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Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.
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Membrana Celular/química , Sistema Enzimático do Citocromo P-450/genética , Citocromo-B(5) Redutase/genética , Ácidos Graxos Insaturados/metabolismo , Ferroptose/genética , NADP/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Concanavalina A/farmacologia , Sistema Enzimático do Citocromo P-450/deficiência , Citocromo-B(5) Redutase/deficiência , Transporte de Elétrons/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Oxigênio/metabolismo , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Sorafenibe/farmacologiaRESUMO
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
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Proteínas de Transporte/metabolismo , Micropartículas Derivadas de Células/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patologia , Quimiocina CCL1/metabolismo , Progressão da Doença , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Prognóstico , Fator de Transcrição STAT3/metabolismo , Hormônios Tireóideos/genética , Microambiente Tumoral , Proteínas de Ligação a Hormônio da TireoideRESUMO
Shape transformation, a key mechanism for organismal survival and adaptation, has gained importance in developing synthetic shape-shifting systems with diverse applications ranging from robotics to bioengineering. However, designing and controlling microscale shape-shifting materials remains a fundamental challenge in various actuation modalities. As materials and structures are scaled down to the microscale, they often exhibit size-dependent characteristics, and the underlying physical mechanisms can be significantly affected or rendered ineffective. Additionally, surface forces such as van der Waals forces and electrostatic forces become dominant at the microscale, resulting in stiction and adhesion between small structures, making them fracture and more difficult to deform. Furthermore, despite various actuation approaches, acoustics have received limited attention despite their potential advantages. Here, we introduce "SonoTransformer," the acoustically activated micromachine that delivers shape transformability using preprogrammed soft hinges with different stiffnesses. When exposed to an acoustic field, these hinges concentrate sound energy through intensified oscillation and provide the necessary force and torque for the transformation of the entire micromachine within milliseconds. We have created machine designs to predetermine the folding state, enabling precise programming and customization of the acoustic transformation. Additionally, we have shown selective shape transformable microrobots by adjusting acoustic power, realizing high degrees of control and functional versatility. Our findings open new research avenues in acoustics, physics, and soft matter, offering new design paradigms and development opportunities in robotics, metamaterials, adaptive optics, flexible electronics, and microtechnology.
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Impaired clearance of beta-amyloid (Aß) is a primary cause of sporadic Alzheimer's disease (AD). Aß clearance in the periphery contributes to reducing brain Aß levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aß-degrading enzymes, and Aß clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aß-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aß levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aß clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.
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Doença de Alzheimer , Eritropoetina , Animais , Camundongos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Encéfalo/metabolismo , Macrófagos/metabolismo , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
Enteroviruses are the causative agents associated with several human and animal diseases, posing a significant threat to human and animal health. As one of the host immune defense strategies, innate immunity plays a crucial role in defending against invading pathogens, where the host utilizes a variety of mechanisms to inhibit or eliminate the pathogen. Here, we report a new strategy for the host to repress enterovirus replication by the 78 kDa glucose-regulated protein (GRP78), also known as heat shock protein family A member 5 (HSPA5). The GRP78 recognizes the EV-encoded RNA-dependent RNA polymerases (RdRPs) 3D protein and interacts with the nuclear factor kappa B kinase complex (CHUK) and subunit beta gene (IKBKB) to facilitate the phosphorylation and nuclear translocation of NF-κB, which induces the production of inflammatory factors and leads to a broad inhibition of enterovirus replication. These findings demonstrate a new role of GRP78 in regulating host innate immunity in response to viral infection and provide new insights into the mechanism underlying enterovirus replication and NF-κB activation.IMPORTANCEGRP78 is known as a molecular chaperone for protein folding and plays a critical role in maintaining protein folding and participating in cell proliferation, cell survival, apoptosis, and metabolism. However, the functions of GRP78 to participate in enterovirus genome replication and innate immune responses are rarely documented. In this study, we explored the functions of the EV-3D-interacting protein GRP78 and found that GRP78 inhibits enterovirus replication by activating NF-κB through binding to EV-F 3D and interacting with the NF-κB signaling molecules CHUK/IKBKB. This is the first report that GRP78 interacts with CHUK/IKBKB to activate the NF-κB signaling pathway, which leads to the expression of the proinflammatory cytokines and inhibition of enterovirus replication. These results demonstrate a unique mechanism of virus replication regulation by GRP78 and provide insights into the prevention and treatment of viral infections.
