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1.
Heliyon ; 10(11): e30950, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38947437

RESUMO

Understanding who adopt green production and why they choose this strategy is an important issue that needs to be addressed in the context of increasingly severe agricultural pollution. Previous studies have generally investigated subsistence-oriented smallholders, typically employing profit maximization or risk minimization models. However, Chinese farmers have differentiated, and have unique characteristics. This study collected data from 960 random samples of rice farmers and conducted quantitative analysis. The findings reveal that 94.9 % of the farmers had less than 2-ha rice-planting area, and 80.21 % of farmers reported that their purpose of planting rice was for family self-feeding. Furthermore, the new standard to define smallholder based on whether their production purpose is self-feeding or selling and found that non-smallholders had an overall advantage and passed the t-test. Even more non-smallholder (76.32 %) intentionally chose green pesticide than smallholders (66.1 %), but their decision-making logic was different. Binary logistic regression results show that three aspects of self-actualization (environmental, market, and personal) positively and significantly affected the green production behavior of smallholders, but not significant for non-smallholders. This study suggests that in China, where smallholders are the mainstay of agriculture production, green production by smallholders will greatly improve the ecological environment and provide high quality agricultural products.

2.
Plants (Basel) ; 13(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38999577

RESUMO

Fungi as heterotrophs are key participants in the decomposition of organic materials and the transformation of nutrients in agroecosystems. Ditch-buried straw return as a novel conservation management strategy can improve soil fertility and alter hydrothermal processes. However, how ditch-buried straw return strategies affect the soil fungal community is still unclear. Herein, a 7-year field trial was conducted to test the influences of burial depth (0, 10, 20, 30, and 40 cm) and the amount of ditch-buried straw (half, full, double) on the diversity, composition, and predicted functions of a soil fungal community, as well as the activities of carbon-degraded enzymes. Under the full amount of straw burial, the abundance of phylum Ascomycota was 7.5% higher as compared to other burial amount treatments. This further increased the activity of cellobiohydrolase by 32%, as revealed by the positive correlation between Ascomycota and cellobiohydrolase. With deeper straw burial, however, the abundance of Ascomycota and ß-D-glucopyranoside activity decreased. Moreover, genus Alternaria and Fusarium increased while Mortierella decreased with straw burial amount and depth. FUNgild prediction showed that plant fungal pathogens were 1- to 2-fold higher, whilst arbuscular mycorrhizal fungi were 64% lower under straw buried with double the amount and at a depth of 40 cm. Collectively, these findings suggest that ditch-buried straw return with a full amount and buried at a depth less than 30 cm could improve soil nutrient cycles and health and may be beneficial to subsequent crop production.

3.
BMC Plant Biol ; 24(1): 590, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38902595

RESUMO

BACKGROUND: The Prunus sibirica seeds with rich oils has great utilization, but contain amygdalin that can be hydrolyzed to release toxic HCN. Thus, how to effectively reduce seed amygdalin content of P. sibirica is an interesting question. Mandelonitrile is known as one key intermediate of amygdalin metabolism, but which mandelonitrile lyase (MDL) family member essential for its dissociation destined to low amygdalin accumulation in P. sibirica seeds still remains enigmatic. An integration of our recent 454 RNA-seq data, amygdalin and mandelonitrile content detection, qRT-PCR analysis and function determination is described as a critical attempt to determine key MDL and to highlight its function in governing mandelonitrile catabolism with low amygdalin accumulation in Prunus sibirica seeds for better developing edible oil and biodiesel in China. RESULTS: To identify key MDL and to unravel its function in governing seed mandelonitrile catabolism with low amygdalin accumulation in P. sibirica. Global identification of mandelonitrile catabolism-associated MDLs, integrated with the across-accessions/developing stages association of accumulative amount of amygdalin and mandelonitrile with transcriptional level of MDLs was performed on P. sibirica seeds of 5 accessions to determine crucial MDL2 for seed mandelonitrile catabolism of P. sibirica. MDL2 gene was cloned from the seeds of P. sibirica, and yeast eukaryotic expression revealed an ability of MDL2 to specifically catalyze the dissociation of mandelonitrile with the ideal values of Km (0.22 mM) and Vmax (178.57 U/mg). A combination of overexpression and mutation was conducted in Arabidopsis. Overexpression of PsMDL2 decreased seed mandelonitrile content with an increase of oil accumulation, upregulated transcript of mandelonitrile metabolic enzymes and oil synthesis enzymes (involving FA biosynthesis and TAG assembly), but exhibited an opposite situation in mdl2 mutant, revealing a role of PsMDL2-mediated regulation in seed amygdalin and oil biosynthesis. The PsMDL2 gene has shown as key molecular target for bioengineering high seed oil production with low amygdalin in oilseed plants. CONCLUSIONS: This work presents the first integrated assay of genome-wide identification of mandelonitrile catabolism-related MDLs and the comparative association of transcriptional level of MDLs with accumulative amount of amygdalin and mandelonitrile in the seeds across different germplasms and developmental periods of P. sibirica to determine MDL2 for mandelonitrile dissociation, and an effective combination of PsMDL2 expression and mutation, oil and mandelonitrile content detection and qRT-PCR assay was performed to unravel a mechanism of PsMDL2 for controlling amygdalin and oil production in P. sibirica seeds. These findings could offer new bioengineering strategy for high oil production with low amygdalin in oil plants.


