Parkinson's disease(PD) is an aging-associated neurodegenerative movement disorder with increasing morbidity and mortality rates.The current gold standard for diagnosing PD is clinical evaluation,which is often ch...Parkinson's disease(PD) is an aging-associated neurodegenerative movement disorder with increasing morbidity and mortality rates.The current gold standard for diagnosing PD is clinical evaluation,which is often challenging and inaccurate.Metabolomics and lipidomics approaches have been extensively applied because of their potential in discovering valuable biomarkers for medical diagnostics.Here,we used comprehensive untargeted metabolomics and lipidomics methodologies based on liquid chromatographymass spectrometry to evaluate metabolic abnormalities linked with PD.Two well-characterized cohorts of288 plasma samples(143 PD patients and 145 control subjects in total) were used to examine metabolic alterations and identify diagnostic biomarkers.Unbiased multivariate and univariate studies were combined to identify the promising metabolic signatures,based on which the discriminant models for PD were established by integrating multiple machine learning algorithms.A 6-biomarker predictive model was constructed based on the omics profile in the discovery cohort,and the discriminant performance of the biomarker panel was evaluated with an accuracy over 81.6% both in the discovery cohort and validation cohort.The results indicated that PC(40:7),eicosatrienoic acid were negatively correlated with severity of PD,and pentalenic acid,PC(40:6p) and aspartic acid were positively correlated with severity of PD.In summary,we developed a multi-metabolite predictive model which can diagnose PD with over81.6% accuracy based on this unique metabolic signature.Future clinical diagnosis of PD may benefit from the biomarker panel reported in this study.展开更多
Multidrug resistance(MDR)is a serious obstacle encountered in cancer treatment.This study was performed to explore the reversal MDR activity of ivermectin(IVM)from avermectin family and moxidectin(MOX)belonging to mil...Multidrug resistance(MDR)is a serious obstacle encountered in cancer treatment.This study was performed to explore the reversal MDR activity of ivermectin(IVM)from avermectin family and moxidectin(MOX)belonging to milbemycin family.The two compounds(5μmol•L-1)showed strong potency to increase adriamycin cytotoxicity toward adriamycin-resistant rat glioma cells C6/adr with fold reversal(FR)of 31.02 and 13.40,respectively.In addition,the mechanisms of them on p-glycoprotein(P-gp)-mediated MDR demonstrated that the two compounds significantly increased the intracellular accumulations of adriamycin and Rh123 via inhibiting P-gp efflux.Based on the analysis of P-gp,MDR1 and MRP1 gene expressions by using immunofluorescence flow cytometry and RT-PCR,the results revealed that the two compounds could down regulate the expression of P-gp,and that MDR1 and MRP1 gene expressions were down regulated.These findings suggested that ivermectin and moxidectin probably represented potent agents for reversing MDR in cancer therapy,and especially ivermectin was a better modulator.展开更多
Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is ne...Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 μM dantrolene, hypothermia（at 33°C）, or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.展开更多
Excess production of reactive oxygen species （ROS） critically contributes to occurrence of reperfusion injury, the paradoxical response of ischemic brain tissue to restoration of cerebral blood flow. However, the en...Excess production of reactive oxygen species （ROS） critically contributes to occurrence of reperfusion injury, the paradoxical response of ischemic brain tissue to restoration of cerebral blood flow. However, the enzymatic sources of ROS generation remain to be unclear. This study examined Nox2-ontaining NADPH oxidase （Nox2） expression and its activity in ischemic brain tissue following post-ischemic reperfusion to clarify the mechanism of enzymatic reaction of ROS. Male Sprague-Dawley rats were subjected to 90-minute middle cerebral artery occlusion, followed by 3 or 22.5 hours of reperfusion. Quantitative reverse transcriptase PCR and western blot assay were performed to measure mRNA and protein expression of Nox2. Lucigenin fluorescence assays were performed to assess Nox activity. Our data showed that Nox2 mRNA and protein expression levels were significantly increased （3.7-fold for mRNA and 3.6-fold for protein） in ischemic brain tissue at 22.5 hours but not at 3 hours following post-ischemic reperfusion. Similar results were obtained for the changes of NADPH oxidase activity in ischemic cerebral tissue at the two reperfusion time points. Our results suggest that Nox2 may not contribute to the early burst of reperfusion-related ROS generation, but is rather an important source of ROS generation during prolonged reperfusion.展开更多
<strong>Objective:</strong> Abnormal miRNA expression is observed in several human tumors;moreover, normal cell regulation can be disrupted by tumor-suppressive or oncogenic miRNAs. We aimed to investigate...<strong>Objective:</strong> Abnormal miRNA expression is observed in several human tumors;moreover, normal cell regulation can be disrupted by tumor-suppressive or oncogenic miRNAs. We aimed to investigate the role of miR-637 in gliomas. <strong>Methods: </strong>We assessed miR-637 expression in 98 and 16 gliomas and non-tumoral brain tissues, respectively, using in situ hybridization. We calculated receiver operating characteristic curves to determine the specificity and sensitivity of miR-637 biomarkers. Next, the effects of miR-637 on glioma cell migration and invasion were determined by using the transwell assay. Candidate target genes were identified through Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. <strong>Results: </strong>There was significant miR-637 downregulation in glioma tissues (P < 0.001). Further, it showed potential as a diagnostic biomarker for gliomas. In addition, miR-637 suppressed glioma cell migration and invasion. <strong>Conclusions: </strong>Our findings suggest that miR-637 inhibits glioma invasion and migration and could be a potential diagnostic marker for gliomas. Future studies should examine the potential mechanisms underlying miR-637 as a diagnostic marker and therapeutic target for gliomas.展开更多
