The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the u...The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.展开更多
目的探讨转录因子Nrf2/Bach1在枸杞多糖(LBP)防御紫外线(UV)致Ha Ca T细胞光损伤的作用。方法体外培养的Ha Ca T细胞经300μg/m L LBP预处理24 h后,分别接受30 J/cm^2UVA及300 m J/cm^2UVB照射,孵育24h。以噻唑蓝(MTT法)检测细胞增殖活...目的探讨转录因子Nrf2/Bach1在枸杞多糖(LBP)防御紫外线(UV)致Ha Ca T细胞光损伤的作用。方法体外培养的Ha Ca T细胞经300μg/m L LBP预处理24 h后,分别接受30 J/cm^2UVA及300 m J/cm^2UVB照射,孵育24h。以噻唑蓝(MTT法)检测细胞增殖活性;尼罗红荧光染色法检测过氧化脂质含量;采用单细胞凝胶电泳法检测DNA损伤;RT-q PCR法检测Nrf2和Bach1 mRNA及下游II相解毒酶基因的表达,Western blot法检测Nrf2及Bach1蛋白在细胞内分布及表达情况。结果强度为30 J/cm^2UVA及300 m J/cm^2UVB均可造成Ha Ca T细胞增殖能力下降,过氧化脂质含量及DNA荧光强度、迁移距离增加,与空白组相比,差异均有统计学意义(P<0.05);300μg/m L LBP预处理可显著提高细胞增殖活性,降低过氧化脂质水平,减轻DNA链断裂损伤,且增加Nrf2核蛋白及Bach1质蛋白的量,促进Nrf2 mRNA及下游II相解毒酶SOD,CAT,NQO1,GCLC,GCLM mRNA的表达,抑制Bach1mRNA的表达(均P<0.05)。结论枸杞多糖可有效减轻UV诱导的HaCaT细胞氧化损伤,其机制可能是通过激活Nrf2/Bach1转位及下游II相解毒酶基因的表达,发挥光防护作用。展开更多
The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overa...The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overall survival.Here we developed a strategy by employing tumor-targeted selfassembled nanoparticles to coordinately regulate BACH1(BTB domain and CNC homology 1)and mitochondrial metabolism.The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative(BD)were used to prepare nanoparticles(BH NPs)followed by the modification of chondroitin sulfate(CS)on the surface of BH NPs to achieve tumor targeting(CS/BH NPs).CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites,glycolysis and metastasis-associated proteins,which were related to the inhibition of BACH1 function.Meanwhile,decreased mitochondrial membrane potential,activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism.In a xenograft mice model of breast cancer,CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs.In sum,the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82172736,81972886,and 82172735]the State Key Laboratory of Systems Medicine for Cancer(No.ZZ94-2306)。
文摘The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.
文摘目的探讨转录因子Nrf2/Bach1在枸杞多糖(LBP)防御紫外线(UV)致Ha Ca T细胞光损伤的作用。方法体外培养的Ha Ca T细胞经300μg/m L LBP预处理24 h后,分别接受30 J/cm^2UVA及300 m J/cm^2UVB照射,孵育24h。以噻唑蓝(MTT法)检测细胞增殖活性;尼罗红荧光染色法检测过氧化脂质含量;采用单细胞凝胶电泳法检测DNA损伤;RT-q PCR法检测Nrf2和Bach1 mRNA及下游II相解毒酶基因的表达,Western blot法检测Nrf2及Bach1蛋白在细胞内分布及表达情况。结果强度为30 J/cm^2UVA及300 m J/cm^2UVB均可造成Ha Ca T细胞增殖能力下降,过氧化脂质含量及DNA荧光强度、迁移距离增加,与空白组相比,差异均有统计学意义(P<0.05);300μg/m L LBP预处理可显著提高细胞增殖活性,降低过氧化脂质水平,减轻DNA链断裂损伤,且增加Nrf2核蛋白及Bach1质蛋白的量,促进Nrf2 mRNA及下游II相解毒酶SOD,CAT,NQO1,GCLC,GCLM mRNA的表达,抑制Bach1mRNA的表达(均P<0.05)。结论枸杞多糖可有效减轻UV诱导的HaCaT细胞氧化损伤,其机制可能是通过激活Nrf2/Bach1转位及下游II相解毒酶基因的表达,发挥光防护作用。
基金supported by the National Natural Science Foundation of China(Nos.81973264,82104080 and 81773659)Guangdong Basic and Applied Basic Research Foundation,China(Nos.2020A1515010593,2019A1515011954 and 2021A1515012621)+1 种基金Guangdong Provincial Key Laboratory of Construction Foundation,Sun Yat-sen University(No.2019B030301005,China)the Fundamental Research Funds for the Central Universities,Sun Yat-sen University(No.22qntd4509,China).
文摘The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overall survival.Here we developed a strategy by employing tumor-targeted selfassembled nanoparticles to coordinately regulate BACH1(BTB domain and CNC homology 1)and mitochondrial metabolism.The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative(BD)were used to prepare nanoparticles(BH NPs)followed by the modification of chondroitin sulfate(CS)on the surface of BH NPs to achieve tumor targeting(CS/BH NPs).CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites,glycolysis and metastasis-associated proteins,which were related to the inhibition of BACH1 function.Meanwhile,decreased mitochondrial membrane potential,activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism.In a xenograft mice model of breast cancer,CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs.In sum,the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.