Assuntos
Amigdalina , Prunus , Sementes , Amigdalina/metabolismo , Prunus/genética , Prunus/metabolismo , Prunus/enzimologia , Sementes/metabolismo , Sementes/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Óleos de Plantas/metabolismo , Aldeído Liases/metabolismo , Aldeído Liases/genética , Regulação da Expressão Gênica de Plantas
4.
Mol Psychiatry ; 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704506

RESUMO

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2BY29X mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

5.
J Org Chem ; 89(10): 7076-7083, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38701135

RESUMO

A method has been developed for the rapid synthesis of highly substituted 3-methylpyridones via the condensation of Baylis-Hillman amines and ketones under benzoic acid catalysis. The process features readily available starting materials, broad substrate scope, high functional group tolerance, excellent regioselectivity, and gram-scale synthesis. We envision that this on-demand construction of 3-methylpyridones will provide exciting opportunities in biological research, therapeutics, and material sciences.

6.
Org Lett ; 26(20): 4318-4322, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38752547

RESUMO

Herein, we first report a γ-selective deuteration reaction of pyridines via H/D exchange without the need for preinstalled directing groups and transformable functional groups. The electrochemical process offers an attractive approach to producing γ-deuterated pyridines under gentle conditions. The broad substrate scope, excellent deuterium incorporation, and remarkable selectivity of the electrochemical method make it applicable for the late-stage modification of pharmaceutical molecules.

7.
Nat Commun ; 15(1): 3034, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589429

RESUMO

Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.


Assuntos
Ansiedade , Córtex Pré-Frontal , Humanos , Lipocalina-2/metabolismo , Córtex Pré-Frontal/fisiologia , Ansiedade/metabolismo , Transtornos de Ansiedade , Fígado/metabolismo
8.
Int J Mol Sci ; 25(6)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38542472

RESUMO

In recent years, the field of biology has witnessed a surge of interest in genomics research due to the advancements in biotechnology. Gene expression pattern analysis plays a crucial role in this research, as it enables us to understand the regulatory mechanism of gene expression and the associated biological processes. Real-time quantitative polymerase chain reaction (q-PCR) is an efficient method to analyze the gene expression patterns, for which accuracy relies on the standardized analysis of reference genes. However, numerous studies have shown that no reference gene is universal in all conditions, so screening a suitable reference gene under certain conditions is of great importance. Cinnamomum burmannii (C. burmannii) is rich in volatile components and has high medicinal and economic value. However, knowledge of the screening of reference genes for the gene expression analysis of C. burmannii is insufficient. Aiming at this problem, we evaluated and screened the reference genes in C. burmannii under different experimental conditions, including different abiotic stresses (Cold-treated, PEG-treated and Nacl-treated), different tissues, leaves at different developmental stages and different chemical types. In this study, different algorithms (∆Ct, geNorm, NormFinder and BestKeeper) were used to evaluate the stability of the candidate reference genes, and RefFinder further merged the output data to screen out the optimum reference gene under various experimental conditions in C. burmannii. The results showed that the optimal reference gene number for gene standardization was 2 under different experimental conditions. RPL27|RPS15 was the most suitable combination under the Nacl-treated and PEG-treated samples. RPL27|APT was the optimum combination under the Cold-treated samples. The optimal combinations of other samples were EF1α|ACT7 for different tissues, eIF-5A|Gllα for different borneol clones in C. burmannii, RPS15|ACT7 for leaves at different developmental stages and RPS15|TATA for all samples. Additionally, two terpenoid synthesis-related genes (CbWRKY4 and CbDXS2) were standardized to verify the feasibility of the selected reference genes under different experimental conditions. This study will be helpful for the subsequent molecular genetic mechanism study of C. burmannii.


