RESUMO
Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.
Assuntos
Calgranulina A , Calgranulina B , Camundongos Transgênicos , Doença de Parkinson , Ubiquitina Tiolesterase , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Animais , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/deficiência , Humanos , Camundongos , Feminino , Masculino , Calgranulina B/metabolismo , Calgranulina B/genética , Calgranulina A/metabolismo , Calgranulina A/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Parkinson's disease (PD) is a progressive movement disorder characterized by dopaminergic (DA) neuron degeneration and the existence of Lewy bodies formed by misfolded α-synuclein. Emerging evidence supports the benefits of dietary interventions in PD due to their safety and practicality. Previously, dietary intake of α-ketoglutarate (AKG) was proved to extend the lifespan of various species and protect mice from frailty. However, the mechanism of dietary AKG's effects in PD remains undetermined. In the present study, we report that an AKG-based diet significantly ameliorated α-synuclein pathology, and rescued DA neuron degeneration and impaired DA synapses in adeno-associated virus (AAV)-loaded human α-synuclein mice and transgenic A53T α-synuclein (A53T α-Syn) mice. Moreover, AKG diet increased nigral docosahexaenoic acid (DHA) levels and DHA supplementation reproduced the anti-α-synuclein effects in the PD mouse model. Our study reveals that AKG and DHA induced microglia to phagocytose and degrade α-synuclein via promoting C1q and suppressed pro-inflammatory reactions. Furthermore, results indicate that modulating gut polyunsaturated fatty acid metabolism and microbiota Lachnospiraceae_NK4A136_group in the gut-brain axis may underlie AKG's benefits in treating α-synucleinopathy in mice. Together, our findings propose that dietary intake of AKG is a feasible and promising therapeutic approach for PD.
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Doença de Parkinson , Sinucleinopatias , Camundongos , Animais , Humanos , Doença de Parkinson/patologia , Ácidos Cetoglutáricos/farmacologia , Camundongos Transgênicos , Degeneração Neural/patologia , Dopamina , Ingestão de Alimentos , Modelos Animais de DoençasRESUMO
The interaction between tumor cells and the tumor microenvironment (TME) significantly influences tumorigenesis, so TME-targeted therapy has attracted widespread attention. We have previously demonstrated that the combination of dipyridamole, bestatin, and dexamethasone (DBD mix, DBDx) is effective against heterogeneous human pancreatic cancer and hepatocellular carcinoma in mouse xenograft models. To further expand the therapeutic potential of this drug combination, herein, we investigated the antitumor efficacy and the underlying mechanism of DBDx and the combination of DBDx and gefitinib in different mouse xenograft models of human non-small-cell lung cancer (NSCLC). Three human cancer cell lines H460, PG, and A431 were used to determine the apoptosis and growth inhibition induced by DBDx, gefitinib, and their combinations. Changes in epidermal growth factor receptor (EGFR) signaling pathway-related proteins were analyzed following treatment using western blotting. In vitro, DBDx strongly inhibited the proliferation of tumor cells, whereas the combined treatment exhibited a significant synergistic effect. Compared with DBDx, the combination treatment further induced apoptosis and downregulated the expression of molecules associated with EGFR signaling pathway. In vivo, compared with DBDx alone, the combination treatment distinctly inhibited tumor growth in mouse xenograft models of human NSCLC. Overall, our results indicate that the combination of DBDx and gefitinib in the treatment of human NSCLC is very promising, which warrants further translational studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/farmacologia , Neoplasias Pulmonares/dietoterapia , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The synthetic control method (SCM) is a useful tool in providing unbiased analysis on the policy effect in real-world health policy evaluations. Through controlling for a few confounding factors, we aim to apply SCM in analyzing the impact of the pricing reform on medical expenditure structure in Jiangsu Province, China. METHODS: We constructed a synthetic control for Zhenjiang, a city where the reform was piloted in Jiangsu, by selecting weights on those potential control units to define a linear combination of the control outcomes to replicate the counterfactual as if the intervention is in absence. The policy effect was measured by the differences in the percentage of drug expenditure among average outpatient and inpatient care cost per visit in the post-policy period between Zhenjiang and its synthetic control. We also examined the significance of the estimated results by performing placebo tests, and cross-validated the results with a difference-in-differences analysis. RESULTS: The medical pricing reform was found to be effective in reducing the drug expenditure proportions in both outpatient and inpatient care by an estimated mean level of 7.7 and 3.2% (or 16.3 and 9.2% relative decrease to their 2012 levels) respectively. This reform effect was estimated to be significant in the placebo tests and was further confirmed by a cross-validation. CONCLUSION: We conclude that the pricing reform in public hospitals has significantly reduced drug expenditure incurred in both outpatient and inpatient care. This study also highlights the applicability of SCM method as an effective tool for health policy evaluation using publicly available data in the context of Chinese healthcare system.