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Chaperona BiP do Retículo Endoplasmático , Quinase I-kappa B , NF-kappa B , Proteínas Virais , Replicação Viral , Animais , Humanos , Chlorocebus aethiops , Chaperona BiP do Retículo Endoplasmático/metabolismo , Enterovirus/crescimento & desenvolvimento , Enterovirus/imunologia , Enterovirus/metabolismo , Enterovirus/fisiologia , Infecções por Enterovirus/virologia , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/imunologia , Proteínas de Choque Térmico/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno/imunologia , Quinase I-kappa B/metabolismo , Imunidade Inata , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Fosforilação , Ligação Proteica , RNA Polimerase Dependente de RNA/metabolismo , Transdução de Sinais , Células Vero , Proteínas Virais/metabolismoRESUMO
Identification of viruses and further assembly of viral genomes from the next-generation-sequencing data are essential steps in virome studies. This study presented a one-stop tool named VIGA (available at https://github.com/viralInformatics/VIGA) for eukaryotic virus identification and genome assembly from NGS data. It was composed of four modules, namely, identification, taxonomic annotation, assembly and novel virus discovery, which integrated several third-party tools such as BLAST, Trinity, MetaCompass and RagTag. Evaluation on multiple simulated and real virome datasets showed that VIGA assembled more complete virus genomes than its competitors on both the metatranscriptomic and metagenomic data and performed well in assembling virus genomes at the strain level. Finally, VIGA was used to investigate the virome in metatranscriptomic data from the Human Microbiome Project and revealed different composition and positive rate of viromes in diseases of prediabetes, Crohn's disease and ulcerative colitis. Overall, VIGA would help much in identification and characterization of viromes, especially the known viruses, in future studies.
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Colite Ulcerativa , Doença de Crohn , Humanos , Sequenciamento de Nucleotídeos em Larga Escala , Genoma Viral , MetagenomaRESUMO
SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.
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Diabetes Mellitus , Neuropatias Diabéticas , Animais , Axônios , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/prevenção & controle , Humanos , Camundongos , Bainha de Mielina , Nervos Periféricos , Proteínas Quinases , Células de Schwann/fisiologiaRESUMO
Trichomes, the outward projection of plant epidermal tissue, provide an effective defense against stress and insect pests. Although numerous genes have been identified to be involved in trichome development, the molecular mechanism for trichome cell fate determination is not well enunciated. Here, we reported GoSTR functions as a master repressor for stem trichome formation, which was isolated by map-based cloning based on a large F2 segregating population derived from a cross between TM-1 (pubescent stem) and J220 (smooth stem). Sequence alignment revealed a critical G-to-T point mutation in GoSTR's coding region that converted codon 2 from GCA (Alanine) to TCA (Serine). This mutation occurred between the majority of Gossypium hirsutum with pubescent stem (GG-haplotype) and G. barbadense with glabrous stem (TT-haplotype). Silencing of GoSTR in J220 and Hai7124 via virus-induced gene silencing resulted in the pubescent stems but no visible change in leaf trichomes, suggesting stem trichomes and leaf trichomes are genetically distinct. Yeast two-hybrid assay and luciferase complementation imaging assay showed GoSTR interacts with GoHD1 and GoHOX3, two key regulators of trichome development. Comparative transcriptomic analysis further indicated that many transcription factors such as GhMYB109, GhTTG1, and GhMYC1/GhDEL65 which function as positive regulators of trichomes were significantly upregulated in the stem from the GoSTR-silencing plant. Taken together, these results indicate that GoSTR functions as an essential negative modulator of stem trichomes and its transcripts will greatly repress trichome cell differentiation and growth. This study provided valuable insights for plant epidermal hair initiation and differentiation research.
