2-Oxoglutarate(2OG)-dependent dioxygenases(2-ODDs)are omnipresent iron-containing non-heme enzymes that catalyze various oxidation-reduction reactions in plant growth and development,nucleic acid modification and seco...2-Oxoglutarate(2OG)-dependent dioxygenases(2-ODDs)are omnipresent iron-containing non-heme enzymes that catalyze various oxidation-reduction reactions in plant growth and development,nucleic acid modification and secondary metabolism.We systematically summarized recent research on the oxidative modifications of plant 2-ODDs and related enzymes,their vital importance in the biosynthesis of plant special metabolites,and their catalytic specificity/flexibility,and discussed the potential of 2-ODD as a new approach for the identification of pivotal genes and the elucidation of biosynthetic pathway.展开更多
Owing to their diverse coordination patterns and catalytic mechanisms,non-heme iron-dependent dioxygenases catalyze a variety of biochemical reactions involved in the synthesis of numerous natural products and valuabl...Owing to their diverse coordination patterns and catalytic mechanisms,non-heme iron-dependent dioxygenases catalyze a variety of biochemical reactions involved in the synthesis of numerous natural products and valuable compounds.Recently,we discovered a novel and atypical non-heme iron-dependent dioxygenase,BTG13,that features a unique coordination center consisting of four histidines and a carboxylated lysine(Kcx).This enzyme catalyzes the C–C bond cleavage of anthraquinone through two unconventional steps,with modified Kcx playing a key role in facilitating these processes,as revealed by molecular dynamics simulations and quantum chemical calculations.Phylogenetic analyses and other studies suggest that BTG13-related metalloenzymes are widespread in various organisms.Here,we highlight the significance of this new class of non-heme iron-dependent oxygenases and their potential as novel tools for practical applications in synthetic biology.展开更多
Enantioselective cis-dihydroxylation of alkenes represents an ideal route to synthesize enantioenriched syn-2,3-dihydroxy esters that are important structural motifs in numerous biologically and pharmaceutically relev...Enantioselective cis-dihydroxylation of alkenes represents an ideal route to synthesize enantioenriched syn-2,3-dihydroxy esters that are important structural motifs in numerous biologically and pharmaceutically relevant molecules.Bioinspired nonheme iron-catalyzed enantioselective cis-dihydroxylation meets the requirement of the modern synthetic chemistry from the atomic economy,green chemistry,and sustainable development perspectives.However,nonheme iron-catalyzed enantioselective cis-dihydroxylation is much underdeveloped because of the formidable challenges of controlling chemo-and enantioselectivities and product selectivity caused by the competitive epoxidation,cis-dihydroxylation,and overoxidation reactions.Herein,we disclose the fabrication of a biologically inspired nonheme iron complex-catalyzed enantioselective cis-dihydroxylation of multisubstituted acrylates using hydrogen peroxide(H_(2)O_(2))as the terminal oxidant by controlling the non-ligating or weakly ligating counterions of iron(Ⅱ)complexes,demonstrating a dramatic counteranion effect on the enantioselective cisdihydroxylation of olefins by H_(2)O_(2) catalyzed by nonheme iron complexes.A range of structurally disparate alkenes were transformed to the corresponding syn-2,3-dihydroxy esters in practically useful yields with exquisite chemo-and enantioselectivities(up to 99% ee).Given the mild and benign nature of this biologically inspired oxidation system as well as the ubiquity and synthetic utility of enantioenriched syn-2,3-dihydroxy esters as pharmaceuticals candidates and natural products,we expect that this strategy could serve as a promising complement to the well-known Sharpless asymmetric dihydroxylation,which is the chemical reaction of an alkene with OsO_(4) to produce a vicinal diol.展开更多
Major depression during pregnancy is a common psychiatric disorder that arises from a complex and mul- tifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggeri...Major depression during pregnancy is a common psychiatric disorder that arises from a complex and mul- tifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic-pituitary-adrenal axis hyperactivity. Dysregulation of this intricate neu- roimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neu- ropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during preg- nancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Thl/Th2 bias towards a predominant Thl/Thl7 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.展开更多
Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes cur...Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.展开更多
The carotenoid-derived volatileβ-ionone makes an important contribution to tea fragrance.Here,we qualitatively and quantitatively analysed 15 carotenoids in tea leaves of 13 cultivars by UHPLC-APCI-MS/MS.The 13 culti...The carotenoid-derived volatileβ-ionone makes an important contribution to tea fragrance.Here,we qualitatively and quantitatively analysed 15 carotenoids in tea leaves of 13 cultivars by UHPLC-APCI-MS/MS.The 13 cultivars were divided into two groups by PCA(Principal Component Analysis)clustering analysis of their carotenoid content,and OPLS-DA(Orthogonal projections to latent structures)indicated that the levels ofβ-carotene(VIP=2.89)and lutein(VIP=2.30)were responsible for much of the variation between the two groups.Interestingly,theβ-carotene toβ-ionone conversion rates in Group 1 were higher than in Group 2,while theβ-carotene content was significantly lower in Group 1 than in Group 2.Theβ-ionone content was significantly higher in Group 1.Pearson Correlation Coefficient calculation between the transcription level of candidate genes(CsCCD1 and CsCCD4)and the accumulation ofβ-ionone indicated that CsCCD1 may involve in the formation ofβ-ionone in 13 cultivars.Prokaryotic expression and in vitro enzyme activity assays showed that‘Chuanhuang 1’had an amino acid mutation in carotenoid cleavage dioxygenases 1(CsCCD1)compared with‘Shuchazao’,resulting in a significantly higherβ-ionone content in‘Chuanhuang 1’.Sequence analysis showed that‘Chuanhuang 1’and‘Huangdan’had different CsCCD1 promoter sequences,leading to significantly higher CsCCD1 expression andβ-ionone accumulation in‘Chuanhuang 1’.These results indicated that the promoter and coding sequence diversity of CsCCD1 might contribute to the differential accumulation ofβ-ionone in different tea cultivars.展开更多
Armillaria sp. F022, a white rot fungus isolated from tropical rain forest （Samarinda, Indonesia） was used to biodegrade naphthalene in cultured medium. Transformation of naphthalene by Armillaria sp. F022 which is ...Armillaria sp. F022, a white rot fungus isolated from tropical rain forest （Samarinda, Indonesia） was used to biodegrade naphthalene in cultured medium. Transformation of naphthalene by Armillaria sp. F022 which is able to use naphthalene, a two ring-polycyclic aromatic hydrocarbon （PAH） as a source of carbon and energy was investigated. The metabolic pathway was elucidated by identifying metabolites, biotransformation studies and monitoring enzyme activities in cell-free extracts. The identification of metabolites suggests that Armillaria sp. F022 initiates its attack on naphthalene by dioxygenation at its C-1 and C-4 positions to give 1,4-naphthoquinone. The intermediate 2-hydroxybenzaldebyde and salicylic acid, and the characteristic of the meta-cleavage of the resulting diol were identified in the long-term incubation. A part from typical metabolites of naphthalene degradation known from mesophiles, benzoic acid was identified as the next intermediate for the naphthalene pathway of this Armillaria sp. F022. Neither phthalic acid, catechol and cis, cis-muconic acid metabolites were detected in culture extracts. Several enzymes （manganese peroxidase, lignin peroxidase, laccase, 1,2-dioxygenase and 2,3-dioxygenase） produced by ArmiUaria sp. F022 were detected during the incubation.展开更多
Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.App...Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.展开更多
A novel biphenyl-degrading bacterial strain LA-4 was isolated from activated sludge.It was identified as Dyella ginsengisoli according to phylogenetic similarity of 16S rRNA gene sequence.This isolate could utilize bi...A novel biphenyl-degrading bacterial strain LA-4 was isolated from activated sludge.It was identified as Dyella ginsengisoli according to phylogenetic similarity of 16S rRNA gene sequence.This isolate could utilize biphenyl as sole source of carbon and energy,which degraded over 95 mg/L biphenyl within 36 h.The major metabolites formed from biphenyl,such as 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid(HOPDA)and benzoic acid,were identified by LC-MS.The crude cell extract of strain LA-4 exhibited the activity of 2,3-dihydroxybiphenyl 1,2-dioxygenase(2,3-DHBD)and the kinetic parameters Km was 26.48μmol/L and Vmax was 8.12 U/mg protein.A conserved region of the biphenyl dioxygenase gene bphA1 of strain LA-4 was amplified by PCR and confirmed by DNA sequencing.展开更多
