AIM:To investigate the protective effects of combinations of probiotic(Bifico)on interleukin(IL)-10-genedeficient(IL-10 KO)mice and Caco-2 cell monolayers.METHODS:IL-10 KO mice were used to assess the benefits of Bifi...AIM:To investigate the protective effects of combinations of probiotic(Bifico)on interleukin(IL)-10-genedeficient(IL-10 KO)mice and Caco-2 cell monolayers.METHODS:IL-10 KO mice were used to assess the benefits of Bifico in vivo.IL-10 KO and control mice received approximately 1.5×108 cfu/d of Bifico for 4 wk.Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber,while an ELISA was used to evaluate proinflammatory cytokines.The colon epithelial cell line,Caco-2,was used to test the benefit of Bifico in vitro.Enteroinvasive Escherichia coli(EIEC)and the probiotic mixture Bifico,or single probiotic strains,were applied to cultured Caco-2 monolayers.Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression.RESULTS:Treatment of IL-10 KO mice with Bifico partially restored body weight,colon length,and epithelial barrier integrity to wild-type levels.In addition,IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-αand interferon-γ,and attenuated colonic disease.Moreover,treatment of Caco-2 monolayers with Bifico or singlestrain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines.CONCLUSION:Bifico reduced colon inflammation in IL-10 KO mice,and promoted and improved epithelialbarrier function,enhanced resistance to EIEC invasion,and decreased proinflammatory cytokine secretion.展开更多
Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disinteg...Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.展开更多
Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many...Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers.Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and gliomatargeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs.The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of mentholmodified casein nanoparticles(M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-MCA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining ofthe organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.展开更多
基金Supported by The National Natural Science Foundation Key Projects of China,No.81230057National Natural Science Foundation of China,No.81172325The Major Basic Research Program of Shanghai,No.12DZ1930502
文摘AIM:To investigate the protective effects of combinations of probiotic(Bifico)on interleukin(IL)-10-genedeficient(IL-10 KO)mice and Caco-2 cell monolayers.METHODS:IL-10 KO mice were used to assess the benefits of Bifico in vivo.IL-10 KO and control mice received approximately 1.5×108 cfu/d of Bifico for 4 wk.Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber,while an ELISA was used to evaluate proinflammatory cytokines.The colon epithelial cell line,Caco-2,was used to test the benefit of Bifico in vitro.Enteroinvasive Escherichia coli(EIEC)and the probiotic mixture Bifico,or single probiotic strains,were applied to cultured Caco-2 monolayers.Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression.RESULTS:Treatment of IL-10 KO mice with Bifico partially restored body weight,colon length,and epithelial barrier integrity to wild-type levels.In addition,IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-αand interferon-γ,and attenuated colonic disease.Moreover,treatment of Caco-2 monolayers with Bifico or singlestrain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines.CONCLUSION:Bifico reduced colon inflammation in IL-10 KO mice,and promoted and improved epithelialbarrier function,enhanced resistance to EIEC invasion,and decreased proinflammatory cytokine secretion.
基金supported by the National Natural Science Foundation of China(U22A20523,32172912,and 32102722)the Interdisciplinary Integration and Innovation Project of Jilin University(JLUXKJC2021QZ04)。
文摘Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.
基金financial support from the National Natural Science Foundation of China(No.81573616,81690263 and81773911,China)the Development Project of Shanghai Peak Disciplines-Integrated Medicine(No.20150407,China)
文摘Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers.Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and gliomatargeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs.The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of mentholmodified casein nanoparticles(M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-MCA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining ofthe organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.
