RESUMO
The exploration of deep space significantly increases the probability of spacecraft failures due to surface electrostatic discharge, which imposes higher vacuum insulation protection requirements on polyimide, the external insulation material of spacecrafts. To address this challenge, this study proposes using silane coupling agent KH550 for organic grafting treatment of Cr2O3 nanoparticles, which are then used to dope and modify polyimide to enhance the vacuum surface insulation of polyimide films. The KH550 grafting improves the interface strength between the fillers and the matrix, allowing the fillers to be uniformly dispersed in the matrix. Compared to pure polyimide films, the prepared PI-Cr2O3@KH550 composite films exhibit significantly enhanced vacuum surface flashover voltage, improved surface/volume resistivity, and dielectric properties. The results demonstrate that polyimide composite films with 0.8% by mass of Cr2O3@KH550 show the most notable performance improvement, with the DC flashover voltage and impulse flashover voltage in vacuum increasing by 20.7% and 27.8%, respectively. The doping of chromium oxide nanoparticles introduces more deep traps into the polyimide films and reduce the surface resistivity. The higher deep trap density inhibits charge migration, thereby alleviating secondary electron emission and surface electric field distortion. Simultaneously, the lower surface resistivity facilitates dissipating surface charges and improves the surface insulation. These findings are of significant reference value for promoting the enhancement of aerospace insulation performance.
RESUMO
Background: The clinical role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined. Methods: High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8. In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8. A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8. Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC. Results: A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM, ACO2, NDUFS1, PDHB, SDHD, SUCLA2, SUCLG1, and SUCLG2. Conclusions: CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction.
RESUMO
Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Ativação de Macrófagos , Macrófagos , Psoríase , Receptor A2A de Adenosina , Animais , Humanos , Camundongos , Imunidade Adaptativa/efeitos dos fármacos , Adenosina/análogos & derivados , Agonistas do Receptor A2 de Adenosina/farmacologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/imunologia , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Imiquimode/farmacologia , Imunidade Inata/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenetilaminas/farmacologia , Psoríase/imunologia , Receptor A2A de Adenosina/metabolismo , Receptor A2A de Adenosina/genéticaRESUMO
Electrohydrodynamic printing holds both ultrahigh-resolution fabrication capability and unmatched ink-viscosity compatibility yet fails on highly insulating thick/irregular substrates. Herein, we proposed a single-potential driven electrohydrodynamic printing process with submicrometer resolution on arbitrary nonconductive targets, regardless of their geometric shape or sizes, via precoating with an ultrathin dielectric nanoparticle layer. Benefiting from the favorable Maxwell-Wagner polarization, the reversely polarized spot brought about a significant drop (â¼57% for ceramics) in the operation voltage as its induced electric field and a negligible residual charge accumulation. Thus, ordered micro/nanostructures with line widths down to 300 nm were directly written at a stage speed as low as 5 mm/s, and silver features with width of â¼2 µm or interval of â¼4 µm were achieved on insulating substrates separately. Flexible sensors and curved heaters were then high-precision printed and demonstrated successfully, presenting this technique with huge potential for fabricating flexible/conformal electronics on arbitrary 3D structures.
RESUMO
In this study, maleic anhydride-modified lignin (LG-M), a ROS-cleavable thioketal (TK) bond, and polyethylene glycol (PEG) were used to synthesize a lignin-based copolymer (LG-M(TK)-PEG). Doxorubicin (DOX) was attached to the ROS-cleavable bond in the LG-M(TK)-PEG for the preparation of the ROS-activatable DOX prodrug (LG-M(TK-DOX)-PEG). Nanoparticles (NPs) with a size of 125.7 ± 3.1 nm were prepared by using LG-M(TK-DOX)-PEG, and they exhibited enhanced uptake by cancer cells compared to free DOX. Notably, the presence of lignin in the nanoparticles could boost ROS production in breast cancer 4T1 cells while showing little effect on L929 normal cells. This selective effect facilitated the specific activation of the DOX prodrug in the tumor microenvironment, resulting in the superior tumor inhibitory effects and enhanced biosafety relative to free DOX. This work demonstrates the potential of the LG-M(TK-DOX)-PEG NPs as an efficient drug delivery system for cancer treatment.
