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1.
Nat Immunol ; 25(3): 525-536, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38356061

RESUMEN

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.


Asunto(s)
Enfermedades Autoinmunes , Humanos , Citocinas , Epigenómica , Histona Demetilasas , Homeostasis , Oxidorreductasas N-Desmetilantes , Histona Demetilasas con Dominio de Jumonji/genética
2.
Immunity ; 54(4): 632-647.e9, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33667382

RESUMEN

Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4+ T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4+ T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4+ T cells that potentiates aging-related autoimmunity.


Asunto(s)
Envejecimiento/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Citoplasma/inmunología , Proteína Quinasa Activada por ADN/inmunología , ADN/inmunología , Inflamación/inmunología , Animales , Línea Celular , Línea Celular Tumoral , Núcleo Celular/inmunología , Proliferación Celular/fisiología , Reparación del ADN/inmunología , Células HEK293 , Humanos , Células Jurkat , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células U937
3.
Plant J ; 119(3): 1239-1257, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38776519

RESUMEN

The essence of wound healing is the accumulation of suberin at wounds, which is formed by suberin polyphenolic (SPP) and suberin polyaliphatic (SPA). The biosynthesis of SPP and SPA monomers is catalyzed by several enzyme classes related to phenylpropanoid metabolism and fatty acid metabolism, respectively. However, how suberin biosynthesis is regulated at the transcriptional level during potato (Solanum tuberosum) tuber wound healing remains largely unknown. Here, 6 target genes and 15 transcription factors related to suberin biosynthesis in tuber wound healing were identified by RNA-seq technology and qRT-PCR. Dual luciferase and yeast one-hybrid assays showed that StMYB168 activated the target genes StPAL, StOMT, and St4CL in phenylpropanoid metabolism. Meanwhile, StMYB24 and StMYB144 activated the target genes StLTP, StLACS, and StCYP in fatty acid metabolism, and StFHT involved in the assembly of SPP and SPA domains in both native and wound periderms. More importantly, virus-induced gene silencing in S. tuberosum and transient overexpression in Nicotiana benthamiana assays confirmed that StMYB168 regulates the biosynthesis of free phenolic acids, such as ferulic acid. Furthermore, StMYB24/144 regulated the accumulation of suberin monomers, such as ferulates, α, ω-diacids, and ω-hydroxy acids. In conclusion, StMYB24, StMYB144, and StMYB168 have an elaborate division of labor in regulating the synthesis of suberin during tuber wound healing.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Lípidos , Proteínas de Plantas , Tubérculos de la Planta , Solanum tuberosum , Factores de Transcripción , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tubérculos de la Planta/genética , Tubérculos de la Planta/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Lípidos/biosíntesis , Nicotiana/genética , Nicotiana/metabolismo , Plantas Modificadas Genéticamente , Ácidos Cumáricos/metabolismo
4.
J Virol ; 98(5): e0045124, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38591877

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide range of hosts, including hippopotami, which are semi-aquatic mammals and phylogenetically closely related to Cetacea. In this study, we characterized the binding properties of hippopotamus angiotensin-converting enzyme 2 (hiACE2) to the spike (S) protein receptor binding domains (RBDs) of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs). Furthermore, the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 PT S protein complexed with hiACE2 was resolved. Structural and mutational analyses revealed that L30 and F83, which are specific to hiACE2, played a crucial role in the hiACE2/SARS-CoV-2 RBD interaction. In addition, comparative and structural analysis of ACE2 orthologs suggested that the cetaceans may have the potential to be infected by SARS-CoV-2. These results provide crucial molecular insights into the susceptibility of hippopotami to SARS-CoV-2 and suggest the potential risk of SARS-CoV-2 VOCs spillover and the necessity for surveillance. IMPORTANCE: The hippopotami are the first semi-aquatic artiodactyl mammals wherein SARS-CoV-2 infection has been reported. Exploration of the invasion mechanism of SARS-CoV-2 will provide important information for the surveillance of SARS-CoV-2 in hippopotami, as well as other semi-aquatic mammals and cetaceans. Here, we found that hippopotamus ACE2 (hiACE2) could efficiently bind to the RBDs of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs) and facilitate the transduction of SARS-CoV-2 PT and VOCs pseudoviruses into hiACE2-expressing cells. The cryo-EM structure of the SARS-CoV-2 PT S protein complexed with hiACE2 elucidated a few critical residues in the RBD/hiACE2 interface, especially L30 and F83 of hiACE2 which are unique to hiACE2 and contributed to the decreased binding affinity to PT RBD compared to human ACE2. Our work provides insight into cross-species transmission and highlights the necessity for monitoring host jumps and spillover events on SARS-CoV-2 in semi-aquatic/aquatic mammals.


