The pathophysiology of ischemic stroke is complex and multifactorial,involving various forms of cell death such as apoptosis,autophagy,and necrosis.A recent study suggests that oxidative and inflammatory stress can in...The pathophysiology of ischemic stroke is complex and multifactorial,involving various forms of cell death such as apoptosis,autophagy,and necrosis.A recent study suggests that oxidative and inflammatory stress can induce ferroptosis,a specialized form of cell death characterized by the accumulation of lipid peroxides dependent on intracellular iron overload(Li and Jia,2023).展开更多
Although poly(lactic acid)(PLA)is a good environmentally-friendly bio-degradable polymer which is used to substitute traditional petrochemical-based polymer packaging films,the barrier properties of PLA films are stil...Although poly(lactic acid)(PLA)is a good environmentally-friendly bio-degradable polymer which is used to substitute traditional petrochemical-based polymer packaging films,the barrier properties of PLA films are still insufficient for high-barrier packaging applications.In this study,oxygen scavenger hydroxyl-terminated polybutadiene(HTPB)and cobalt salt catalyst were incorporated into the PLA/poly(butylene adipate-co-terephthalate)(PLA/PBAT),followed by melting extrusion and three-layer co-extrusion blown film process to prepare the composite films.The oxygen permeability coefficient of the composite film combined with 6 wt%oxygen scavenger and 0.4 wt%catalyst was decreased significantly from 377.00 cc·mil·m^(-2)·day^(-1)·0.1 MPa^(-1) to 0.98 cc·mil·m^(-2)·day^(-1)·0.1 MPa^(-1),showing a remarkable enhancement of 384.69 times compared with the PLA/PBAT composite film.Meanwhile,the degradation behavior of the composite film was also accelerated,exhibiting a mass loss of nearly 60%of the original mass after seven days of degradation in an alkaline environment,whereas PLA/PBAT composite film only showed a mass loss of 32%.This work has successfully prepared PLA/PBAT composite films with simultaneously improved oxygen barrier property and degradation behavior,which has great potential for high-demanding green chemistry packaging industries,including food,agricultural,and military packaging.展开更多
The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation.It tightly modulates the ion transport and nutrient influx,while restricting...The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation.It tightly modulates the ion transport and nutrient influx,while restricting the entry of harmful factors,and selectively limiting the migration of immune cells,thereby maintaining brain homeostasis.Despite the well-established association between blood–brain barrier disruption and most neurodegenerative/neuroinflammatory diseases,much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown.Moreover,the role of blood–brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood.This review aims to revisit this concept of“blood–brain barrier breakdown,”delving into the most controversial aspects,prevalent challenges,and knowledge gaps concerning the lack of blood–brain barrier integrity.By moving beyond the oversimplistic dichotomy of an“open”/“bad”or a“closed”/“good”barrier,our objective is to provide a more comprehensive insight into blood–brain barrier dynamics,to identify novel targets and/or therapeutic approaches aimed at mitigating blood–brain barrier dysfunction.Furthermore,in this review,we advocate for considering the diverse time-and location-dependent alterations in the blood–brain barrier,which go beyond tight-junction disruption or brain endothelial cell breakdown,illustrated through the dynamics of ischemic stroke as a case study.Through this exploration,we seek to underscore the complexity of blood–brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.展开更多
This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid acc...This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.展开更多
Rectifying circuit,as a crucial component for converting alternating current into direct current,plays a pivotal role in energy harvesting microsystems.Traditional silicon-based or germanium-based rectifier diodes hin...Rectifying circuit,as a crucial component for converting alternating current into direct current,plays a pivotal role in energy harvesting microsystems.Traditional silicon-based or germanium-based rectifier diodes hinder system integration due to their specific manufacturing processes.Conversely,metal oxide diodes,with their simple fabrication techniques,offer advantages for system integration.The oxygen vacancy defect of oxide semiconductor will greatly affect the electrical performance of the device,so the performance of the diode can be effectively controlled by adjusting the oxygen vacancy concentration.This study centers on optimizing the performance of diodes by modulating the oxygen vacancy concentration within InGaZnO films through control of oxygen flows during the sputtering process.Experimental results demonstrate that the diode exhibits a forward current density of 43.82 A·cm^(−2),with a rectification ratio of 6.94×10^(4),efficiently rectifying input sine signals with 1 kHz frequency and 5 V magnitude.These results demonstrate its potential in energy conversion and management.By adjusting the oxygen vacancy,a methodology is provided for optimizing the performance of rectifying diodes.展开更多
Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)...Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.展开更多
The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the bloo...The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.展开更多
Dear Editor,Reproductive healthcare and autonomy are integral to overall health,well-being,and human fundamental rights[1].However,for individuals with disabilities,access to reproductive healthcare and their autonomy...Dear Editor,Reproductive healthcare and autonomy are integral to overall health,well-being,and human fundamental rights[1].However,for individuals with disabilities,access to reproductive healthcare and their autonomy is significantly jeopardized due to a combination of parameters[1].Disabled people have to deal with a wide range of social barriers while they decide to access healthcare facilities for reproductive health[2,3].展开更多
Objective:To understand the facilitators and barriers for frail kidney transplant recipients(KTRs)practicing Baduanjin,and to provide a theoretical basis for developing intervention strategies.Subjects and Methods:Sem...Objective:To understand the facilitators and barriers for frail kidney transplant recipients(KTRs)practicing Baduanjin,and to provide a theoretical basis for developing intervention strategies.Subjects and Methods:Semi-structured interviews were conducted with 10 frail KTRs who participated in a 3-month Baduanjin practice.The Colaizzi seven-step analysis method was used to analyze,summarize,and extract themes from the interview data.Results:Two themes were extracted:facilitators and barriers.Facilitators included intrinsic motivation and perceived benefits,while barriers included conflicts with practice time,worsening physical condition,lack of immediate benefits,and difficulty integrating into daily life.Conclusion:The practice of Baduanjin by frail KTRs is influenced by various factors.Healthcare professionals should develop personalized intervention plans that take into account these factors and the needs of the patients.展开更多
Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-indu...Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.展开更多
Lactobacillus species have excellent abilities to reduce intestinal inflammation and enhance gut barrier function.This study elucidated the potential mechanisms through which Lactobacillus mitigates lipopolysaccharide...Lactobacillus species have excellent abilities to reduce intestinal inflammation and enhance gut barrier function.This study elucidated the potential mechanisms through which Lactobacillus mitigates lipopolysaccharide(LPS)-induced intestinal injury from the perspective of macrophage-intestinal epithelial cell interactions.Lactobacillus intervention improved the histopathological score;elevated ZO-1 and Occludin protein production;reduced CD16^(+)cell numbers;diminished IL-1β,IL-6,and TNF-αlevels;decreased inducible nitric oxide synthase(iNOS)expression;increased CD163^(+)cell numbers;elevated IL-10 concentration;and increased arginase-1(Arg1)expression in LPS-challenged piglets.Lactobacillus pretreatment also altered the colonic microbiota,thereby increasing the butyric acid concentration and GPR43 expression in the LPS-challenged piglets.Compared with those in the LPS group,sodium butyrate(SB)pretreatment decreased IL-1β,IL-6 and TNF-αsecretion and iNOS expression but increased IL-10 secretion and Arg1 expression in macrophages.The SB-pretreated macrophages reduced the protein expression of TLR4,MyD88,and phosphorylated NF-κB p65 but increased the protein expression of ZO-1 and Occludin in intestinal epithelial cells.Moreover,GLPG0974 blocked the beneficial effects of SB on macrophages and intestinal epithelial cells.This study demonstrated that Lactobacillus improves intestinal barrier function by regulating the macrophage phenotype through the control of butyric acid and GPR43 levels to further control inflammation.展开更多