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Gossypium , Tricomas , Gossypium/genética , Tricomas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Epiderme Vegetal/metabolismo , Regulação da Expressão Gênica de Plantas/genéticaRESUMO
Electrochemical CO2 reduction reaction (CO2RR) in acid can solve alkalinity issues while highly corrosive and reductive acidic electrolytes usually cause catalyst degradation. Inhibiting catalyst degradation is crucial for the stability of acidic CO2RR. Here, we reveal the microenvironment changes of dynamic Bi-based catalysts and develop a pulse chronoamperometry (CA) strategy to improve the stability of acidic CO2RR. In situ fluorescence mappings show that the local pH changes from neutral to acid, and the in situ Raman spectra reveal the dynamic evolution of interfacial water structures in the microenvironment. We propose that the surface charge properties of dynamic catalysts affect the competitive adsorption of K+ and protons, thereby causing the differences in local pH and CO2RR intermediate adsorption. We also develop a pulse CA strategy to reactivate catalysts, and the stability of acidic CO2RR is improved by 2 orders of magnitude for 100 h operation, which is higher than most reports on the stability of acidic CO2RR. This work gives insights on how microenvironment changes affecting the stability of acidic CO2RR, and provides guidance for designing stable catalysts in acidic electrolytes.
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Neutrophil extracellular trap (NET) is one of the defense functions of neutrophils, which has a rapid ability to kill infections and is also crucial in a variety of immune-associated diseases including infections, tumors and autoimmune diseases. Recent studies have shown that NETs are closely related to the development of tumors. The regulatory role of NETs in tumors has been of interest to researchers. In addition to awakening latent tumor cells, NETs can also promote the proliferation and development of tumor cells and their metastasis to other sites. At the same time, NETs also have the effect of inhibiting tumors. At present, there are some new advances in the impact of NETs on tumor development, which will provide a more theoretical basis for developing NET-targeted drugs. Therefore, this review just summarized the formation process of NETs, the regulation of tumor development and the treatment methods based on NETs.
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Doenças Autoimunes , Armadilhas Extracelulares , Neoplasias , Humanos , Neutrófilos , Neoplasias/patologiaRESUMO
BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.
Assuntos
Antineoplásicos , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Neoplasias de Cabeça e Pescoço , Melanoma , Piperidinas , Piridinas , Pirimidinas , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Amplificação de Genes , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Pirimidinas/efeitos adversosRESUMO
Interference colors hold significant importance in optics and arts. Current methods for printing interference colors entail complex procedures and large-scale printing systems for the scarcity of inks that exhibit both sensitivity and tunability to external fields. The production of highly transparent inks capable of rendering transmissive colors has presented ongoing challenges. Here, a type of paramagnetic ink based on 2D materials that exhibit polychrome in one magnetic field is invented. By precisely manipulating the doping ratio of magnetic elements within titanate nanosheets, the magneto-optical sensitivity named Cotton-Mouton coefficient is engineerable from 728 to a record high value of 3272 m-1 T-2, with negligible influence on its intrinsic wide optical bandgap. Combined with the sensitive and controllable magneto-responsiveness of the ink, modulate and non-invasively print transmissive interference colors using small permanent magnets are precised. This work paves the way for preparing transmissive interference colors in an energy-saving and damage-free manner, which can expand its use in widespread areas.
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The carbon dioxide reduction reaction (CO2RR) driven by electricity can transform CO2 into high-value multi-carbon (C2+) products. Copper (Cu)-based catalysts are efficient but suffer from low C2+ selectivity at high current densities. Here La(OH)3 in Cu catalyst is introduced to modify its electronic structure towards efficient CO2RR to C2+ products at ampere-level current densities. The La(OH)3/Cu catalyst has a remarkable C2+ Faradaic efficiency (FEC2+) of 71.2% which is 2.2 times that of the pure Cu catalyst at a current density of 1,000 mA cm-2 and keeps stable for 8 h. In situ spectroscopy and density functional theory calculations both show that La(OH)3 modifies the electronic structure of Cu. This modification favors *CO adsorption, subsequent hydrogenation, *COâ*COH coupling, and consequently increases C2+ selectivity. This work provides a guidance on facilitating C2+ product formation, and suppressing hydrogen evolution by La(OH)3 modification, enabling efficient CO2RR at ampere-level current densities.