Assuntos
Doxorrubicina , Liberação Controlada de Fármacos , Lignina , Nanopartículas , Estresse Oxidativo , Polietilenoglicóis , Espécies Reativas de Oxigênio , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Lignina/química , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Polietilenoglicóis/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Feminino , Humanos , Portadores de Fármacos/química , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/química , Anidridos Maleicos/químicaRESUMO
BACKGROUND: Patients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors. METHODS: This retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve. RESULT: In training cohort, lower baseline absolute counts of CD3+ (P < 0.001) and CD4+ (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3+ (P < 0.001), CD4+ (P < 0.001), CD8+ (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation. CONCLUSION: We constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Nomogramas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Subpopulações de Linfócitos/imunologia , Adulto , Contagem de LinfócitosRESUMO
To explore the role of YAP, a key effector of the Hippo pathway, in temporomandibular joint (TMJ) ankylosis. The temporal and spatial expression of YAP was detected via immunohistochemistry and multiplex immunohistochemistry on postoperative Days 1, 4, 7, 9, 11, 14 and 28 in a sheep model. Isolated mesenchymal stem cells (MSCs) from samples of the Day 14. The relative mRNA expression of YAP was examined before and after the osteogenic induction of MSCs. A YAP-silenced MSC model was constructed, and the effect of YAP knockdown on MSC function was examined. YAP is expressed in the nucleus of the key sites that determine the ankylosis formation, indicating that YAP is activated in a physiological state. The expression of YAP increased gradually over time. Moreover, the number of cells coexpressing of RUNX2 and YAP-with the osteogenic active zone labelled by RUNX2-tended to increase after Day 9. After the osteogenic induction of MSCs, the expression of YAP increased. After silencing YAP, the osteogenic, proliferative and migratory abilities of the MSCs were inhibited. YAP is involved in the early development of TMJ bony ankylosis. Inhibition of YAP using shRNA might be a promising way to prevent or treat TMJ ankylosis.
Assuntos
Anquilose , Células-Tronco Mesenquimais , Osteogênese , Transtornos da Articulação Temporomandibular , Animais , Células-Tronco Mesenquimais/metabolismo , Transtornos da Articulação Temporomandibular/metabolismo , Transtornos da Articulação Temporomandibular/patologia , Transtornos da Articulação Temporomandibular/genética , Anquilose/metabolismo , Anquilose/patologia , Anquilose/genética , Proteínas de Sinalização YAP/metabolismo , Articulação Temporomandibular/metabolismo , Articulação Temporomandibular/patologia , Ovinos , Proliferação de Células , Modelos Animais de Doenças , Diferenciação Celular , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Movimento Celular , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
HLA-A*11:01:127 differs from HLA-A*11:01:01:01 by one nucleotide in exon 3.
Assuntos
Alelos , Povo Asiático , Sequência de Bases , Éxons , Antígeno HLA-A11 , Teste de Histocompatibilidade , Análise de Sequência de DNA , Humanos , Povo Asiático/genética , Análise de Sequência de DNA/métodos , Antígeno HLA-A11/genética , Códon , Alinhamento de Sequência , População do Leste AsiáticoRESUMO
Cannabis sativa (C. sativa) leaves are rich in cannabinoids and flavonoids, which play important antioxidant roles. Since the environmental factors may influence the accumulation of antioxidants in herbal medicines, which affects their activity, this study aimed to investigate the correlation between the chemical composition of C. sativa leaves and their geographical origin and antioxidant activity. Firstly, a high-resolution mass spectrometry method assisted by semi-quantitative feature-based molecular networking (SQFBMN) was established for the characterization and quantitative analysis of C. sativa leaves from various regions. Subsequently, antioxidant activity analysis was conducted on 73 batches of C. sativa leaves, and a partial least squares regression (PLS) model was employed to assess the correlation between the content of cannabinoids and flavonoids in the leaves and their antioxidant activity. A total of 16 cannabinoids and 57 flavonoids were annotated from C. sativa, showing a significant regular geographical distribution. The content of flavonoid-C glycosides in Sichuan leaves is relatively high, and their antioxidant activity is also correspondingly high. However, the leaves in Shaanxi and Xinjiang were primarily composed of flavonoid-O glycosides, and exhibited slightly lower antioxidant activity. A significant positive correlation (p < 0.001) was found between the total flavonoids and cannabinoids and the antioxidant activity of the leaves, and two flavonoids and one cannabinoid were identified as significant contributors.
RESUMO
Cauliflower (Brassica oleracea L. var. botrytis) is a distinctive vegetable that supplies a nutrient-rich edible inflorescence meristem for the human diet. However, the genomic bases of its selective breeding have not been studied extensively. Herein, we present a high-quality reference genome assembly C-8 (V2) and a comprehensive genomic variation map consisting of 971 diverse accessions of cauliflower and its relatives. Genomic selection analysis and deep-mined divergences were used to explore a stepwise domestication process for cauliflower that initially evolved from broccoli (Curd-emergence and Curd-improvement), revealing that three MADS-box genes, CAULIFLOWER1 (CAL1), CAL2 and FRUITFULL (FUL2), could have essential roles during curd formation. Genome-wide association studies identified nine loci significantly associated with morphological and biological characters and demonstrated that a zinc-finger protein (BOB06G135460) positively regulates stem height in cauliflower. This study offers valuable genomic resources for better understanding the genetic bases of curd biogenesis and florescent development in crops.