Dracomolphesin A-E(1-5),five 3,4-seco-phenylpropanoids featuring an aromatic ring opened framework,were isolated from the aerial parts of Dracocephalum moldavica.The structures with absolute configurations were determ...Dracomolphesin A-E(1-5),five 3,4-seco-phenylpropanoids featuring an aromatic ring opened framework,were isolated from the aerial parts of Dracocephalum moldavica.The structures with absolute configurations were determined by spectroscopic methods coupled with Mosher method.Notably,these compounds represented an example of aromatic ring cleavage products of phenylpropanoids.The possible biosynthetic pathway of these compounds was proposed.Compounds 1,2,4 and 5 were demonstrated to be Nrf2 pathway activators.展开更多
High-tillering dwarf mutant gsor23 was generated from an indica rice variety Indica9 radiatied by y-ray. Genetic analysis showed that this phenotype was controlled by one single recessive gene, which was mapped within...High-tillering dwarf mutant gsor23 was generated from an indica rice variety Indica9 radiatied by y-ray. Genetic analysis showed that this phenotype was controlled by one single recessive gene, which was mapped within a physical distance of 386 kb between two insertion-deletion （InDel） markers CI-WT2 and C1-WT4 on the long arm of chromosome 1. There is a known gene DIO within this region, the mutation of which causes high-tillering in rice. Sequence analysis of the DIO allele in gsor23 revealed that the base cytosine （C） at the 404th position in the coding region was deleted, which would cause frameshift mutation after the 134th amino acids. The mutation site and indica background of gsor23 were different from the previously reported japonica mutants d10-1 and d10-2. Therefore, gsor23 is a novel allelic mutant of D10 which encodes the carotenoid-cleaving dioxygenase 8 （CCD8）, a key enzyme involved in the biosynthesis of the new plant hormone strigolactones （SLs）. After treatment with GR24, a synthetic analogue of SLs, the high-tillering phenotype of gsor23 was restored to normal. Real-time RT-PCR analysis showed that D10 expression was high in roots, but low in leaves. Compared with the wild type Indica9, the expression of the SL biosynthesis gene DIO was upregulated, while genes likely involved in the SL signal transduction pathway such as D3 and D14 were down-regulated in the gsor23 mutant.展开更多
4-Hydroxyphenylpyruvate dioxygenase(HPPD)is an important target for both drug and pesticide discovery.As a typical Fe(II)-dependent dioxygenase,HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic a...4-Hydroxyphenylpyruvate dioxygenase(HPPD)is an important target for both drug and pesticide discovery.As a typical Fe(II)-dependent dioxygenase,HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic acid(HPPA)to homogentisic acid(HGA).The binding mode of HPPA in the catalytic pocket of HPPD is a focus of research interests.Recently,we reported the crystal structure of Arabidopsis thaliana HPPD(At HPPD)complexed with HPPA and a cobalt ion,which was supposed to mimic the pre-reactive structure of At HPPD-HPPA-Fe(II).Unexpectedly,the present study shows that the restored At HPPD-HPPA-Fe(II)complex is still nonreactive toward the bound dioxygen.QM/MM and QM calculations reveal that the HPPA resists the electrophilic attacking of the bound dioxygen by the trim of its phenyl ring,and the residue Phe381 plays a key role in orienting the phenyl ring.Kinetic study on the F381 A mutant reveals that the HPPD-HPPA complex observed in the crystal structure should be an intermediate of the substrate transportation instead of the pre-reactive complex.More importantly,the binding mode of the HPPA in this complex is shared with several well-known HPPD inhibitors,suggesting that these inhibitors resist the association of dioxygen(and exert their inhibitory roles)in the same way as the HPPA.The present study provides insights into the inhibition mechanism of HPPD inhibitors.展开更多
Lutein,a type of carotenoids,is found to delay the onset and progression of age-related macular degeneration(AMD).Several lutein supplementation studies showed that after an initial increase,lutein serum levels demons...Lutein,a type of carotenoids,is found to delay the onset and progression of age-related macular degeneration(AMD).Several lutein supplementation studies showed that after an initial increase,lutein serum levels demonstrated a subsequent decrease despite continuous supplementation.In this systematic literature review,this obscure phenomenon was tried to be explained.The subsequent drop in lutein levels was postulated due to down-regulation of lutein receptors scavenger receptor class B typeⅠ(SR-BI)in the gastrointestinal tract,upregulation of lutein degrading enzymeβ-carotene dioxygenase(BCDO2),or perhaps a combination of both.Some single nucleotides polymorphisms(SNPs)that could have influence on the occurrence of this phenomenon.To date,an exact scientific explanation for this phenomenon has not been established.Further research is needed to investigate this phenomenon in depth to reach an irrefutable explanation,giving that lutein is proven to be effective in delaying the onset and progression of AMD and its metabolism in the human body becomes of equal importance.展开更多
