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1.
Pharmaceutics ; 14(2)2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35214146

RESUMO

We developed safe and stable mixed polymeric micelles with low lipids and free propofol for intravenous administration, to overcome the biological barrier of the reticuloendothelial system (RES), reduce pain upon injection, and complications of marketed propofol formulation. The propofol-mixed micelles were composed of distearoyl-phosphatidylethanolamine-methoxy-poly (ethylene glycol 2000) (DSPE mPEG2k) and Solutol HS 15 and were optimized using Box Behnken design (BBD). The optimized formulation was evaluated for globule size, zeta potential, loading content, encapsulation efficiency, pain on injection, histological evaluation, hemolysis test, in vivo anesthetic action, and pharmacokinetics, in comparison to the commercialized emulsion Diprivan. The optimized micelle formulation displayed homogenous particle sizes, and the free drug concentration in the micelles was 60.9% lower than that of Diprivan. The paw-lick study demonstrated that propofol-mixed micelles significantly reduced pain symptoms. The anesthetic action of the mixed micelles were similar with the Diprivan. Therefore, we conclude that the novel propofol-mixed micelle reduces injection-site pain and the risk of hyperlipidemia due to the low content of free propofol and low-lipid constituent. It may be a more promising clinical alternative for anesthetic.

2.
EClinicalMedicine ; 36: 100897, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34136775

RESUMO

BACKGROUND: Current prognostic scores for pulmonary embolism (PE) were partly based on patients without PE confirmation via computed tomographic pulmonary angiography (CTPA), involving subjective parameters and complicated scoring methods. Therefore, we sought to develop an objective, accurate, and simple prognostic model in CTPA-confirmed patients to predict the risk of 30-day mortality. METHODS: We retrospectively evaluated 509 patients with objectively confirmed PE by CTPA from 2010 to 2017 in the Minhang Hospital, which is affiliated to Fudan University. Patients were randomly divided into the training and validation cohorts. The primary end point was 30-day mortality. The secondary end points were the time to recovery in 30 days and mortality in 15 days. We compared the predictive performance of Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI), and the PE risk score we developed, called PERFORM. FINDINGS: PERFORM (ranging from 0 to 12 score) is based on the patient's age, heart rate, and partial pressure of arterial oxygen. The area under the curve was 0.718 (95% confidence interval [CI], 0.627-0.809) for the training cohort and 0.906 (95% CI, 0.846-0.966) for the validation cohort. PERFORM was as good as PESI and sPESI in predicting mortality. Patients in the low-risk group (PERFORM score < 5) had a shorter time to recovery, whereas those in the high-risk group (PERFORM score ≥ 5) had a high mortality. INTERPRETATION: PERFORM in CTPA-confirmed patients is an objective, accurate, and simple tool to predict the risk of 30-day mortality. FUNDING: Research Project of Shanghai Municipal Commission of Health and Family Planning (201740127), Shanghai Medical Key Subject Construction Project (ZK2019B08).

3.
Iran J Immunol ; 17(4): 303-312, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382387

RESUMO

BACKGROUND: There is a close relationship between neutrophil extracellular traps (NETs) and venous thromboembolism (VTE). The regulatory role and mechanism of glucocorticoids (GC) in the formation of NETs are unclear. OBJECTIVE: This study was conducted to assess the effect of GC on the formation of NETs. METHODS: We constructed a mouse VTE model and treated them with GC to observe the effect of GC on the formation of NETs. In this regard, peripheral blood neutrophils were isolated, and the effect and mechanism of GC in neutrophil activation were analyzed. RESULTS: Following LPS treatment, the colony-forming ability of neutrophils and their ability to form NETs increased significantly. The analysis of cytokine changes by RT-PCR combined with ELISA showed that the level of inflammatory factors in LPS-activated neutrophils increased significantly; however, these factors were significantly inhibited after GC treatment, and the inhibitory effect was positively correlated with the concentration of GC. LPS treatment was able to activate the production of ROS and lipid peroxides, however, this activation was significantly inhibited after GC treatment, and the inhibition increased with increasing doses of GC. Further examination of the changes in NF-κB signaling activation revealed that LPS-induced NF-κB signaling was significantly inhibited after GC treatment, and this inhibition increased with increasing the GC concentration. CONCLUSION: Glucocorticoids were able to inhibit neutrophil activation and reduce the formation of NETs. The research results provided a new research direction for clinical antithrombotic treatment.