Mastitis often occurs during women's lactation period,causing great psychological and physical pain to women.Fucoidan,a sulfated polysaccharide obtained from brown algae,has much broader biological properties.Howe...Mastitis often occurs during women's lactation period,causing great psychological and physical pain to women.Fucoidan,a sulfated polysaccharide obtained from brown algae,has much broader biological properties.However,the roles of fucoidan in lipopolysaccharides(LPS)-induced mastitis are still undiscovered.The present study was aimed to evaluate the influences of fucoidan on LPS-induced mouse mastitis and investigate its possible mechanisms.The expression profiles of fucoidan acting on mastitis were analyzed by network pharmacology.Additionally,mechanism experiments verified the mechanism of fucoidan on mastitis.The results of in vivo study displayed that the treatment of fucoidan to LPS-stimulated mouse mastitis decreased the inflammatory damage,proinflammatory cytokines level and repaired the completeness of bloodmilk barrier.In the study of mouse mammary epithelial cells,fucoidan suppressed the secretion of reactive oxygen species(ROS)and enhanced the activity of antioxidant enzymes.Molecular experiments suggested that fucoidan promoted nuclear factor erythroid 2-related factor 2(Nrf2)nuclear import and autophagy via activating the adenosine 5'-monophosphate-activated protein kinase(AMPK)signaling pathway.The above results indicated that in mastitis,fucoidan promoted Nrf2 nuclear import and autophagy via activating the AMPK signaling pathway,thereby suppressing oxidative stress and inflammatory injury to the mammary glands and protecting the blood-milk barrier.展开更多
As a popular approach to producing atmospheric pressure non-thermal plasma,dielectric barrier discharge(DBD)has been extensively used in various application fields.In this paper,DBD with wavy dielectric layers is nume...As a popular approach to producing atmospheric pressure non-thermal plasma,dielectric barrier discharge(DBD)has been extensively used in various application fields.In this paper,DBD with wavy dielectric layers is numerically simulated in atmospheric pressure helium mixed with trace nitrogen based on a fluid model.With varying relative position(phase difference(Δφ))of the wavy surfaces,there is a positive discharge and a negative discharge per voltage cycle,each of which consists of a pulse stage and a hump stage.For the pulse stage,maximal current increases with increasingΔφ.Results show that DBD with the wavy surfaces appears as discrete micro-discharges(MDs),which are self-organized to different patterns with varyingΔφ.The MDs are vertical and uniformly-spaced withΔφ=0,which are self-organized in pairs withΔφ=π/4.These MD pairs are merged into some bright wide MDs withΔφ=π/2.In addition,narrow MDs appear between tilted wide MDs withΔφ=3π/4.WithΔφ=π,the pattern is composed of wide and narrow MDs,which are vertical and appear alternately.To elucidate the formation mechanism of the patterns with differentΔφ,temporal evolutions of electron density and electric field are investigated for the positive discharge.Moreover,surface charge on the wavy dielectric layers has also been compared with differentΔφ.展开更多
After 20 years of rapid development,China's photovoltaic industry has become a leading industry in the international market.In recent years,photovoltaic power,a renewable and clean energy,has attracted global atte...After 20 years of rapid development,China's photovoltaic industry has become a leading industry in the international market.In recent years,photovoltaic power,a renewable and clean energy,has attracted global attention.This paper sorts out the technical barriers to trade related to the photovoltaic industry in Europe and the United States,analyzes the short-term and long-term impact on China,and finally puts forward countermeasures.展开更多
The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran so...The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran sodium sulfate.Several Lactobacillus strains isolated from the healthy human fecal sample was found to utilize Trp to produce indole derivatives.The results of Trp metabolism indicated that the ability of Lactobacillus to metabolize Trp to produce indole-3-lactic acid(ILA),indole-3-carboxaldehyde(I3C),and indole-3-acetic acid varies in vitro and in vivo.The effect of Lactobacillus with high-yielding indole derivatives on disease activity index,colon length,and intestinal permeability was significantly better than that of Lactobacillus with low-yielding indole derivatives in a high Trp diet.And Lactobacillus combined with Trp intervention also had a certain regulatory effect on the intestinal flora of male BALB/c mice.Among them,Lactiplantibacillus plantarum DPUL-S164 produced more ILA both in vivo and in