The upregulation of 4-hydroxyphenylpyruvate dioxygenase(HPPD)can protect plants from adverse abiotic stress.Therefore,studying the changes of HPPD under abiotic stress is extremely valuable.In this study,we employed a...The upregulation of 4-hydroxyphenylpyruvate dioxygenase(HPPD)can protect plants from adverse abiotic stress.Therefore,studying the changes of HPPD under abiotic stress is extremely valuable.In this study,we employed a rational molecular design strategy to prepare an HPPD-responsive fluorescent probe consisting of a pyrene fluorophore,a linker and a benquitrione skeleton recognition moiety that functions via an aggregation–disaggregation sensing mechanism.As predicted,this probe exhibited an obvious turn-on fluorescence response towards HPPD.In addition,in vivo imaging demonstrated the excellent capability of this probe to track HPPD in Arabidopsis thaliana,and the dynamic changes in HPPD were monitored under different stress degrees of high temperature and Cadmium(II)ion(Cd^(2+))stress.This work provides an efficient design strategy for acquiring a noninvasive HPPD fluorescence probe,which could evaluate the degree of stress and be further employed for exploring the stress resistance mechanism in plants.展开更多
4-Hydrophenylpyruvate dioxygenase(HPPD),a key enzyme involved in tyrosine catabolism,has long been considered a promising target for herbicides and drugs.Several types of HPPD inhibitors have been developed as high-po...4-Hydrophenylpyruvate dioxygenase(HPPD),a key enzyme involved in tyrosine catabolism,has long been considered a promising target for herbicides and drugs.Several types of HPPD inhibitors have been developed as high-potency drugs or herbicides.Understanding the structural basis of the binding of these inhibitors with HPPD will be beneficial for the development of inhibitors containing novel scaffolds.However,only limited structural information regarding the binding of triketone and pyrazole derivatives with HPPD has been reported.Here,the crystal structures of HPPD complexed with inhibitors containing different scaffolds,including triketone,pyrazole,isoxazole,heterocyclic amide,and quinazolindione derivatives,were comprehensively analyzed.Detailed binding modes of isoxazole and heterocyclic amide derivatives with HPPD were first revealed,facilitating further structural optimization.The binding mode of compound 2 with HPPD suggests that both oxygen and nitrogen atoms can mediate coordination with the metal ion.These results will provide the structure-based rational design of novel HPPD inhibitors.展开更多
We reported the characterization of a novel brassicicene diterpene biosynthetic gene cluster,which contains a uniqueα-ketoglutarate-dependent dioxygenase(αKGD)enzyme,AbnI.Our findings revealed that AbnI demonstrates...We reported the characterization of a novel brassicicene diterpene biosynthetic gene cluster,which contains a uniqueα-ketoglutarate-dependent dioxygenase(αKGD)enzyme,AbnI.Our findings revealed that AbnI demonstrates remarkable substrate promiscuity and is capable of activating multiple sites on both 5-8-5 and 5-9-5 brassicicene skeletons,resulting in skeleton modifications and an unexpected ring system rearrangement.These results suggested the potential utility of AbnI as an enzymatic tool for terpene C-H functionalization.In addition,the catalytic mechanism of AbnI and its potential ecological implications were discussed.展开更多
基金This work was supported by the National Key R&D Program of China(2020YFA0908000)the National Natural Science Foundation of China(81773830)+1 种基金the Key Project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302-1806-03)National Program for Special Support of Eminent Professionals.
文摘2-Oxoglutarate(2OG)-dependent dioxygenases(2-ODDs)are omnipresent iron-containing non-heme enzymes that catalyze various oxidation-reduction reactions in plant growth and development,nucleic acid modification and secondary metabolism.We systematically summarized recent research on the oxidative modifications of plant 2-ODDs and related enzymes,their vital importance in the biosynthesis of plant special metabolites,and their catalytic specificity/flexibility,and discussed the potential of 2-ODD as a new approach for the identification of pivotal genes and the elucidation of biosynthetic pathway.
