Objective The metabolic reprogramming of acute myeloid leukemia(AML)cells is a compensatory adaptation to meet energy requirements for rapid proliferation.This study aimed to examine the synergistic effects of glutami...Objective The metabolic reprogramming of acute myeloid leukemia(AML)cells is a compensatory adaptation to meet energy requirements for rapid proliferation.This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells.Methods SKM-1 cells(an AML cell line)were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide(BPTES,a glutaminase inhibitor)or cytarabine.Cell viability was detected by Cell Counting Kit-8(CCK-8)assay,and cell apoptosis and reactive oxygen species(ROS)by flow cytometry.Western blotting was conducted to examine the levels of apoptotic proteins,including cleaved caspase-3 and poly(ADP-ribose)polymerase(PARP).Moreover,the human long noncoding RNA(lncRNA)microarray was used to analyze gene expression after glutamine deprivation,and results were confirmed with quantitative RT-PCR(qRT-PCR).The expression of metallothionein 2A(MT2A)was suppressed using siRNA.Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry,respectively,in cells with MT2A knockdown.Results Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells.The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation.MT2A knockdown increased apoptosis,while proliferation was not affected in SKM-1 cells.In addition,metformin inhibited cell growth and induced apoptosis in SKM-1 cells.Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine.Furthermore,the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells.Conclusion Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.展开更多
Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemo...Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.展开更多
Viola×wittrockiana(pansy)is an important ornamental plant,particularly during winter and spring.In previous studies,we found that the tyrosine decarboxylase gene of pansy(VwTYDC)was expressed differently in blotc...Viola×wittrockiana(pansy)is an important ornamental plant,particularly during winter and spring.In previous studies,we found that the tyrosine decarboxylase gene of pansy(VwTYDC)was expressed differently in blotched and non-blotched areas of pansy petals,suggesting that tyrosine may have a role in anthocyanin biosynthesis.In this study,we found that virus-induced gene silencing of VwTYDC caused an accumulation of pink pigmentation in pansy petals.Likewise,exogenous tyrosine treatment(TYRT)induced the formation of black stripes in nonblotched petal areas.Metabolome analysis indicated that the contents of two anthocyanins,cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside,increased significantly in the TYRT areas.RT-qPCR results revealed that the anthocyanin-related genes VwHCT,VwC3′H,VwCHS,and VwUGT were upregulated in the same areas.Transcriptome analysis revealed that four genes involved in the abscisic acid(ABA)biosynthesis pathway(VwNCED,VwABA2,VwAAO3,and VwCYP707A)were significantly upregulated in the same TYRT areas.ABA content was measured by ESI-HPLCMS/MS,and ABA content was significantly higher in TYRT areas than in control areas.In addition,when exogenous ABA was spread onto nonblotched petal areas,anthocyanin biosynthesis genes were upregulated just as with tyrosine.Thus,transcriptome and metabolite analyses revealed a possible novel regulatory network for anthocyanin biosynthesis in which tyrosine induces ABA synthesis and ABA then promotes anthocyanin biosynthesis in pansy petals.展开更多
The real-world vaccine protection rates(VPRs)against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection are critical in formulating future vaccination strategies against the virus.Based on a vary...The real-world vaccine protection rates(VPRs)against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection are critical in formulating future vaccination strategies against the virus.Based on a varying coefficient stochastic epidemic model,we obtain 7 countries’real-world VPRs using daily epidemiological and vaccination data,and find that the VPRs improved with more vaccine doses.The average VPR of the full vaccination was 82%(SE:4%)and 61%(SE:3%)in the pre-Delta and Deltadominated periods,respectively.The Omicron variant reduced the average VPR of the full vaccination to 39%(SE:2%).However,the booster dose restored the VPR to 63%(SE:1%)which was significantly above the 50%threshold in the Omicron-dominated period.Scenario analyses show that the existing vaccination strategies have significantly delayed and reduced the timing and the magnitude of the infection peaks,respectively,and doubling the existing booster coverage would lead to 29%fewer confirmed cases and 17%fewer deaths in the 7 countries compared to the outcomes at the existing booster taking rates.These call for higher full vaccine and booster coverage for all countries.展开更多