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Numerous endogenous and environmental signals regulate the intricate and highly orchestrated process of plant senescence. Ethylene (ET), which accumulates as senescence progresses, is a major promoter of leaf senescence. The master transcription activator ETHYLENE INSENSITIVE3 (EIN3) activates the expression of a wide range of downstream genes during leaf senescence. Here, we found that a unique EIN3-LIKE 1 (EIL1) gene, cotton LINT YIELD INCREASING (GhLYI), encodes a truncated EIN3 protein in upland cotton (Gossypium hirsutum L.) that functions as an ET signal response factor and a positive regulator of senescence. Ectopic expression or overexpression of GhLYI accelerated leaf senescence in both Arabidopsis (Arabidopsis thaliana) and cotton. Cleavage under targets and tagmentation (CUT&Tag) analyses revealed that SENESCENCE-ASSOCIATED GENE 20 (SAG20) was a target of GhLYI. Electrophoretic mobility shift assay (EMSA), yeast 1-hybrid (Y1H), and dual-luciferase transient expression assay confirmed that GhLYI directly bound the promoter of SAG20 to activate its expression. Transcriptome analysis revealed that transcript levels of a series of senescence-related genes, SAG12, NAC-LIKE, ACTIVATED by APETALA 3/PISTILLATA (NAP/ANAC029), and WRKY53, are substantially induced in GhLYI overexpression plants compared with wild-type (WT) plants. Virus-induced gene silencing (VIGS) preliminarily confirmed that knockdown of GhSAG20 delayed leaf senescence. Collectively, our findings provide a regulatory module involving GhLYI-GhSAG20 in controlling senescence in cotton.
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Proteínas de Arabidopsis , Arabidopsis , Gossypium/metabolismo , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Etilenos/metabolismo , Folhas de Planta/metabolismoRESUMO
Ethylene is an important phytohormone with pleotropic roles in plant growth, development, and stress responses. ETHYLENE INSENSITIVE2 (EIN2) mediates the transduction of the ethylene signal from the endoplasmic reticulum membrane to the nucleus, where its C-terminus (EIN2-C) regulates histone acetylation to mediate transcriptional regulation by EIN3. However, no direct interaction between EIN2-C and EIN3 has been detected. To determine how EIN2-C and EIN3 act together, we followed a synthetic approach and engineered a chimeric EIN2-C with EIN3 DNA-binding activity but lacking its transactivation activity (EIN2C-EIN3DB). The overexpression of EIN2C-EIN3DB in either wild-type or in the ethylene-insensitive mutant ein3-1 eil1-1 led to a partial constitutive ethylene response. Chromatin immunoprecipitation sequencing showed that EIN2C-EIN3DB has DNA-binding activity, indicating that EIN3DB is functional in EIN2C-EIN3DB. Furthermore, native EIN3 protein levels determine EIN2C-EIN3DB binding activity and binding targets in a positive feedback loop by interacting with EIN2C-EIN3DB to form a heterodimer. Additionally, although EIN3 does not direct affect histone acetylation levels in the absence of EIN2, it is required for the ethylene-induced elevation of H3K14Ac and H3K23Ac in the presence of EIN2. Together, we reveal efficient and specific DNA-binding by dimerized EIN3 in the presence of ethylene to mediate positive feedback regulation, which is required for EIN2-directed elevation of histone acetylation to integrate into an EIN3-dependent transcriptional activation.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas de Ligação a DNA/metabolismo , Etilenos/farmacologia , Retroalimentação Fisiológica , Histonas/metabolismo , Receptores de Superfície Celular/metabolismo , Fatores de Transcrição/metabolismo , Acetilação/efeitos dos fármacos , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/química , Sequência de Bases , DNA de Plantas/metabolismo , Proteínas de Ligação a DNA/química , Domínios Proteicos , Multimerização Proteica/efeitos dos fármacos , Receptores de Superfície Celular/química , Fatores de Transcrição/químicaRESUMO
PURPOSE OF REVIEW: Our work is to establish more distinct association between specific stress and vascular smooth muscle cells (VSMCs) phenotypes to alleviate atherosclerotic plaque burden and delay atherosclerosis (AS) progression. RECENT FINDING: In recent years, VSMCs phenotypic transition has received significant interests. Different stresses were found to be associated with VSMCs phenotypic transition. However, the explicit correlation between VSMCs phenotype and specific stress has not been elucidated clearly yet. We discover that VSMCs phenotypic transition, which is widely involved in the progression of AS, is associated with specific stress. We discuss approaches targeting stresses to intervene VSMCs phenotypic transition, which may contribute to develop innovative therapies for AS.
