BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
OBJECTIVE:To explore the mechanism of Baitouweng Tang(白头翁汤,Pulsatilla decoction,PD)alleviates dextran sulfate sodium(DSS)-induced ulcerative colitis(UC)in mice by integrating network pharmacology prediction with e...OBJECTIVE:To explore the mechanism of Baitouweng Tang(白头翁汤,Pulsatilla decoction,PD)alleviates dextran sulfate sodium(DSS)-induced ulcerative colitis(UC)in mice by integrating network pharmacology prediction with experimental validation,focusing on the modulation of inflammatory signaling.METHODS:A chronic UC model was induced in C57BL/6 mice by cyclical administration of DSS.Mice were treated with either a low(15 m L/kg)or high(30 m L/kg)dose of PD.Disease severity was assessed clinically and via histopathology.Serum levels of inflammatory cytokines were quantified.A network pharmacology approach was employed to predict the core targets and pathways of PD against UC.Key predictions concerning the toll-like receptor 4/nuclear factor-kappa B(TLR4/NF-κB)pathway were subsequently verified in colonic tissue using quantitative polymerase chain reaction and Western blotting.RESULTS:PD treatment significantly ameliorated DSSinduced UC symptoms,including reducing disease activity,preventing colon shortening,and improving histological architecture.PD effectively rebalanced the systemic inflammatory milieu by decreasing proinflammatory cytokines interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)and elevating anti-inflammatory cytokines interleukin-10(IL-10).Network pharmacology analysis identified the TLR4/NF-κB signaling pathway as a central target.Experimental validation confirmed that PD markedly suppressed the upregulation of both TLR4 and NF-κB at the transcriptional and protein levels in the inflamed colon.CONCLUSION:PD demonstrates protective effects against experimental UC.Its mechanism is associated with the inhibition of the TLR4/NF-κB signaling pathway and the subsequent attenuation of inflammatory responses.This study provides a modern pharmacological basis for the classical application of PD in treating heat-toxin related intestinal disorders,bridging traditional use and mechanistic understanding.展开更多
OBJECTIVE:To elucidate the anti-inflammatory mechanisms of modified Shoutai pills(改良寿胎丸,MSTP)in miscarriages,we performed transcriptome sequencing on the decidua and placental tissues of pregnancy mice.METHODS:Th...OBJECTIVE:To elucidate the anti-inflammatory mechanisms of modified Shoutai pills(改良寿胎丸,MSTP)in miscarriages,we performed transcriptome sequencing on the decidua and placental tissues of pregnancy mice.METHODS:The therapeutic effects and antiinflammatory mechanisms of MSTP were studied in mice with lipopolysaccharide(LPS)-induced miscarriage.First,the effects of MSTP on pregnancy outcomes and the maternal-fetal interface,in LPS-induced miscarriage mice were examined.RNA sequencing was used to further investigate gene expression changes in LPS-induced miscarriage mice and to assess the effects of MSTP intervention.Finally,the expression levels of inflammation-related genes in the decidua and placental tissues were determined using quantitative real-time polymerase chain reaction(q RT-PCR).RESULTS:A high dose of MSTP significantly decreased the resorption rate(P<0.05)and reduced apoptosis of the decidua and placental tissues in mice.Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that inflammatory and immune-related signals were enriched.q RT-PCR results confirmed that in decidual and placental tissues,MSTP reduced the gene expression levels of toll-like receptor 4(TLR4),nuclear factor kappa-B(NF-κB),c-Jun N-terminal kinase 1,p38,and tumor necrosis factor-α.CONCLUSIONS:In this study,we demonstrated that MSTP effectively prevented embryo loss with an antiinflammatory mechanism through downregulation of the TLR4-NF-κB/MAPK signaling pathway,in LPS-induced miscarriage mice model.To our knowledge,this is the first study to reveal the therapeutic mechanism of MSTP in LPS-induced miscarriage in mice.展开更多
Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of...Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.展开更多
Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,...Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,leading to direct neuronal damage as well as initiating a cascade of inflammatory responses.This oxidative stress can also disturb the equilibrium of the gut microbiota,resulting in dysbiosis.In turn,an imbalance in gut microbiota can further exacerbate the production of reactive oxygen species and contribute to a pro-inflammatory environment within the body.This creates a vicious cycle that not only promotes the progression of stroke but also leads to adverse functional outcomes.The neuroinflammation and intestinal microbiota dysbiosis that occur following ischemic stroke are critical contributors to stroke progression and adverse functional outcomes.We previously developed manganese-iron Prussian blue nanozymes,characterized by a multi-enzyme structure and a porous design,that exhibit strong antioxidant properties.However,the therapeutic effects of manganese-iron Prussian blue nanozymes on ischemic