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Comércio , Reforma dos Serviços de Saúde/economia , Gastos em Saúde/tendências , Política de Saúde , Hospitais Públicos , China , Atenção à Saúde , Hospitalização , Humanos , Pessoa de Meia-Idade , Pacientes AmbulatoriaisRESUMO
The impacts of sonication on the photosynthetic activity of Synedra sp. (diatom) and its mechanism were investigated for the first time. Three photosynthetic parameters, i.e., effective quantum yield (Φe), initial slope of rapid light curves (α) and maximum relative electron transport rate (rETRmax) were employed to evaluate its photosynthetic activity during sonication for the first time. The results showed that 600â¯kHz is the optimal frequency for the inhibition of the photosynthetic activity and biomass as the ultrasonic frequencies varied from 100 to 800â¯kHz. When the photosynthetic activity was inhibited to be not detected by sonication, Φe, α and rETRmax gradually recovered from 0 to 36.4%, 35.2% and 48.3% of that in the blank group, respectively, after 12-day cultivation (no sonication). However, the biomass was still suppressed to 9.2% of that in the blank after the same cultivation. A single time sonication treatment achieved better inhibition efficiency than the multiple times modes when their total sonication time was equal. The inhibition mechanism for the photosynthetic activity of Synedra sp. by sonication can be concluded as follows: at the early stage, the thylakoids membrane expansion and oscillation can lead to the structure damage of thylakoids; subsequently, OH oxidation is responsible for the chlorophyll-a degradation.
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Diatomáceas , Clorofila , Luz , Fotossíntese , SonicaçãoRESUMO
Vicagrel, a novel acetate analogue of clopidogrel, exerts more potent antiplatelet effect than clopidogrel in rodents. Relevant evidence indicated that aspirin and vicagrel are the drug substrate for carboxylesterase 2. Accordingly, it is deduced that concomitant use of aspirin could attenuate the bioactivation of and platelet response to vicagrel. To clarify whether there could be such an important drug-drug interaction, the differences in both the formation of vicagrel active metabolite H4 and the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel were measured and compared between mice treated with vicagrel alone or in combination with aspirin. The plasma H4 concentration was determined by liquid chromatography-tandem mass spectrometry, and the inhibition of platelet aggregation by vicagrel was assessed by whole-blood platelet aggregation. Compared with vicagrel (2.5 mg·kg) alone, concurrent use of aspirin (5, 10, or 20 mg·kg) significantly decreased systemic exposure of H4, an average of 38% and 41% decrease in Cmax and AUC0-∞ in mice when in combination with aspirin at 10 mg·kg, respectively. Furthermore, concomitant use of aspirin (10 mg·kg) and vicagrel (2.5 mg·kg) resulted in an average of 66% reduction in the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel. We conclude that aspirin significantly attenuates the formation of vicagrel active metabolite H4 and platelet response to vicagrel in mice, and that such an important drug-drug interaction would appear in clinical settings if vicagrel is taken with aspirin concomitantly when marketed in the future.