vitro,and the combination of L.plantarum DPUL-S164 and Trp significantly decreased the expression level of the serum pro-inflammatory cytokine interleukin(IL)-6 and increased the expression level of the anti-inflammatory cytokine IL-10,significantly improved the number of goblet cells in the mouse mucous layer and increased mucin and tight junction protein expression.Furthermore,L.plantarum DPUL-S164 combined with Trp intervention activated the aryl hydrocarbon receptors(Ah R)signaling pathway.Furthermore,we found that the expression of colonic tight junction protein was positively correlated with the expression of colonic Ah R,and the expression of Ah R was positively correlated with the concentrations of ILA and I3C in vivo.Therefore,we conclude that the ILA as Ah R ligand produced by L.plantarum DPUL-S164 regulated the Ah R pathway,thus up-regulating the expression of the tight junction protein and protecting the integrity of the epithelial barrier.展开更多
The anti-inflammatory properties of silkworm pupa peptide(SPP)have been recognized for their potential benefits in colitis treatment.However,the underlying mechanism of SPP in colitis animal models remains unclear.The...The anti-inflammatory properties of silkworm pupa peptide(SPP)have been recognized for their potential benefits in colitis treatment.However,the underlying mechanism of SPP in colitis animal models remains unclear.The objective of our work was to investigate the improving effect and the mechanism of action of SPP on a mouse model of dextran sulfate sodium(DSS)-induced colitis.The findings suggested that SPP effectively eased ulcerative colitis(UC)symptoms in mice by decreasing disease activity index,ameliorating histopathological injury,and decreasing serum and colonic markers of inflammation.In addition,our research findings demonstrated that SPP restored intestinal barrier function by increasing the production of tight junction proteins such as zonula occludens-1(ZO-1),claudin-1,claudin-3,occludin,and adherens junction protein E-cadherin1.Further,SPP supplementation enhanced the concentration of short-chain fatty acids and positively altered the makeup of the gut bacteria in the mice's gut.These findings underscore SPP's ability to slow the progression of colitis and point to its possible use as a functional component in dietary supplements for the prevention of early-stage colitis.展开更多
The blood-brain barrier(BBB)keeps poisons and infections out of the brain.Some viruses can pass through this barrier and replicate in the central nervous system(CNS).Velogenic Newcastle disease virus(VNDV)is a neurotr...The blood-brain barrier(BBB)keeps poisons and infections out of the brain.Some viruses can pass through this barrier and replicate in the central nervous system(CNS).Velogenic Newcastle disease virus(VNDV)is a neurotropic virus that causes avian nonsuppurative encephalitis.VNDV often develops into a chronic infection that seriously affects poultry health in partially immune birds.The routes by which the virus enters the chicken brain are poorly understood.In this study,we discovered that VNDV increased BBB permeability in vivo and in vitro by breaking the tight junction protein zona occludens-1(ZO-1)continuity of chicken brain microvascular endothelial cells(chBMECs).By investigating the susceptibility of chBMECs to NDV infection,we found that VNDV but not lentogenic NDV was detected in the basolateral compartment in transwell assays after apical infection,suggesting that efficient replication and transcellular transport of the virus across the BBB in vitro.Furthermore,viral replication and BBB permeability were reduced during the early stage of infection by using the dynamin inhibitor dynasore.Our data demonstrate that VNDV invades the chicken brain by infecting and damaging the tight junction of chBMECs directly to increase BBB permeability.VNDV could infect chBMECs via endocytosis.As a result,our findings provide compelling evidence for VNDV entrance into the brain via the BBB,paving the way for the development of medications for NDV prevention and therapy.展开更多
Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dieta...Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.展开更多
BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome prolifer...BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.展开更多
文摘The pathophysiology of ischemic stroke is complex and multifactorial,involving various forms of cell death such as apoptosis,autophagy,and necrosis.A recent study suggests that oxidative and inflammatory stress can induce ferroptosis,a specialized form of cell death characterized by the accumulation of lipid peroxides dependent on intracellular iron overload(Li and Jia,2023).
