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1.
Lancet ; 403(10441): 2317-2325, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38280389

RESUMO

BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.


Assuntos
Dependovirus , Terapia Genética , Humanos , Terapia Genética/métodos , Dependovirus/genética , Criança , Masculino , Pré-Escolar , Feminino , Adolescente , Lactente , Vetores Genéticos , Resultado do Tratamento , Surdez/genética , Surdez/terapia , Mutação , Proteínas de Membrana
2.
Acta Pharmacol Sin ; 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39379684

RESUMO

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents. Krüppel-like factor 5 (KLF5) is an oncogenic transcription factor that is highly expressed in BLBC. The deubiquitinase (DUB) BRCA1-associated protein 1 (BAP1) stabilizes KLF5 and promotes BLBC growth and metastasis. Therefore, pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC. Here, through screening, we identified a series of tetrahydro-ß-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity. Among the investigated compounds, the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression. LN-439A suppressed the proliferation and migration of BLBC cells, induced G2/M arrest, and induced apoptosis. Mechanistically, LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1, leading to the ubiquitination and degradation of KLF5. Consistent with this finding, the overexpression of KLF5 suppressed the antitumour effects of LN-439A. In summary, LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis.

3.
Sensors (Basel) ; 24(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38475031

RESUMO

High-rise building machines (HBMs) play a critical role in the successful construction of super-high skyscrapers, providing essential support and ensuring safety. The HBM's climbing system relies on a jacking mechanism consisting of several independent jacking cylinders. A reliable control system is imperative to maintain the smooth posture of the construction steel platform (SP) under the action of the jacking mechanism. Long Short-Term Memory (LSTM), Gated Recurrent Unit (GRU), and Temporal Convolutional Network (TCN) are three multivariate time series (MTS) neural network models that are used in this study to predict the posture of HBMs. The models take pressure and stroke measurements from the jacking cylinders as inputs, and their outputs determine the levelness of the SP and the posture of the HBM at various climbing stages. The development and training of these neural networks are based on historical on-site data, with the predictions subjected to thorough comparative analysis. The proposed LSTM and GRU prediction models have similar performances in the prediction process of HBM posture, with medians R2 of 0.903 and 0.871, respectively. However, the median MAE of the GRU prediction model is more petite at 0.4, which exhibits stronger robustness. Additionally, sensitivity analysis showed that the change in the levelness of the position of the SP portion of the HBM exhibited high sensitivity to the stroke and pressure of the jacking cylinder, which clarified the position of the cylinder for adjusting the posture of the HBM. The results show that the MTS neural network-based prediction model can change the HBM posture and improve work stability by adjusting the jacking cylinder pressure value of the HBM.

4.
Development ; 147(21)2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376680

RESUMO

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule neuron progenitors (CGNPs) and its mis-regulation is linked to various disorders, including the cerebellar cancer medulloblastoma (MB). We recently identified RNF220, a ubiquitin E3 ligase promoting K63-linked polyubiquitylation and nuclear exportation of Gli transcription factors, as an Shh/Gli regulator involved in ventral neural patterning. Here, we report that RNF220 is required for the proliferation of CGNPs and Daoy cells (an Shh-grouped MB cell line), working as a positive regulator of Shh signaling. Mechanistic investigation demonstrated that RNF220 promotes Shh target gene expression by targeting the PRC2 component EED, and alters levels of epigenetic modification marks on Shh target promoters. We provided evidence that RNF220+/-; Ptch1+/- mice showed lower spontaneous MB occurrence compared with Ptch1+/- mice. Furthermore, in human clinical MB samples, RNF220 expression correlated well with that of GAB1, an Shh-group MB marker. Our findings provide new insights into the epigenetic regulation of Shh signaling and identify RNF220 as a potential new diagnostic marker and therapeutic target for Shh-group MB.


Assuntos
Cerebelo/embriologia , Progressão da Doença , Epigênese Genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , Meduloblastoma/patologia , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Cerebelo/patologia , Grânulos Citoplasmáticos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Development ; 147(6)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32094113

RESUMO

Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.