Assuntos
Cinnamomum , Regulação da Expressão Gênica de Plantas , Cloreto de Sódio , Cinnamomum/genética , Perfilação da Expressão Gênica , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de Referência
9.
Int J Biol Macromol ; 264(Pt 2): 130763, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38467223

RESUMO

Lindera glauca with rich resource and fruit terpene has emerged as potential material for utilization in China, but different germplasms show a variation for essential oil content and volatile profiling. This work aimed to determine key regulators (enzymes or transporters) and unravel mechanism of governing high production of essential oil of L. glauca fruit (EO-LGF). Temporal analysis of fruit growth and EO-LGF accumulation (yield, volatile compounds and contents) during development revealed a notable change in the contents of EO-LGF and its 45 compounds in developing fruits, and the major groups were monoterpene and sesquiterpene, showing good antioxidant and antimicrobial activities. To highlight molecular mechanism that govern such difference in terpene content and compound in developing fruits, Genome-wide assay was used to annotate 104 genes for terpene-synthesis pathway based on recent transcriptome data, and the comparative associations of terpene accumulative amount with gene transcriptional level were conducted on developing fruits to identify some crucial determinants (enzymes and transporters) with metabolic regulation model for high-quality terpene accumulation, involving in carbon allocation (sucrose cleavage, glycolysis and OPP pathway), metabolite transport, isoprene precursor production, C5-unit formation (MEP and MVA pathways), and mono-/sesqui-terpene synthesis. Our findings may present strategy for engineering terpene accumulation for utilization.


Assuntos
Lindera , Óleos Voláteis , Terpenos/metabolismo , Frutas , Lindera/genética , Lindera/metabolismo , Óleos Voláteis/metabolismo , Monoterpenos/metabolismo
10.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474323

RESUMO

This work aimed to identify the chemical compounds of Cinnamomum burmannii leaf essential oil (CBLEO) and to unravel the antibacterial mechanism of CBLEO at the molecular level for developing antimicrobials. CBLEO had 37 volatile compounds with abundant borneol (28.40%) and showed good potential to control foodborne pathogens, of which Staphylococcus aureus had the greatest inhibition zone diameter (28.72 mm) with the lowest values of minimum inhibitory concentration (1.0 µg/mL) and bactericidal concentration (2.0 µg/mL). To unravel the antibacterial action of CBLEO on S. aureus, a dynamic exploration of antibacterial growth, material leakage, ROS formation, protein oxidation, cell morphology, and interaction with genome DNA was conducted on S. aureus exposed to CBLEO at different doses (1/2-2×MIC) and times (0-24 h), indicating that CBLEO acts as an inducer for ROS production and the oxidative stress of S. aureus. To highlight the antibacterial action of CBLEO on S. aureus at the molecular level, we performed a comparative association of ROS accumulation with some key virulence-related gene (sigB/agrA/sarA/icaA/cidA/rsbU) transcription, protease production, and biofilm formation in S. aureus subjected to CBLEO at different levels and times, revealing that CBLEO-induced oxidative stress caused transcript suppression of virulence regulators (RsbU and SigB) and its targeted genes, causing a protease level increase destined for the biofilm formation and growth inhibition of S. aureus, which may be a key bactericidal action. Our findings provide valuable information for studying the antibacterial mechanism of essential oil against pathogens.