stroke and their mechanisms of action remain have not been fully elucidated.To investigate this,we constructed a mouse model of middle cerebral artery occlusion and administered manganese-iron Prussian blue nanozymes via gastric gavage.Our results demonstrated that these nanozymes substantially reduced infarct volume,improved neurological function,restored gut microbiota balance,and increased levels of short-chain fatty acids in the mouse model.Treatment of lipopolysaccharide-treated BV-2 cells with short-chain fatty acids markedly decreased the expression levels of components of the Toll-like receptor 4/nuclear factor kappa B signaling pathway,including Toll-like receptor 4,inhibitor of nuclear factor kappa-B kinase subunit alpha,and pp65.These findings suggest that manganese-iron Prussian blue nanozymes can correct gut microbiota dysbiosis and increase short-chain fatty acid production by modulating the Toll-like receptor 4/nuclear factor kappa B signaling pathway,thereby providing therapeutic benefits in the context of ischemic stroke.展开更多
Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic...Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.展开更多
OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in ...OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in the treatment of LPS-induced lung inflammation.METHODS:The pneumonia model was established by intraperitoneal injection of 5 mg/kg LPS in mice.Cytokines were detected by enzyme-linked immuneosorbent assay(ELISA),macrophages in lung tissue were determined by immunofluorescence,and pathwayrelated data were determined by quantitative real-time polymerase chain reaction(qPCR)and Western blot.RESULTS:The liver,thymus,and spleen index values and the levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)obviously increased in LPS-treated mice.FZXF decreased the white blood cell count and reduced the increase in the lung wet weight/dry weight ratio caused by LPS.The hematoxylin-eosin staining result showed that FZXF could maintain the integrity of lung tissue structure,alleviate interstitial oedema and alveolar wall thickening,and reduce inflammatory cell infiltration.Moreover,FZXF markedly reduced the expression of proinflammatory cytokines.FZXF also significantly reduced LPS-induced malondialdehyde production and increased superoxide dismutase level in the lung.By immunofluorescence,we found that FZXF could reduce macrophage infiltration.The mRNA expression levels of cyclooxygenase-2(COX-2),prostaglandin E2(PGE2),toll-like receptor 4(TLR4)and nuclear transcription factorκB(NF-κB)in the lung tissue of mice were decreased by treatment with FZXF.In addition,FZXF inhibited the protein expression of TLR4,p-p65 and COX-2.These results indicated that FZXF could inhibit the inflammatory response of LPS induced cytokine storm in mice through TLR4/NF-κB and COX-2/PGE2 signaling pathway.CONCLUSION:These findings were suggested that FZXF prescription suppresses inflammation in LPSinduced pneumonia in mice via TLR4/NF-κB and COX-2/PGE2 pathway.展开更多
BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed th...BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.展开更多
BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pa...BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pain,rebound tenderness,and rapid onset.Its pathogenesis is complex and potentially linked to infection,environment,and genetics.Timely intervention is crucial to prevent complications.While surgery is the primary treatment,it carries risks,including postoperative infections that may necessitate re-operation.Gram-negative bacteria release endotoxin(ETX),which induces inflammation and is recognized by toll-like receptor 4(TLR4).This study evaluated ETX and TLR4 levels in patients with acute appendicitis to assess the risk of postoperative incision infections,aiding in prevention and treatment.AIM To explore ETX and TLR4 expression in the blood of patients with acute appendicitis and its association with in postoperative incision infection.METHODS A total of 153 patients with acute appendicitis treated at our hospital between April 2022 and March 2024(n=153)were included in the study.Patients were categorized into infected(n=36)and uninfected(n=117)groups according to the development of postoperative incision infections.General characteristics and blood levels of ETX and TLR4 were compared,and the factors influencing postoperative infection were identified using multivariate logistic regression.ETX and TLR4 predictive values were analyzed using receiver operating characteristic curves.RESULTS No statistically significant differences were observed between the two groups in terms of sex,age,or other general characteristics(P>0.05).Compared to the uninfected group,the infected group had a higher proportion of patients with suppurative or gangrenous appendicitis,longer surgical times,longer incision lengths,and elevated ETX and TLR4 levels(P<0.05).Multivariate logistic regression analysis identified pathological type,surgical method,surgical time,and incision length as factors influencing postoperative incision infection in acute appendicitis.Receiver operating characteristic curve analysis revealed that both ETX and TLR4 levels were predictive factors for postoperative incision infection,with higher prediction efficiency when combined.CONCLUSION Pathological type,surgical method,surgical time,and incision length significantly influence postoperative incision infection risk in patients with acute appendicitis.Elevated ETX and TLR4 levels serve as valuable predictors of post-appendectomy infections.展开更多
Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor ...Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.展开更多
BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primar...BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.展开更多
Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induce...Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.展开更多
Background Konjac oligosaccharide(KOS),which is produced through the degradation of konjac glucomannan via enzymatic,chemical,or physical treatments,has been found to have laxative effects.The current study aimed to e...Background Konjac oligosaccharide(KOS),which is produced through the degradation of konjac glucomannan via enzymatic,chemical,or physical treatments,has been found to have laxative effects.The current study aimed to elucidate the mechanisms underlying the laxative effect of KOS.Methods KOS was administered by gavage to wild-type and 5-hydroxytryptamine 4 receptor(5-HT4R)-knockout C57BL/6 mice subjected to loperamide-induced constipation for four weeks.Following treatment,feces,blood,small intestine,colonic tissue,and intestinal contents were collected.Constipation-related parameters,gastrointestinal hormones,and Ca2+concentrations were evaluated.Histopathological changes were examined via hematoxylin and eosin staining.Immunofluorescence staining,Western blotting,and immunohistochemical staining were performed to detect the 5-HT4R/cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)pathway.Isolated smooth muscle cells(SMCs)were treated with KOS and GR113808(a 5-HT4R antagonist),morphologically observed under an inverted microscope,and identified byα-SMA immunofluorescence staining.Cell viability was assessed via CCK-8 assays.5-HT4R/cAMP/PKA/p-CREB pathway activity in SMCs was detected via Western blotting.Results KOS alleviated loperamide-induced constipation in mice.KOS activated the 5-HT4R/cAMP/PKA/p-CREB pathway in loperamide-induced constipated mice.The protective effect of KOS was significantly diminished in 5-HT4R−/−mice.KOS promoted the proliferation of SMCs by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.Conclusion KOS improves loperamide-induced constipation by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.展开更多
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
基金Supported by Shandong Provincial Natural Science,Study on the Structure-Activity Relationship and Mechanism of Licorice Chalcone Components in Synergizing with Immune Checkpoint Inhibitors for Anticancer Therapy(No.ZR2020MH380)Mechanisms of the Novel Flavone C-Glycoside 6'-ORhamnosyllutonarin from Dianthus superbus Improves Non-alcoholic Fatty Liver Disease via Modulating the Juxtaposed with Another Zinc Finger gene 1/Adenosine Monophosphate-activated Protein Kinase/Sterol Regulatory Element-Binding Protein Pathway(No.ZR2024MC209)。
文摘OBJECTIVE:To explore the mechanism of Baitouweng Tang(白头翁汤,Pulsatilla decoction,PD)alleviates dextran sulfate sodium(DSS)-induced ulcerative colitis(UC)in mice by integrating network pharmacology prediction with experimental validation,focusing on the modulation of inflammatory signaling.METHODS:A chronic UC model was induced in C57BL/6 mice by cyclical administration of DSS.Mice were treated with either a low(15 m L/kg)or high(30 m L/kg)dose of PD.Disease severity was assessed clinically and via histopathology.Serum levels of inflammatory cytokines were quantified.A network pharmacology approach was employed to predict the core targets and pathways of PD against UC.Key predictions concerning the toll-like receptor 4/nuclear factor-kappa B(TLR4/NF-κB)pathway were subsequently verified in colonic tissue using quantitative polymerase chain reaction and Western blotting.RESULTS:PD treatment significantly ameliorated DSSinduced UC symptoms,including reducing disease activity,preventing colon shortening,and improving histological architecture.PD effectively rebalanced the systemic inflammatory milieu by decreasing proinflammatory cytokines interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)and elevating anti-inflammatory cytokines interleukin-10(IL-10).Network pharmacology analysis identified the TLR4/NF-κB signaling pathway as a central target.Experimental validation confirmed that PD markedly suppressed the upregulation of both TLR4 and NF-κB at the transcriptional and protein levels in the inflamed colon.CONCLUSION:PD demonstrates protective effects against experimental UC.Its mechanism is associated with the inhibition of the TLR4/NF-κB signaling pathway and the subsequent attenuation of inflammatory responses.This study provides a modern pharmacological basis for the classical application of PD in treating heat-toxin related intestinal disorders,bridging traditional use and mechanistic understanding.