Assuntos
Neurônios Adrenérgicos/fisiologia , Proteínas de Homeodomínio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neurogênese/fisiologia , Proteínas Nucleares/fisiologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação/genética , Neurônios Adrenérgicos/metabolismo , Animais , Diferenciação Celular/genética , Embrião de Galinha , Embrião de Mamíferos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Norepinefrina/metabolismo
6.
Clin Exp Hypertens ; 45(1): 2276029, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37943619

RESUMO

BACKGROUND: Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and essential hypertension remains unclear. The present study was aimed to investigate the association of circulating TSP2 with blood pressure and nocturnal urine Na+ excretion and evaluate the predictive value of circulating TSP2 in subjects with hypertension. METHODS AND RESULTS: 603 newly diagnosed essential hypertensive subjects and 508 healthy subjects were preliminarily screened, 47 healthy subjects and 40 newly diagnosed essential hypertensive subjects without any chronic diseases were recruited. The results showed that the levels of circulating TSP2 were elevated in essential hypertensive subjects. The levels of TSP2 positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and other clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity, and serum triglycerides, but negatively associated with nocturnal urine Na+ concentration and excretion and high-density lipoprotein cholesterol. Results of multiple linear regressions showed that HOMA-IR and nocturnal Na+ excretion were independent factors related to circulating TSP2. Mantel-Haenszel chi-square test displayed linear relationships between TSP2 and SBP (χ2 = 35.737) and DBP (χ2 = 26.652). The area under receiver operating characteristic curve (AUROC) of hypertension prediction was 0.901. CONCLUSION: Our study suggests for the first time that the circulating levels of TSP2 may be a novel potential biomarker for essential hypertension. The association between TSP2 and blood pressure may be, at least in part, related to the regulation of renal Na+ excretion, insulin resistance, and/or endothelial function.


Assuntos
Hipertensão , Resistência à Insulina , Humanos , Índice Tornozelo-Braço , Análise de Onda de Pulso , Trombospondinas , Sódio , Pressão Sanguínea , Hipertensão Essencial/complicações , Biomarcadores
7.
J Environ Manage ; 344: 118691, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37536239

RESUMO

Incineration is a promising disposal method for sewage sludge (SS), enriching more than 90% of phosphorus (P) in the influent into the powdered product, sewage sludge ash (SSA), which is convenient for further P recovery. Due to insufficient bioavailable P and enriched heavy metals (HMs) in SSA, it is limited to be used directly as fertilizer. Hence, this paper provides an overview of P transformation in SS incineration, characterization of SSA components, and wet-chemical and thermochemical processes for P recovery with a comprehensive technical, economic, and environmental assessment. P extraction and purification is an important technical step to achieve P recovery from SSA, where the key to all technologies is how to achieve efficient separation of P and HMs at a low economic and environmental cost. It can be clear seen from the review that the economics of P recovery from SSA are often weak due to many factors. For example, the cost of wet-chemical methods is approximately 5∼6 €/kg P, while the cost of recovering P by thermochemical methods is about 2∼3 €/kg P, which is slightly higher than the current P fertilizer (1 €/kg P). So, for now, legislation is significant for promoting P recovery from SSA. In this regard, the relevant experience in Europe is worth learning from countries that have not yet carried out P recovery from SSA, and to develop appropriate policies and legislation according to their own national conditions.


Assuntos
Metais Pesados , Fósforo , Fósforo/análise , Esgotos/química , Fertilizantes , Incineração , Europa (Continente) , Metais Pesados/química
8.
J Transl Med ; 20(1): 547, 2022 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-36435781

RESUMO

BACKGROUND: Accumulating evidence supports the implication of circular RNAs (circRNAs) in systemic lupus erythematosus (SLE). However, little is known about the detailed mechanisms and roles of circRNAs in the pathogenesis of SLE. METHODS: Quantitative real-time PCR was used to determine the levels of circLOC101928570 and miR-150-5p in peripheral blood mononuclear cells of SLE. Overexpression and knockdown experiments were conducted to assess the effects of circLOC101928570. Fluorescence in situ hybridization, RNA immunoprecipitation, luciferase reporter assays, Western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were used to investigate the molecular mechanisms underlying the function of circLOC101928570. RESULTS: The results showed that the level of circLOC101928570 was significantly downregulated in SLE and correlated with the systemic lupus erythematosus disease activity index. Functionally, circLOC101928570 acted as a miR-150-5p sponge to relieve the repressive effect on its target c-myb, which modulates the activation of immune inflammatory responses. CircLOC101928570 knockdown enhanced apoptosis. Moreover, circLOC101928570 promoted the transcriptional level of IL2RA by directly regulating the miR-150-5p/c-myb axis. CONCLUSION: Overall, our findings demonstrated that circLOC101928570 played a critical role in SLE. The downregulation of circLOC101928570 suppressed SLE progression through the miR-150-5p/c-myb/IL2RA axis. Our findings identified that circLOC101928570 serves as a potential biomarker for the diagnosis and therapy of SLE.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Humanos , RNA Circular/genética , Leucócitos Mononucleares , Hibridização in Situ Fluorescente , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética
9.
Environ Sci Technol ; 56(2): 1300-1309, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34965096