基金financial support of this work by the National Natural Science Foundation of China(Nos.22378332,52003219)the Open Fund of Zhejiang Key Laboratory of Flexible Electronics(No.2022FE008)+1 种基金the Natural Science Foundation of Ningbo(NO.2022J058)Ministry of Industry and Information Technology high quality development project(TC220A04A-206).
文摘Although poly(lactic acid)(PLA)is a good environmentally-friendly bio-degradable polymer which is used to substitute traditional petrochemical-based polymer packaging films,the barrier properties of PLA films are still insufficient for high-barrier packaging applications.In this study,oxygen scavenger hydroxyl-terminated polybutadiene(HTPB)and cobalt salt catalyst were incorporated into the PLA/poly(butylene adipate-co-terephthalate)(PLA/PBAT),followed by melting extrusion and three-layer co-extrusion blown film process to prepare the composite films.The oxygen permeability coefficient of the composite film combined with 6 wt%oxygen scavenger and 0.4 wt%catalyst was decreased significantly from 377.00 cc·mil·m^(-2)·day^(-1)·0.1 MPa^(-1) to 0.98 cc·mil·m^(-2)·day^(-1)·0.1 MPa^(-1),showing a remarkable enhancement of 384.69 times compared with the PLA/PBAT composite film.Meanwhile,the degradation behavior of the composite film was also accelerated,exhibiting a mass loss of nearly 60%of the original mass after seven days of degradation in an alkaline environment,whereas PLA/PBAT composite film only showed a mass loss of 32%.This work has successfully prepared PLA/PBAT composite films with simultaneously improved oxygen barrier property and degradation behavior,which has great potential for high-demanding green chemistry packaging industries,including food,agricultural,and military packaging.
基金supported by the grants from the Spanish Ministry of Economy and Competitiveness(SAF2017-85602-R)the Spanish Ministry of Science and Innovation(PID2020-119638RB-I00 to EGR)FPU-program(FPU17/02616 to JCG)。
文摘The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation.It tightly modulates the ion transport and nutrient influx,while restricting the entry of harmful factors,and selectively limiting the migration of immune cells,thereby maintaining brain homeostasis.Despite the well-established association between blood–brain barrier disruption and most neurodegenerative/neuroinflammatory diseases,much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown.Moreover,the role of blood–brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood.This review aims to revisit this concept of“blood–brain barrier breakdown,”delving into the most controversial aspects,prevalent challenges,and knowledge gaps concerning the lack of blood–brain barrier integrity.By moving beyond the oversimplistic dichotomy of an“open”/“bad”or a“closed”/“good”barrier,our objective is to provide a more comprehensive insight into blood–brain barrier dynamics,to identify novel targets and/or therapeutic approaches aimed at mitigating blood–brain barrier dysfunction.Furthermore,in this review,we advocate for considering the diverse time-and location-dependent alterations in the blood–brain barrier,which go beyond tight-junction disruption or brain endothelial cell breakdown,illustrated through the dynamics of ischemic stroke as a case study.Through this exploration,we seek to underscore the complexity of blood–brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.
文摘This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.
文摘Rectifying circuit,as a crucial component for converting alternating current into direct current,plays a pivotal role in energy harvesting microsystems.Traditional silicon-based or germanium-based rectifier diodes hinder system integration due to their specific manufacturing processes.Conversely,metal oxide diodes,with their simple fabrication techniques,offer advantages for system integration.The oxygen vacancy defect of oxide semiconductor will greatly affect the electrical performance of the device,so the performance of the diode can be effectively controlled by adjusting the oxygen vacancy concentration.This study centers on optimizing the performance of diodes by modulating the oxygen vacancy concentration within InGaZnO films through control of oxygen flows during the sputtering process.Experimental results demonstrate that the diode exhibits a forward current density of 43.82 A·cm^(−2),with a rectification ratio of 6.94×10^(4),efficiently rectifying input sine signals with 1 kHz frequency and 5 V magnitude.These results demonstrate its potential in energy conversion and management.By adjusting the oxygen vacancy,a methodology is provided for optimizing the performance of rectifying diodes.
