Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds ...Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds candidates for further development into botanical supplements or drugs for inflammation related diseases,including cancer,acute liver hepatitis,and sepsis.Comparative″OMICS″technology platforms in combination with various in vitro and in vivo cell-and gene-based bioassays,murine skin inflammatory and syngeneic and xenograft mammary tumor and melanoma models are employed to validate the pharmacological effects and the underlying mechanistic insights of the identified bioactive phytocompounds.The therapeutic potential of phytoagents,alone or in combination,in sensitizing the chemotherapeutic drug efficacy and/or reduction of its side effects in tumor-bearing mice are investigated.In addition,how phytoagents modulate pro-or anti-inflammatory lipid mediators,such as oxylipins,and related signaling cascades systemically or at organ levels are also addressed for understanding sepsis or cancer pathogenesis and the modes of action of bioactive phytoagents.展开更多
OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in at...OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.展开更多
Flower color is one of the most attractive characteristics in ornamental plants,contributing to the major value in the floricultural market. Anthocyanins are a major colored class of flavonoids that are responsible fo...Flower color is one of the most attractive characteristics in ornamental plants,contributing to the major value in the floricultural market. Anthocyanins are a major colored class of flavonoids that are responsible for the pink,展开更多
Aurones belong to a small class of flavonoids that provide yellow color in some floricultural plants including snapdragon. To explore novel flower coloration, two full-length cDNAs encoding chalcone 4'-O-glucosylt...Aurones belong to a small class of flavonoids that provide yellow color in some floricultural plants including snapdragon. To explore novel flower coloration, two full-length cDNAs encoding chalcone 4'-O-glucosyltransferase (designated as SRY4'CGT) and aureusidin synthase (designated as SRYAS1) in the aurone biosynthetic pathway were cloned from yellow flowers of snapdragon (Antirrhinum majus cv. Ribbon Yellow). Binary vectors were constructed and transformed separately into Petunia hybrida harboring blue flowers. Only a few flowers in 4 out of 9 transgenic SRY4'CGT plants showed variegated blue-white sectors;as time passed, amounts of variegated flowers and proportion of white sectors in the background blue color of the new-born flowers gradually increased, until finally, the petal color was completely white in all late-born flowers. In contrast, a few flowers in 3 out of 13 transgenic SRYAS1 plants showed variegated blue-white sectors;but, the amounts of variegated flowers did not increase over the whole flowering stage, and no complete white flowers were observed. RNA samples isolated from blue and white sectors of T1 transgenic SRY4'CGT plants were analyzed by reverse transcription-PCR, transgenic SRY4'CGT transcripts were detected in both sectors;however, transcripts of an upstream gene, chalcone synthase (CHS), were abundantly detected in the blue sectors but largely reduced in the white sectors, suggesting that the expression of CHS gene was suppressed in white sectors of transgenic plants. Furthermore, HPLC coupled with mass spectrometry demonstrated cyandin, malvidin and their derivatives were absent in white sectors, causing the white phenotype. Our findings may be attractive to molecular breeders.展开更多
A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to b...A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to balance host immune evasion and plant-damaging effects.The genus Potyvirus comprises plant viruses characterized by RNA genomes that encode large polyproteins led by the P1 protease.A P1 autoinhibitory domain controls polyprotein processing,the release of a downstream functional RNAsilencing suppressor,and viral replication.Here,we show that P1Pro,a plum pox virus clone that lacks the P1 autoinhibitory domain,triggers complex reprogramming of the host transcriptome and high levels of abscisic acid(ABA)accumulation.A meta-analysis highlighted ABA connections with host pathways known to control RNA stability,turnover,maturation,and translation.Transcriptomic changes triggered by P1Pro infection or ABA showed similarities in host RNA abundance and diversity.Genetic and hormone treatment assays showed that ABA promotes plant resistance to potyviral infection.Finally,quantitative mathematical modeling of viral replication in the presence of defense pathways supported self-control of polyprotein processing kinetics as a viral mechanism that attenuates the magnitude of the host antiviral response.Overall,our findings indicate that ABA is an active player in plant antiviral immunity,which is nonetheless evaded by a self-controlled RNA virus.展开更多
