Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer tre...Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer treatment.While its efficacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufficiently explored.This study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)models.Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug resistance.Ourfindings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells.However,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway activation.Introducing TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efficacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size reduction.In conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.展开更多
Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely r...Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely related to their physicochemical properties,and establishment of a structure-activity relationship for nanomaterials at the nano-bio interface is of great significance for deep understanding antibacterial toxicity mechanisms of nanomaterials and designing safer antibacterial nanomaterials.In this study,the antibacterial behaviors of well-defined crystallographic facets of a series of Au nanocrystals,including{100}-facet cubes,{110}-facet rhombic dodecahedra,{111}-facet octahedra,{221}-facet trisoctahedra and{720}-facet concave cubes,was investigated,using the model bacteria Staphylococcus aureus.We find that Au nanocrystals display substantial facet-dependent antibacterial activities.The low-index facets of cubes,octahedra,and rhombic dodecahedra show considerable antibacterial activity,whereas the high-index facets of trisoctahedra and concave cubes remained inert under biological conditions.This result is in stark contrast to the previous paradigm that the high-index facets were considered to have higher bioactivity as compared with low-index facets.The antibacterial mechanism studies have shown that the facet-dependent antibacterial behaviors of Au nanocrystals are mainly caused by differential bacterial membrane damage as well as inhibition of cellular enzymatic activity and energy metabolism.The faceted Au nanocrystals are unique in that they do not induce generation of reactive oxygen species,as validated for most antibiotics and antimicrobial nanostructures.Our findings may provide a deeper understanding of facet-dependent toxicological responses and suggest the complexities of the na no material-cell interactions,shedding some light on the development of high performance Au nanomaterials-based antibacterial therapeutics.展开更多
Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological functio...Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.展开更多
Mitophagy,essential for mitochondrial health,selectively degrades damaged mitochondria.It is intricately linked to the cGAS-STING pathway,which is crucial for innate immunity.This pathway responds to mitochondrial DNA...Mitophagy,essential for mitochondrial health,selectively degrades damaged mitochondria.It is intricately linked to the cGAS-STING pathway,which is crucial for innate immunity.This pathway responds to mitochondrial DNA and is associated with cellular stress response.Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway.We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions,primarily through the accumulation of damaged mitochondria,which activates the cGAS-STING pathway.This activation prompts the production of pro-inflammatory cytokines,exacerbating neuroinflammation.This review emphasizes the interaction between mitophagy and the cGAS-STING pathways.Effective mitophagy may suppress the cGAS-STING pathway,offering protection against neuroinflammation.Conversely,impaired mitophagy may activate the cGAS-STING pathway,leading to chronic neuroinflammation.Additionally,we explored how this interaction influences neurodegenerative disorders,suggesting a common mechanism underlying these diseases.In conclusion,there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration.This review highlights potential therapies targeting these pathways,potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions.This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.展开更多
Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients ...Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.展开更多
基金supported by the Sichuan Science and Technology Program(Grant Nos.2020YJ0494,24GJHZ0058,21RCYJ0021,and 2022YFS0620)the National Natural Science Foundation of China(Grant No.81903829)+1 种基金the Southwest Medical University Science and Technology Program(Grant Nos.2021ZKZD015,2021ZKZD018,and 2021ZKMS046)the Macao Science and Technology Development Fund of Macao SAR(Project Nos.SKLQRCM(MUST)-2020-2022 and MUST-SKL-2021-005).
文摘Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer treatment.While its efficacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufficiently explored.This study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)models.Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug resistance.Ourfindings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells.However,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway activation.Introducing TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efficacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size reduction.In conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.