Objective:To investigate the effects of lactoferrin(Lf)on hepatic pyroptosis(an inflammatory form of programmed cell death)in mice exposed to radiation.Methods:A total of thirty-six BALB/c male mice were randomly divi...Objective:To investigate the effects of lactoferrin(Lf)on hepatic pyroptosis(an inflammatory form of programmed cell death)in mice exposed to radiation.Methods:A total of thirty-six BALB/c male mice were randomly divided into four groups,namely the control group,5 Gy group,5 Gyþ2 mg Lf group,and 5 Gyþ4 mg Lf group.The mice were administered whole-body ionizing radiation using a PRIMUS accelerator,with a single dose of 5 Gy and an absorbed dose rate of 2.0 Gy/min at a source-skin distance of 100 cm.Lf solution was intraperitoneally injected into the mice 2 h before and per day after radiation.The mice were sacrificed 1,3,and 9 d after radiation,and their livers were used for histopathologic examination,immunohistochemistry analysis,and Western blot analysis for absent in melanoma 2(AIM2)inflammasome pathway.Results:Histopathologic examination showed the disorder of the hepatocellular structure and the accumulation of inflammatory cells after radiation.Lf intervention inhibited hepatocellular proliferation and decreased the infiltration of inflammatory cells.Immunohistochemistry analysis indicated that AIM2 overexpression was significantly attenuated by 4 mg of Lf(t=3.065,P<0.05)3 d after radiation and by 2 mg and 4 mg of Lf(t=4.032,t=2.786,P<0.05)9 d after radiation.Western blot analysis showed that Lf downregulated the hepatic overexpression of AIM2,apoptosis-associated speck-like protein containing a caspase activation and recruitment domain(ASC),IL-1β,and IL-18.2 mg of Lf significantly downregulated the abovementioned protein expression 3 d(t=7.934,4.092,5.193,2.916,P<0.05)and 9 d after radiation(t=5.016,3.882,9.528,P<0.05 for AIM2,ASC,IL-1β).Conclusions:Lf intervention suppressed the hepatic pyroptosis in mice exposed to ionizing radiation by downregulating the protein expression of AIM2 inflammasome.展开更多
基金supported by the National Natural Science Foundation of China(No.82270177).
文摘Objective The metabolic reprogramming of acute myeloid leukemia(AML)cells is a compensatory adaptation to meet energy requirements for rapid proliferation.This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells.Methods SKM-1 cells(an AML cell line)were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide(BPTES,a glutaminase inhibitor)or cytarabine.Cell viability was detected by Cell Counting Kit-8(CCK-8)assay,and cell apoptosis and reactive oxygen species(ROS)by flow cytometry.Western blotting was conducted to examine the levels of apoptotic proteins,including cleaved caspase-3 and poly(ADP-ribose)polymerase(PARP).Moreover,the human long noncoding RNA(lncRNA)microarray was used to analyze gene expression after glutamine deprivation,and results were confirmed with quantitative RT-PCR(qRT-PCR).The expression of metallothionein 2A(MT2A)was suppressed using siRNA.Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry,respectively,in cells with MT2A knockdown.Results Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells.The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation.MT2A knockdown increased apoptosis,while proliferation was not affected in SKM-1 cells.In addition,metformin inhibited cell growth and induced apoptosis in SKM-1 cells.Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine.Furthermore,the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells.Conclusion Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.
基金the National Natural Science Foundation of China(No.81770211)。
文摘Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.
基金supported by the National Natural Science Foundation of China(Grant No.32160719,32060365 and 31760590)the Natural Science Foundation of Guizhou Province(No.ZK[2022]095)the Cultivation Research Program of Guizhou University(No.[2018]5781).