Asunto(s)
Enzima Convertidora de Angiotensina 2 , Artiodáctilos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Artiodáctilos/virología , Betacoronavirus/genética , Betacoronavirus/metabolismo , Sitios de Unión , COVID-19/virología , COVID-19/metabolismo , Microscopía por Crioelectrón , Unión Proteica , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética
5.
Plant J ; 113(1): 75-91, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36416176

RESUMEN

Soloist is a member of a distinct and small subfamily within the AP2/ERF transcriptional factor family that play important roles in plant biotic and abiotic stress responses. There are limited studies of Soloist genes and their functions are poorly understood. We characterized the abiotic and biotic stress tolerance function of the ScSoloist gene (designated as ScAPD1-like) from the desert moss Syntrichia caninervis. ScAPD1-like responded to multiple abiotic, biotic stresses and plant hormone treatments. ScAPD1-like protein located to the nucleus and bound to several DNA elements. Overexpression of ScAPD1-like in Arabidopsis did not alter abiotic stress resistance or inhibit Pseudomonas syringae pv. tomato (Pst) DC3000 infection. However, overexpression of ScAPD1-like significantly increased the resistance of transgenic Arabidopsis and S. caninervis to Verticillium dahliae infection, decreased reactive oxygen species accumulation and improved reactive oxygen species scavenging activity. ScAPD1-like overexpression plants altered the abundance of transcripts for lignin synthesis and promoted lignin accumulation in Arabidopsis. ScAPD1-like directly bind to RAV1, AC elements, and TATA-box in the promoters of AtPAL1 and AtC4H genes, respectively, in vitro. Chromatin immunoprecipitation-quantitative polymerase chain reaction assays demonstrated ScAPD1-like directly bound to PAL and C4H genes promoters in Arabidopsis and their homologs in S. caninervis. In S. caninervis, ScAPD1-like overexpression and RNAi directly regulated the abundance of ScPAL and ScC4H transcripts and modified the metabolites of phenylpropanoid pathway. We provide insight into the function of Soloist in plant defense mechanisms that likely occurs through activation of the phenylpropanoid biosynthesis pathway. ScAPD1-like is a promising candidate gene for breeding strategies to improve resistance to Verticillium wilt.


Asunto(s)
Arabidopsis , Ascomicetos , Briófitas , Bryopsida , Verticillium , Especies Reactivas de Oxígeno/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Lignina/metabolismo , Fitomejoramiento , Briófitas/metabolismo , Bryopsida/genética , Ascomicetos/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/genética , Gossypium/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
6.
J Biochem Mol Toxicol ; 38(4): e23693, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38622980

RESUMEN

IGSF10, a protein that belongs to the immunoglobulin superfamily, is involved in regulating the early migration of neurons that produce gonadotropin-releasing hormone and performs a fundamental function in development. Our previous study confirmed that the mRNA expression level of IGSF10 may be a protective prognosis factor for lung adenocarcinoma (LUAD) patients. However, the specific mechanisms of IGSF10 are still unclear. In this research, it was shown that the protein level of IGSF10 was down-modulated in LUAD tissues and had a link to the clinical and pathological characteristics as well as the patient's prognosis in LUAD. Importantly, IGSF10 regulates the metastatic ability of LUAD cells in vitro and in vivo. It was proven in a mechanistic sense that IGSF10 inhibits the capacity of LUAD cells to metastasize through the Spi-B/Integrin-ß1 signaling pathway. These findings gave credence to the premise that IGSF10 performed a crucial function in LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Integrinas/genética , Integrinas/metabolismo , Neoplasias Pulmonares/metabolismo , Transducción de Señal
7.
Plant Cell Rep ; 43(2): 57, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38319523

RESUMEN

KEY MESSAGE: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding.


