Mouse peritoneal macrophages were incubated in DMEM with pox-LDL and Rradlx Salviae Miltiorrhizae (RSM) to investigate the effects of RSM on the internalization of peroxidized low density lipoprotein (pox-LDL) by usin...Mouse peritoneal macrophages were incubated in DMEM with pox-LDL and Rradlx Salviae Miltiorrhizae (RSM) to investigate the effects of RSM on the internalization of peroxidized low density lipoprotein (pox-LDL) by using lipid analysis and electron microscopy. Lipid peroxide (LPO) concentrations were increased slightly in the medium after incubation of macrophages with normal LDL (n-LDL), while decreased significantly in the media after incubation of macrophages with pox-LDL. In the three groups with pox-LDL, it could be found that there was a dose-dependent decrease of concentrations of LPO and total cholesterol (TCH) in the two RSM groups, and the decrease in the two RSM groups was much greater than in the group without RSM. RSM accelerated a more decrease of LPO than cholesterol contents in the media containing pox-LDL. The ultrastructural studies also showed that RSM induced the accumulation of lipid droplets in the cytoplasm of mouse peritoneal macrophages. The results suggested that RSM could accelerate the phagocytosis and degradation of pox-LDL by macrophages.展开更多
Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Myc...Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis(Mtb) multidrug-resistant(MDR) isolates, extensively drug-resistant(XDR) isolates, and the H37 RV strain. BP/CL activity against the H37 Rv strain was assessed in liquid cultures, in macrophages, and in mice. Results BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units(CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment(isoniazid + rifampin + pyrazinamide) after 2 months of treatment. Conclusion BP/CL may provide a new option to clinically treat MDR tuberculosis.展开更多
Background:The heterogeneity of prognosis and treatment benefits among patients with gliomas is due to tumor microenvironment characteristics.However,biomarkers that reflect microenvironmental characteristics and predic...Background:The heterogeneity of prognosis and treatment benefits among patients with gliomas is due to tumor microenvironment characteristics.However,biomarkers that reflect microenvironmental characteristics and predict the prognosis of gliomas are limited.Therefore,we aimed to develop a model that can effectively predict prognosis,differentiate microenvironment signatures,and optimize drug selection for patients with glioma.Materials and Methods:The CIBERSORT algorithm,bulk sequencing analysis,and single-cell RNA(scRNA)analysis were employed to identify significant cross-talk genes between M2 macrophages and cancer cells in glioma tissues.A predictive model was constructed based on cross-talk gene expression,and its effect on prognosis,recurrence prediction,and microenvironment characteristics was validated in multiple cohorts.The effect of the predictive model on drug selection was evaluated using the OncoPredict algorithm and relevant cellular biology experiments.Results:A high abundance of M2 macrophages in glioma tissues indicates poor prognosis,and cross-talk between macrophages and cancer cells plays a crucial role in shaping the tumor microenvironment.Eight genes involved in the cross-talk between macrophages and cancer cells were identified.Among them,periostin(POSTN),chitinase 3 like 1(CHI3L1),serum amyloid A1(SAA1),and matrix metallopeptidase 9(MMP9)were selected to construct a predictive model.The developed model demonstrated significant efficacy in distinguishing patient prognosis,recurrent cases,and characteristics of high inflammation,hypoxia,and immunosuppression.Furthermore,this model can serve as a valuable tool for guiding the use of trametinib.Conclusions:In summary,this study provides a comprehensive understanding of the interplay between M2 macrophages and cancer cells in glioma;utilizes a cross-talk gene signature to develop a predictive model that can predict the differentiation of patient prognosis,recurrence instances,and microenvironment characteristics;and aids in optimizing the application of trametinib in glioma patients.展开更多
Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therape...Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therapeutic targets.In the clinic,delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges.Within the scope of our study,high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples.Notably,TNBC exhibited significant specificity regarding cell proliferation,differentiation,and disease progression.Significant associations between tumor grade,prognosis,and TNBC oncogenes were established via pseudotime trajectory analysis.Consequently,we further performed comprehensive characterization of the TNBC microenvironment.A crucial epithelial subcluster,E8,was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC.Additionally,epithelial-mesenchymal transition(EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions,contributing to tumor growth.Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC.The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs,such as pelitinib.We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model.Overall,our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.展开更多
The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavail...The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.展开更多
As a natural immune cell and antigen presenting cell,macrophages have been studied and engineered to treat human diseases.Macrophages are well-suited for use as drug carriers because of their biological characteristic...As a natural immune cell and antigen presenting cell,macrophages have been studied and engineered to treat human diseases.Macrophages are well-suited for use as drug carriers because of their biological characteristics,such as excellent biocompatibility,long circulation,intrinsic inflammatory homing and phagocytosis.Meanwhile,macrophages’uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors.Although recent studies have demonstrated promising advances in macrophage-based drug delivery,several challenges currently hinder further improvement of therapeutic effect and clinical application.This article focuses on the main challenges of utilizing macrophage-based drug delivery,from the selection of macrophage sources,drug loading,and maintenance of macrophage phenotypes,to drug migration and release at target sites.In addition,corresponding strategies and insights related to these challenges are described.Finally,we also provide perspective on shortcomings on the road to clinical translation and production.展开更多
Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI...Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to months.Recent knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic targets.Hepatic macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental cues.In this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.展开更多
文摘Mouse peritoneal macrophages were incubated in DMEM with pox-LDL and Rradlx Salviae Miltiorrhizae (RSM) to investigate the effects of RSM on the internalization of peroxidized low density lipoprotein (pox-LDL) by using lipid analysis and electron microscopy. Lipid peroxide (LPO) concentrations were increased slightly in the medium after incubation of macrophages with normal LDL (n-LDL), while decreased significantly in the media after incubation of macrophages with pox-LDL. In the three groups with pox-LDL, it could be found that there was a dose-dependent decrease of concentrations of LPO and total cholesterol (TCH) in the two RSM groups, and the decrease in the two RSM groups was much greater than in the group without RSM. RSM accelerated a more decrease of LPO than cholesterol contents in the media containing pox-LDL. The ultrastructural studies also showed that RSM induced the accumulation of lipid droplets in the cytoplasm of mouse peritoneal macrophages. The results suggested that RSM could accelerate the phagocytosis and degradation of pox-LDL by macrophages.
