A dual-site fluorescent probe with double bond and aldehyde as reactive sites, was designed for the selective detection of sulfite and biothiols. Sulfite reacts with conjugate bond selectively, while Cys responses wit...A dual-site fluorescent probe with double bond and aldehyde as reactive sites, was designed for the selective detection of sulfite and biothiols. Sulfite reacts with conjugate bond selectively, while Cys responses with aldehyde and GSH occurs substitution reaction. Different interactions cause different absorption and fluorescence responses. Moreover, it could be further applied in imaging in living cells.展开更多
Background:T cell dysfunction,which includes exhaustion,anergy,and senescence,is a distinct T cell differentiation state that occurs after antigen exposure.Although T cell dysfunction has been a cornerstone of cancer ...Background:T cell dysfunction,which includes exhaustion,anergy,and senescence,is a distinct T cell differentiation state that occurs after antigen exposure.Although T cell dysfunction has been a cornerstone of cancer immunotherapy,its potential in transplant research,while not yet as extensively explored,is attracting growing interest.Interferon regulatory factor 4(IRF4)has been shown to play a pivotal role in inducing T cell dysfunction.Methods:A novel ultra-low-dose combination of Trametinib and Rapamycin,targeting IRF4 inhibition,was employed to investigate T cell proliferation,apoptosis,cytokine secretion,expression of T-cell dysfunction-associated molecules,effects of mitogen-activated protein kinase(MAPK)and mammalian target of rapamycin(mTOR)signaling pathways,and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.Results:In vitro,blockade of IRF4 in T cells effectively inhibited T cell proliferation,increased apoptosis,and significantly upregulated the expression of programmed cell death protein 1(PD-1),Helios,CD160,and cytotoxic T lymphocyte-associated antigen(CTLA-4),markers of T cell dysfunction.Furthermore,it suppressed the secretion of pro-inflammatory cytokines interferon(IFN)-γand interleukin(IL)-17.Combining ultra-low-dose Trametinib(0.1 mg·kg^(-1)·day^(-1))and Rapamycin(0.1 mg·kg^(-1)·day^(-1))demonstrably extended graft survival,with 4 out of 5 mice exceeding 100 days post-transplantation.Moreover,analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4(IRF4)inhibition,enhanced PD-1 expression,and suppressed IFN-γsecretion,reinforcing the in vivo efficacy of this IRF4-targeting approach.The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network,leading to a more pronounced suppression of IRF4 expression.Conclusions:Targeting IRF4,a key regulator of T cell dysfunction,presents a promising avenue for inducing transplant immune tolerance.In this study,we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network,leading to profound IRF4 inhibition,promoting allograft acceptance,and offering a potential new therapeutic strategy for improved transplant outcomes.However,further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.展开更多
Innovative advancements in the development of high-performance,eco-friendly adhesives are critical for meeting the demands of diverse applications in various industries.This study reports a significant leap in adhesiv...Innovative advancements in the development of high-performance,eco-friendly adhesives are critical for meeting the demands of diverse applications in various industries.This study reports a significant leap in adhesive technology by enhancing the interfacial toughness and versatility of polyvinyl alcohol(PVA)through complexation with 1-nm Keggin-type polyoxotungstate clusters(POTs)carrying specific negative charges.The POT-PVA nanocomposites exhibit superior adhesion to hydrophilic surfaces,attributed to their high crosslinking densities and exceptional fracture energies surpassing 6.23 kJ·m^(-2).These adhesives,endowed with high flexibility and a wealth of surface hydroxyl groups,are uniquely suited for application on a wide array of substrates including glass,steel,aluminum,and beyond,demonstrating their broad applicability.Specifically,the reduction in PVA crystallinity due to the chaotropic effect of POTs,which significantly enhances polymer chain dynamics.This enhancement confers robust adhesive properties at extreme temperatures,from the cryogenic−196℃ to the high-temperature threshold of 100℃.By capitalizing on the chaotropic effects of charged POTs,the study achieves a notable enhancement in the adhesive capabilities of the POT-PVA nanocomposites,paving the way for the development of for eco-friendly and cost effective adhesives engineered to withstand extreme conditions.展开更多
