;, and ＆quot;treatment＆quot;. Study Selection： Articles on relationships between corticosteroid and ONFH were selected for this review. Articles on the diagnosis, prognosis, and intervention of earlier-stage ONFH were also reviewed. Results： The incidence of corticosteroid-induced ONFH was associated with high doses of corticosteroids, and underlying diseases in certain predisposed individuals mainly occurred in the first 3 months of corticosteroid prescription. The enhanced awareness and minimized exposure to the established risk factors and earlier definitive diagnosis are essential for the success of joint preservation. When following up patients with ONFH, treatment should be started if necessary. Surgical treatment yielded better results than conservative therapy in earlier-stage ONFH. The ideal purpose of earlier intervention and treatment is permanent preservation of the femoral head without physical restrictions in daily living. Conclusions： Clinicians should enhance their precaution awareness of corticosteroid-induced ONFH. For high-risk patients, regular follow-up is very important in the 1st year after high-dose prescription of corticosteroids. Patients with suspected ONFH should be referred to orthopedists for diagnosis and treatment in its earlier stage to preserve the joint.

Pericollapse Stage of Osteonecrosis of the Femoral Head： A Last Chance for Joint Preservation

Objective： To propose a new definition of the pericollapse stage of osteonecrosis of the femoral head （ONFH） and review its significance in disease diagnosis and treatment selection. Data Sources： A search for eligible studies was conducted in three electronic databases including PubMed, Cochrane Library, and Embase up to August 10, 2018, using the following keywords： ＂osteonecrosis＂, ＂prognosis＂, and ＂treatment＂. Study Selection： Investigations appraising the clinical signs, symptoms, and imaging manifestations in different stages of ONFH were included. Articles evaluating the prognosis of various joint-preserving procedures were also reviewed. Results： The pericollapse stage refers to a continuous period in the development of ONFH from the occurrence of subchondral fracture to early collapse （〈2 mm）, possessing specific imaging features that mainly consist of bone marrow edema and joint effusion on magnetic resonance imaging （MR1）, crescent signs on X-ray films, and clinical manifestations such as the sudden worsening of hip pain. Accumulating evidence has indicated that these findings may be secondary to the changes after subchondral fractures. Of note. computed tomography provides more information for identifying possible subchondral fractures than does MRI and serves as the most sensitive tool for grading the pericollapse lesion stage. The pericollapse stage may indicate a high possibility of progressive disease but also demonstrates satisfactory long- and medium-term outcomes fbr joint-preserving techniques. In tact, if the articular surface subsides more than 2 mm, total hip arthroplasty is preferable. Conclusions： The pericollapse stage with distinct clinical and imaging characteristics provides a last good opportunity for the use of joint-preserving techniques. It is necessary to separate the pericollapse stage as an independent state in evaluating the natural progression of ONFH and selecting an appropriate treatment regimen.

An update on the role of intestinal cytochrome P450 enzymes in drug disposition

Oral administration is the most commonly used route for drug treatment.Intestinal cytochrome P450(CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation,while leaving the passage of other drugs unimpeded.A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species,including the identification of the CYP enzymes expressed,their regulation,and the relative importance of intestinal metabolism compared to hepatic metabolism,is important for improving bioavailability of current drugs and new drugs in development.Here,we briefly review the expression of drug-metabolizing P450 enzymes in the small intestine of humans and several preclinical animal species,and provide an update of the various factors or events that regulate intestinal P450 expression,including a cross talk between the liver and the intestine.We further compare various clinical and preclinical approaches for assessing the impact of intestinal drug metabolism on bioavailability,and discuss the utility of the intestinal epithelium–specific NADPH-cytochrome P450 reductasenull(IECN) mouse as a useful model for studying in vivo roles of intestinal P450 in the disposition of orally administered drugs.

Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model

We examined the impact of gut inflammation on the expression of cytochrome P450(P450)and other biotransformation genes in male mice using a dextran sulfate sodium(DSS)-induced colitis model.Several P450 isoforms,including CYPIA,CYP2B,CYP2C,and CYP3A,were downregulated,accompanied by decreases in microsomal metabolism of diclofenac and nifedipine,in the liver and small intestine.The impact of the colitis on in vivo clearance of oral drugs varied for four different drugs tested:a small decrease for nifedipine,a relatively large decrease for lovastatin,but no change for pravastatin,and a large decrease in the absorption of cyclosporine A.To further assess the scope of influence of gut inflammation on gene expression,we performed genome-wide expression analysis using RNA-seq,which showed down-regulation of many CYPs,non-CYP phase-Ⅰenzymes,phase-Ⅱenzymes and transporters,and up-regulation of many other members of these gene families,in both liver and intestine of adult C57BL/6 mice,by DSS-induced colitis.Overall,our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver,and alters the pharmacokinetics for some but not all drugs,potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.

Focused extra-corporeal shockwave treatment during early stage of osteonecrosis of femoral head

In recent years,increasing evidence has demonstrated that extra-corporeal shockwave therapy (ESWT) can offer an effective and non-invasive method for the treatment of musculoskeletal disorders,such as shoulder tendinopathies,lateral epicondylopathy of the elbow,greater trochanteric pain syndrome,patellar tendinopathy,Achilles tendinopathy,plantar fasciitis,and bone disorders.[1,2]As a safe,cheap,and non-invasive therapeutic method,ESWT has played a promising role in orthopedic medicine.[3-5] Inspired by this,several researchers have attempted to investigate its use for treating osteonecrosis of the femoral head.ESWT deserves being recommended as the optimal choice for osteonecrosis of the femoral head (ONFH).

Modelling of urban ambient N,N-dimethylformamide concentrations in a small-scale synthetic leather industrial zone

A method to model small-scale ambient concentrations of N, N-dimethylformamide (DMF) in a synthetic leather industrial zone was developed. Longwan, a district of Wenzhou City in Southeast China, was selected as the study area. DMF emissions at the synthetic leather industrial zone were inventoried, during 2007, and an AMS/EPA regulatory model (AERMOD) was used to simulate DMF concentrations using 10 000 100 m×100 m grids for the 2006 period. In 2007, actual DMF concentrations were recorded at seven DMF monitoring stations, and were compared with simulated results for the same timeframe. Simulated DMF concentrations were predicted to be in the range of 0.012-2.31 mg/m3, which is similar to the range of the monitored dataset results. A large majority (93%) of relative errors (REs) between simulated and monitored concentrations ranged from 0.48% to 189.4%. While DMF emissions within factories did not exceed the regulated emission limit, simulations indicated that, in 2006, 20% of the daily average ambient DMF concentrations exceeded this limit. This Modelling method could be applied in evaluating regional atmospheric environmental capacities and human exposure to DMF.

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

Zika virus(ZIKV)causes significant human diseases without specific therapy.Previously we found erythrosin B,an FDA-approved food additive,inhibited viral NS2B−NS3 interactions,leading to inhibition of ZIKV infection in cell culture.In this study,we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models.Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model.Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile,mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B,compared to vehicle control.Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions,protease activity and antiviral efficacy.In contrast,introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities,suggesting that the isobenzofuran ring is well tolerated for modifications.Cytotoxicity studies indicated that all derivatives are nontoxic to human cells.Overall,our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.

The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

Pyrrolizidine alkaloids(PAs) are the most common phytotoxins with documented human hepatotoxicity.PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts,thereby causing cytotoxicity.This study investigated the role of the gut-liver axis in PA intoxication and the underlying mechanisms.We exposed mice to retrorsine(RTS),a representative PA,and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function.Using mice with tissue-selective ablation of P450 activity,we found that hepatic P450 s,but not intestinal P450 s,were essential for PA bioactivation.Besides,in RTS-exposed,bile duct-cannulated rats,we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity.The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium(DSS)-induced chronic colitis.DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione,thereby suppressing the PA detoxification pathway.Compared to RTS-exposed normal mice,the colitic mice displayed more severe RTS-induced hepatic vasculature damage,fibrosis,and steatosis.Overall,our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.