RESUMO

Peracetic acid (PAA) is an emerging oxidant and disinfectant for wastewater (WW) treatment due to limited harmful disinfection byproduct (DBP) formation. Nitrite (NO2-) is a ubiquitous anion in water, but the impact of NO2- on PAA oxidation and disinfection has been largely overlooked. This work found for the first time that NO2- could significantly promote the oxidation of sulfonamide antibiotics (SAs) by PAA. Unexpectedly, the reactive nitrogen species (RNS), for example, peroxynitrite (ONOO-), rather than conventional organic radicals (R-O•) or reactive oxygen species (ROS), played major roles in SAs degradation. A kinetic model based on first-principles was developed to elucidate the reaction mechanism and simulate reaction kinetics of the PAA/NO2- process. Structural activity assessment and quantum chemical calculations showed that RNS tended to react with an aromatic amine group, resulting in more conversion of NO2--N to organic-N. The formation of nitrated and nitrosated byproducts and the enhancement of trichloronitromethane formation potential might be a prevalent problem in the PAA/NO2- process. This study provides new insights into the reaction of PAA with NO2- and sheds light on the potential risks of PAA in WW treatment in the presence of NO2-.


Assuntos
Ácido Peracético , Purificação da Água , Antibacterianos , Desinfecção , Nitritos , Espécies Reativas de Nitrogênio , Sulfonamidas , Purificação da Água/métodos
10.
Phys Chem Chem Phys ; 24(28): 17263-17270, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35797730

RESUMO

It has been found that magnetism in two-dimensional (2D) transition metal dichalcogenides can be realized by properly introducing vacancies and applying strain. However, no work has clearly clarified the modulation of such 2D magnetism under a sweeping strain. Thus we were motivated in this work to investigate the mechanical and electronic properties of the monolayer MS2 (M = Mo, W) with symmetric S vacancy defects under sweeping strain. The results show that the local structure of the M atoms in MS2 around the defect undergoes a reversible phase transition from a triangular shape (Tri-3M) with short M-M bonds, to a circular one (Cir-6M-12S) with larger M-M bonds as the planar strain increases. The critical tensile strain for the transition from Tri-3M to Cir-6M-12S are 12.53% for MoS2 and 11.46% for WS2, while the critical compressive strain for the reversal from Cir-6M-12S to Tri-3M are -3.60% and -2.16%, respectively. In particular, we find that the magnetism can be continuously modulated and undergoes a hysteresis loop behavior under the sweeping strains, with the residual magnetism being 2 µB. Our work theoretically predicts the promising prospect for exploring low-dimensional semiconductor spintronic devices working without applying a magnetic field.

11.
Phys Chem Chem Phys ; 24(12): 7451-7457, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35274655

RESUMO

Perovskite quantum dots (PQDs) are promising interface modification materials for perovskite solar cells (PSCs). However, due to the limitation of the preparation method, it is hard to use PQDs as substrates for the growth of perovskite films by the common solution process. In this work, by introducing the rare earth element Ce into PQDs with the vacuum freezing and drying technology, we have successfully improved the solvent stability of PQDs. Moreover, we propose a technology, PQD dynamically mediated growth of perovskite film (PDMG), to prepare high-quality perovskite films, which can avoid the formation of PQD charge-blocking layers. Thanks to the improvement of perovskite crystallinity and the charge transport ability, the PCE is improved from 10.44% to 12.14% for CsPbI2Br PSCs and from 14.43% to 16.38% for CsPbI3 PSCs. Our work opens an avenue for using PQDs as substrates in the fabrication of highly efficient PSCs.

