RESUMO
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that remains incurable. Herein, we demonstrated that ilepcimide (Antiepilepsirine), an antiepileptic drug used for decades, protects mice from experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our studies found that ilepcimide treatment effectively ameliorates demyelination, blood-brain barrier leakage and infiltration of CD4+ and CD8+ T cells in EAE mice. On the one hand, ilepcimide can inhibit dihydroorotate dehydrogenase (DHODH), an important therapeutic target for MS. Computer molecular docking, thermal shift and fluorescence quenching assay demonstrated the directly interaction between ilepcimide and DHODH. Accordingly, ilepcimide observably repressed T cell proliferation in mixed lymphocyte reaction (MLR) assay and concanavalin A (Con-A) model in a DHODH-dependent manner. On the other hand, ilepcimide exhibited neuroprotective effect possibly through activating NRF2 antioxidant pathway in mouse neural crest-derived Neuro2a cells. Collectively, our findings have revealed the therapeutic potential of ilepcimide in EAE mouse model via restricting inflammatory response and oxidative stress, offering a potential opportunity for repurposing existing drug ilepcimide for MS therapy.
Assuntos
Reposicionamento de Medicamentos , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Linfócitos T CD8-Positivos , Di-Hidro-Orotato Desidrogenase , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Esclerose Múltipla/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Inflamação/tratamento farmacológicoRESUMO
Triple-negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component of Lithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver-Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA-MB-231, and murine TNBC cell line, 4T1 in a dose-dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti-TNBC activity, impelling its further study in clinical trials.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Naftoquinonas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lithospermum/química , Camundongos , Simulação de Acoplamento Molecular , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Animais , Apoptose/genética , Biomarcadores Tumorais , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Di-Hidro-Orotato Desidrogenase , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Camundongos , Modelos Moleculares , Estrutura Molecular , Células-Tronco Neoplásicas/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Prognóstico , Interferência de RNA , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50â¯=â¯10.0⯵M), PfDHFR (IC50â¯=â¯84.1â¯nM), P. falciparum 3D7 (IC50â¯=â¯53.1â¯nM), clinical isolated strains Fab9 (IC50â¯=â¯14.2â¯nM) and GB4 (IC50â¯=â¯23.4â¯nM). The in vivo inhibition assays against P. berghei in 10â¯days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.
Assuntos
Antimaláricos/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Tetra-Hidrofolato Desidrogenase/metabolismo , Animais , Antimaláricos/síntese química , Antimaláricos/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Malária/tratamento farmacológico , Malária/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans-proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteína 1 Associada a ECH Semelhante a Kelch , Neoplasias Pulmonares , Fator 2 Relacionado a NF-E2 , Peptidilprolil Isomerase , Estabilidade Proteica , Ubiquitinação , Animais , Feminino , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Progressão da Doença , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Camundongos Nus , Fator 2 Relacionado a NF-E2/metabolismo , Proteólise , Peptidilprolil Isomerase/metabolismoRESUMO
The ubiquitous coexistence of majority insulating 245 phases and minority superconducting (SC) phases in A(x)Fe(2-y)Se(2) (A = K, Cs, Rb, Tl/Rb, Tl/K) formed by high-temperature routes makes pure SC phases highly desirable for studying the intrinsic properties of this SC family. Here we report that there are at least two pure SC phases, K(x)Fe(2)Se(2)(NH(3))(y) (x ≈ 0.3 and 0.6), determined mainly by potassium concentration in the K-intercalated iron selenides formed via the liquid ammonia route. K(0.3)Fe(2)Se(2)(NH(3))(0.47) corresponds to the 44 K phase with lattice constant c = 15.56(1) Å and K(0.6)Fe(2)Se(2)(NH(3))(0.37) to the 30 K phase with c = 14.84(1) Å. With higher potassium doping, the 44 K phase can be converted into the 30 K phase. NH(3) has little, if any, effect on superconductivity. Thus, the conclusions should apply to both K(0.3)Fe(2)Se(2) and K(0.6)Fe(2)Se(2) SC phases. K(0.3)Fe(2)Se(2)(NH(3))(0.47) and K(0.6)Fe(2)Se(2)(NH(3))(0.37) stand out among known superconductors as their structures are stable only at particular potassium doping levels, and hence the variation of T(c) with doping is not dome-like.
