FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remissio...FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remission rate,patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors(TKIs),such as gilteritinib.And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression.Thus,further investigation is warranted for these FLT3mu,AML patients to achieve a better treatment outcome.4-Hydroxyphenyl retinamide(4-HPR)has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence,with minimal side effects.In this study,we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets.CD34+ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR.Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD.Next,we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD.These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML cells irrespective of stem/progenitor cells or blast cells.4-HPR-induced reactive oxygen species(ROS)production and NF-kB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.展开更多
Objective:Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China.In this study,we aimed to explore its bioactive constituent which contributes to the a...Objective:Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China.In this study,we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity.Methods:Polyphenol-enriched and polyphenol-deprived fractions(PRF and PDF,respectively)were separated from the ethanolic extract by HPD300 macroporous resin-based method,and their antiinflammatory activities were investigated on a lipopolysaccharide(LPS)-induced acute lung injury(ALI)model in rats.The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells.Results:Both Folin-Ciocalteu and^(1)H nuclear magnetic resonance(NMR)analyses showed that polyphenolic content in PRF was approximately 10 times higher than that of PDF,and this observation reflected in their antioxidative capacities.PRF but not PDF significantly decreased the level of malondialdehyde,suppressed the expression of nicotinamide phosphoribosyltransferase(NAMPT)protein,and improved the severity of ALI in rats.PRF at 10μg/mL effectively downregulated the expression of proteins NAMPT,HMGB1,TLR4,and p-p65,and scavenged the intracellular reactive oxygen species(ROS)in LPS-primed RAW264.7 cells.N-acetyl-L-cysteine exhibited similar inhibitory effects on ROS production and NAMPT-mediated TLR4/NF-κB activation in vitro,whereas nicotinamide mononucleotide antagonized all the changes induced by PRF during cotreatments.Conclusion:As an antioxidant,PRF exhibited potent anti-inflammatory activity under both in vivo and in vitro conditions by downregulating NAMPT and TLR4/NF-κB.Accordingly,polyphenols were identified as important bioactive constituents in S.inappendiculata targeting oxidative stress-sensitive proinflammatory pathways.展开更多
基金This work was partially funded by the National Natural Science Foundation of China(No.81300401)St.Baldrick’s Foundation International Scholar(No.581580)+1 种基金Natural Science Foundation of Guangdong Province(No.2015A030313460)Guangzhou Women and Children’s Medical Center(No.IP-2008-001 and No.GCP-2019-006).
文摘FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remission rate,patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors(TKIs),such as gilteritinib.And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression.Thus,further investigation is warranted for these FLT3mu,AML patients to achieve a better treatment outcome.4-Hydroxyphenyl retinamide(4-HPR)has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence,with minimal side effects.In this study,we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets.CD34+ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR.Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD.Next,we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD.These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML cells irrespective of stem/progenitor cells or blast cells.4-HPR-induced reactive oxygen species(ROS)production and NF-kB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.
基金supported by National Natural Science Foundation of China(81603388,81973828 and 81173596)Major Project of Natural Science Foundation of the Department of Education of Anhui province(KJ2019ZD32)+1 种基金Funding of"Peak"Training Program for Scientific Research of Yijishan Hospital,Wannan Medical College(GF2019J01)Key Project of Natural Science Foundation of Anhui Province for College Scholar(KJ2019A0416 and KJ2018A0249)。
文摘Objective:Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China.In this study,we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity.Methods:Polyphenol-enriched and polyphenol-deprived fractions(PRF and PDF,respectively)were separated from the ethanolic extract by HPD300 macroporous resin-based method,and their antiinflammatory activities were investigated on a lipopolysaccharide(LPS)-induced acute lung injury(ALI)model in rats.The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells.Results:Both Folin-Ciocalteu and^(1)H nuclear magnetic resonance(NMR)analyses showed that polyphenolic content in PRF was approximately 10 times higher than that of PDF,and this observation reflected in their antioxidative capacities.PRF but not PDF significantly decreased the level of malondialdehyde,suppressed the expression of nicotinamide phosphoribosyltransferase(NAMPT)protein,and improved the severity of ALI in rats.PRF at 10μg/mL effectively downregulated the expression of proteins NAMPT,HMGB1,TLR4,and p-p65,and scavenged the intracellular reactive oxygen species(ROS)in LPS-primed RAW264.7 cells.N-acetyl-L-cysteine exhibited similar inhibitory effects on ROS production and NAMPT-mediated TLR4/NF-κB activation in vitro,whereas nicotinamide mononucleotide antagonized all the changes induced by PRF during cotreatments.Conclusion:As an antioxidant,PRF exhibited potent anti-inflammatory activity under both in vivo and in vitro conditions by downregulating NAMPT and TLR4/NF-κB.Accordingly,polyphenols were identified as important bioactive constituents in S.inappendiculata targeting oxidative stress-sensitive proinflammatory pathways.