Asunto(s)
Resistencia a la Enfermedad , MicroARNs , Phytophthora infestans , ARN Largo no Codificante , Solanum lycopersicum , Resistencia a la Enfermedad/genética , Phytophthora infestans/patogenicidad , Fitomejoramiento , Especies Reactivas de Oxígeno , Solanum lycopersicum/genética , Solanum lycopersicum/microbiología , MicroARNs/genética , ARN Largo no Codificante/genética , Enfermedades de las Plantas
8.
Nucleic Acids Res ; 50(11): e66, 2022 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-35288753

RESUMEN

Alternative polyadenylation increases transcript diversities at the 3' end, regulating biological processes including cell differentiation, embryonic development and cancer progression. Here, we present a Bayesian method SCAPE, which enables de novo identification and quantification of polyadenylation (pA) sites at single-cell level by utilizing insert size information. We demonstrated its accuracy and robustness and identified 31 558 sites from 36 mouse organs, 43.8% (13 807) of which were novel. We illustrated that APA isoforms were associated with miRNAs binding and regulated in tissue-, cell type-and tumor-specific manners where no difference was found at gene expression level, providing an extra layer of information for cell clustering. Furthermore, we found genome-wide dynamic changes of APA usage during erythropoiesis and induced pluripotent stem cell (iPSC) differentiation, suggesting APA contributes to the functional flexibility and diversity of single cells. We expect SCAPE to aid the analyses of cellular dynamics and diversities in health and disease.


Asunto(s)
Células Madre Pluripotentes Inducidas , MicroARNs , Regiones no Traducidas 3'/genética , Animales , Teorema de Bayes , Diferenciación Celular/genética , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Poliadenilación
9.
Plant Cell Physiol ; 64(11): 1419-1432, 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-37706231

RESUMEN

Desiccation-tolerant (DT) plants can survive extreme dehydration and tolerate the loss of up to 95% of their water content, making them ideal systems to determine the mechanism behind extreme drought stress and identify potential approaches for developing drought-tolerant crops. The desert moss Syntrichia caninervis is an emerging model for extreme desiccation tolerance that has benefited from high-throughput sequencing analyses, allowing identification of stress-tolerant genes; however, its metabolic response to desiccation is unknown. A liquid chromatography-mass spectrometry analysis of S. caninervis at six dehydration-rehydration stages revealed 912 differentially abundant compounds, belonging to 93 metabolic classes. Many (256) metabolites accumulated during rehydration in S. caninervis, whereas only 71 accumulated during the dehydration period, in contrast to the pattern observed in vascular DT plants. During dehydration, nitrogenous amino acids (l-glutamic acid and cysteinylglycine), alkaloids (vinleurosine) and steroids (physalin D) accumulated, whereas glucose 6-phosphate decreased. During rehydration, γ-aminobutyric acid, glucose 6-phosphate and flavonoids (karanjin and aromadendrin) accumulated, as did the plant hormones 12-oxo phytodienoic acid (12-OPDA) and trans-zeatin riboside. The contents ofl-arginine, maltose, turanose, lactulose and sucrose remained high throughout dehydration-rehydration. Syntrichia caninervis thus accumulates antioxidants to scavenge reactive oxygen species, accumulating nitrogenous amino acids and cytoprotective metabolites and decreasing energy metabolism to enter a protective state from dehydration-induced damage. During subsequent rehydration, many metabolites rapidly accumulated to prevent oxidative stress and restore physiological activities while repairing cells, representing a more elaborate rehydration repair mechanism than vascular DT plants, with a faster and greater accumulation of metabolites. This metabolic kinetics analysis in S. caninervis deepens our understanding of its dehydration mechanisms and provides new insights into the different strategies of plant responses to dehydration and rehydration.


Asunto(s)
Briófitas , Bryopsida , Deshidratación , Bryopsida/genética , Fluidoterapia , Aminoácidos , Fosfatos , Glucosa
10.
J Transl Med ; 21(1): 212, 2023 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-36949448

RESUMEN

BACKGROUND: COVID-19, the current global pandemic caused by SARS-CoV-2 infection, can damage the heart and lead to heart failure (HF) and even cardiac death. The 2',5'-oligoadenylate synthetase (OAS) gene family encode interferon (IFN)-induced antiviral proteins which is associated with the antiviral immune responses of COVID-19. While the potential association of OAS gene family with cardiac injury and failure in COVID-19 has not been determined. METHODS: The expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. The associated microRNAs (miRNAs) were explored from Targetscan and GSE104150. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database. RESULTS: The OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expressed genes (DEGs) in the two datasets were enriched in both cardiovascular disease and COVID-19 related pathways. The miRNAs-target analysis indicated that 10 miRNAs could increase the expression of OAS genes. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family especially estradiol. CONCLUSION: OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19.