基金Supported by the‘Pioneer’R&D Program of Zhejiang:Research on Key Technologies for the Development of Traditional Chinese Medicine New Drugs(No.2023C03004)National Key Research and Development Program of China:Mechanism Study and Clinical Exploration of Electroacupuncture Promoting Immune Normalization+4 种基金Supporting the Body and Inhibiting Cancer,Synergistic Programmed Death Receptor 1/Programmed Cell Death Ligand 1 Monoclonal Antibody therapy for Intestinal and Biliary Tumors(No.2023YFC3504600)Zhejiang Province Traditional Chinese Medicine Science and Technology Project:Clinical Metabolomics Based Discovery of Effective Markers for Nourishing Yin of Radix Ophiopogonis in the Treatment of Gestational Diabetes(No.GZY-ZJKJ-24076)the‘Pioneer’R&D Program of Zhejiang:Analysis of the Complex System of Traditional Chinese Medicine and Development of New Chinese Medicine Drugs-Analysis of the Complex Cross Organ Action Mode of Traditional Chinese Medicine for Anti-Coronary Heart Disease and Blood Stasis Syndrome and Development of New Drugs(No.2024C03106)Health and Medicinal Research Fund from Health Burden,Hong Kong Special Administrative Region of the People's Republic of China:Chinese Versus Western Medicine for Threatened Miscarriage:Abridged Secondary Publication(No.15160971)Transverse Research Project of Zhejiang University:Development of Traditional Chinese Medicine Big Health Formula for Reproductive Health(No.2023-KYY-A070350007)。
文摘OBJECTIVE:To elucidate the anti-inflammatory mechanisms of modified Shoutai pills(改良寿胎丸,MSTP)in miscarriages,we performed transcriptome sequencing on the decidua and placental tissues of pregnancy mice.METHODS:The therapeutic effects and antiinflammatory mechanisms of MSTP were studied in mice with lipopolysaccharide(LPS)-induced miscarriage.First,the effects of MSTP on pregnancy outcomes and the maternal-fetal interface,in LPS-induced miscarriage mice were examined.RNA sequencing was used to further investigate gene expression changes in LPS-induced miscarriage mice and to assess the effects of MSTP intervention.Finally,the expression levels of inflammation-related genes in the decidua and placental tissues were determined using quantitative real-time polymerase chain reaction(q RT-PCR).RESULTS:A high dose of MSTP significantly decreased the resorption rate(P<0.05)and reduced apoptosis of the decidua and placental tissues in mice.Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that inflammatory and immune-related signals were enriched.q RT-PCR results confirmed that in decidual and placental tissues,MSTP reduced the gene expression levels of toll-like receptor 4(TLR4),nuclear factor kappa-B(NF-κB),c-Jun N-terminal kinase 1,p38,and tumor necrosis factor-α.CONCLUSIONS:In this study,we demonstrated that MSTP effectively prevented embryo loss with an antiinflammatory mechanism through downregulation of the TLR4-NF-κB/MAPK signaling pathway,in LPS-induced miscarriage mice model.To our knowledge,this is the first study to reveal the therapeutic mechanism of MSTP in LPS-induced miscarriage in mice.
基金National Natural Science Foundation of China,No.82271440Jiangxi Provincial Health Technology Project,No.202510009(both to LX).
