In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids(Mito HCAs) were synthesized by conjugation with a...In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids(Mito HCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH? àand ROO? àinduced lipid peroxidation. H_2O_2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines(HepG2, L02 and WI38) indicated that the Mito HCAs were selective for cancer cells. Interestingly, the Mito HCAs both with or without Ca^(2+)triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore(m PTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that m PTP may be involved in the antiproliferative activity of Mito HCAs.Further studies focused on structural optimization of these compounds are onging.展开更多
Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic a...Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic acids（HCAs）. The stabilities were studied in buffers at p H 1.3, p H 5.0, and p H 7.4 including the human plasma. All the compounds were found highly stable at acidic p H, but underwent hydrolysis at neutral p H. Furthermore, the hydrolysis proceeded much faster in plasma in the following order as indicated by half-life values（t1/2）, 2c（1.21 h）〈2e（1.52 h）〈2d（1.85 h）〈2b（3.38 h）〈2a（3.88 h）, correlating with the number of electron-donating groups. It has been proven by UV spectrum that 2c, 2d, and 2e displayed red shift of more than 50 nm as compared to 2a and 2b, because of the presence of OH and OCH3 groups. In addition, the compounds（2b–e） showed no cytotoxicity on normal HUVEC cells as DA, although 2a displayed a 16% inhibition of proliferation at 40 μM following 48 h incubation. Their free radical-scavenging activities were evaluated using ABTS^＊＋ and superoxide anion assays and the mechanisms were proposed. It was found that they all exhibited higher activities than trolox, a recognized antioxidant. Amazingly, in the case of the hybrids（2a–e）, their activity was higher than that of HCAs while lower or comparable to that of DA, suggesting that there may be a ＂saturation effect＂ with the hybrid molecules in the antioxidant activities.展开更多
Genomic clustering of non-homologous genes for the biosynthesis of plant defensive compounds is an emerging theme, but insights into their formation and physiological function remain limited. Here we report the identi...Genomic clustering of non-homologous genes for the biosynthesis of plant defensive compounds is an emerging theme, but insights into their formation and physiological function remain limited. Here we report the identification of a newly discovered hydroxycinnamoyl tyramine(HT) gene cluster in rice.This cluster contains a pyridoxamine 50-phosphate oxidase(Os PDX3) producing the cofactor pyridoxal50-phosphate(PLP), a PLP-dependent tyrosine decarboxylase(Os Ty DC1), and two duplicated hydroxycinnamoyl transferases(Os THT1 and Os THT2). These members were combined to represent an enzymological innovation gene cluster. Natural variation analysis showed that the abundance of the toxic tyramine intermediate of the gene cluster among different rice accessions is mainly determined by the coordinated transcription of Os Ty DC1 and Os THT1. Further pathogen incubation assays demonstrated that the end products of the HT gene cluster displayed enhanced resistance to the bacterial pathogen Xanthomonas oryzae pv. Oryzae(Xoo) and fungal pathogen Magnaporthe oryzae(M. oryzae), and the enhanced resistance is associated with the boost of phytoalexins and the activation of defense response. The unique presence of the HT gene cluster in Oryza AA genome, together with the enrichment of transposon elements within this gene cluster region, provides an evolutionary background to accelerate cluster member combinations. Our study not only discovered a gene cluster involved in the phenylpropanoid metabolism but also addressed the key aspects of gene cluster formation. In addition, our results provide a new metabolic pool for plant defense against pathogens.展开更多
基金supported by the National Natural Sciences Foundation of China (Grant No. 21302079)the Fundamental Research Funds for the Central Universities (No. lzujbky2014151)
文摘In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids(Mito HCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH? àand ROO? àinduced lipid peroxidation. H_2O_2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines(HepG2, L02 and WI38) indicated that the Mito HCAs were selective for cancer cells. Interestingly, the Mito HCAs both with or without Ca^(2+)triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore(m PTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that m PTP may be involved in the antiproliferative activity of Mito HCAs.Further studies focused on structural optimization of these compounds are onging.
基金The National Natural Science Foundation of China(Grant No.21302079)the Fundamental Research Funds for the Central Universities(Grant No.lzujbky-2014-151)
文摘Hybrid antioxidants cinnamoyldopamine（2a）, p-coumaroyldopamine（2b）, caffeoyldopamine（2c）, feruloyldopamine（2d） and sinapoyldopamine（2e） were synthesized by conjugation of dopamine（DA） and hydroxycinnamic acids（HCAs）. The stabilities were studied in buffers at p H 1.3, p H 5.0, and p H 7.4 including the human plasma. All the compounds were found highly stable at acidic p H, but underwent hydrolysis at neutral p H. Furthermore, the hydrolysis proceeded much faster in plasma in the following order as indicated by half-life values（t1/2）, 2c（1.21 h）〈2e（1.52 h）〈2d（1.85 h）〈2b（3.38 h）〈2a（3.88 h）, correlating with the number of electron-donating groups. It has been proven by UV spectrum that 2c, 2d, and 2e displayed red shift of more than 50 nm as compared to 2a and 2b, because of the presence of OH and OCH3 groups. In addition, the compounds（2b–e） showed no cytotoxicity on normal HUVEC cells as DA, although 2a displayed a 16% inhibition of proliferation at 40 μM following 48 h incubation. Their free radical-scavenging activities were evaluated using ABTS^＊＋ and superoxide anion assays and the mechanisms were proposed. It was found that they all exhibited higher activities than trolox, a recognized antioxidant. Amazingly, in the case of the hybrids（2a–e）, their activity was higher than that of HCAs while lower or comparable to that of DA, suggesting that there may be a ＂saturation effect＂ with the hybrid molecules in the antioxidant activities.
基金supported by the National Science Fund for Distinguished Young Scholars of China (31625021)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (31821005)+1 种基金the State Key Program of National Natural Science Foundation of China (31530052)the Hainan University Startup Fund (KYQD(ZR)1866)。
文摘Genomic clustering of non-homologous genes for the biosynthesis of plant defensive compounds is an emerging theme, but insights into their formation and physiological function remain limited. Here we report the identification of a newly discovered hydroxycinnamoyl tyramine(HT) gene cluster in rice.This cluster contains a pyridoxamine 50-phosphate oxidase(Os PDX3) producing the cofactor pyridoxal50-phosphate(PLP), a PLP-dependent tyrosine decarboxylase(Os Ty DC1), and two duplicated hydroxycinnamoyl transferases(Os THT1 and Os THT2). These members were combined to represent an enzymological innovation gene cluster. Natural variation analysis showed that the abundance of the toxic tyramine intermediate of the gene cluster among different rice accessions is mainly determined by the coordinated transcription of Os Ty DC1 and Os THT1. Further pathogen incubation assays demonstrated that the end products of the HT gene cluster displayed enhanced resistance to the bacterial pathogen Xanthomonas oryzae pv. Oryzae(Xoo) and fungal pathogen Magnaporthe oryzae(M. oryzae), and the enhanced resistance is associated with the boost of phytoalexins and the activation of defense response. The unique presence of the HT gene cluster in Oryza AA genome, together with the enrichment of transposon elements within this gene cluster region, provides an evolutionary background to accelerate cluster member combinations. Our study not only discovered a gene cluster involved in the phenylpropanoid metabolism but also addressed the key aspects of gene cluster formation. In addition, our results provide a new metabolic pool for plant defense against pathogens.