Asunto(s)
COVID-19 , Insuficiencia Cardíaca , MicroARNs , Humanos , COVID-19/complicaciones , COVID-19/genética , SARS-CoV-2 , Insuficiencia Cardíaca/genética , Antivirales , MicroARNs/genética
11.
Acta Pharmacol Sin ; 44(2): 475-485, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35918411

RESUMEN

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL­2­dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Dominios Proteicos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Apoptosis
12.
Acta Pharmacol Sin ; 44(4): 791-800, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36229599

RESUMEN

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.


Asunto(s)
Inmunidad Innata , Enfermedades Inflamatorias del Intestino , Nucleotidiltransferasas , Animales , Ratones , ADN/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Nucleotidiltransferasas/antagonistas & inhibidores , Transducción de Señal , Pirroles/química , Pirroles/farmacología , Pirazinas/química , Pirazinas/farmacología
13.
Int J Mol Sci ; 24(7)2023 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-37047111

RESUMEN

Transcription factor (TF) families play important roles in plant stress responses. S. caninervis is a new model moss for plant desiccation tolerance studies. Here, we report a high-confidence identification and characterization of 591 TFs representing 52 families that covered all chromosomes in S. caninervis. GO term and KEGG pathway analysis showed that TFs were involved in the regulation of transcription, DNA-templated, gene expression, binding activities, plant hormone signal transduction, and circadian rhythm. A number of TF promoter regions have a mixture of various hormones-related cis-regulatory elements. AP2/ERF, bHLH, MYB, and C2H2-zinc finger TFs were the overrepresented TF families in S. caninervis, and the detailed classification of each family is performed based on structural features. Transcriptome analysis revealed the transcript abundances of some ScAP2/ERF, bHLH, MYB, and C2H2 genes were accumulated in the treated S. caninervis under cold, dehydration, and rehydration stresses. The RT-qPCR results strongly agreed with RNA-seq analysis, indicating these TFs might play a key role in S. caninervis response to abiotic stress. Our comparative TF characterization and classification provide the foundations for functional investigations of the dominant TF genes involved in S. caninervis stress response, as well as excellent stress tolerance gene resources for plant stress resistance breeding.


Asunto(s)
Bryopsida , Factores de Transcripción , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica de las Plantas , Fitomejoramiento , Estrés Fisiológico/genética , Bryopsida/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
14.
Insect Mol Biol ; 31(3): 317-333, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35084067

RESUMEN

The 26S proteasome is the major engine of protein degradation in all eukaryotic cells. Adenosine triphosphatase (ATPase) regulatory subunits (Rpts) are constituents of the proteasome that are involved in the unfolding and translocation of substrate proteins into the core particle. In this study, by using the brown planthopper Nilaparvata lugens as a model insect, we report the biological importance of Rpts in female reproduction. We identified six homologous Rpt genes (Rpt1-6) in N. lugens. These genes were detected at high transcript levels in eggs and ovaries of females but at low transcript levels in males. RNA interference-mediated knockdown of N. lugens Rpt genes significantly decreased the proteolytic activity of the proteasome and impeded the transcription of triacylglycerol lipase and vitellogenin genes in the fat bodies and ovaries of adult females and reduced the triglyceride content in the ovaries. The decrease in the proteolytic activity of the proteasome via knockdown of Rpts also downregulated the transcription of the CYP307A2 gene encoding an important rate-limiting enzyme in the 20-hydroxyecdysone biosynthetic pathway in the ovaries, reduced 20E production in adult females and impaired ovarian development and oocyte maturation, leading to the failure of egg production and egg-laying. These novel findings indicate that Rpts are required for the proteolytic activity of the proteasome, which is important for female reproductive success in N. lugens.