基金supported by the National Natural Science Foundation of China,No.8227050826(to PL)Tianjin Science and Technology Bureau Foundation,No.20201194(to PL)Tianjin Graduate Research and Innovation Project,No.2022BKY174(to CW).
文摘Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
基金supported by the National Natural Science Foundation of China,No.82104412(to TD)Shaanxi Provincial Key R&D Program,No.2023-YBSF-165(to TD)+1 种基金the Natural Science Foundation of Shaanxi Department of Science and Technology,No.2018JM7022(to FM)Shaanxi Provincial Key Industry Chain Project,No.2021ZDLSF04-11(to PW)。
文摘The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.
文摘Dear Editor,Reproductive healthcare and autonomy are integral to overall health,well-being,and human fundamental rights[1].However,for individuals with disabilities,access to reproductive healthcare and their autonomy is significantly jeopardized due to a combination of parameters[1].Disabled people have to deal with a wide range of social barriers while they decide to access healthcare facilities for reproductive health[2,3].
基金funded by the General Program of the National Natural Science Foundation of China(82072553)the Fundamental Research Funds for the Central Universities(2022-JYB-JBZR-026).
文摘Objective:To understand the facilitators and barriers for frail kidney transplant recipients(KTRs)practicing Baduanjin,and to provide a theoretical basis for developing intervention strategies.Subjects and Methods:Semi-structured interviews were conducted with 10 frail KTRs who participated in a 3-month Baduanjin practice.The Colaizzi seven-step analysis method was used to analyze,summarize,and extract themes from the interview data.Results:Two themes were extracted:facilitators and barriers.Facilitators included intrinsic motivation and perceived benefits,while barriers included conflicts with practice time,worsening physical condition,lack of immediate benefits,and difficulty integrating into daily life.Conclusion:The practice of Baduanjin by frail KTRs is influenced by various factors.Healthcare professionals should develop personalized intervention plans that take into account these factors and the needs of the patients.
基金supported by the Special Funds of Basic Research of Central Public Welfare Institute(JY2010 and ZX2410)。
文摘Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.
基金supported by the National Nature Science Foundation of China(32272898)the National Key Research and Development Program(2021YFA0805904)the Fundamental Research Funds for the Central Universities(2662020DKQD004).
文摘Lactobacillus species have excellent abilities to reduce intestinal inflammation and enhance gut barrier function.This study elucidated the potential mechanisms through which Lactobacillus mitigates lipopolysaccharide(LPS)-induced intestinal injury from the perspective of macrophage-intestinal epithelial cell interactions.Lactobacillus intervention improved the histopathological score;elevated ZO-1 and Occludin protein production;reduced CD16^(+)cell numbers;diminished IL-1β,IL-6,and TNF-αlevels;decreased inducible nitric oxide synthase(iNOS)expression;increased CD163^(+)cell numbers;elevated IL-10 concentration;and increased arginase-1(Arg1)expression in LPS-challenged piglets.Lactobacillus pretreatment also altered the colonic microbiota,thereby increasing the butyric acid concentration and GPR43 expression in the LPS-challenged piglets.Compared with those in the LPS group,sodium butyrate(SB)pretreatment decreased IL-1β,IL-6 and TNF-αsecretion and iNOS expression but increased IL-10 secretion and Arg1 expression in macrophages.The SB-pretreated macrophages reduced the protein expression of TLR4,MyD88,and phosphorylated NF-κB p65 but increased the protein expression of ZO-1 and Occludin in intestinal epithelial cells.Moreover,GLPG0974 blocked the beneficial effects of SB on macrophages and intestinal epithelial cells.This study demonstrated that Lactobacillus improves intestinal barrier function by regulating the macrophage phenotype through the control of butyric acid and GPR43 levels to further control inflammation.
