Background:Myeloid differentiation factor 88(MyD88)is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction.Howeve...Background:Myeloid differentiation factor 88(MyD88)is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction.However,the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial.This study aims to investigate the impact of MyD88 on intestinal inflammation and theunderlyingmechanism.Methods:MyD88 knockout(MyD88^(-/-))mice and the MyD88 inhibitor(TJ-M2010-5)were used to investigate the impact of MyD88 on acute dextran sodium sulfate(Dss)-induced colitis.Disease activity index,colon length,histological score,and inflammatory cytokines were examined to evaluate the severity of colitis.RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism.Results:In an acute DSS-colitis model,the severity of colitis was not alleviated in MyD88^(-/-)mice and TJ-M2010-5-treated mice,despite significantly lower levels of NF-kB activation being exhibited compared to control mice.Meanwhile,16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the nucleotide oligomerization domain-like receptors(NLRs)signaling pathway in colitis mice following MyD88 suppression.Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DsS-induced colitis mice treated with TJ-M2010-5 ameiorated the disease severity,which was not improved solely by MyD88 inhibition.After treatment with broad-spectrum antibiotics,downregulation of the NLR signaling pathway was observed.Conclusion:Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota,leading to NLR-mediated immune activation and intestinal inflammation.展开更多
Objective:To study the therapeutic effect of crocin on diabetic retinopathy(DR)in rats based on toll-like receptor 4(TLR4)/myeloid differentiation factor 88(My D88)/nuclear factor-κB(NF-κB)pathway.Methods:Thirty SPF...Objective:To study the therapeutic effect of crocin on diabetic retinopathy(DR)in rats based on toll-like receptor 4(TLR4)/myeloid differentiation factor 88(My D88)/nuclear factor-κB(NF-κB)pathway.Methods:Thirty SPF SD rats were used in the experiment,which were randomly divided into DR group,control group and crocin group,with 10 rats in each group.The DR rat model was established by feeding the rats in both the DR group and crocin group with a high glucose and high fat diet,along with intraperitoneal injection(IP)of streptozotocin.Crocin IP was administered to the rats in the crocin group,whereas the rats in the DR group and control group received an equivalent dosage of saline IP for 12 weeks.A comparison was made among the three groups regarding retinal thickness,vascular permeability,expression of TLR4/My D88/NF-κB pathway protein,levels of inflammatory factors,and levels of Bcl-2,Bax,and Bcl-2/Bax.Results:The DR group and crocins group exhibited a lower retinal thickness compared to the control group,while the crocins group displayed a higher thickness than the DR group.The DR group and crocins group had higher retinal vascular permeability than the control group,and the crocins group had lower retinal vascular permeability than the DR group(P<0.05).TLR4,My D88,and P-NF-κB relative expressions were higher in the DR and crocin groups than in the control group,whereas TLR4,My D88,and P-NF-κB relative expressions were lower in the crocin group than in the DR group(P<0.05).The DR group and crocin group exhibited elevated levels of inflammatory cytokines compared to the control group,while the crocin group displayed decreased levels in comparison to the DR group(P<0.05).The DR group and crocin group exhibited lower levels of Bcl-2 and Bcl-2/Bax compared to the control group,whereas the control group displayed higher levels of Bax.The crocin group exhibited elevated levels of Bcl-2 and Bcl-2/Bax compared to the DR group,whereas the DR group displayed diminished levels of Bax(P<0.05).Conclusion:Crocin has the potential to enhance the retinal thickness and vascular permeability of DR rats,and the inhibition of the TLR4/My D88/NF-κB pathway by crocin could play a crucial role in impeding the advancement of DR.展开更多
基金the National Natural Science Foundation of China(Grant Nos.81873556 and 82170546 to FX)China Crohn's&Colitis Foundation(Grant No.CCCF-QF-2022B67-3 to FX)the Tongji Hospital Clinical Research Flagship Program(Grant No.2019CR209 to DT).We thank Prof.Ping Zhou for providing the inhibitor of MyD88 TJ-M2010-5(TJ5).
文摘Background:Myeloid differentiation factor 88(MyD88)is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction.However,the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial.This study aims to investigate the impact of MyD88 on intestinal inflammation and theunderlyingmechanism.Methods:MyD88 knockout(MyD88^(-/-))mice and the MyD88 inhibitor(TJ-M2010-5)were used to investigate the impact of MyD88 on acute dextran sodium sulfate(Dss)-induced colitis.Disease activity index,colon length,histological score,and inflammatory cytokines were examined to evaluate the severity of colitis.RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism.Results:In an acute DSS-colitis model,the severity of colitis was not alleviated in MyD88^(-/-)mice and TJ-M2010-5-treated mice,despite significantly lower levels of NF-kB activation being exhibited compared to control mice.Meanwhile,16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the nucleotide oligomerization domain-like receptors(NLRs)signaling pathway in colitis mice following MyD88 suppression.Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DsS-induced colitis mice treated with TJ-M2010-5 ameiorated the disease severity,which was not improved solely by MyD88 inhibition.After treatment with broad-spectrum antibiotics,downregulation of the NLR signaling pathway was observed.Conclusion:Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota,leading to NLR-mediated immune activation and intestinal inflammation.
文摘Objective:To study the therapeutic effect of crocin on diabetic retinopathy(DR)in rats based on toll-like receptor 4(TLR4)/myeloid differentiation factor 88(My D88)/nuclear factor-κB(NF-κB)pathway.Methods:Thirty SPF SD rats were used in the experiment,which were randomly divided into DR group,control group and crocin group,with 10 rats in each group.The DR rat model was established by feeding the rats in both the DR group and crocin group with a high glucose and high fat diet,along with intraperitoneal injection(IP)of streptozotocin.Crocin IP was administered to the rats in the crocin group,whereas the rats in the DR group and control group received an equivalent dosage of saline IP for 12 weeks.A comparison was made among the three groups regarding retinal thickness,vascular permeability,expression of TLR4/My D88/NF-κB pathway protein,levels of inflammatory factors,and levels of Bcl-2,Bax,and Bcl-2/Bax.Results:The DR group and crocins group exhibited a lower retinal thickness compared to the control group,while the crocins group displayed a higher thickness than the DR group.The DR group and crocins group had higher retinal vascular permeability than the control group,and the crocins group had lower retinal vascular permeability than the DR group(P<0.05).TLR4,My D88,and P-NF-κB relative expressions were higher in the DR and crocin groups than in the control group,whereas TLR4,My D88,and P-NF-κB relative expressions were lower in the crocin group than in the DR group(P<0.05).The DR group and crocin group exhibited elevated levels of inflammatory cytokines compared to the control group,while the crocin group displayed decreased levels in comparison to the DR group(P<0.05).The DR group and crocin group exhibited lower levels of Bcl-2 and Bcl-2/Bax compared to the control group,whereas the control group displayed higher levels of Bax.The crocin group exhibited elevated levels of Bcl-2 and Bcl-2/Bax compared to the DR group,whereas the DR group displayed diminished levels of Bax(P<0.05).Conclusion:Crocin has the potential to enhance the retinal thickness and vascular permeability of DR rats,and the inhibition of the TLR4/My D88/NF-κB pathway by crocin could play a crucial role in impeding the advancement of DR.