文摘Viola×wittrockiana(pansy)is an important ornamental plant,particularly during winter and spring.In previous studies,we found that the tyrosine decarboxylase gene of pansy(VwTYDC)was expressed differently in blotched and non-blotched areas of pansy petals,suggesting that tyrosine may have a role in anthocyanin biosynthesis.In this study,we found that virus-induced gene silencing of VwTYDC caused an accumulation of pink pigmentation in pansy petals.Likewise,exogenous tyrosine treatment(TYRT)induced the formation of black stripes in nonblotched petal areas.Metabolome analysis indicated that the contents of two anthocyanins,cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside,increased significantly in the TYRT areas.RT-qPCR results revealed that the anthocyanin-related genes VwHCT,VwC3′H,VwCHS,and VwUGT were upregulated in the same areas.Transcriptome analysis revealed that four genes involved in the abscisic acid(ABA)biosynthesis pathway(VwNCED,VwABA2,VwAAO3,and VwCYP707A)were significantly upregulated in the same TYRT areas.ABA content was measured by ESI-HPLCMS/MS,and ABA content was significantly higher in TYRT areas than in control areas.In addition,when exogenous ABA was spread onto nonblotched petal areas,anthocyanin biosynthesis genes were upregulated just as with tyrosine.Thus,transcriptome and metabolite analyses revealed a possible novel regulatory network for anthocyanin biosynthesis in which tyrosine induces ABA synthesis and ABA then promotes anthocyanin biosynthesis in pansy petals.
基金This research is funded by National Natural Science Foundation of China Grants 92046021,12071013,and 12026607.
文摘The real-world vaccine protection rates(VPRs)against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection are critical in formulating future vaccination strategies against the virus.Based on a varying coefficient stochastic epidemic model,we obtain 7 countries’real-world VPRs using daily epidemiological and vaccination data,and find that the VPRs improved with more vaccine doses.The average VPR of the full vaccination was 82%(SE:4%)and 61%(SE:3%)in the pre-Delta and Deltadominated periods,respectively.The Omicron variant reduced the average VPR of the full vaccination to 39%(SE:2%).However,the booster dose restored the VPR to 63%(SE:1%)which was significantly above the 50%threshold in the Omicron-dominated period.Scenario analyses show that the existing vaccination strategies have significantly delayed and reduced the timing and the magnitude of the infection peaks,respectively,and doubling the existing booster coverage would lead to 29%fewer confirmed cases and 17%fewer deaths in the 7 countries compared to the outcomes at the existing booster taking rates.These call for higher full vaccine and booster coverage for all countries.
基金The study was supported by the National Natural Science Foundation of China(82073482).
文摘Objective:To investigate the effects of lactoferrin(Lf)on hepatic pyroptosis(an inflammatory form of programmed cell death)in mice exposed to radiation.Methods:A total of thirty-six BALB/c male mice were randomly divided into four groups,namely the control group,5 Gy group,5 Gyþ2 mg Lf group,and 5 Gyþ4 mg Lf group.The mice were administered whole-body ionizing radiation using a PRIMUS accelerator,with a single dose of 5 Gy and an absorbed dose rate of 2.0 Gy/min at a source-skin distance of 100 cm.Lf solution was intraperitoneally injected into the mice 2 h before and per day after radiation.The mice were sacrificed 1,3,and 9 d after radiation,and their livers were used for histopathologic examination,immunohistochemistry analysis,and Western blot analysis for absent in melanoma 2(AIM2)inflammasome pathway.Results:Histopathologic examination showed the disorder of the hepatocellular structure and the accumulation of inflammatory cells after radiation.Lf intervention inhibited hepatocellular proliferation and decreased the infiltration of inflammatory cells.Immunohistochemistry analysis indicated that AIM2 overexpression was significantly attenuated by 4 mg of Lf(t=3.065,P<0.05)3 d after radiation and by 2 mg and 4 mg of Lf(t=4.032,t=2.786,P<0.05)9 d after radiation.Western blot analysis showed that Lf downregulated the hepatic overexpression of AIM2,apoptosis-associated speck-like protein containing a caspase activation and recruitment domain(ASC),IL-1β,and IL-18.2 mg of Lf significantly downregulated the abovementioned protein expression 3 d(t=7.934,4.092,5.193,2.916,P<0.05)and 9 d after radiation(t=5.016,3.882,9.528,P<0.05 for AIM2,ASC,IL-1β).Conclusions:Lf intervention suppressed the hepatic pyroptosis in mice exposed to ionizing radiation by downregulating the protein expression of AIM2 inflammasome.