RESUMO
Na was intercalated between [Fe2S2] layers for the first time, giving a novel compound NaFe(1.6)S2. This material adopts a CaAl2Si2-type structure with ~20% iron vacancies and represents the first layered compound in a ternary Na-M-X (M = Fe, Co, Ni; X = S, Se) system. First-principles calculations reveal that phonon dynamics is an important factor for it to prefer the CaAl2Si2-type rather than the ThCr2Si2-type structure. It features a magnetic transition at 205 K and is a narrow-band-gap semiconductor.
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Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting reaction in the de novo synthesis pathway of guanine nucleotides that is highly required for cancer cell outgrowth. Herein, we found that IMPDH isoform 2 (IMPDH2) is highly expressed in colorectal cancer (CRC) and is correlated with poor patient prognosis. Via structure-based virtual screening, we identified berberrubine, a critical ingredient of the medical plant Coptis chinensis, as a novel, selective, and competitive inhibitor of IMPDH2, which demonstrated over 15-fold selectivity to IMPDH2 than IMPDH1. Besides, we also confirmed the interaction between berberrubine and IMPDH2. Of note, berberrubine treatment significantly impairs the growth of human CRC cells in a dose-dependent manner, which can be rescued by supplementing with guanosine. Furthermore, oral administration of berberrubine remarkably reduced tumor volume and weight in a human cell line-derived xenograft model. Importantly, the anti-cancer activity of berberrubine was also confirmed by using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced spontaneous CRC mouse model. Taken together, our study highlights that berberrubine acts as a novel IMPDH2 inhibitor, suppressing the growth of CRC in vitro and in vivo, providing a fresh perspective for its potential application in the treatment of CRC.
Assuntos
Berberina , Neoplasias Colorretais , Animais , Camundongos , Humanos , Linhagem Celular , Berberina/farmacologia , Berberina/uso terapêutico , Isoformas de Proteínas , Neoplasias Colorretais/tratamento farmacológico , IMP DesidrogenaseRESUMO
Four new oxyselenides with nominal formula Sr(2)AO(2)M(2)Se(2) (A=Co, Mn; M=Cu, Ag) have been synthesized. They all crystallize in an I4/mmm space group and consist of alternating perovskite-like (Sr(2)AO(2))(2+) blocks and antiflourie (M(2)Se(2))(2-) layers, which are relatively rare layered oxyselenides reported so far that are isostructural to Sr(2)Mn(3)Sb(2)O(2). From powder X-ray diffraction data, compounds Sr(2)CoO(2)Cu(2)Se(2) and Sr(2)CoO(2)Ag(2)Se(2) are found near stoichiometric, whereas Sr(2)MnO(2)Cu(2-δ)Se(2) and Sr(2)MnO(2)Ag(2-δ)Se(2) possess substantial copper or silver vacancies (δ≈0.5), consistent with their oxysulfide analogues. X-ray photoelectron spectroscopy measurements indicate the readily oxidization of Mn(2+) ions should be responsible for the occurrence of Cu/Ag vacancies. The rigid (Sr(2)AO(2))(2+) blocks within these compounds constrain the basal lattice parameters in the ab plane and result in largely deformed tetrahedral sites for the large silver ions. Magnetic susceptibility measurements of Sr(2)CoO(2)M(2)Se(2) (M=Cu, Ag) show complex antiferromagnetic transitions, while Sr(2)MnO(2)M(2-δ)Se(2) (M=Cu, Ag) show high-temperature Curie-Weiss behavior, followed by low-temperature antiferromagnetic transitions at 54 K and 67 K, respectively. Except for Sr(2)MnO(2)Ag(2-δ)Se(2), the other three compounds exhibit p-type semiconducting transport properties, with the measured resistivities several orders lower than their oxysulfide analogues. Hall measurement reveals high mobilities of Sr(2)CoO(2)M(2)Se(2) (M=Cu, Ag) compounds at room temperature. The unusually small optical band gaps (~0.07 eV) of Sr(2)CoO(2)Cu(2)Se(2), Sr(2)CoO(2)Ag(2)Se(2), and Sr(2)MnO(2)Cu(2-δ)Se(2) are also reported.