Assuntos
Cinnamomum , Óleos Voláteis , Óleos Voláteis/farmacologia , Cinnamomum/genética , Staphylococcus aureus/fisiologia , Virulência , Espécies Reativas de Oxigênio , Antibacterianos/farmacologia , Biofilmes , Estresse Oxidativo , Transcrição Gênica , Peptídeo Hidrolases/genética , Testes de Sensibilidade Microbiana
11.
Int J Mol Sci ; 25(4)2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38396847

RESUMO

Schima superba is a precious timber and fire-resistant tree species widely distributed in southern China. Currently, there is little knowledge related to its growth traits, especially with respect to molecular breeding. The lack of relevant information has delayed the development of modern breeding. The purpose is to identify probable functional genes involved in S. superba growth through whole transcriptome sequencing. In this study, a total of 32,711 mRNAs, 525 miRNAs, 54,312 lncRNAs, and 1522 circRNAs were identified from 10 S. superba individuals containing different volumes of wood. Four possible regulators, comprising three lncRNAs, one circRNA, and eleven key miRNAs, were identified from the regulatory networks of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA to supply information on ncRNAs. Several candidate genes involved in phenylpropane and cellulose biosynthesis pathways, including Ss4CL2, SsCSL1, and SsCSL2, and transcription factors, including SsDELLA2 (SsSLR), SsDELLA3 (SsSLN), SsDELLA5 (SsGAI-like2), and SsNAM1, were identified to reveal the molecular regulatory mechanisms regulating the growth traits of S. superba. The results not merely provide candidate functional genes related to S. superba growth trait and will be useful to carry out molecular breeding, but the strategy and method also provide scientists with an effective approach to revealing mechanisms behind important economic traits in other species.


Assuntos
MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Circular/genética , RNA Longo não Codificante/genética , Melhoramento Vegetal , Redes Reguladoras de Genes
12.
J Exp Bot ; 75(8): 2545-2557, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38271585

RESUMO

Non-structural carbohydrates (NSCs) are building blocks for biomass and fuel metabolic processes. However, it remains unclear how tropical forests mobilize, export, and transport NSCs to cope with extreme droughts. We combined drought manipulation and ecosystem 13CO2 pulse-labeling in an enclosed rainforest at Biosphere 2, assessed changes in NSCs, and traced newly assimilated carbohydrates in plant species with diverse hydraulic traits and canopy positions. We show that drought caused a depletion of leaf starch reserves and slowed export and transport of newly assimilated carbohydrates below ground. Drought effects were more pronounced in conservative canopy trees with limited supply of new photosynthates and relatively constant water status than in those with continual photosynthetic supply and deteriorated water status. We provide experimental evidence that local utilization, export, and transport of newly assimilated carbon are closely coupled with plant water use in canopy trees. We highlight that these processes are critical for understanding and predicting tree resistance and ecosystem fluxes in tropical forest under drought.


Assuntos
Carbono , Floresta Úmida , Carbono/metabolismo , Ecossistema , Secas , Água/metabolismo , Árvores/metabolismo , Carboidratos , Folhas de Planta/metabolismo
13.
Nucleic Acids Res ; 52(D1): D1588-D1596, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37933857

RESUMO

Perennial woody plants hold vital ecological significance, distinguished by their unique traits. While significant progress has been made in their genomic and functional studies, a major challenge persists: the absence of a comprehensive reference platform for collection, integration and in-depth analysis of the vast amount of data. Here, we present PPGR (Resource for Perennial Plant Genomes and Regulation; https://ngdc.cncb.ac.cn/ppgr/) to address this critical gap, by collecting, integrating, analyzing and visualizing genomic, gene regulation and functional data of perennial plants. PPGR currently includes 60 species, 847 million protein-protein/TF (transcription factor)-target interactions, 9016 transcriptome samples under various environmental conditions and genetic backgrounds. Noteworthy is the focus on genes that regulate wood production, seasonal dormancy, terpene biosynthesis and leaf senescence representing a wealth of information derived from experimental data, literature mining, public databases and genomic predictions. Furthermore, PPGR incorporates a range of multi-omics search and analysis tools to facilitate browsing and application of these extensive datasets. PPGR represents a comprehensive and high-quality resource for perennial plants, substantiated by an illustrative case study that demonstrates its capacity in unraveling gene functions and shedding light on potential regulatory processes.