Parkinson’s disease(PD)is a complex neurological disorder that typically worsens with age.A wide range of pathologies makes PD a very heterogeneous condition,and there are currently no reliable diagnostic tests for t...Parkinson’s disease(PD)is a complex neurological disorder that typically worsens with age.A wide range of pathologies makes PD a very heterogeneous condition,and there are currently no reliable diagnostic tests for this disease.The application of metabolomics to the study of PD has the potential to identify disease biomarkers through the systematic evaluation of metabolites.In this study,urine metabolic profiles of 215 urine samples from 104 PD patients and 111 healthy individuals were assessed based on liquid chromatography-mass spectrometry.The urine metabolic profile was first evaluated with partial leastsquares discriminant analysis,and then we integrated the metabolomic data with ensemble machine learning techniques using the voting strategy to achieve better predictive performance.A combination of 8-metabolite predictive panel performed well with an accuracy of over 90.7%.Compared to control subjects,PD patients had higher levels of 3-methoxytyramine,N-acetyl-l-tyrosine,orotic acid,uric acid,vanillic acid,and xanthine,and lower levels of 3,3-dimethylglutaric acid and imidazolelactic acid in their urine.The multi-metabolite prediction model developed in this study can serve as an initial point for future clinical studies.展开更多
Glioblastoma multiforme(GBM)is a highly aggressive brain tumor with an extremely low survival rate.New and effective approaches for treatment are therefore urgently needed.Here,we successfully developed M1-like macrop...Glioblastoma multiforme(GBM)is a highly aggressive brain tumor with an extremely low survival rate.New and effective approaches for treatment are therefore urgently needed.Here,we successfully developed M1-like macrophage-derived extracellular vesicles(M1EVs)that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients:enrichment of M2 macrophages in GBM;and origination of a majority of infiltrating macrophage from peripheral blood.To maximize the synergistic effect,we further functionalized the membranes of M1EVs with two hydrophobic agents(the chemical excitation source CPPO(C)and the photosensitizer Ce6(C))and loaded the hydrophilic hypoxiaactivated prodrug AQ4N(A)into the inner core of the M1EVs.After intravenous injection,the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration,and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization,which increased hydrogen peroxide(H_(2)O_(2))levels.Furthermore,the reaction between H_(2)O_(2) and CPPO produced chemical energy,which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy(CDT).As this reaction consumed oxygen,the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy.Therefore,CCA-M1EVs achieved synergistic immunomodulation,CDT,and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect.Finally,we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models,underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.展开更多
Multiple myeloma(MM)is the second most common hematological tumor.It is characterized by high drug resistance,easy recurrence,and poor prognosis,and remains incurable.Various models or scoring modalities can be used t...Multiple myeloma(MM)is the second most common hematological tumor.It is characterized by high drug resistance,easy recurrence,and poor prognosis,and remains incurable.Various models or scoring modalities can be used to predict the survival prognosis of MM patients;however,these predictions are still not accurate enough.We have previously found that scorings related to bone marrow microenvironment metabolism can improve predictive efficacy.展开更多
基金support from the Collaborative Research Fund (No.C2011-21GF)Guangdong Province Basic and Applied Basic Research Foundation (No.2021B1515120051)。
文摘Parkinson's disease(PD) is an aging-associated neurodegenerative movement disorder with increasing morbidity and mortality rates.The current gold standard for diagnosing PD is clinical evaluation,which is often challenging and inaccurate.Metabolomics and lipidomics approaches have been extensively applied because of their potential in discovering valuable biomarkers for medical diagnostics.Here,we used comprehensive untargeted metabolomics and lipidomics methodologies based on liquid chromatographymass spectrometry to evaluate metabolic abnormalities linked with PD.Two well-characterized cohorts of288 plasma samples(143 PD patients and 145 control subjects in total) were used to examine metabolic alterations and identify diagnostic biomarkers.Unbiased multivariate and univariate studies were combined to identify the promising metabolic signatures,based on which the discriminant models for PD were established by integrating multiple machine learning algorithms.A 6-biomarker predictive model was constructed based on the omics profile in the discovery cohort,and the discriminant performance of the biomarker panel was evaluated with an accuracy over 81.6% both in the discovery cohort and validation cohort.The results indicated that PC(40:7),eicosatrienoic acid were negatively correlated with severity of PD,and pentalenic acid,PC(40:6p) and aspartic acid were positively correlated with severity of PD.In summary,we developed a multi-metabolite predictive model which can diagnose PD with over81.6% accuracy based on this unique metabolic signature.Future clinical diagnosis of PD may benefit from the biomarker panel reported in this study.