Marine streptomycetes are rich sources of natural products with novel structures and interesting biological activities,and genome mining of marine streptomycetes facilitates rapid discovery of their useful products.In...Marine streptomycetes are rich sources of natural products with novel structures and interesting biological activities,and genome mining of marine streptomycetes facilitates rapid discovery of their useful products.In this study,a marine-derived Streptomyces sp.M10 was revealed to share a 99.02%16S rDNA sequence identity with that of Streptomyces marokkonensis Ap1T,and was thus named S.marokkonensis M10.To further evaluate its biosynthetic potential,the 7,207,169 bps of S.marokkonensis M10 genome was sequenced.Genomic sequence analysis for potential secondary metaboliteassociated gene clusters led to the identification of at least three polyketide synthases(PKSs),six non-ribosomal peptide synthases(NRPSs),one hybrid NRPS-PKS,two lantibiotic and five terpene biosynthetic gene clusters.One type I PKS gene cluster was revealed to share high nucleotide similarity with the candicidin/FR008 gene cluster,indicating the capacity of this microorganism to produce polyene macrolides.This assumption was further verified by isolation of two polyene family compounds PF1 and PF2,which have the characteristic UV adsorption at 269,278,290 nm(PF1)and 363,386 and 408 nm(PF2),respectively.S.marokkonensis M10 is therefore a new source of polyene metabolites.Further studies on S.marokkonensis M10 will provide more insights into natural product biosynthesis potential of related streptomycetes.This is also the first report to describe the genome sequence of S.marokkonensis-related strain.展开更多
文摘Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds candidates for further development into botanical supplements or drugs for inflammation related diseases,including cancer,acute liver hepatitis,and sepsis.Comparative″OMICS″technology platforms in combination with various in vitro and in vivo cell-and gene-based bioassays,murine skin inflammatory and syngeneic and xenograft mammary tumor and melanoma models are employed to validate the pharmacological effects and the underlying mechanistic insights of the identified bioactive phytocompounds.The therapeutic potential of phytoagents,alone or in combination,in sensitizing the chemotherapeutic drug efficacy and/or reduction of its side effects in tumor-bearing mice are investigated.In addition,how phytoagents modulate pro-or anti-inflammatory lipid mediators,such as oxylipins,and related signaling cascades systemically or at organ levels are also addressed for understanding sepsis or cancer pathogenesis and the modes of action of bioactive phytoagents.
基金The project supported by a research grant from Ministry of Science and Technology(MOST 103-2320-B-001-008-MY3),Chinese Taipei
文摘OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.
文摘Flower color is one of the most attractive characteristics in ornamental plants,contributing to the major value in the floricultural market. Anthocyanins are a major colored class of flavonoids that are responsible for the pink,
文摘Aurones belong to a small class of flavonoids that provide yellow color in some floricultural plants including snapdragon. To explore novel flower coloration, two full-length cDNAs encoding chalcone 4'-O-glucosyltransferase (designated as SRY4'CGT) and aureusidin synthase (designated as SRYAS1) in the aurone biosynthetic pathway were cloned from yellow flowers of snapdragon (Antirrhinum majus cv. Ribbon Yellow). Binary vectors were constructed and transformed separately into Petunia hybrida harboring blue flowers. Only a few flowers in 4 out of 9 transgenic SRY4'CGT plants showed variegated blue-white sectors;as time passed, amounts of variegated flowers and proportion of white sectors in the background blue color of the new-born flowers gradually increased, until finally, the petal color was completely white in all late-born flowers. In contrast, a few flowers in 3 out of 13 transgenic SRYAS1 plants showed variegated blue-white sectors;but, the amounts of variegated flowers did not increase over the whole flowering stage, and no complete white flowers were observed. RNA samples isolated from blue and white sectors of T1 transgenic SRY4'CGT plants were analyzed by reverse transcription-PCR, transgenic SRY4'CGT transcripts were detected in both sectors;however, transcripts of an upstream gene, chalcone synthase (CHS), were abundantly detected in the blue sectors but largely reduced in the white sectors, suggesting that the expression of CHS gene was suppressed in white sectors of transgenic plants. Furthermore, HPLC coupled with mass spectrometry demonstrated cyandin, malvidin and their derivatives were absent in white sectors, causing the white phenotype. Our findings may be attractive to molecular breeders.