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Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Fenilacetatos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Ativação Metabólica , Animais , Aspirina/metabolismo , Plaquetas/metabolismo , Carboxilesterase , Hidrolases de Éster Carboxílico/metabolismo , Cromatografia Líquida , Interações Medicamentosas , Masculino , Camundongos Endogâmicos C57BL , Fenilacetatos/sangue , Fenilacetatos/farmacocinética , Inibidores da Agregação Plaquetária/sangue , Inibidores da Agregação Plaquetária/farmacocinética , Testes de Função Plaquetária , Espectrometria de Massas em Tandem , Tiofenos/sangue , Tiofenos/farmacocinéticaRESUMO
BACKGROUND: Single disease payment program based on clinical pathway (CP-based SDP) plays an increasingly important role in reducing health expenditure in china and there is a clear need to explore the scheme from different perspectives. This study aimed at evaluating the effect of the scheme in rural county public hospitals within Anhui, a typical province of China,using uterine leiomyoma as an example. METHODS: The study data were extracted from the data platform of the New Rural Cooperative Medical Office of Anhui Province using stratified-random sampling. Means, constituent ratios and coefficients of variations were calculated and/or compared between control versus experiment groups and between different years. RESULTS: The total hospitalization expenditure (per-time) dropped from 919.08 ± 274.92 USD to 834.91 ± 225.29 USD and length of hospital stay reduced from 9.96 ± 2.39 days to 8.83 ± 1.95 days(P < 0.01), after CP-based SDP had implemented. The yearly total hospitalization expenditure manifested an atypical U-shaped trend. Medicine expense, nursing expense, assay cost and treatment cost reduced; while the fee of operation and examination increased (P < 0.05). The expense constituent ratios of medicine, assay and treatment decreased with the medicine expense dropped the most (by 4.4%). The expense constituent ratios of materials, ward, operation, examination and anesthetic increased,with the examination fee elevated the most (by 3.9%).The coefficient of variation(CVs) of treatment cost declined the most (- 0.360); while the CV of materials expense increased the most (0.186). CONCLUSION: There existed huge discrepancies in inpatient care for uterine leiomyoma patients. Implementation of CP-based SDP can help not only in controlling hospitalization costs of uterine leiomyoma in county-level hospitals but also in standardizing the diagnosis and treatment procedures.
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Procedimentos Clínicos/economia , Hospitalização/economia , Leiomioma/economia , Sistema de Fonte Pagadora Única/economia , Neoplasias Uterinas/economia , China , Feminino , Custos de Cuidados de Saúde , Gastos em Saúde , Custos Hospitalares , Hospitais , Hospitais de Condado/economia , Humanos , Leiomioma/terapia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Saúde da População Rural/economia , Neoplasias Uterinas/terapiaRESUMO
Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120.9 pmol/min/mg protein, 3- to 12-fold higher than that of the other rUGT isoforms tested. According to relative activity factor approach, the relative contribution of rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed Michaelis-Menten kinetics with a mean Km value of 372.9 µM and 296.4 µM for pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The formation of CAG was significantly inhibited by azidothymidine and gemfibrozil (well-characterized UGT2B7 substrates) in a concentration-dependent manner, or by fluconazole (a typical UGT2B7-selective inhibitor) in a time-dependent manner, for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs and rUGT2B7 in a concentration-dependent manner, indicating that CCA is a substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug-drug interactions between clopidogrel and the other substrate drugs of UGT2B7.
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Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Ticlopidina/análogos & derivados , Clopidogrel , Interações Medicamentosas , Fluconazol/farmacologia , Genfibrozila/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Isoenzimas/metabolismo , Cinética , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/metabolismo , Ticlopidina/metabolismo , Zidovudina/farmacologiaRESUMO
OBJECTIVE: To investigate the potential correlation between miR-223 level in leukocytes and platelet responses to clopidogrel in patients with coronary artery disease.â© Methods: A cohort of 188 outpatients, who conducted percutaneous coronary intervention (PCI) and received dual antiplatelet therapy, were recruited. The patient's electronic health data were collected, and their blood samples were obtained for measurement of adenosine diphosphate (ADP)-induced whole-blood platelet aggregation. Extreme cases of platelet responses to clopidogrel (ultra- vs. non-responder) were measured with miR-223-3p levels in leukocytes.â© Results: Both groups had similar miR-223-3p levels in leukocytes. There were no significant differences in other demographic and clinical data except for metrics of ADP-induced whole-blood platelet aggregation between the 2 group.â© Conclusion: MiR-223-3p in peripheral leukocytes is not associated with the altered platelet responses to clopidogrel in PCI outpatients.
Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Leucócitos/metabolismo , MicroRNAs/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Difosfato de Adenosina/sangue , Clopidogrel , Doença da Artéria Coronariana/sangue , Humanos , Intervenção Coronária Percutânea , Ticlopidina/uso terapêuticoRESUMO
Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased messenger RNA expression of ABCC3 that encodes MRP3 (multidrug resistance-associated protein 3). However, there is no evidence showing the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the presence or absence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knockout (KO) versus wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of adenosine diphosphate-induced platelet aggregation by clopidogrel after administration of a single oral dose of clopidogrel to KO and WT mice, respectively. Results indicated that Abcc3 KO mice exhibited increased formation of CAM and greater systemic exposure to clopidogrel and enhanced inhibition of adenosine diphosphate-induced platelet aggregation ex vivo by clopidogrel when compared with well-matched WT mice. We conclude that Abcc3 KO mice have enhanced platelet response to clopidogrel due to increased formation of CAM.
Assuntos
Plaquetas/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/deficiência , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Ticlopidina/análogos & derivados , Animais , Plaquetas/metabolismo , Clopidogrel , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Knockout , Ativação Plaquetária/fisiologia , Inibidores da Agregação Plaquetária/metabolismo , Ticlopidina/metabolismo , Ticlopidina/farmacologiaRESUMO
The tumor necrosis factor (TNF) receptor associated factors (TRAFs) are the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily, which regulate a variety of cellular activities and innate immune responses. TRAF genes have been extensively studied in various species, including vertebrates and invertebrates. However, as one of the key component of NF-κB pathway, TRAF genes have not been systematically characterized in marine invertebrates. In this study, we identified and characterized five TRAF genes, PyTRAF2, PyTRAF3, PyTRAF4, PyTRAF6 and PyTRAF7, in the Yesso scallop (Patinopecten yessoensis). Phylogenetic and protein structural analyses were conducted to determine their identities and evolutionary relationships. In comparison with the TRAF genes from vertebrate species, the structural features were all relatively conserved in the PyTRAF genes. To gain insights into the roles of TRAF genes during scallop innate immune responses, quantitative real-time PCR was used to investigate the expression profiles in the different stages of scallop development, in the healthy adult tissues, and in the hemocytes after bacterial infection with Micrococcus luteus and Vibrio anguillarum. Based on the qRT-PCR analysis, the expression of most of the PyTRAFs was significantly induced in the acute phases (3-6 h) after infection with Gram-positive (M. luteus) and Gram-negative (V. anguillarum) bacteria, and many more dramatic changes in PyTRAFs expression were observed after V. anguillarum challenge. Notably, the strong response in the up-regulation of PyTRAF6 post-bacterial challenge was distinct from that previously reported in scallops and crabs but was similar to that of other shellfish, Echinodermata and even teleost fish. The high level expressions of PyTRAFs in the hemocytes and the gill, and their specific expression patterns after challenges provide insights into the versatile roles and responses of TRAFs in the innate immune system against Gram-negative bacterial pathogens in bivalves.
