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 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
BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with n...BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.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
Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However...Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.展开更多
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.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BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.
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.
基金This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-047 and 2019-I2M-5-049)National Science Funds of China(82073181,81802870 and 82102371)+5 种基金Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT310-006,2019XK310002 and 2018TX31001)as well as NIH R01AI069120,AI158154,and AI140718 grants,the UCLA AIDS InstituteUCLA David Geffen School of Medicine-Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award ProgramH.Y.is supported by science funds from Jiangsu Province(BK20211554,BK20170407)the Innovative and Entrepreneurial Team grant(2018-2021)from Jiangsu ProvinceL.L.is supported by Innovative and Entrepreneurial Doctor grant(2020-2022)from Jiangsu Province.
文摘Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.