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Chickpea (Cicer arietinum L.) is one of the major pulse crops, rich in protein, and widely consumed all over the world. Most legumes, including chickpeas, possess noticeable amounts of raffinose family oligosaccharides (RFOs) in their seeds. RFOs are seed oligosaccharides abundant in nature, which are non-digestible by humans and animals and cause flatulence and severe abdominal discomforts. So, this study aims to identify genetic factors associated with seed oligosaccharides in chickpea using the mini-core panel. We have quantified the RFOs (raffinose and stachyose), ciceritol, and sucrose contents in chickpea using high-performance liquid chromatography. A wide range of variations for the seed oligosaccharides was observed between the accessions: 0.16 to 15.13 mg g-1 raffinose, 2.77 to 59.43 mg g-1 stachyose, 4.36 to 90.65 mg g-1 ciceritol, and 3.57 to 54.12 mg g-1 for sucrose. Kabuli types showed desirable sugar profiles with high sucrose, whereas desi types had high concentrations RFOs. In total, 48 single nucleotide polymorphisms (SNPs) were identified for all the targeted sugar types, and nine genes (Ca_06204, Ca_04353, and Ca_20828: Phosphatidylinositol N-acetylglucosaminyltransferase; Ca_17399 and Ca_22050: Remorin proteins; Ca_11152: Protein-serine/threonine phosphatase; Ca_10185, Ca_14209, and Ca_27229: UDP-glucose dehydrogenase) were identified as potential candidate genes for sugar metabolism and transport in chickpea. The accessions with low RFOs and high sucrose contents may be utilized in breeding specialty chickpeas. The identified candidate genes could be exploited in marker-assisted breeding, genomic selection, and genetic engineering to improve the sugar profiles in legumes and other crop species.
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Raffinose family oligosaccharides (RFOs) are widespread across the plant kingdom, and their concentrations are related to the environment, genotype, and harvest time. RFOs are known to carry out many functions in plants and humans. In this paper, we provide a comprehensive review of RFOs, including their beneficial and anti-nutritional properties. RFOs are considered anti-nutritional factors since they cause flatulence in humans and animals. Flatulence is the single most important factor that deters consumption and utilization of legumes in human and animal diets. In plants, RFOs have been reported to impart tolerance to heat, drought, cold, salinity, and disease resistance besides regulating seed germination, vigor, and longevity. In humans, RFOs have beneficial effects in the large intestine and have shown prebiotic potential by promoting the growth of beneficial bacteria reducing pathogens and putrefactive bacteria present in the colon. In addition to their prebiotic potential, RFOs have many other biological functions in humans and animals, such as anti-allergic, anti-obesity, anti-diabetic, prevention of non-alcoholic fatty liver disease, and cryoprotection. The wide-ranging applications of RFOs make them useful in food, feed, cosmetics, health, pharmaceuticals, and plant stress tolerance; therefore, we review the composition and diversity of RFOs, describe the metabolism and genetics of RFOs, evaluate their role in plant and human health, with a primary focus in grain legumes.
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Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.
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Somatic gain-of-function mutations within estrogen receptor alpha (ERα) are highly associated with hormone therapy resistance in breast cancer. However, current understanding of abnormal activity of ERα mutants and their relevant targeted intervention is still very limited. Herein, we developed a new, real-time, and reliably Gaussia luciferase-based protein-fragment complementation assay (GLPCA) for evaluating ERα mutants activities. We found that, compared with ER WT, ERα mutants (Y537S/N and D538G) exhibit high ligand-independent activity, suggesting the gain-of-function phenotype of these ERα mutants. Notably, Y537S, the most common ERα mutant type, has the highest intrinsic activation. We then collected and screened a natural product library for potential ERα antagonists via GLPCA and identified celastrol and gambogic acid as new antagonists of the ERα Y537S mutant. Moreover, interactions between these two compounds and the ERα Y537S mutant were confirmed by molecular docking and cellular thermal shift assay. Importantly, we further demonstrated that celastrol and gambogic acid exhibit synergistic antiproliferative and pro-apoptotic effects when combined with an approved CDK4/6 inhibitor abemaciclib in breast cancer cells expressing ERα Y537S. In summary, GLPCA provides a powerful platform for exploring innovative functional biology and drug discovery of antagonists targeting ERα mutants.
Assuntos
Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Mutação/efeitos dos fármacos , Triterpenos Pentacíclicos/uso terapêutico , Xantonas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/genética , Feminino , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/fisiologia , Triterpenos Pentacíclicos/farmacologia , Estrutura Secundária de Proteína , Xantonas/farmacologiaRESUMO
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.