12.
Mar Drugs ; 20(10)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36286476

RESUMO

Fucosylated chondroitin sulfate (FCS) from the sea cucumber Acaudina molpadioides (FCSAm) is the first one that was reported to be branched by disaccharide GalNAc-(α1,2)-Fuc3S4S (15%) and sulfated Fuc (85%). Here, four size-homogenous fractions, and seven oligosaccharides, were separated from its ß-eliminative depolymerized products. Detailed NMR spectroscopic and MS analyses revealed the oligomers as hexa-, hepta-, octa-, and nonasaccharide, which further confirmed the precise structure of native FCSAm: it was composed of the CS-E-like backbone with a full content of sulfation at O-4 and O-6 of GalNAc in the disaccharide repeating unit, and the branches consisting of sulfated fucose (Fuc4S and Fuc2S4S) and heterodisaccharide [GalNAc-(α1,2)-Fuc3S4S]. Pharmacologically, FCSAm and its depolymerized derivatives, including fractions and oligosaccharides, showed potent neurite outgrowth-promoting activity in a chain length-dependent manner. A comparison of analyses among oligosaccharides revealed that the sulfate pattern of the Fuc branches, instead of the heterodisaccharide, could affect the promotion intensity. Fuc2S4S and the saccharide length endowed the neurite outgrowth stimulation activity most.


Assuntos
Pepinos-do-Mar , Animais , Pepinos-do-Mar/química , Sulfatos de Condroitina/farmacologia , Sulfatos de Condroitina/química , Fucose/química , Oligossacarídeos/farmacologia , Oligossacarídeos/química , Dissacarídeos , Crescimento Neuronal , Sulfatos/química
13.
Int J Mol Sci ; 23(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36142608

RESUMO

Gut microbiota have important implications for health by affecting the metabolism of diet and drugs. However, the specific microbial mediators and their mechanisms in modulating specific key intermediate metabolites from fungal origins still remain largely unclear. Toluquinol, as a key versatile precursor metabolite, is commonly distributed in many fungi, including Penicillium species and their strains for food production. The common 17 gut microbes were cultivated and fed with and without toluquinol. Metabolic analysis revealed that four strains, including the predominant Enterococcus species, could metabolize toluquinol and produce different metabolites. Chemical investigation on large-scale cultures led to isolation of four targeted metabolites and their structures were characterized with NMR, MS, and X-ray diffraction analysis, as four toluquinol derivatives (1-4) through O1/O4-acetyl and C5/C6-methylsulfonyl substitutions, respectively. The four metabolites were first synthesized in living organisms. Further experiments suggested that the rare methylsulfonyl groups in 3-4 were donated from solvent DMSO through Fenton's reaction. Metabolite 1 displayed the strongest inhibitory effect on cancer cells A549, A2780, and G401 with IC50 values at 0.224, 0.204, and 0.597 µM, respectively, while metabolite 3 displayed no effect. Our results suggest that the dominant Enterococcus species could modulate potential precursors of fungal origin and change their biological activity.


Assuntos
Microbioma Gastrointestinal , Neoplasias Ovarianas , Linhagem Celular Tumoral , Dimetil Sulfóxido/farmacologia , Feminino , Humanos , Hidroquinonas , Solventes/farmacologia
14.
Int J Mol Sci ; 23(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36293209

RESUMO

Human mitochondrial transcription termination factor 1 (MTERF1) has been demonstrated to play an important role in mitochondrial gene expression regulation. However, the molecular mechanism of MTERF1 in colorectal cancer (CRC) remains largely unknown. Here, we found that MTERF1 expression was significantly increased in colon cancer tissues compared with normal colorectal tissue by Western blotting, immunohistochemistry, and tissue microarrays (TMA). Overexpression of MTERF1 in the HT29 cell promoted cell proliferation, migration, invasion, and xenograft tumor formation, whereas knockdown of MTERF1 in HCT116 cells appeared to be the opposite phenotype to HT29 cells. Furthermore, MTERF1 can increase mitochondrial DNA (mtDNA) replication, transcription, and protein synthesis in colorectal cancer cells; increase ATP levels, the mitochondrial crista density, mitochondrial membrane potential, and oxygen consumption rate (OCR); and reduce the ROS production in colorectal cancer cells, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS) activity. Mechanistically, we revealed that MTERF1 regulates the AMPK/mTOR signaling pathway in cancerous cell lines, and we also confirmed the involvement of the AMPK/mTOR signaling pathway in both xenograft tumor tissues and colorectal cancer tissues. In summary, our data reveal an oncogenic role of MTERF1 in CRC progression, indicating that MTERF1 may represent a new therapeutic target in the future.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/genética , DNA Mitocondrial/genética , Mitocôndrias/metabolismo , Células HCT116 , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Trifosfato de Adenosina/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica
15.
Biochem Biophys Res Commun ; 571: 66-73, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34303965