基金funded by the National Natural Science Foundation of China(32270082 and 22207044)the Natural Science Foundation of Jiangsu Province(BK20202002)the Basic Research Program of Jiangsu and the Jiangsu Basic Research Center for Synthetic Biology(BK20233003).
文摘Owing to their diverse coordination patterns and catalytic mechanisms,non-heme iron-dependent dioxygenases catalyze a variety of biochemical reactions involved in the synthesis of numerous natural products and valuable compounds.Recently,we discovered a novel and atypical non-heme iron-dependent dioxygenase,BTG13,that features a unique coordination center consisting of four histidines and a carboxylated lysine(Kcx).This enzyme catalyzes the C–C bond cleavage of anthraquinone through two unconventional steps,with modified Kcx playing a key role in facilitating these processes,as revealed by molecular dynamics simulations and quantum chemical calculations.Phylogenetic analyses and other studies suggest that BTG13-related metalloenzymes are widespread in various organisms.Here,we highlight the significance of this new class of non-heme iron-dependent oxygenases and their potential as novel tools for practical applications in synthetic biology.
基金the National Natural Science Foundation of China(no.21771087 to B.W and no.21703080 to J.C)the NSF of Shandong Province(no.ZR2020YQ10 to B.W)+1 种基金Taishan Scholar Program of Shandong Province(no.tsqn201812078 to B.W.)the NRF of Korea(no.NRF-2021R1A3B1076539 to W.N.and no.NRF-2020R1I1A1A01074630 to Y.-M.L.).
文摘Enantioselective cis-dihydroxylation of alkenes represents an ideal route to synthesize enantioenriched syn-2,3-dihydroxy esters that are important structural motifs in numerous biologically and pharmaceutically relevant molecules.Bioinspired nonheme iron-catalyzed enantioselective cis-dihydroxylation meets the requirement of the modern synthetic chemistry from the atomic economy,green chemistry,and sustainable development perspectives.However,nonheme iron-catalyzed enantioselective cis-dihydroxylation is much underdeveloped because of the formidable challenges of controlling chemo-and enantioselectivities and product selectivity caused by the competitive epoxidation,cis-dihydroxylation,and overoxidation reactions.Herein,we disclose the fabrication of a biologically inspired nonheme iron complex-catalyzed enantioselective cis-dihydroxylation of multisubstituted acrylates using hydrogen peroxide(H_(2)O_(2))as the terminal oxidant by controlling the non-ligating or weakly ligating counterions of iron(Ⅱ)complexes,demonstrating a dramatic counteranion effect on the enantioselective cisdihydroxylation of olefins by H_(2)O_(2) catalyzed by nonheme iron complexes.A range of structurally disparate alkenes were transformed to the corresponding syn-2,3-dihydroxy esters in practically useful yields with exquisite chemo-and enantioselectivities(up to 99% ee).Given the mild and benign nature of this biologically inspired oxidation system as well as the ubiquity and synthetic utility of enantioenriched syn-2,3-dihydroxy esters as pharmaceuticals candidates and natural products,we expect that this strategy could serve as a promising complement to the well-known Sharpless asymmetric dihydroxylation,which is the chemical reaction of an alkene with OsO_(4) to produce a vicinal diol.
基金supported by the National Institute of Perinatology,Mexico City(234560)FONSEC SSA/IMSS/ISSSTE 2015-1(261435)
文摘Major depression during pregnancy is a common psychiatric disorder that arises from a complex and mul- tifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic-pituitary-adrenal axis hyperactivity. Dysregulation of this intricate neu- roimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neu- ropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during preg- nancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Thl/Th2 bias towards a predominant Thl/Thl7 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.
文摘Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.
基金financially supported by National Natural Science Foundation of China(Grant Nos.31961133030,31870678,32022076)Science Fund for Distinguished Young Scientists of Anhui Province(Grant No.1908085J12).