Assuntos
Epigênese Genética , Genoma , Chaperonas Moleculares/genética , Neoplasias/genética , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Animais , Feminino , Xenoenxertos , Humanos , Camundongos , Transdução de SinaisRESUMO
Short rotation woody biomass cultivars developed from fast-growing shrub species of willow (Salix spp.) have superior properties as perennial energy crops for the Northeast and Midwest US. However, the insect pest potato leafhopper (PLH) Empoasca fabae (Harris) can cause serious damage and reduce yield of susceptible genotypes. Currently, the willow cultivars in use display varying levels of susceptibility under PLH infestation. However, genes and markers for resistance to PLH are not yet available for marker-assisted selection in breeding. In this study, transcriptome differences between a resistant genotype 94006 (S. purpurea) and a susceptible cultivar 'Jorr' (S. viminalis), and their hybrid progeny were determined. Over 600 million RNA-Seq reads were generated and mapped to the Salix purpurea reference transcriptome. Gene expression analyses revealed the unique defense mechanism in resistant genotype 94006 that involves PLH-induced secondary cell wall modification. In the susceptible genotypes, genes involved in programed cell death were highly expressed, explaining the necrosis symptoms after PLH feeding. Overall, the discovery of resistance genes and defense mechanisms provides new resources for shrub willow breeding and research in the future.
Assuntos
Salix/genética , Transcriptoma , Animais , Apoptose/genética , Parede Celular/química , Parede Celular/metabolismo , Produtos Agrícolas , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Genótipo , Hemípteros/fisiologia , Herbivoria , Interações Hospedeiro-Parasita/genética , Fenótipo , Análise de Componente Principal , RNA de Plantas/química , RNA de Plantas/metabolismo , Salix/parasitologiaRESUMO
Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 µM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.
Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/química , Alcaloides/metabolismo , Animais , Benzodioxóis/química , Benzodioxóis/metabolismo , Produtos Biológicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Cristalografia por Raios X , Di-Hidro-Orotato Desidrogenase , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Modelos Moleculares , Terapia de Alvo Molecular , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fragmentos de Peptídeos/toxicidade , Piperidinas/química , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/metabolismo , Baço/citologiaRESUMO
Glassy ferromagnetism is observed in diluted magnetic semiconductor Al-doped 4H-SiC. We propose a possible explanation for the origin of ferromagnetism order that is the coeffect of sp(2)/sp(3) configuration along with the structural defects. This result unambiguously demonstrates the existence of intrinsic ferromagnetism order in nonmagnetic sp systems.
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In this article, we report a new modified solid-state metathesis pathway to synthesize nitrides using Li(3)N as a nitrification reagent to transform single element to nitrides. In this process, not only binary (including mono- and multinitrides) but also ternary nitrides can be approached by varying the molar ratio of Li(3)N to a single element. A possible two-step reaction mechanism for Li(3)N and single elements was proposed. This study provides a promising route to meet the increasing demand in energy savings and environmental protection for materials synthesis.
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The title compound, potassium cadmium metaborate, crystallizes in a monoclinic cell, featuring infinite one-dimensional CdO(5) chains and trigonal planar B atoms in hexagonal B(3)O(6) metaborate ions. The trigonal bipyramidal CdO(5) chains and metaborate ions are interlinked to form a three-dimensional framework, creating channels running parallel to the [101] direction in which the potassium ions reside.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and is the most common type of cognitive impairment and dementia. There is a pressing need to improve the clinical efficacy and quality of life for AD patients, as limited treatments options for AD patients have been developed until now. In this study, we aim to investigate the protective effect of CH(II), a cerebroprotein hydrolysate consisted of abundant biological peptides, on preclinical model of AD. We found that CH(II) treatment effectively protects oxygen glucose deprivation (OGD)-induced N2A cell viability impairment and cell apoptosis. In addition, CH(II) significantly reduces H2O2-induced ROS accumulation and exhibits the protective activities against H2O2-induced oxidative injury. Intriguingly, we found that CH(II) treatment can effectively promote neurite outgrowth of N2A cells. Moreover, CH(II) obviously improve the cognitive and memorial function in scopolamine-induced amnesia mice model. Taken together, this study provides evidences of the neuroprotective activities of CH(II) and offers a potential therapeutic strategy for AD patients.