基金supported by the Beijing Medical Award Foundation [YJHYXKYJJ-104]
文摘Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate(BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis(Mtb) multidrug-resistant(MDR) isolates, extensively drug-resistant(XDR) isolates, and the H37 RV strain. BP/CL activity against the H37 Rv strain was assessed in liquid cultures, in macrophages, and in mice. Results BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units(CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment(isoniazid + rifampin + pyrazinamide) after 2 months of treatment. Conclusion BP/CL may provide a new option to clinically treat MDR tuberculosis.
基金funded by the Scientific Research Project of the Higher Education Department of Guizhou Province[Qianjiaoji 2022(187)]Department of Education of Guizhou Province[Guizhou Teaching and Technology(2023)015]+1 种基金Guizhou Medical University National Natural Science Foundation Cultivation Project(22NSFCP45)China Postdoctoral Science Foundation Project(General Program No.2022M720929).
文摘Background:The heterogeneity of prognosis and treatment benefits among patients with gliomas is due to tumor microenvironment characteristics.However,biomarkers that reflect microenvironmental characteristics and predict the prognosis of gliomas are limited.Therefore,we aimed to develop a model that can effectively predict prognosis,differentiate microenvironment signatures,and optimize drug selection for patients with glioma.Materials and Methods:The CIBERSORT algorithm,bulk sequencing analysis,and single-cell RNA(scRNA)analysis were employed to identify significant cross-talk genes between M2 macrophages and cancer cells in glioma tissues.A predictive model was constructed based on cross-talk gene expression,and its effect on prognosis,recurrence prediction,and microenvironment characteristics was validated in multiple cohorts.The effect of the predictive model on drug selection was evaluated using the OncoPredict algorithm and relevant cellular biology experiments.Results:A high abundance of M2 macrophages in glioma tissues indicates poor prognosis,and cross-talk between macrophages and cancer cells plays a crucial role in shaping the tumor microenvironment.Eight genes involved in the cross-talk between macrophages and cancer cells were identified.Among them,periostin(POSTN),chitinase 3 like 1(CHI3L1),serum amyloid A1(SAA1),and matrix metallopeptidase 9(MMP9)were selected to construct a predictive model.The developed model demonstrated significant efficacy in distinguishing patient prognosis,recurrent cases,and characteristics of high inflammation,hypoxia,and immunosuppression.Furthermore,this model can serve as a valuable tool for guiding the use of trametinib.Conclusions:In summary,this study provides a comprehensive understanding of the interplay between M2 macrophages and cancer cells in glioma;utilizes a cross-talk gene signature to develop a predictive model that can predict the differentiation of patient prognosis,recurrence instances,and microenvironment characteristics;and aids in optimizing the application of trametinib in glioma patients.
基金funded by the National Natural Science Foundation of China(Grant Nos:62172131 and 81872135)the Outstanding Youth Foundation of Heilongjiang Province of China(Grant No.:YQ2021C026).
文摘Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therapeutic targets.In the clinic,delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges.Within the scope of our study,high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples.Notably,TNBC exhibited significant specificity regarding cell proliferation,differentiation,and disease progression.Significant associations between tumor grade,prognosis,and TNBC oncogenes were established via pseudotime trajectory analysis.Consequently,we further performed comprehensive characterization of the TNBC microenvironment.A crucial epithelial subcluster,E8,was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC.Additionally,epithelial-mesenchymal transition(EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions,contributing to tumor growth.Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC.The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs,such as pelitinib.We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model.Overall,our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.
基金supported by Military Medical Innovation Project(16CXZ032)National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(No.2018ZX09J18107-03,2018ZX09721003-005-009)。
文摘The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.
基金supported by National Natural Science Foundation of China(NSFC82003702,NSFC31571195).
文摘As a natural immune cell and antigen presenting cell,macrophages have been studied and engineered to treat human diseases.Macrophages are well-suited for use as drug carriers because of their biological characteristics,such as excellent biocompatibility,long circulation,intrinsic inflammatory homing and phagocytosis.Meanwhile,macrophages’uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors.Although recent studies have demonstrated promising advances in macrophage-based drug delivery,several challenges currently hinder further improvement of therapeutic effect and clinical application.This article focuses on the main challenges of utilizing macrophage-based drug delivery,from the selection of macrophage sources,drug loading,and maintenance of macrophage phenotypes,to drug migration and release at target sites.In addition,corresponding strategies and insights related to these challenges are described.Finally,we also provide perspective on shortcomings on the road to clinical translation and production.
基金supported by USA National Institutes of Health(NIH)funds R01DK109574 and R01DK122708(C.Ju).
文摘Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to months.Recent knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic targets.Hepatic macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental cues.In this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.