Assuntos
Brassica , Domesticação , Genoma de Planta , Estudo de Associação Genômica Ampla , Genômica , Brassica/genética , Genômica/métodos , Proteínas de Plantas/genética , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Domínio MADS/genéticaRESUMO
Electrochemical oxidation (EO) can effectively reduce the degree of humification and toxicity of landfill leachate by generating highly active oxidative species in situ. However, the selective and competitive oxidation of humic acid (HA) and ammonia (NH4+) and the role of different oxidative species during the EO process in complex aqueous conditions remain unclear. In this study, a nanostructured tin-antimony electrode (Ti/Sb-SnO2 NFs) was prepared and compared with three types of commercial electrodes (Ti/Ir-RuO2, Ti4O7, Ti/Sb-SnO2) in terms of electrochemical properties and electrocatalytic oxidation of HA and NH4+. The de-humification capacity, interactive effects of HA and NH4+ on each other's oxidation by different oxidative species, as well as the related oxidation byproducts were investigated. The differences in pollutant electrooxidation among the different electrodes were found to be insignificant. The presence of HA was found to be detrimental to NH4+ degradation while reducing the N2 conversion rate. Interestingly, NH4+ initially inhibited the degradation rates of HA while promoted the degradation and reduced the accumulation of organic chlorine during the later EO process. A proposed mechanism accounts for both competitive and promotional effects for simultaneous HA and NH4+ oxidation during the EO process.
RESUMO
PURPOSE: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. METHODS: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. RESULTS: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug-drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. CONCLUSION: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option.
Assuntos
Antibacterianos , Infecções por Bactérias Gram-Positivas , Oxazolidinonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Humanos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Animais , PiridonasRESUMO
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 µM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.
Assuntos
Antineoplásicos , Autofagia , Complexos de Coordenação , Mitocôndrias , Espécies Reativas de Oxigênio , Rutênio , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Autofagia/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Rutênio/química , Rutênio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.
Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Glicólise , Fosforilação Oxidativa , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Animais , Irídio/química , Irídio/farmacologia , Relação Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Alkynes are readily available and multifunctional synthetic intermediates, but their 1,1-oxofunctionalization remains challenging. Herein, we report a 1,1-oxycarbonation of terminal alkynes to construct ketones through sequential borylation, 1,2-carbon migration, and oxidation with Oxone as the proton source and oxidant. The synthetic potential of this transformation is showcased by the broad functional groups, scale-up synthesis, and diverse product transformations.
RESUMO
Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.
Assuntos
Adenina , Hipertensão , Interleucina-11 , Animais , Humanos , Camundongos , Adenina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase , Angiotensina II , Cardiotônicos , Macrófagos , Miofibroblastos , RNARESUMO
The construction of hybrid heterojunction photocatalysts is an effective strategy to improve the utilization of photogenerated carriers and photocatalytic activity. To enhance the separation distance of photogenerated carriers and accelerate the effective separation at the heterojunction of the interface, a unique 0D-2D hierarchical nanostructured p-n heterojunction was successfully fabricated in this work. BiOCl (BOC) nanosheets (p-type) were in situ grown on BiVO4 (BVO) nanoparticles (n-type) using the microemulsion-calcination method for highly efficient visible-light-driven organic dye degradation. Compared with pure BVO (the degradation rate of rhodamine B (RhB): about 32.0% in 55 min, the mineralization rate: 24.9% in 120 min), the RhB degradation rate can reach about 99.5% in 55 min and the mineralization rate of 62.1% in 120 min by utilizing BVO/25%BOC heterojunction photocatalyst under visible light irradiation. Various characterizations demonstrate that the formation of BVO/BOC p-n heterojunction greatly facilitates photogenerated carriers separation efficiency. Meanwhile, the results of the scavenging experiments and electron spin resonance tests indicate that ·O2- and h+ are the prominent active species for Rh B degradation. In addition, possible degradation pathways for Rh B were proposed using LC-MS tests. This work proves that building low dimensional p-n heterojunction photocatalysts is a promising strategy for developing photocatalysts with high efficiency.
Assuntos
Nanopartículas , Nanoestruturas , Corantes , Espectroscopia de Ressonância de Spin Eletrônica , LuzRESUMO
PURPOSE: To explore the role and mechanism of heat shock protein 27 (HSP27) in SACC VM formation. STUDY DESIGN: Immunohistochemistry and double staining with cluster of differentiation 31 (CD31) and periodic acid-Schiff (PAS) were used to detect HSP27 expression and VM in 70 SACC tissue samples separately. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and immunofluorescence were used to detect gene and protein expression. HSP27 in SACC cells were overexpression or downregulated by transfecting HSP27 or short hairpin RNA target HSP27 (sh-HSP27). The migration and invasion abilities of SACC cells were detected using wound healing and Transwell invasion assays. The VM formation ability of the cells in vitro was detected using a Matrigel 3-dimensional culture. RESULTS: HSP27 expression was positively correlated with VM formation and affected the prognosis of patients. In vitro, HSP27 upregulation engendered VM formation and the invasion and migration of SACC cells. Mechanistically, HSP27 upregulation increased Akt phosphorylation and subsequently increased downstream matrix metalloproteinase 2 and 9 expressions. CONCLUSION: HSP27 may plays an important role in VM formation in SACC via the AKT-MMP-2/9 signalling pathway.