基金funded by the National Natural Science Foundation of China(32102733)the Zhejiang Provincial Natural Science Foundation of China(LQ22C180004)the Longyan University&Fujian Provincial Key Laboratory for Prevention and Control of Animal Infectious Diseases and Biotechnology(ZDSYS2022002)。
文摘Mastitis often occurs during women's lactation period,causing great psychological and physical pain to women.Fucoidan,a sulfated polysaccharide obtained from brown algae,has much broader biological properties.However,the roles of fucoidan in lipopolysaccharides(LPS)-induced mastitis are still undiscovered.The present study was aimed to evaluate the influences of fucoidan on LPS-induced mouse mastitis and investigate its possible mechanisms.The expression profiles of fucoidan acting on mastitis were analyzed by network pharmacology.Additionally,mechanism experiments verified the mechanism of fucoidan on mastitis.The results of in vivo study displayed that the treatment of fucoidan to LPS-stimulated mouse mastitis decreased the inflammatory damage,proinflammatory cytokines level and repaired the completeness of bloodmilk barrier.In the study of mouse mammary epithelial cells,fucoidan suppressed the secretion of reactive oxygen species(ROS)and enhanced the activity of antioxidant enzymes.Molecular experiments suggested that fucoidan promoted nuclear factor erythroid 2-related factor 2(Nrf2)nuclear import and autophagy via activating the adenosine 5'-monophosphate-activated protein kinase(AMPK)signaling pathway.The above results indicated that in mastitis,fucoidan promoted Nrf2 nuclear import and autophagy via activating the AMPK signaling pathway,thereby suppressing oxidative stress and inflammatory injury to the mammary glands and protecting the blood-milk barrier.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12375250,11875121,51977057,11805013)the Natural Science Foundation of Hebei Province,China(Grant Nos.A2020201025 and A2022201036)+3 种基金the Hebei Province Optoelectronic Information Materials Laboratory Performance Subsidy Fund Project(Grant No.22567634H)the Funds for Distinguished Young Scientists of Hebei Province,China(Grant No.A2012201045)the Natural Science Interdisciplinary Research Program of Hebei University(Grant Nos.DXK201908 and DXK202011)the Post-graduate’s Innovation Fund Project of Hebei University(Grant No.HBU2022bs004)。
文摘As a popular approach to producing atmospheric pressure non-thermal plasma,dielectric barrier discharge(DBD)has been extensively used in various application fields.In this paper,DBD with wavy dielectric layers is numerically simulated in atmospheric pressure helium mixed with trace nitrogen based on a fluid model.With varying relative position(phase difference(Δφ))of the wavy surfaces,there is a positive discharge and a negative discharge per voltage cycle,each of which consists of a pulse stage and a hump stage.For the pulse stage,maximal current increases with increasingΔφ.Results show that DBD with the wavy surfaces appears as discrete micro-discharges(MDs),which are self-organized to different patterns with varyingΔφ.The MDs are vertical and uniformly-spaced withΔφ=0,which are self-organized in pairs withΔφ=π/4.These MD pairs are merged into some bright wide MDs withΔφ=π/2.In addition,narrow MDs appear between tilted wide MDs withΔφ=3π/4.WithΔφ=π,the pattern is composed of wide and narrow MDs,which are vertical and appear alternately.To elucidate the formation mechanism of the patterns with differentΔφ,temporal evolutions of electron density and electric field are investigated for the positive discharge.Moreover,surface charge on the wavy dielectric layers has also been compared with differentΔφ.
文摘After 20 years of rapid development,China's photovoltaic industry has become a leading industry in the international market.In recent years,photovoltaic power,a renewable and clean energy,has attracted global attention.This paper sorts out the technical barriers to trade related to the photovoltaic industry in Europe and the United States,analyzes the short-term and long-term impact on China,and finally puts forward countermeasures.