Asunto(s)
Hemípteros , Complejo de la Endopetidasa Proteasomal , Adenosina Trifosfatasas/genética , Animales , Femenino , Hemípteros/genética , Hemípteros/metabolismo , Masculino , Oocitos/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo
15.
Biochem Biophys Res Commun ; 528(2): 292-298, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32499110

RESUMEN

Abscisic acid (ABA) is an important plant hormone that mediates abiotic stresses in plant growth and development. A number of E3 ligases have been reported to be involved in ABA signaling pathway. In this study, we identified a C3H2C3 RING-type E3 ligase, Arabidopsis thaliana Tόxicos en Levadura 61 (ATL61), which regulated drought stress in planta. Enzyme assay in vitro demonstrated that ATL61 had E3 ubiquitin ligase activity, while point mutation of ATL61H109A, H122A (mATL61) abolished its E3 ubiquitin ligase activity. ATL61 overexpression plants exhibited ABA hypersensitivity and were more tolerant to drought, while the atl61 mutant plants were insensitive to ABA. Moreover, mATL61 overexpression lines exhibited similar ABA-related phenotypes with wild type (WT) plants. The transcript abundances of ABA-mediated drought stress-related genes RD20 and RD22 were higher in ATL61 overexpression plants than those in WT, atl61, and mATL61 plants. Our results indicated that ATL61 acted as a positive regulator in the ABA-mediated drought stress response.


Asunto(s)
Ácido Abscísico/farmacología , Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Arabidopsis/fisiología , Sequías , Arabidopsis/efectos de los fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Presión Osmótica/efectos de los fármacos , Fenotipo , Plantas Modificadas Genéticamente , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Ubiquitinación/efectos de los fármacos
16.
Bioorg Chem ; 100: 103958, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32470762

RESUMEN

Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor facilitating innate immune signaling. Activation of STING leads to expression of interferons (IFNs) and pro-inflammatory cytokines which is associated with antiviral and antitumor responses. It is imperative to discovery potent compounds that precisely modulate STING. Herein, we describe the discovery of triazoloquinoxaline 1a as a novel STING agonist via Structure-based Virtual Screening. Specifically, biochemical and cell-based assays suggested that 1a stimulated concentration-dependently mRNA expression of IFNß, CXCL-10 and IL-6. Furthermore, 1a significantly induced phosphorylation of STING, TANK-binding kinases1 (TBK1) and interferon regulatory factor 3 (IRF3), suggesting the activation of STING and its downstream TBK1-IRF3 signaling axis. In addition, 1a activated secretion of secreted alkaline phosphatase (SEAP) in dose-dependent manner and EC50 was 16.77 ± 3.814 µM, which is comparable with EC50 of 2'3'-cGAMP (9.212 ± 2.229 µM). These studies revealed that 1a is a promising STING agonist possessing the potential to be further developed for antiviral and antitumor treatment.


Asunto(s)
Proteínas de la Membrana/agonistas , Simulación del Acoplamiento Molecular , Quinoxalinas/química , Triazoles/química , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Diseño de Fármacos , Humanos , Factor 3 Regulador del Interferón/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Quinoxalinas/metabolismo , Quinoxalinas/farmacología , Transducción de Señal/efectos de los fármacos
17.
Bioorg Chem ; 96: 103620, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32028064

RESUMEN

Glycolysis is enhanced in cancer cells. Cancer cells utilize glycolysis as their primary energy source, even under aerobic conditions. This is known as the Warburg effect. Thus, effective inhibition of the glycolytic pathway is a crucial component of cancer therapy. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme in glycolysis and overexpresses in cancers. Therefore, targeting GAPDH to inhibit its role in glycolysis is important for GAPDH functional studies and the treatment of cancers. However, only a few GAPDH inhibitors have been reported. In our current study, we identified a GAPDH inhibitor, DC-5163, using docking-based virtual screening and biochemical and biophysical analysis. DC-5163 is a small molecule compound that inhibits GAPDH enzyme activity and cancer cell proliferation (normal cells were tolerant to it). It can inhibit glycolysis pathway partially, which was manifested by decreased glucose uptake and lactic acid production. And it also leaded to cell death through apoptotic pathways. This study reflects the pivotal role of GAPDH in cancer cells and demonstrates that DC-5163 is a useful inhibitor and can be of value in studying the role of GAPDH and the development of new clinical cancer treatments.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Gliceraldehído-3-Fosfato Deshidrogenasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Descubrimiento de Drogas , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
18.
Molecules ; 22(6)2017 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-28635656