RESUMO

Pleckstrin homology-like domain family A, member 3 (PHLDA3) is a novel tumor-related protein that mediates carcinogenesis of multiple cancers. However, the relevance of PHLDA3 in prostate cancer has not been explored. The purpose of this work was to illustrate the possible roles and mechanisms of PHLDA3 in prostate cancer. Our data showed strikingly lower abundance of PHLDA3 in prostate cancer, and that low levels of PHLDA3 in prostate cancer patients was associated with reduced survival. PHLDA3 was also weakly expressed in prostate cancer cells, and demethylation treatment dramatically up-regulated the expression level of PHLDA3. Up-regulation of PHLDA3 restrained proliferation, induced G1 cell cycle arrest, suppressed epithelial-mesenchymal transition of prostate cancer cells. In addition, up-regulation of PHLDA3 increased the sensitivity of prostate cancer cells to docetaxel In-depth research into the mechanism elucidated that PHLDA3 overexpression decreased the phosphorylation of Akt and suppressed the activation of Wnt/ß-catenin signaling. Overexpression of constitutively active Akt strikingly abolished PHLDA3-mediated inactivation of Wnt/ß-catenin pathway. A xenograft assay revealed that prostate cancer cells with PHLDA3 overexpression displayed reduced tumorigenicity in vivo. Collectively, these data document that PHLDA3 exerts an outstanding cancer-inhibiting role in prostate cancer by down-regulating Wnt/ß-catenin pathway via the inhibition of Akt. This work highlights PHLDA3 as a novel anticancer target for prostate cancer.


Assuntos
Regulação para Baixo , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Via de Sinalização Wnt
16.
J Transl Med ; 19(1): 35, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33468161

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystemic, chronic inflammatory disease characterized by destructive systemic organ involvement, which could cause the decreased functional capacity, increased morbidity and mortality. Previous studies show that SLE is characterized by autoimmune, inflammatory processes, and tissue destruction. Some seriously-ill patients could develop into lupus nephritis. However, the cause and underlying molecular events of SLE needs to be further resolved. METHODS: The expression profiles of GSE144390, GSE4588, GSE50772 and GSE81622 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between SLE and healthy samples. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed by metascape etc. online analyses. The protein-protein interaction (PPI) networks of the DEGs were constructed by GENEMANIA software. We performed Gene Set Enrichment Analysis (GSEA) to further understand the functions of the hub gene, Weighted gene co-expression network analysis (WGCNA) would be utilized to build a gene co-expression network, and the most significant module and hub genes was identified. CIBERSORT tools have facilitated the analysis of immune cell infiltration patterns of diseases. The receiver operating characteristic (ROC) analyses were conducted to explore the value of DEGs for SLE diagnosis. RESULTS: In total, 6 DEGs (IFI27, IFI44, IFI44L, IFI6, EPSTI1 and OAS1) were screened, Biological functions analysis identified key related pathways, gene modules and co-expression networks in SLE. IFI27 may be closely correlated with the occurrence of SLE. We found that an increased infiltration of moncytes, while NK cells resting infiltrated less may be related to the occurrence of SLE. CONCLUSION: IFI27 may be closely related pathogenesis of SLE, and represents a new candidate molecular marker of the occurrence and progression of SLE. Moreover immune cell infiltration plays important role in the progession of SLE.