文摘The carotenoid-derived volatileβ-ionone makes an important contribution to tea fragrance.Here,we qualitatively and quantitatively analysed 15 carotenoids in tea leaves of 13 cultivars by UHPLC-APCI-MS/MS.The 13 cultivars were divided into two groups by PCA(Principal Component Analysis)clustering analysis of their carotenoid content,and OPLS-DA(Orthogonal projections to latent structures)indicated that the levels ofβ-carotene(VIP=2.89)and lutein(VIP=2.30)were responsible for much of the variation between the two groups.Interestingly,theβ-carotene toβ-ionone conversion rates in Group 1 were higher than in Group 2,while theβ-carotene content was significantly lower in Group 1 than in Group 2.Theβ-ionone content was significantly higher in Group 1.Pearson Correlation Coefficient calculation between the transcription level of candidate genes(CsCCD1 and CsCCD4)and the accumulation ofβ-ionone indicated that CsCCD1 may involve in the formation ofβ-ionone in 13 cultivars.Prokaryotic expression and in vitro enzyme activity assays showed that‘Chuanhuang 1’had an amino acid mutation in carotenoid cleavage dioxygenases 1(CsCCD1)compared with‘Shuchazao’,resulting in a significantly higherβ-ionone content in‘Chuanhuang 1’.Sequence analysis showed that‘Chuanhuang 1’and‘Huangdan’had different CsCCD1 promoter sequences,leading to significantly higher CsCCD1 expression andβ-ionone accumulation in‘Chuanhuang 1’.These results indicated that the promoter and coding sequence diversity of CsCCD1 might contribute to the differential accumulation ofβ-ionone in different tea cultivars.
基金supported by Research University Grant of Universiti Teknologi Malaysia(No. Q.J13000.7122.00J31)
文摘Armillaria sp. F022, a white rot fungus isolated from tropical rain forest （Samarinda, Indonesia） was used to biodegrade naphthalene in cultured medium. Transformation of naphthalene by Armillaria sp. F022 which is able to use naphthalene, a two ring-polycyclic aromatic hydrocarbon （PAH） as a source of carbon and energy was investigated. The metabolic pathway was elucidated by identifying metabolites, biotransformation studies and monitoring enzyme activities in cell-free extracts. The identification of metabolites suggests that Armillaria sp. F022 initiates its attack on naphthalene by dioxygenation at its C-1 and C-4 positions to give 1,4-naphthoquinone. The intermediate 2-hydroxybenzaldebyde and salicylic acid, and the characteristic of the meta-cleavage of the resulting diol were identified in the long-term incubation. A part from typical metabolites of naphthalene degradation known from mesophiles, benzoic acid was identified as the next intermediate for the naphthalene pathway of this Armillaria sp. F022. Neither phthalic acid, catechol and cis, cis-muconic acid metabolites were detected in culture extracts. Several enzymes （manganese peroxidase, lignin peroxidase, laccase, 1,2-dioxygenase and 2,3-dioxygenase） produced by ArmiUaria sp. F022 were detected during the incubation.
基金Science and Technology Program of Gansu Province Grant,No.18JR3RA339 and No.18JR3RA363Fund of the First Hospital of Lanzhou University Grant,No.ldyyyn2018-63+3 种基金Teaching and Research Project of the First Clinical Medical College of Lanzhou University in 2018 Grant,No.2018007NIH awards,No.R21NS106430 and No.R01OD026594Cystic Fibrosis Foundation Research Grant,No.ZHAO19G0an American Cancer Society-IRG Junior Faculty Development Grant,a UAB CCC Neuro-oncology Research Acceleration Grant,and a UAB Faculty Development Grant Program Award.
文摘Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.
基金supported by the National Natural Science Foundation of China(No.50608011)the 39th Postdoctoral Funds of China.
文摘A novel biphenyl-degrading bacterial strain LA-4 was isolated from activated sludge.It was identified as Dyella ginsengisoli according to phylogenetic similarity of 16S rRNA gene sequence.This isolate could utilize biphenyl as sole source of carbon and energy,which degraded over 95 mg/L biphenyl within 36 h.The major metabolites formed from biphenyl,such as 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid(HOPDA)and benzoic acid,were identified by LC-MS.The crude cell extract of strain LA-4 exhibited the activity of 2,3-dihydroxybiphenyl 1,2-dioxygenase(2,3-DHBD)and the kinetic parameters Km was 26.48μmol/L and Vmax was 8.12 U/mg protein.A conserved region of the biphenyl dioxygenase gene bphA1 of strain LA-4 was amplified by PCR and confirmed by DNA sequencing.