基金project was supported by the National Key Research and Development Program(2021YFD2100700)。
文摘The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran sodium sulfate.Several Lactobacillus strains isolated from the healthy human fecal sample was found to utilize Trp to produce indole derivatives.The results of Trp metabolism indicated that the ability of Lactobacillus to metabolize Trp to produce indole-3-lactic acid(ILA),indole-3-carboxaldehyde(I3C),and indole-3-acetic acid varies in vitro and in vivo.The effect of Lactobacillus with high-yielding indole derivatives on disease activity index,colon length,and intestinal permeability was significantly better than that of Lactobacillus with low-yielding indole derivatives in a high Trp diet.And Lactobacillus combined with Trp intervention also had a certain regulatory effect on the intestinal flora of male BALB/c mice.Among them,Lactiplantibacillus plantarum DPUL-S164 produced more ILA both in vivo and in vitro,and the combination of L.plantarum DPUL-S164 and Trp significantly decreased the expression level of the serum pro-inflammatory cytokine interleukin(IL)-6 and increased the expression level of the anti-inflammatory cytokine IL-10,significantly improved the number of goblet cells in the mouse mucous layer and increased mucin and tight junction protein expression.Furthermore,L.plantarum DPUL-S164 combined with Trp intervention activated the aryl hydrocarbon receptors(Ah R)signaling pathway.Furthermore,we found that the expression of colonic tight junction protein was positively correlated with the expression of colonic Ah R,and the expression of Ah R was positively correlated with the concentrations of ILA and I3C in vivo.Therefore,we conclude that the ILA as Ah R ligand produced by L.plantarum DPUL-S164 regulated the Ah R pathway,thus up-regulating the expression of the tight junction protein and protecting the integrity of the epithelial barrier.
基金supported by the National Key Research and Development Program of China(2023YFF1103802)。
文摘The anti-inflammatory properties of silkworm pupa peptide(SPP)have been recognized for their potential benefits in colitis treatment.However,the underlying mechanism of SPP in colitis animal models remains unclear.The objective of our work was to investigate the improving effect and the mechanism of action of SPP on a mouse model of dextran sulfate sodium(DSS)-induced colitis.The findings suggested that SPP effectively eased ulcerative colitis(UC)symptoms in mice by decreasing disease activity index,ameliorating histopathological injury,and decreasing serum and colonic markers of inflammation.In addition,our research findings demonstrated that SPP restored intestinal barrier function by increasing the production of tight junction proteins such as zonula occludens-1(ZO-1),claudin-1,claudin-3,occludin,and adherens junction protein E-cadherin1.Further,SPP supplementation enhanced the concentration of short-chain fatty acids and positively altered the makeup of the gut bacteria in the mice's gut.These findings underscore SPP's ability to slow the progression of colitis and point to its possible use as a functional component in dietary supplements for the prevention of early-stage colitis.
基金supported by the National Natural Science Foundation of China(32302864 and 31572533)the Shandong Provincial Natural Science Foundation,China(ZR2021QC185)the Agricultural Science and Technology Innovation Project of Shandong Academy of Agricultural Sciences,China(CXGC2023F11)。
文摘The blood-brain barrier(BBB)keeps poisons and infections out of the brain.Some viruses can pass through this barrier and replicate in the central nervous system(CNS).Velogenic Newcastle disease virus(VNDV)is a neurotropic virus that causes avian nonsuppurative encephalitis.VNDV often develops into a chronic infection that seriously affects poultry health in partially immune birds.The routes by which the virus enters the chicken brain are poorly understood.In this study,we discovered that VNDV increased BBB permeability in vivo and in vitro by breaking the tight junction protein zona occludens-1(ZO-1)continuity of chicken brain microvascular endothelial cells(chBMECs).By investigating the susceptibility of chBMECs to NDV infection,we found that VNDV but not lentogenic NDV was detected in the basolateral compartment in transwell assays after apical infection,suggesting that efficient replication and transcellular transport of the virus across the BBB in vitro.Furthermore,viral replication and BBB permeability were reduced during the early stage of infection by using the dynamin inhibitor dynasore.Our data demonstrate that VNDV invades the chicken brain by infecting and damaging the tight junction of chBMECs directly to increase BBB permeability.VNDV could infect chBMECs via endocytosis.As a result,our findings provide compelling evidence for VNDV entrance into the brain via the BBB,paving the way for the development of medications for NDV prevention and therapy.
基金supported by Hong Kong Research Grants Council General Research Fund(CUHK 14102321,14103722 and 14104923)。
文摘Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.
文摘BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