Assuntos
Regulação da Expressão Gênica , Micrococcus luteus/fisiologia , Pectinidae/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Vibrio/fisiologia , Animais , Hemócitos/imunologia , Imunidade Inata , Dados de Sequência Molecular , Especificidade de Órgãos , Pectinidae/imunologia , Pectinidae/metabolismo , Pectinidae/microbiologia , Filogenia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Análise de Sequência de Proteína , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/química , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Myeloid differentiation factor 88 (MyD88) is a pivotal adaptor in the TLR/IL-1R signaling pathway, which plays an important role in activating the innate immune system. Although MyD88 genes have been identified in a variety of species, they have not been systematically characterized in scallops. In this study, five MyD88 genes were identified in Yesso scallop (Patinopecten yessoensis), PyMyD88-1, PyMyD88-2a, PyMyD88-2b, PyMyD88-3 and PyMyD88-4, which consisted of two pairs of tandem duplications located on the same chromosome. To our knowledge, this is the largest number of MyD88 genes found in an invertebrate. Phylogenetic and protein structural analyses were carried out to determine the identities and evolutionary relationships of these genes. PyMyD88s have highly conserved structures compared to MyD88 genes from other invertebrate species, except for PyMyD88-4, which contains only a DD domain, suggesting the evolutionarily conserved form of this particular gene member. We investigated the expression profiles of PyMyD88 genes at different developmental stages and in healthy adult tissues and hemocytes after Micrococcus luteus and Vibrio anguillarum infection using quantitative real-time PCR (qRT-PCR). The expression of most PyMyD88s was significantly induced in the acute phase (3-6 h) after infection with both gram-positive (M. luteus) and gram-negative (V. anguillarum) bacteria, with much more dramatic changes in PyMyD88 expression being observed after V. anguillarum challenge. Collectively, the abundance of MyD88s and their specific expression patterns provide insight into their versatile roles in the response of the bivalve innate immune system to gram-negative bacterial pathogens.
Assuntos
Imunidade Inata , Fator 88 de Diferenciação Mieloide/genética , Pectinidae/genética , Pectinidae/imunologia , Sequência de Aminoácidos , Animais , Micrococcus luteus/fisiologia , Dados de Sequência Molecular , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/metabolismo , Especificidade de Órgãos , Pectinidae/metabolismo , Pectinidae/microbiologia , Filogenia , Reação em Cadeia da Polimerase em Tempo Real , Alinhamento de Sequência , Vibrio/fisiologiaRESUMO
Hepatitis C virus (HCV) core protein stimulates many signaling pathways related to apoptosis inhibition resulting in hepatocellular carcinoma (HCC). It has been reported that sirt1 is involved in regulating apoptosis; therefore, we investigated the influence of HCV core protein on sirt1 expression and apoptosis in human HepG2 cells. Our study showed that HCV core protein inhibited apoptosis of HepG2 cells as well as caspase-3 expression and activity (P < 0.05). At the same time, sirt1 expression was increased at both the mRNA (P < 0.05) and protein (P < 0.05) levels. Furthermore, apoptosis inhibition was reversed when sirt1 was knocked down (P < 0.05). Our study provides further evidence that the sirt1-p53-Bax signaling pathway plays an important role in regulating the suppression of cell apoptosis induced by HCV core protein.
Assuntos
Apoptose/efeitos dos fármacos , Células Hep G2/virologia , Hepacivirus/fisiologia , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/metabolismo , Proteína X Associada a bcl-2/metabolismo , Sequência de Bases , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Técnicas de Silenciamento de Genes , Células Hep G2/citologia , Hepacivirus/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Dados de Sequência Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais , Sirtuína 1/farmacocinética , Proteínas do Core Viral/genéticaRESUMO
[This corrects the article DOI: 10.1021/acsomega.3c04101.].
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Supercritical cyclohexane (SC-cyclohexane) shows significant advantages in mild operating conditions and the modulation of product distribution. To gain insights into the upgrading process of heavy oil in SC-cyclohexane, the dissolution process of polycyclic aromatic hydrocarbons (PAHs) contained in heavy oil was simulated based on molecular dynamics with the use of naphthalene, benzopyrene, and mixtures of naphthalene and benzopyrene as the model compounds. As indicated by the radial distribution function results, in SC-cyclohexane exhibiting low density, cyclohexane formed a solvent shell around PAHs such that the local concentration was reduced and the aggregation of PAHs was inhibited. The results of the solvation free energy suggested that van der Waals forces between PAHs and cyclohexane were mainly dominant. As revealed by the dissolution process of the model compounds in SC-cyclohexane, a low density and a suitable temperature contributed to the solubilization of PAHs. An appropriate temperature and a low density can be selected for the upgrading reaction to limit coke formation.