基金supported by the National Natural Science Foundation of China(No.81973202)the Key Research and Development Program of Shandong Province (No. 2018GSF118085)。
文摘Dracomolphesin A-E(1-5),five 3,4-seco-phenylpropanoids featuring an aromatic ring opened framework,were isolated from the aerial parts of Dracocephalum moldavica.The structures with absolute configurations were determined by spectroscopic methods coupled with Mosher method.Notably,these compounds represented an example of aromatic ring cleavage products of phenylpropanoids.The possible biosynthetic pathway of these compounds was proposed.Compounds 1,2,4 and 5 were demonstrated to be Nrf2 pathway activators.
基金supported by grants from the National Natural Science Foundation of China(GrantNo.31271311)the Ministry of Agriculture of China(Grant No.2011ZX08009-003)
文摘High-tillering dwarf mutant gsor23 was generated from an indica rice variety Indica9 radiatied by y-ray. Genetic analysis showed that this phenotype was controlled by one single recessive gene, which was mapped within a physical distance of 386 kb between two insertion-deletion （InDel） markers CI-WT2 and C1-WT4 on the long arm of chromosome 1. There is a known gene DIO within this region, the mutation of which causes high-tillering in rice. Sequence analysis of the DIO allele in gsor23 revealed that the base cytosine （C） at the 404th position in the coding region was deleted, which would cause frameshift mutation after the 134th amino acids. The mutation site and indica background of gsor23 were different from the previously reported japonica mutants d10-1 and d10-2. Therefore, gsor23 is a novel allelic mutant of D10 which encodes the carotenoid-cleaving dioxygenase 8 （CCD8）, a key enzyme involved in the biosynthesis of the new plant hormone strigolactones （SLs）. After treatment with GR24, a synthetic analogue of SLs, the high-tillering phenotype of gsor23 was restored to normal. Real-time RT-PCR analysis showed that D10 expression was high in roots, but low in leaves. Compared with the wild type Indica9, the expression of the SL biosynthesis gene DIO was upregulated, while genes likely involved in the SL signal transduction pathway such as D3 and D14 were down-regulated in the gsor23 mutant.
基金supported by the National Key R&D Program(No.2018YFD0200100)National Natural Science Foundation of China(Nos.21837001,21273089,22007035,U20A2038)+3 种基金the Open Project Fund of the Key Laboratory of the Pesticides and Chemical Biology of Central China Normal University(No.2018-A01)the Fundamental Research Funds for the South-Central University for Nationalities(No.CZW20020)the Fundamental Research Funds for the Central Universities(No.KJ02072020-0657)Hubei Province Natural Science Foundation(No.2020CFB487)。
文摘4-Hydroxyphenylpyruvate dioxygenase(HPPD)is an important target for both drug and pesticide discovery.As a typical Fe(II)-dependent dioxygenase,HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic acid(HPPA)to homogentisic acid(HGA).The binding mode of HPPA in the catalytic pocket of HPPD is a focus of research interests.Recently,we reported the crystal structure of Arabidopsis thaliana HPPD(At HPPD)complexed with HPPA and a cobalt ion,which was supposed to mimic the pre-reactive structure of At HPPD-HPPA-Fe(II).Unexpectedly,the present study shows that the restored At HPPD-HPPA-Fe(II)complex is still nonreactive toward the bound dioxygen.QM/MM and QM calculations reveal that the HPPA resists the electrophilic attacking of the bound dioxygen by the trim of its phenyl ring,and the residue Phe381 plays a key role in orienting the phenyl ring.Kinetic study on the F381 A mutant reveals that the HPPD-HPPA complex observed in the crystal structure should be an intermediate of the substrate transportation instead of the pre-reactive complex.More importantly,the binding mode of the HPPA in this complex is shared with several well-known HPPD inhibitors,suggesting that these inhibitors resist the association of dioxygen(and exert their inhibitory roles)in the same way as the HPPA.The present study provides insights into the inhibition mechanism of HPPD inhibitors.