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Aterosclerose , Músculo Liso Vascular , Miócitos de Músculo Liso , Fenótipo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Aterosclerose/patologia , Aterosclerose/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Animais , Placa Aterosclerótica/patologia , Estresse Fisiológico/fisiologiaRESUMO
BACKGROUND AND AIM: Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux. METHODS AND RESULTS: We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane. CONCLUSION: These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.
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Lesão Pulmonar Aguda , Histonas , Macrófagos Alveolares , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Potássio , Sepse , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/complicações , Sepse/metabolismo , Sepse/imunologia , Potássio/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/imunologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Histonas/metabolismo , Masculino , Camundongos , Líquido da Lavagem Broncoalveolar , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Linhagem Celular , Canais de Potássio/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Inflamassomos/metabolismo , LipopolissacarídeosRESUMO
A metal-free, mild, and efficient method for the synthesis of amides has been developed from the amination of aldehydes with hydroxylamines promoted by TBAF·3H2O in the presence of KOH. Control experiments showed that the nitrone was the intermediate of this amination. By this method, a series of amides, biologically active compounds bebenil and a COX inhibitor were obtained in moderate to good yields.
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Although 1,10-phenanthroline has been proven to hold a strong complexing capacity for f-block elements and their derivatives have been applied in many fields, research on more highly or completely rigid phenanthroline ligands is still rare due to the challenging syntheses. Here, we reported three tetradentate ligands 2,9-di(pyridin-2-yl)-1,10-phenanthroline (L1), 12-(pyridin-2-yl)-5,6-dihydroquinolino[8,7b][1,10]phenanthroline (L2), and 5,6,11,12-tetrahydrobenzo[2,1-b:3,4-b']bis([1,10]phenanthroline) (L3) with increasing preorganization on the side chain; among which, L3 is fully preorganized. Their complexation reactions with Eu(III) were systematically investigated by electrospray ionization mass spectrometry (ESI-MS), UV-vis titrations, and single-crystal structures. It is found that all three ligands form only 1:1 M/L complexes with Eu(III). The single-crystal structures revealed that the three ligands hold similar coordination modes, while their stability constants determined by UV-vis titrations were L3 (4.80 ± 0.01) > L2 (4.38 ± 0.01) > L1 (3.88 ± 0.01). This trend is supported not only by the thermodynamic stability of rigid ligands compared to free ligands but also by the conclusion that rigid ligands exhibit faster reaction rates (lower energy barrier) than free ligands kinetically. This work is helpful in providing theoretical guidance for the subsequent development of highly preorganized chelating ligands with strong coordination ability and high selectivity for f-block elements.
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Zero-order waveplates are widely used in the manufacture of laser polarizer waves, which are important in polarimetry and the laser industry. However, there are still challenges in designing deep-ultraviolet (DUV) waveplate materials that satisfy large band gaps and small optical anisotropy simultaneously. Herein, three cases of aluminum sulfate fluorides: Na2AlSO4F3, Li4NH4Al(SO4)2F4, and Li6K3Al(SO4)4F4, with novel [AlSO4F3] layers or isolated [AlS2O8F4] trimers were designed and synthesized by the rational assembly of [AlO2F4] and [SO4] groups through a hydrothermal method. Experiments and theoretical calculations imply that these three possess short cutoff edges (λ < 200 nm) and small birefringence (0.0014-0.0076 @ 1064 nm), which fulfils the prerequisite for potential DUV zero-order waveplate materials. This work extends the exploration of DUV zero-order waveplate materials to the aluminum sulfate fluoride systems.