基金Supported by the National Natural Science Foundation of China(81201723)。
文摘Multidrug resistance(MDR)is a serious obstacle encountered in cancer treatment.This study was performed to explore the reversal MDR activity of ivermectin(IVM)from avermectin family and moxidectin(MOX)belonging to milbemycin family.The two compounds(5μmol•L-1)showed strong potency to increase adriamycin cytotoxicity toward adriamycin-resistant rat glioma cells C6/adr with fold reversal(FR)of 31.02 and 13.40,respectively.In addition,the mechanisms of them on p-glycoprotein(P-gp)-mediated MDR demonstrated that the two compounds significantly increased the intracellular accumulations of adriamycin and Rh123 via inhibiting P-gp efflux.Based on the analysis of P-gp,MDR1 and MRP1 gene expressions by using immunofluorescence flow cytometry and RT-PCR,the results revealed that the two compounds could down regulate the expression of P-gp,and that MDR1 and MRP1 gene expressions were down regulated.These findings suggested that ivermectin and moxidectin probably represented potent agents for reversing MDR in cancer therapy,and especially ivermectin was a better modulator.
基金supported by a grant from the Guangdong Science&Technology Plan Program in China,No.2014A020212043the a grant from the Shenzhen Science&Technology Plan Program in China,No.JCYJ20140414170821242+1 种基金the a grant from Shenzhen Collaborative Innovation Plan Program in China,No.GJHZ20120614154914623a grant from the Science&Technology Project of Shanxi Health and Family Planning Commission in China,No.201201060
文摘Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 μM dantrolene, hypothermia（at 33°C）, or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.
基金financially supported by grants from Shenzhen Science and Technology Innovation Commission of China,No.JCYJ20150330102401097,KQCX20140521101427034,JCYJ20140414170821291China Postdoctoral Science Foundation,No.2015M572388
文摘Excess production of reactive oxygen species （ROS） critically contributes to occurrence of reperfusion injury, the paradoxical response of ischemic brain tissue to restoration of cerebral blood flow. However, the enzymatic sources of ROS generation remain to be unclear. This study examined Nox2-ontaining NADPH oxidase （Nox2） expression and its activity in ischemic brain tissue following post-ischemic reperfusion to clarify the mechanism of enzymatic reaction of ROS. Male Sprague-Dawley rats were subjected to 90-minute middle cerebral artery occlusion, followed by 3 or 22.5 hours of reperfusion. Quantitative reverse transcriptase PCR and western blot assay were performed to measure mRNA and protein expression of Nox2. Lucigenin fluorescence assays were performed to assess Nox activity. Our data showed that Nox2 mRNA and protein expression levels were significantly increased （3.7-fold for mRNA and 3.6-fold for protein） in ischemic brain tissue at 22.5 hours but not at 3 hours following post-ischemic reperfusion. Similar results were obtained for the changes of NADPH oxidase activity in ischemic cerebral tissue at the two reperfusion time points. Our results suggest that Nox2 may not contribute to the early burst of reperfusion-related ROS generation, but is rather an important source of ROS generation during prolonged reperfusion.