基金the National Key Research and Development Program of China(No.2017YFA0205300)the National Natural Science Foundation of China(Nos.21675023 and 91753106)the Scientific Research Foundation of Southwest Medical University(No.19120200037)。
文摘Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely related to their physicochemical properties,and establishment of a structure-activity relationship for nanomaterials at the nano-bio interface is of great significance for deep understanding antibacterial toxicity mechanisms of nanomaterials and designing safer antibacterial nanomaterials.In this study,the antibacterial behaviors of well-defined crystallographic facets of a series of Au nanocrystals,including{100}-facet cubes,{110}-facet rhombic dodecahedra,{111}-facet octahedra,{221}-facet trisoctahedra and{720}-facet concave cubes,was investigated,using the model bacteria Staphylococcus aureus.We find that Au nanocrystals display substantial facet-dependent antibacterial activities.The low-index facets of cubes,octahedra,and rhombic dodecahedra show considerable antibacterial activity,whereas the high-index facets of trisoctahedra and concave cubes remained inert under biological conditions.This result is in stark contrast to the previous paradigm that the high-index facets were considered to have higher bioactivity as compared with low-index facets.The antibacterial mechanism studies have shown that the facet-dependent antibacterial behaviors of Au nanocrystals are mainly caused by differential bacterial membrane damage as well as inhibition of cellular enzymatic activity and energy metabolism.The faceted Au nanocrystals are unique in that they do not induce generation of reactive oxygen species,as validated for most antibiotics and antimicrobial nanostructures.Our findings may provide a deeper understanding of facet-dependent toxicological responses and suggest the complexities of the na no material-cell interactions,shedding some light on the development of high performance Au nanomaterials-based antibacterial therapeutics.
基金We thank Dr.Chirlmin Joo for help in preparing the figure of the TIRFM setup and Dr.Tom Thompson for help with the CD experiments.B.B.,D.L.,L.Z.,W.D.,and B.J.were supported by funds from the National Natural Science Foundation of China(NSFC 11932017,11772054,11772055,11532009,11902051,and 31871031)W.D.was supported by the Sichuan Science and Technology Program(2019YJ0481)+1 种基金D.L.was supported by the Fundamental Research Funds for the Central Universities(Grant no.2019QNA4060)J.D.was supported by the Michael J Fox Foundation(ID 16661).
文摘Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.
基金supported by Natural Science Foundation of China(No.81903829,China)Department of Science and Technology of Sichuan Province(Nos.2022YFS0620,2024YFHZ0361,and 22ZDYF3784,China)+3 种基金Macao Science and Technology Development Fund of Macao SAR(Nos.SKL-QRCM(MUST)-2020-2022 and MUST-SKL-2021-005,China)Southwest Medical University(Nos.2021ZKZD015,2021ZKZD018,and 2021ZKMS046,China)Central Government Funds of Guiding Local Scientific and Technological Development(No.23ZYZYTS0211,China)Luzhou Science and Technology Project,China(No.2022-SYF73,China).
文摘Mitophagy,essential for mitochondrial health,selectively degrades damaged mitochondria.It is intricately linked to the cGAS-STING pathway,which is crucial for innate immunity.This pathway responds to mitochondrial DNA and is associated with cellular stress response.Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway.We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions,primarily through the accumulation of damaged mitochondria,which activates the cGAS-STING pathway.This activation prompts the production of pro-inflammatory cytokines,exacerbating neuroinflammation.This review emphasizes the interaction between mitophagy and the cGAS-STING pathways.Effective mitophagy may suppress the cGAS-STING pathway,offering protection against neuroinflammation.Conversely,impaired mitophagy may activate the cGAS-STING pathway,leading to chronic neuroinflammation.Additionally,we explored how this interaction influences neurodegenerative disorders,suggesting a common mechanism underlying these diseases.In conclusion,there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration.This review highlights potential therapies targeting these pathways,potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions.This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
基金supported by the National Natural Science Foundation of China (81000107,30670835,81071072,31171088)the National Basic Research Program of China (2011CB933500)grants from Key Laboratory of Medical Electrophysiology of Sichuan Province (MEPSCKL2011-01)
文摘Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.