Assuntos
Biologia Computacional , Lúpus Eritematoso Sistêmico , Biomarcadores , Ontologia Genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Mapas de Interação de Proteínas
17.
Phys Chem Chem Phys ; 23(39): 22685-22691, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34604887

RESUMO

Bulk-heterojunction (BHJ) organic solar cells (OSCs) exhibit ultrafast charge separation (UCS) which enables lower geminate charge recombination and high internal quantum efficiency. Unravelling why UCS occurs in BHJ-OSCs is important for the exploration of devices in future, however it is still far from clear. In this work, we build a multichain tight-binding model to study the conditions for realizing UCS. We propose that two conditions are important: (i) the BHJ-OSC has a morphology with donor and acceptor molecules being individually aggregated; (ii) the ratio of the donor/acceptor interfacial coupling to the internal donor/donor and acceptor/acceptor coupling should be smaller than a threshold. In addition, we suggest that increasing the donor/acceptor energetic offset will boost the UCS efficiency. As a fundamental theoretical analysis on the underlying mechanism of UCS, our work provides design rules for optimizing high-performance BHJ OSCs.

18.
Nanotechnology ; 31(22): 225206, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32050184

RESUMO

A multiple-layer thin film of Pt/Ga2O3-x/SiC/Pt-based resistive switching is systematically investigated. Excellent bipolar resistive switching behavior is observed with a high resistance switching ratio of OFF/ON up to 103. The current-voltage relations plot implies the Ohmic conductance of the ON state, while the space and interface charge limited the current of the OFF state. The micro mechanism of resistive switching is explained by the formation/rupture of conductive filaments formed out of oxygen vacancies within the Ga2O3-x and SiC region. In particular, these devices exhibit excellent stability. The high OFF/ON resistance ratio can be completely retained for a number of days without degradation.

19.
Molecules ; 25(12)2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545498

RESUMO

Advanced oxidation processes (AOPs) are effective ways to degrade refractory organic contaminants, relying on the generation of inorganic radicals (e.g., •OH and SO4•-). Herein, a novel AOP with organic radicals (R-O•) was reported to degrade contaminants. Lanthanum cobaltite perovskite (LaCoO3) was used to activate peracetic acid (PAA) for organic radical generation to degrade sulfamethoxazole (SMX). The results show that LaCoO3 exhibited an excellent performance on PAA activation and SMX degradation at neutral pH, with low cobalt leaching. Meanwhile, LaCoO3 also showed an excellent reusability during PAA activation. In-depth investigation confirmed CH3C(O)O• and CH3C(O)OO• as the key reactive species for SMX degradation in LaCoO3/PAA system. The presence of Cl- (1-100 mM) slightly inhibited the degradation of SMX in the LaCoO3/PAA system, whereas the addition of HCO3- (0.1-1 mM) and humic aid (1-10 mg/L) could significantly inhibit SMX degradation. This work highlights the generation of organic radicals via the heterogeneous activation of PAA and thus provides a promising way to destruct contaminants in wastewater treatment.


Assuntos
Lantânio/química , Ácido Peracético/química , Sulfametoxazol/química , Compostos de Cálcio/química , Peróxido de Hidrogênio , Concentração de Íons de Hidrogênio , Minerais/química , Oxirredução , Óxidos/química , Titânio/química , Poluentes Químicos da Água/análise , Purificação da Água/métodos
20.
Chemistry ; 25(2): 573-581, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30357937

RESUMO

Five organic luminophores, 1,2,5-triphenylpyrrole (TPP) derivatives 3 a-e bearing electron-withdrawing or electron-donating groups, have been synthesized by Pd-catalyzed Suzuki coupling of 1-phenyl-2,5-di(4'-bromophenyl)pyrrole and para-substituted phenylboronic acid derivatives. They possess good thermal stabilities with high decomposition temperatures above 310 °C. Investigation of the photophysical properties of the luminogens 3 a-e indicated that they exhibited dual intense photoluminescence in both solution and the solid state due to their twisted conformations, and their fluorescence quantum yields (ΦF ) were determined as 68.7-94.9 % in THF solution and 19.1-52.0 % in solid powder form. Compounds 3 a-c bearing electron-accepting groups exhibited remarkable solvatochromism with large Stokes shifts, attributable to their D-π-A structure and intramolecular charge-transfer effect. In particular, 3 a, bearing aldehyde groups, displayed an obvious red-shift of the emission band from 445 to 564 nm with increasing solvent polarity. However, no obvious solvatochromic behavior was observed for compounds 3 d,e bearing electron-donating groups. The luminophore 3 a exhibited polymorphic luminescence properties and crystallization-induced emission enhancement.

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