Assuntos
Bases de Dados Genéticas , Genoma de Planta , Genômica , Plantas/genética , Transcriptoma
15.
Sci Rep ; 13(1): 21607, 2023 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-38062199

RESUMO

The recently discovered APRO (anti-proliferative protein) family encodes a group of trans-membrane glycoproteins and includes 6 members: TOB1, TOB2, BTG1, BTG2, BTG3 and BTG4. The APRO family is reportedly associated with the initiation and progression of cancers. This study aims to undertake a comprehensive investigation of the APRO family of proteins as a prognostic biomarker in various human tumors. We performed a pan-cancer analysis of the APRO family based on The Cancer Genome Atlas (TCGA). With the bioinformatics methods, we explored the prognostic value of the APRO family and the correlation between APRO family expression and tumor mutation burden (TMB), microsatellite instability (MSI), drug sensitivity, and immunotherapy in numerous cancers. Our results show that the APRO family was primarily down-regulated in cancer samples. The expression of APRO family members was linked with patient prognosis. In addition, APRO family genes showed significant association with immune infiltrate subtypes, tumor microenvironment, and tumor cell stemness. Finally, our study also demonstrated the relationship between APRO family genes and drug sensitivity. This study provides comprehensive information to understand the APRO family's role as an oncogene and predictor of survival in some tumor types.


Assuntos
Proteínas Imediatamente Precoces , Neoplasias , Humanos , Oncogenes , Imunoterapia , Cognição , Biologia Computacional , Neoplasias/tratamento farmacológico , Neoplasias/genética , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética
16.
J Mater Chem B ; 11(40): 9757-9764, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37807767

RESUMO

Stimuli-responsive/smart drug delivery systems (DDSs), particularly those that use temperature as a stimuli-response factor to activate drug release, are the subject of recent research. A phase change material (PCM) is a popular thermally responsive material that can be used as a drug carrier and only when the system temperature is above the phase change point is the drug released following the phase change material changing from solid to liquid. In this study, a novel NIR light-triggered temperature-sensitive drug delivery system is developed for controllable release of acyclovir (ACV). For this purpose, a mixture of a phase change material (T38) and an ACV compound is first emulsified with copper oxide nanoparticles (CuO NPs) as a Pickering stabilizer and a photothermal conversion material, and then encapsulated with SiO2 to form a photothermal stimuli-responsive delivery system. This system shows a uniform spherical shape with a well-distinct core-shell structure, and is further experimentally proven to be able to controllably release drugs with solid-liquid transition of the phase change carrier upon temperature change. These results indicate that cumulative release of ACV can reach 51.2% at 40 °C within 20 hours, which is much higher than 27.3% release achieved below the melting point of T38. In addition, CuO NPs with excellent photothermal conversion ability endow the system with precisely controllable drug delivery via NIR light stimulation, where the cumulative drug release can reach 83.6% after 7 cycles of light stimulation, allowing controlled release at a specific time or location.


Assuntos
Doxorrubicina , Dióxido de Silício , Temperatura , Cápsulas , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos
17.
Int J Biol Macromol ; 253(Pt 1): 126650, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37666400

RESUMO

Oleosin (OLE) is vital to stabilize lipid droplet for seed triacylglycerol (TAG) storage. This work aimed to determine key OLE and to unravel mechanism that governed seed oil accumulation of Prunus sibirica for developing biodiesel. An integrated assay of global identification of LD-related protein and the cross-accessions/developing stages comparisons associated with oil accumulative amount and OLE transcript level was performed on seeds of 12 plus trees of P. sibirica to identify OLE1 (15.5 kDa) as key oleosin protein crucial for high seed oil accumulation. The OLE1 gene and its promoter were cloned from P. sibirica seeds, and overexpression of PsOLE1 in Arabidopsis was conducted under the controls of native promoter and constitutive CaMV35S promoter, respectively. PsOLE1 promoter had seed-specific cis-elements and showed seed specificity, by which PsOLE1 was specifically expressed in seeds. Ectopic overexpression of PsOLE1, especially driven by its promoter, could facilitate seed development and oil accumulation with an increase in unsaturated FAs, and upregulate transcript of TAG assembly enzymes, but suppress transcript of LD/TAG-hydrolyzed lipases and transporters, revealing a role of native promoter-mediated transcription of PsOLE1 in seed development and oil accumulation. PsOLE1 and its promoter have considerable potential for engineering oil accumulation in oilseed plants.