文摘<strong>Objective:</strong> Abnormal miRNA expression is observed in several human tumors;moreover, normal cell regulation can be disrupted by tumor-suppressive or oncogenic miRNAs. We aimed to investigate the role of miR-637 in gliomas. <strong>Methods: </strong>We assessed miR-637 expression in 98 and 16 gliomas and non-tumoral brain tissues, respectively, using in situ hybridization. We calculated receiver operating characteristic curves to determine the specificity and sensitivity of miR-637 biomarkers. Next, the effects of miR-637 on glioma cell migration and invasion were determined by using the transwell assay. Candidate target genes were identified through Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. <strong>Results: </strong>There was significant miR-637 downregulation in glioma tissues (P < 0.001). Further, it showed potential as a diagnostic biomarker for gliomas. In addition, miR-637 suppressed glioma cell migration and invasion. <strong>Conclusions: </strong>Our findings suggest that miR-637 inhibits glioma invasion and migration and could be a potential diagnostic marker for gliomas. Future studies should examine the potential mechanisms underlying miR-637 as a diagnostic marker and therapeutic target for gliomas.
基金support from the Collaborative Research Fund(No.C2011–21GF)from Guangdong Province Basic and Applied Basic Research Foundation(No.2021B1515120051).
文摘Parkinson’s disease(PD)is a complex neurological disorder that typically worsens with age.A wide range of pathologies makes PD a very heterogeneous condition,and there are currently no reliable diagnostic tests for this disease.The application of metabolomics to the study of PD has the potential to identify disease biomarkers through the systematic evaluation of metabolites.In this study,urine metabolic profiles of 215 urine samples from 104 PD patients and 111 healthy individuals were assessed based on liquid chromatography-mass spectrometry.The urine metabolic profile was first evaluated with partial leastsquares discriminant analysis,and then we integrated the metabolomic data with ensemble machine learning techniques using the voting strategy to achieve better predictive performance.A combination of 8-metabolite predictive panel performed well with an accuracy of over 90.7%.Compared to control subjects,PD patients had higher levels of 3-methoxytyramine,N-acetyl-l-tyrosine,orotic acid,uric acid,vanillic acid,and xanthine,and lower levels of 3,3-dimethylglutaric acid and imidazolelactic acid in their urine.The multi-metabolite prediction model developed in this study can serve as an initial point for future clinical studies.
基金the National Natural Science Foundation of China(82003303,to X.W.,82102205,to H.D.,81772685,to W.L.,21821005,to G.M.,U2001224,to W.W.)the National Key R&D Program of China(2017YFA0207900,to W.W.)+1 种基金the National Key Research and Development Program of China(2020YFC1316900,2020YFC1316901)the Science and Technology Innovation Committee of Shenzhen Municipality(ZDSYS20140509173142601,ZDSYS201707281114196,ZDSYS20200811142600003,JSGG20191129144225464).
文摘Glioblastoma multiforme(GBM)is a highly aggressive brain tumor with an extremely low survival rate.New and effective approaches for treatment are therefore urgently needed.Here,we successfully developed M1-like macrophage-derived extracellular vesicles(M1EVs)that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients:enrichment of M2 macrophages in GBM;and origination of a majority of infiltrating macrophage from peripheral blood.To maximize the synergistic effect,we further functionalized the membranes of M1EVs with two hydrophobic agents(the chemical excitation source CPPO(C)and the photosensitizer Ce6(C))and loaded the hydrophilic hypoxiaactivated prodrug AQ4N(A)into the inner core of the M1EVs.After intravenous injection,the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration,and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization,which increased hydrogen peroxide(H_(2)O_(2))levels.Furthermore,the reaction between H_(2)O_(2) and CPPO produced chemical energy,which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy(CDT).As this reaction consumed oxygen,the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy.Therefore,CCA-M1EVs achieved synergistic immunomodulation,CDT,and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect.Finally,we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models,underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.
基金the Sun Yat-sen University Hundred Talents Program(China)(No.PT19200101)Natural Science Foundation of Guangdong Province,China(No.2022A1515010290)+4 种基金Guangdong Province Science and Technology Planning Project of China(No.2020A1414010033)Guangzhou Science and Technology Planning Project of China(No.202102020430)YL was supported,in part,by Sun Yat-sen University Start-up Funding(China)(No.201603)H-XL was supported by the National Natural Science Foundation of China(No.81773103)the Natural Science Foundation of Guangdong Province,China(No.2017A030313617).
文摘Multiple myeloma(MM)is the second most common hematological tumor.It is characterized by high drug resistance,easy recurrence,and poor prognosis,and remains incurable.Various models or scoring modalities can be used to predict the survival prognosis of MM patients;however,these predictions are still not accurate enough.We have previously found that scorings related to bone marrow microenvironment metabolism can improve predictive efficacy.