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Photocatalytic nitrogen (N2) reduction to ammonia (NH3), adopting H2O as the electron source, suffers from low efficiency owing to the sluggish kinetics of N2 reduction and the requirement of a substantial thermodynamic driving force. Herein, we present a straightforward approach for the construction of an S-scheme heterojunction of BiVO4/VS-MoS2 to successfully achieve photocatalytic N2 fixation, which is manufactured by coupling an N2-activation component (VS-MoS2 nanosheet) and water-oxidation module (BiVO4 nanocrystal) through electrostatic self-assembly. The VS-MoS2 nanosheet, enriched with sulfur vacancies, plays a pivotal role in facilitating N2 adsorption and activation. Additionally, the construction of the S-scheme heterojunction enhances the driving force for water oxidation and improves charge separation. Under simulated sunlight irradiation (100 mW cm-2), BiVO4/VS-MoS2 exhibits efficient photocatalytic N2 reduction activity with H2O as the proton source, yielding NH3 at a rate of 132.8 µmol g-1 h-1, nearly 7 times higher than that of pure VS-MoS2. This study serves as a noteworthy example of efficient N2 reduction to NH3 under mild conditions.
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Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.
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Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the ßactin control western blotting data shown in Fig. 3D on p. 1893 were very similar to the contol data shown in Fig. 4A on p. 1894; furthermore, the data shown for the MMP9 and the INOS protein bands in Fig. 4C were remarkably similar to the data shown for the IL1ß and IL6 proteins, respectively, albeit the backgrounds surrounding the bands were different. Moreover, various of the western blotting data shown in these figures were strikingly similar to data that had already been published in different form in other articles written by (largely) different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, and due to the number of apparent duplications of strikingly similar data between Figs. 3 and 4, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 7: 18891895, 2013; DOI: 10.3892/mmr.2013.1444].
RESUMO
BACKGROUND: Acute Respiratory Distress syndrome (ARDS) is a common complication of Acute Pancreatitis (AP) and is associated with high mortality. This study used Machine Learning (ML) to predict ARDS in patients with AP at admission. METHODS: The authors retrospectively analyzed the data from patients with AP from January 2017 to August 2022. Clinical and laboratory parameters with significant differences between patients with and without ARDS were screened by univariate analysis. Then, Support Vector Machine (SVM), Ensembles of Decision Trees (EDTs), Bayesian Classifier (BC), and nomogram models were constructed and optimized after feature screening based on these parameters. Five-fold cross-validation was used to train each model. A test set was used to evaluate the predictive performance of the four models. RESULTS: A total of 83 (18.04%) of 460 patients with AP developed ARDS. Thirty-one features with significant differences between the groups with and without ARDS in the training set were used for modeling. The Partial Pressure of Oxygen (PaO2), C-reactive protein, procalcitonin, lactic acid, Ca2+, the neutrophil:lymphocyte ratio, white blood cell count, and amylase were identified as the optimal subset of features. The BC algorithm had the best predictive performance with the highest AUC value (0.891) than SVM (0.870), EDTs (0.813), and the nomogram (0.874) in the test set. The EDT algorithm achieved the highest accuracy (0.891), precision (0.800), and F1 score (0.615), but the lowest FDR (0.200) and the second-highest NPV (0.902). CONCLUSIONS: A predictive model of ARDS complicated by AP was successfully developed based on ML. Predictive performance was evaluated by a test set, for which BC showed superior predictive performance and EDTs could be a more promising prediction tool for larger samples.
Assuntos
Pancreatite , Síndrome do Desconforto Respiratório , Humanos , Pancreatite/complicações , Pancreatite/diagnóstico , Estudos Retrospectivos , Doença Aguda , Teorema de Bayes , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Aprendizado de MáquinaRESUMO
Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti-oxidative stress and anti-inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine-specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro-inflammatory TNFR1/NF-κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti-inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial-targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide-induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation-dependent cognitive decline.