基金Supported by DSR Scholarship Support,King Saud University。
文摘Lutein,a type of carotenoids,is found to delay the onset and progression of age-related macular degeneration(AMD).Several lutein supplementation studies showed that after an initial increase,lutein serum levels demonstrated a subsequent decrease despite continuous supplementation.In this systematic literature review,this obscure phenomenon was tried to be explained.The subsequent drop in lutein levels was postulated due to down-regulation of lutein receptors scavenger receptor class B typeⅠ(SR-BI)in the gastrointestinal tract,upregulation of lutein degrading enzymeβ-carotene dioxygenase(BCDO2),or perhaps a combination of both.Some single nucleotides polymorphisms(SNPs)that could have influence on the occurrence of this phenomenon.To date,an exact scientific explanation for this phenomenon has not been established.Further research is needed to investigate this phenomenon in depth to reach an irrefutable explanation,giving that lutein is proven to be effective in delaying the onset and progression of AMD and its metabolism in the human body becomes of equal importance.
基金supported by the National Key R&D Program of China(No.2021YFD1700103)National Natural Science Foundation of China(21837001,21676113,21772054,22007035)+1 种基金the 111 Project B17019,the Scholar support program of CCNU(0900–31101090002)Hubei Province Natural Science Foundation(No.2020CFB487).
文摘The upregulation of 4-hydroxyphenylpyruvate dioxygenase(HPPD)can protect plants from adverse abiotic stress.Therefore,studying the changes of HPPD under abiotic stress is extremely valuable.In this study,we employed a rational molecular design strategy to prepare an HPPD-responsive fluorescent probe consisting of a pyrene fluorophore,a linker and a benquitrione skeleton recognition moiety that functions via an aggregation–disaggregation sensing mechanism.As predicted,this probe exhibited an obvious turn-on fluorescence response towards HPPD.In addition,in vivo imaging demonstrated the excellent capability of this probe to track HPPD in Arabidopsis thaliana,and the dynamic changes in HPPD were monitored under different stress degrees of high temperature and Cadmium(II)ion(Cd^(2+))stress.This work provides an efficient design strategy for acquiring a noninvasive HPPD fluorescence probe,which could evaluate the degree of stress and be further employed for exploring the stress resistance mechanism in plants.
基金funded in part by the National Key Research and Development Program of China(No.2021YFD1700100)National Natural Science Foundation of China(No.22007035,21837001).
文摘4-Hydrophenylpyruvate dioxygenase(HPPD),a key enzyme involved in tyrosine catabolism,has long been considered a promising target for herbicides and drugs.Several types of HPPD inhibitors have been developed as high-potency drugs or herbicides.Understanding the structural basis of the binding of these inhibitors with HPPD will be beneficial for the development of inhibitors containing novel scaffolds.However,only limited structural information regarding the binding of triketone and pyrazole derivatives with HPPD has been reported.Here,the crystal structures of HPPD complexed with inhibitors containing different scaffolds,including triketone,pyrazole,isoxazole,heterocyclic amide,and quinazolindione derivatives,were comprehensively analyzed.Detailed binding modes of isoxazole and heterocyclic amide derivatives with HPPD were first revealed,facilitating further structural optimization.The binding mode of compound 2 with HPPD suggests that both oxygen and nitrogen atoms can mediate coordination with the metal ion.These results will provide the structure-based rational design of novel HPPD inhibitors.
基金financially supported by the National Key R&D Program of China(Nos.2021YFA0910500,2021YFA0910503)the National Natural Science Foundation of China(Nos.22277035,32000045 and 81973205)+4 种基金the Program for Changjiang Scholars of Ministry of Education of the People’s Republic of China(No.T2016088)the National Natural Science Foundation for Distinguished Young Scholars(No.81725021)the National Science and Technology Project of China(No.2018ZX09201001-001-003)Innovative Research Groups of the National Natural Science Foundation of China(No.81721005)the Fundamental Research Funds for the Central Universities(No.2020kfyXJJS043).
文摘We reported the characterization of a novel brassicicene diterpene biosynthetic gene cluster,which contains a uniqueα-ketoglutarate-dependent dioxygenase(αKGD)enzyme,AbnI.Our findings revealed that AbnI demonstrates remarkable substrate promiscuity and is capable of activating multiple sites on both 5-8-5 and 5-9-5 brassicicene skeletons,resulting in skeleton modifications and an unexpected ring system rearrangement.These results suggested the potential utility of AbnI as an enzymatic tool for terpene C-H functionalization.In addition,the catalytic mechanism of AbnI and its potential ecological implications were discussed.