Background:Homoharringtonine(HHT)is an effective anti-inflammatory,anti-viral,and anti-tumor protein synthesis inhibitor that has been applied clinically.Here,we explored the therapeutic effects of HHT in a mouse hear...Background:Homoharringtonine(HHT)is an effective anti-inflammatory,anti-viral,and anti-tumor protein synthesis inhibitor that has been applied clinically.Here,we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods:Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver,kidney,and hematology.A mouse heart transplantation model was constructed,and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis,immunostaining,and bulk RNA sequencing analysis.The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells(Tregs)differentiation.Results:HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo.Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days(P<0.001)without non-immune toxicity.The allografts had long-term survival after continuous HHT treatment for 28 days.HHT significantly reduced lymphocyte infiltration in the graft,and interferon-γ-secreting CD4^(+)and CD8^(+)T cells in the spleen(P<0.01).HHT significantly increased the number of peripheral Tregs(about 20%,P<0.001)and serum interleukin(IL)-10 levels.HHT downregulated the expression of T cell receptor(TCR)signaling pathway-related genes(CD4,H2-Eb1,TRAT1,and CD74)and upregulated the expression of IL-10 and transforming growth factor(TGF)-βpathway-related genes and Treg signature genes(CTLA4,Foxp3,CD74,and ICOS).HHT increased CD4^(+)Foxp3^(+)cells and Foxp3 expression ex vivo,and it enhanced the inhibitory function of inducible Tregs.Conclusions:HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels,thereby promoting mouse heart allograft acceptance.These findings may have therapeutic implications for organ transplant recipients,particularly those with viral infections and malignancies,which require a more suitable anti-rejection medication.展开更多
Molecular clusters(MCs)refer to a class of atom collections with sizes ranging from 1 to 10 nms,which are structurally precise and mono-dispersed.Typically,the MC family contains polyoxometalates(POMs),polyhedral olig...Molecular clusters(MCs)refer to a class of atom collections with sizes ranging from 1 to 10 nms,which are structurally precise and mono-dispersed.Typically,the MC family contains polyoxometalates(POMs),polyhedral oligomeric silsesquioxanes(POSSs),metal-organic poly-hedrons(MOPs),fullerene,metal clusters,etc.展开更多
基金financially supported by the National Natural Science Foundation of China (Nos.21572147, 21232005 and J1103315)
文摘A dual-site fluorescent probe with double bond and aldehyde as reactive sites, was designed for the selective detection of sulfite and biothiols. Sulfite reacts with conjugate bond selectively, while Cys responses with aldehyde and GSH occurs substitution reaction. Different interactions cause different absorption and fluorescence responses. Moreover, it could be further applied in imaging in living cells.
基金This study was supported by grants from the National Natural Science Foundation of China(Nos.82070776,82270796,82200849,and 82370761)The Science and Technology Innovation Program of Hunan Province(No.2022RC3071)+1 种基金Natural Science Foundation of Hunan Province(Nos.2023JJ40872 and 2021JJ30946)Higher Education Teaching Reform Project of Central South University(No.2023jy110).
文摘Background:T cell dysfunction,which includes exhaustion,anergy,and senescence,is a distinct T cell differentiation state that occurs after antigen exposure.Although T cell dysfunction has been a cornerstone of cancer immunotherapy,its potential in transplant research,while not yet as extensively explored,is attracting growing interest.Interferon regulatory factor 4(IRF4)has been shown to play a pivotal role in inducing T cell dysfunction.Methods:A novel ultra-low-dose combination of Trametinib and Rapamycin,targeting IRF4 inhibition,was employed to investigate T cell proliferation,apoptosis,cytokine secretion,expression of T-cell dysfunction-associated molecules,effects of mitogen-activated protein kinase(MAPK)and mammalian target of rapamycin(mTOR)signaling pathways,and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.Results:In vitro,blockade of IRF4 in T cells effectively inhibited T cell proliferation,increased apoptosis,and significantly upregulated the expression of programmed cell death protein 1(PD-1),Helios,CD160,and cytotoxic T lymphocyte-associated antigen(CTLA-4),markers of T cell dysfunction.Furthermore,it suppressed the secretion of pro-inflammatory cytokines interferon(IFN)-γand interleukin(IL)-17.Combining ultra-low-dose Trametinib(0.1 mg·kg^(-1)·day^(-1))and Rapamycin(0.1 mg·kg^(-1)·day^(-1))demonstrably extended graft survival,with 4 out of 5 mice exceeding 100 days post-transplantation.Moreover,analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4(IRF4)inhibition,enhanced PD-1 expression,and suppressed IFN-γsecretion,reinforcing the in vivo efficacy of this IRF4-targeting approach.The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network,leading to a more pronounced suppression of IRF4 expression.Conclusions:Targeting IRF4,a key regulator of T cell dysfunction,presents a promising avenue for inducing transplant immune tolerance.In this study,we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network,leading to profound IRF4 inhibition,promoting allograft acceptance,and offering a potential new therapeutic strategy for improved transplant outcomes.However,further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
基金This study was financially supported by the National Natural Science Foundation of China(No.22101086)Guangdong Basic and Applied Basic Research Foundation(Nos.2023A1515140030 and 2024A1515030212).