Assuntos
Arabidopsis , Prunus , Regiões Promotoras Genéticas/genética , Regulação da Expressão Gênica , Arabidopsis/genética , Arabidopsis/metabolismo , Sementes , Óleos de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas
18.
Bioorg Chem ; 140: 106765, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37582330

RESUMO

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.


Assuntos
Artrite Reumatoide , Inibidores de Janus Quinases , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Janus Quinases , Relação Estrutura-Atividade , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
19.
Free Radic Biol Med ; 208: 348-360, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37634745

RESUMO

Ferroptosis in tubules has been implicated in the pathogenesis of acute kidney injury (AKI), whereas the regulatory mechanism remains unclear. The stimulator of interferon genes (STING) is previously recognized as a critical mediator of innate immunity via a DNA-sensing pathway and has been increasingly linked to lipid peroxidation, a hallmark of ferroptosis. Herein we investigated the role and the underlying mechanism of STING in AKI models established by ischemia/reperfusion (IR) in C57BL mice. The expression level of STING was predominantly increased in tubules of kidney after IR treatment. Besides, STING deficiency markedly alleviated IR-induced lipid peroxidation, tissue damage and renal dysfunction. Consistently, in vitro experiments demonstrated that the increase in ferroptotic cell death, lipid ROS production and the decrease in GSH peroxidase 4 (GPX4) expression in renal tubular cells subjected to ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated by genetic deficiency or pharmacological inhibition of STING, while all exacerbated by STING overexpression. Further, these detrimental effects of STING overexpression relied on the induction of ferritinophagy, i.e. autophagic degradation of ferritin, leading to iron overload. Mechanistically, STING mediated the initiation of ferritinophagy through interacting with nuclear receptor coactivator 4 (NCOA4), a fundamental receptor for the transfer of ferritin into lysosome. Collectively, STING contributes to ferroptosis during ischemic AKI through facilitating NCOA4-mediated ferritinophagy and shows the potential as a promising therapeutic choice for AKI.


Assuntos
Injúria Renal Aguda , Ferroptose , Animais , Camundongos , Injúria Renal Aguda/genética , Ferritinas , Ferroptose/genética , Rim , Camundongos Endogâmicos C57BL
20.
J Anesth ; 37(6): 853-860, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37608132

RESUMO

PURPOSE: Repeated exposure of infant rhesus macaques to sevoflurane induces neurotoxicity and is associated with neurocognitive impairment in later life. We aimed to investigate the effect of repeated sevoflurane exposure on the expression of proteins in the prefrontal cortex of infant rhesus macaques by proteomics. METHODS: Rhesus macaques were exposed to sevoflurane three times, on postnatal days 7, 21 and 35. Quantitative proteomics employing LC-MS with isobaric labeling (TMT10plex), western blotting, and transmission electron microscopy (TEM) were utilized in the studies. RESULTS: The results of a proteomics investigation of the brain revealed that the proteins that were differentially expressed in rhesus macaques after sevoflurane exposures were associated mainly with mitochondrial respiration. Following multiple sevoflurane exposures, the prefrontal cortices of rhesus macaques exhibited increases in NDUFA8 and COX IV protein levels, while no alterations in mitochondrial morphology were observed through TEM. CONCLUSION: Multiple exposures to sevoflurane increased the mitochondrial protein levels in rhesus macaques.


Assuntos
Anestésicos Inalatórios , Humanos , Animais , Sevoflurano/toxicidade , Macaca mulatta , Anestésicos Inalatórios/toxicidade , Proteômica , Córtex Pré-Frontal , Expressão Gênica , Animais Recém-Nascidos
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