文摘Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Ischemic stroke represents a significant global health challenge,frequently associated with intricate pathophysiological alterations.During ischemic stroke,the generation of reactive oxygen species markedly increases,leading to direct neuronal damage as well as initiating a cascade of inflammatory responses.This oxidative stress can also disturb the equilibrium of the gut microbiota,resulting in dysbiosis.In turn,an imbalance in gut microbiota can further exacerbate the production of reactive oxygen species and contribute to a pro-inflammatory environment within the body.This creates a vicious cycle that not only promotes the progression of stroke but also leads to adverse functional outcomes.The neuroinflammation and intestinal microbiota dysbiosis that occur following ischemic stroke are critical contributors to stroke progression and adverse functional outcomes.We previously developed manganese-iron Prussian blue nanozymes,characterized by a multi-enzyme structure and a porous design,that exhibit strong antioxidant properties.However,the therapeutic effects of manganese-iron Prussian blue nanozymes on ischemic stroke and their mechanisms of action remain have not been fully elucidated.To investigate this,we constructed a mouse model of middle cerebral artery occlusion and administered manganese-iron Prussian blue nanozymes via gastric gavage.Our results demonstrated that these nanozymes substantially reduced infarct volume,improved neurological function,restored gut microbiota balance,and increased levels of short-chain fatty acids in the mouse model.Treatment of lipopolysaccharide-treated BV-2 cells with short-chain fatty acids markedly decreased the expression levels of components of the Toll-like receptor 4/nuclear factor kappa B signaling pathway,including Toll-like receptor 4,inhibitor of nuclear factor kappa-B kinase subunit alpha,and pp65.These findings suggest that manganese-iron Prussian blue nanozymes can correct gut microbiota dysbiosis and increase short-chain fatty acid production by modulating the Toll-like receptor 4/nuclear factor kappa B signaling pathway,thereby providing therapeutic benefits in the context of ischemic stroke.
基金National Natural Science Foundation of China,Grant/Award Number:82260007Jilin Province Health Commission,Grant/Award Number:2024A062+1 种基金Jilin Provincial Department of Education,Grant/Award Number:JJKH20240698KJJilin Province Science and Technology Department,Grant/Award Number:20240404025ZP and 20240602100RC。
文摘Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.
基金Emergency Corona Virus Disease 2019(COVID-19)Response Project of Dongguan:Clinical Efficacy Observation and Mechanism Study of Fuzheng Xuanfei Huashi Formula in the Treatment of COVID-19 Based on the Lingnan Theory of Epidemic Diseases(No.202071715002124)National Natural Science Foundation of China:Study on the Mechanism of Lung Inflammatory Injury Induced by Gut-derived Lipopolysaccharide and Skatole in Spleen Deficiency Animals based on Pulmonary Alveolus Macrophage Heterogeneity(No.82274381)Guangdong Basic and Applied Basic Research Foundation:Development and Industrialization of Traditional Chinese Medicine Classic and Famous Prescription Compound Formulations(No.2021ZD006)。
文摘OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in the treatment of LPS-induced lung inflammation.METHODS:The pneumonia model was established by intraperitoneal injection of 5 mg/kg LPS in mice.Cytokines were detected by enzyme-linked immuneosorbent assay(ELISA),macrophages in lung tissue were determined by immunofluorescence,and pathwayrelated data were determined by quantitative real-time polymerase chain reaction(qPCR)and Western blot.RESULTS:The liver,thymus,and spleen index values and the levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)obviously increased in LPS-treated mice.FZXF decreased the white blood cell count and reduced the increase in the lung wet weight/dry weight ratio caused by LPS.The hematoxylin-eosin staining result showed that FZXF could maintain the integrity of lung tissue structure,alleviate interstitial oedema and alveolar wall thickening,and reduce inflammatory cell infiltration.Moreover,FZXF markedly reduced the expression of proinflammatory cytokines.FZXF also significantly reduced LPS-induced malondialdehyde production and increased superoxide dismutase level in the lung.By immunofluorescence,we found that FZXF could reduce macrophage infiltration.The mRNA expression levels of cyclooxygenase-2(COX-2),prostaglandin E2(PGE2),toll-like receptor 4(TLR4)and nuclear transcription factorκB(NF-κB)in the lung tissue of mice were decreased by treatment with FZXF.In addition,FZXF inhibited the protein expression of TLR4,p-p65 and COX-2.These results indicated that FZXF could inhibit the inflammatory response of LPS induced cytokine storm in mice through TLR4/NF-κB and COX-2/PGE2 signaling pathway.CONCLUSION:These findings were suggested that FZXF prescription suppresses inflammation in LPSinduced pneumonia in mice via TLR4/NF-κB and COX-2/PGE2 pathway.