文摘Innovative advancements in the development of high-performance,eco-friendly adhesives are critical for meeting the demands of diverse applications in various industries.This study reports a significant leap in adhesive technology by enhancing the interfacial toughness and versatility of polyvinyl alcohol(PVA)through complexation with 1-nm Keggin-type polyoxotungstate clusters(POTs)carrying specific negative charges.The POT-PVA nanocomposites exhibit superior adhesion to hydrophilic surfaces,attributed to their high crosslinking densities and exceptional fracture energies surpassing 6.23 kJ·m^(-2).These adhesives,endowed with high flexibility and a wealth of surface hydroxyl groups,are uniquely suited for application on a wide array of substrates including glass,steel,aluminum,and beyond,demonstrating their broad applicability.Specifically,the reduction in PVA crystallinity due to the chaotropic effect of POTs,which significantly enhances polymer chain dynamics.This enhancement confers robust adhesive properties at extreme temperatures,from the cryogenic−196℃ to the high-temperature threshold of 100℃.By capitalizing on the chaotropic effects of charged POTs,the study achieves a notable enhancement in the adhesive capabilities of the POT-PVA nanocomposites,paving the way for the development of for eco-friendly and cost effective adhesives engineered to withstand extreme conditions.
基金supported by grants from the National Natural Science Foundation of China(Nos.82070776,81900370,81970655,82270796,and 82200849)the Science and Technology Innovation Program of Hunan Province(No.2022RC3071)the Natural Science Foundation of Hunan Province(Nos.2021JJ30946 and 2022JJ30808)
文摘Background:Homoharringtonine(HHT)is an effective anti-inflammatory,anti-viral,and anti-tumor protein synthesis inhibitor that has been applied clinically.Here,we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods:Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver,kidney,and hematology.A mouse heart transplantation model was constructed,and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis,immunostaining,and bulk RNA sequencing analysis.The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells(Tregs)differentiation.Results:HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo.Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days(P<0.001)without non-immune toxicity.The allografts had long-term survival after continuous HHT treatment for 28 days.HHT significantly reduced lymphocyte infiltration in the graft,and interferon-γ-secreting CD4^(+)and CD8^(+)T cells in the spleen(P<0.01).HHT significantly increased the number of peripheral Tregs(about 20%,P<0.001)and serum interleukin(IL)-10 levels.HHT downregulated the expression of T cell receptor(TCR)signaling pathway-related genes(CD4,H2-Eb1,TRAT1,and CD74)and upregulated the expression of IL-10 and transforming growth factor(TGF)-βpathway-related genes and Treg signature genes(CTLA4,Foxp3,CD74,and ICOS).HHT increased CD4^(+)Foxp3^(+)cells and Foxp3 expression ex vivo,and it enhanced the inhibitory function of inducible Tregs.Conclusions:HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels,thereby promoting mouse heart allograft acceptance.These findings may have therapeutic implications for organ transplant recipients,particularly those with viral infections and malignancies,which require a more suitable anti-rejection medication.
基金supported by the National Natural Science Foundation of China(No.22241501,92261117,52203087)the Fundamental Research Funds for the Central Universities(2022ZYGXZR055)the Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology,TCL science and technology innovation fund(20222056).
文摘Molecular clusters(MCs)refer to a class of atom collections with sizes ranging from 1 to 10 nms,which are structurally precise and mono-dispersed.Typically,the MC family contains polyoxometalates(POMs),polyhedral oligomeric silsesquioxanes(POSSs),metal-organic poly-hedrons(MOPs),fullerene,metal clusters,etc.