RESUMEN

Areca catechu L. nut, a well-known toxic traditional herbal medicine, has been widely used to treat various diseases in China and many other Asian countries for centuries. However, to date the in vivo absorption and metabolism of its multiple bioactive or toxic components still remain unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the major components and their metabolites in rat plasma and urine after oral administration of Areca catechu L. nut extract (ACNE). A total of 12 compounds, including 6 alkaloids, 3 tannins and 3 amino acids, were confirmed or tentatively identified from ACNE. In vivo, 40 constituents, including 8 prototypes and 32 metabolites were identified in rat plasma and urine samples. In summary, this study showed an insight into the metabolism of ACNE in vivo, which may provide helpful chemical information for better understanding of the toxicological and pharmacological profiles of ACNE.


Asunto(s)
Areca/química , Catequina/química , Catequina/metabolismo , Nueces/química , Extractos Vegetales/química , Extractos Vegetales/metabolismo , Administración Oral , Alcaloides/sangre , Alcaloides/química , Alcaloides/orina , Aminoácidos/sangre , Aminoácidos/química , Aminoácidos/orina , Animales , Catequina/administración & dosificación , Cromatografía Líquida de Alta Presión , Masculino , Extractos Vegetales/sangre , Extractos Vegetales/orina , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Taninos/sangre , Taninos/química , Taninos/orina
19.
Zhongguo Zhong Yao Za Zhi ; 42(8): 1532-1538, 2017 Apr.
Artículo en Zh | MEDLINE | ID: mdl-29071858

RESUMEN

Biopharmaceutics classification system of Chinese materia medica (CMMBCS) emphasizes characteristic of the multi-component environment based on the drug solubility and permeability. In this study, the in situ closed-loop method combined with LC-MS technique was utilized to study the intestinal absorption and metabolism of Puerariae Lobatae Radix decoction (PLRD), providing selection basis for intestinal permeability components in CMMBCS. A total of 36 components were identified from PLRD. Among them, 17 components could be detected in the plasma sample, indicating that 17 components could be absorbed into blood, so these 17 components could be used as intestinal permeability evaluation components in CMMBCS. The other 19 components were not detected in the plasma sample, suggesting that they may not be absorbed or metabolized by the gut wall enzymes.


Asunto(s)
Medicamentos Herbarios Chinos/farmacocinética , Absorción Intestinal , Pueraria/química , Humanos , Raíces de Plantas/química
20.
Inorg Chem ; 55(18): 9276-83, 2016 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-27585404

RESUMEN

There emerge great interests in the syntheses of metastable polyborates; however, most are involved with the high-pressure technique. A facile method to synthesize metastable rare earth borates at ambient pressure is eagerly required for the large-scale production and property investigation. Here we demonstrate the critical role of Bi(3+) substitutions in the stabilization of metastable ß-REB3O6 (RE = Sm, Eu, Gd, Tb, Dy, Ho, Er, and Y) at ambient pressure, where the Bi(3+)-to-RE(3+) substitutions would efficiently reduce the synthetic temperatures to 735-820 °C, well below the upper limit of thermodynamically stable window (840-980 °C). Partial solid solutions of ß-RE1-xBixB3O6 were prepared, and the ranges of the solution were also studied experimentally. The thermal behaviors of ß-RE0.8Bi0.2B3O6 were investigated by differential thermal analyses and powder X-ray diffraction, and they were divided into two categories; that is, ß-RE0.8Bi0.2B3O6 (RE = Sm, Eu, Gd) transfers to α-RE0.8Bi0.2B3O6 with further increasing the temperature to 950 °C, while ß-RE0.8Bi0.2B3O6 (RE = Tb, Dy, Ho, Er, and Y) decomposes into hexagonal REBO3 and B2O3. In particular, the allowed concentration of Bi(3+) in ß-Gd1-xBixB3O6 was 0.10 ≤ x ≤ 0.25, and these samples show bright blue emissions under UV excitation, which suggests the high efficiency of light absorption and high potential as phosphors with further doping of other activators.

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