基金Supported by Research Fund for Academician Lin He New Medicine,No.JYHL2022FMS02.
文摘BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
文摘BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pain,rebound tenderness,and rapid onset.Its pathogenesis is complex and potentially linked to infection,environment,and genetics.Timely intervention is crucial to prevent complications.While surgery is the primary treatment,it carries risks,including postoperative infections that may necessitate re-operation.Gram-negative bacteria release endotoxin(ETX),which induces inflammation and is recognized by toll-like receptor 4(TLR4).This study evaluated ETX and TLR4 levels in patients with acute appendicitis to assess the risk of postoperative incision infections,aiding in prevention and treatment.AIM To explore ETX and TLR4 expression in the blood of patients with acute appendicitis and its association with in postoperative incision infection.METHODS A total of 153 patients with acute appendicitis treated at our hospital between April 2022 and March 2024(n=153)were included in the study.Patients were categorized into infected(n=36)and uninfected(n=117)groups according to the development of postoperative incision infections.General characteristics and blood levels of ETX and TLR4 were compared,and the factors influencing postoperative infection were identified using multivariate logistic regression.ETX and TLR4 predictive values were analyzed using receiver operating characteristic curves.RESULTS No statistically significant differences were observed between the two groups in terms of sex,age,or other general characteristics(P>0.05).Compared to the uninfected group,the infected group had a higher proportion of patients with suppurative or gangrenous appendicitis,longer surgical times,longer incision lengths,and elevated ETX and TLR4 levels(P<0.05).Multivariate logistic regression analysis identified pathological type,surgical method,surgical time,and incision length as factors influencing postoperative incision infection in acute appendicitis.Receiver operating characteristic curve analysis revealed that both ETX and TLR4 levels were predictive factors for postoperative incision infection,with higher prediction efficiency when combined.CONCLUSION Pathological type,surgical method,surgical time,and incision length significantly influence postoperative incision infection risk in patients with acute appendicitis.Elevated ETX and TLR4 levels serve as valuable predictors of post-appendectomy infections.
基金Supported by Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH124001-2406National Natural Science Foundation of China,No.U23A20483.
文摘Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.
文摘BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.
基金supported by the National Natural Science Foundation of China(No.82273628).
文摘Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.
文摘Background Konjac oligosaccharide(KOS),which is produced through the degradation of konjac glucomannan via enzymatic,chemical,or physical treatments,has been found to have laxative effects.The current study aimed to elucidate the mechanisms underlying the laxative effect of KOS.Methods KOS was administered by gavage to wild-type and 5-hydroxytryptamine 4 receptor(5-HT4R)-knockout C57BL/6 mice subjected to loperamide-induced constipation for four weeks.Following treatment,feces,blood,small intestine,colonic tissue,and intestinal contents were collected.Constipation-related parameters,gastrointestinal hormones,and Ca2+concentrations were evaluated.Histopathological changes were examined via hematoxylin and eosin staining.Immunofluorescence staining,Western blotting,and immunohistochemical staining were performed to detect the 5-HT4R/cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)pathway.Isolated smooth muscle cells(SMCs)were treated with KOS and GR113808(a 5-HT4R antagonist),morphologically observed under an inverted microscope,and identified byα-SMA immunofluorescence staining.Cell viability was assessed via CCK-8 assays.5-HT4R/cAMP/PKA/p-CREB pathway activity in SMCs was detected via Western blotting.Results KOS alleviated loperamide-induced constipation in mice.KOS activated the 5-HT4R/cAMP/PKA/p-CREB pathway in loperamide-induced constipated mice.The protective effect of KOS was significantly diminished in 5-HT4R−/−mice.KOS promoted the proliferation of SMCs by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.Conclusion KOS improves loperamide-induced constipation by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.