基金supported by funds to J.A.G.from the Ministerio de Ciencia e Innovaciòn(Spain),grants BIO2016-80572-R and PID2019-109380RBI00/AEI/10.13039/501100011033(AEI-FEDER)funded by grant K124705 from the National Research Development and Innovation Office(Hungary)+2 种基金S.M.-B.by grant 2017 SGR 980 from the Generalitat de Catalunya(Spain)supported by NIH grant HG006620the recipient of a post-doctoral fellowship from Academia Sinica(Taiwan).
文摘A complex network of cellular receptors,RNA targeting pathways,and small-molecule signaling provides robust plant immunity and tolerance to viruses.To maximize their fitness,viruses must evolve control mechanisms to balance host immune evasion and plant-damaging effects.The genus Potyvirus comprises plant viruses characterized by RNA genomes that encode large polyproteins led by the P1 protease.A P1 autoinhibitory domain controls polyprotein processing,the release of a downstream functional RNAsilencing suppressor,and viral replication.Here,we show that P1Pro,a plum pox virus clone that lacks the P1 autoinhibitory domain,triggers complex reprogramming of the host transcriptome and high levels of abscisic acid(ABA)accumulation.A meta-analysis highlighted ABA connections with host pathways known to control RNA stability,turnover,maturation,and translation.Transcriptomic changes triggered by P1Pro infection or ABA showed similarities in host RNA abundance and diversity.Genetic and hormone treatment assays showed that ABA promotes plant resistance to potyviral infection.Finally,quantitative mathematical modeling of viral replication in the presence of defense pathways supported self-control of polyprotein processing kinetics as a viral mechanism that attenuates the magnitude of the host antiviral response.Overall,our findings indicate that ABA is an active player in plant antiviral immunity,which is nonetheless evaded by a self-controlled RNA virus.
文摘Marine streptomycetes are rich sources of natural products with novel structures and interesting biological activities,and genome mining of marine streptomycetes facilitates rapid discovery of their useful products.In this study,a marine-derived Streptomyces sp.M10 was revealed to share a 99.02%16S rDNA sequence identity with that of Streptomyces marokkonensis Ap1T,and was thus named S.marokkonensis M10.To further evaluate its biosynthetic potential,the 7,207,169 bps of S.marokkonensis M10 genome was sequenced.Genomic sequence analysis for potential secondary metaboliteassociated gene clusters led to the identification of at least three polyketide synthases(PKSs),six non-ribosomal peptide synthases(NRPSs),one hybrid NRPS-PKS,two lantibiotic and five terpene biosynthetic gene clusters.One type I PKS gene cluster was revealed to share high nucleotide similarity with the candicidin/FR008 gene cluster,indicating the capacity of this microorganism to produce polyene macrolides.This assumption was further verified by isolation of two polyene family compounds PF1 and PF2,which have the characteristic UV adsorption at 269,278,290 nm(PF1)and 363,386 and 408 nm(PF2),respectively.S.marokkonensis M10 is therefore a new source of polyene metabolites.Further studies on S.marokkonensis M10 will provide more insights into natural product biosynthesis potential of related streptomycetes.This is also the first report to describe the genome sequence of S.marokkonensis-related strain.