Assuntos
Armadilhas Extracelulares/metabolismo , Glucocorticoides/metabolismo , Pulmão/imunologia , Neutrófilos/imunologia , Embolia Pulmonar/imunologia , Tromboembolia Venosa/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibrinolíticos/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ativação de Neutrófilo , Embolia Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Tromboembolia Venosa/tratamento farmacológico
4.
ACS Nano ; 14(4): 4950-4962, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32203660

RESUMO

Efficient removal of deadly toxicants by blood purification remains predominant in poisoning treatment. Current strategies mainly rely on absorptive scavengers that normally have no selectivity to the adsorbates, which could result poor clinical outcomes to certain toxic species due to the passivity and inaccuracy of the detoxification procedure. Herein, a positive, accurate, and customized detoxification strategy was proposed. Based on the sophisticated molecule design and thoughtful structure analysis of the aimed toxicant paraquat, a supramolecular hunter stationed on red blood cells (RBC) is developed to continuously track paraquat in the blood. In this construct, a Janus dendrimer amphiphile (JDA) molecule was synthesized with the aim of facilely anchoring onto RBC membranes while bridging to load the antidote WP6 that could precisely recognize paraquat. In vitro and in vivo results demonstrate the effective toxicant-hunting and harm-neutralizing capability of the system through a guest-exchange reaction. This strategy provides a different insight in designing scavengers that can actively, precisely, and continuously hunt toxicants through a supramolecular approach.


Assuntos
Antídotos , Paraquat , Eritrócitos
5.
IUBMB Life ; 72(3): 440-451, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32031750

RESUMO

In this study, we intended to determine the detailed function and mechanism of long noncoding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) in liver injury induced by sepsis. Cecal ligation and perforation (CLP) models were adopted to induce sepsis in vivo with rats, and hepatic epithelial cells L02 were treated with lipopolysaccharide (LPS) to mimic sepsis in vitro. Enzyme-linked immunosorbent assay was conducted to detect the levels of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon-γ (IFN-γ) in the serum of rats. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expressions of CRNDE and microRNA-126-5p (miR-126-5p). Flow cytometry analysis and Cell Counting Kit-8 (CCK-8) method were carried out followed by the up- or downregulation of CRNDE and miR-126-5p to monitor the proliferation and apoptosis of L02 cells, respectively. Western blot was then applied to determine the expressions of cysteinyl aspartate specific proteinase 3 (caspase 3), poly(ADP-ribose)polymerase (PARP), cytochrome c, and BCL2-like 2 (BCL2L2). The interactions between CRNDE with miR-126-5p and miR-126-5p with BCL2L2 were determined through bioinformatics, qRT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation assay. CRNDE was significantly decreased in liver tissues and hepatic cells in sepsis models. Upregulation of CRNDE promoted the viability of L02 cells and inhibited their apoptosis, while downregulation of CRNDE had opposite effects. The expression of CRNDE in liver tissues of septic rats was correlated with the expression miR-126-5p. It was also demonstrated that the transfection of miR-126-5p mimics reversed the inhibitory effect induced by CRNDE on apoptosis of L02 cells. CRNDE could specifically bind to miR-126-5p and reduce its expression, in turn promote the expression of BCL2L2. Additionally, CRNDE overexpression in rats ameliorated liver injury induced by sepsis. Downregulated CRNDE aggravates hepatic injury via regulating miR-126-5p and BCL2L2 during sepsis.


Assuntos
Lesão Pulmonar Aguda/etiologia , RNA Longo não Codificante/genética , Sepse/complicações , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos/toxicidade , Fígado/citologia , Masculino , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos Sprague-Dawley , Sepse/genética
6.
Int Immunopharmacol ; 79: 105933, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877497

RESUMO

Long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is reported to be linked to inflammation and cell apoptosis. However its role in sepsis induced kidney injury remains unclear. This study aims to explore the possible mechanism of CRNDE in kidney injury induced by sepsis. In vivo urine-derived sepsis (US) rat model and in vitro LPS-induced HK-2 and HEK293 cells were established. Kidney function was measured in rats from different groups. Relative levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß(IL-1ß) in kidney tissue were detected via Enzyme-linked immune sorbent assay (ELISA). Then we up- or down-regulated CRNDE and miRNA-181a-5p expression in the cells. The biological influence of CRNDE and miR-181a-5p on cells was studied using CCK-8 assay and Annexin V assay. Interaction between CRNDE and miR-181a-5p was determined by bioinformatics analysis, RT-PCR, and dual luciferase reporter assay. Peroxisome proliferator-activated receptor-α (PPARα) and cell apoptosis related molecules were detected by western blot. We demonstrated that CRNDE was markedly down-regulated while miR-181a-5p was significantly up-regulated in sepsis models. CRNDE interacted with miR-181a-5p, and negatively regulated its expression level. CRNDE knockdown in rats increased the urea nitrogen and serum creatinine in plasma. Knockdown of CRNDE or transfection of miR-181a-5p significantly inhibited proliferation and promoted apoptosis of HK-2 and HEK293 cells, while overexpression of CRNDE and transfection of miR-181a-5p inhibitors had opposite effects. For mechanism, miR-181a-5p directly targeted the 3' untranslated region of PPARα, and depressed its protein level, and PPARα was regulated indirectly by CRNDE. We concluded that CRNDE protected renal cell from sepsis-induced injury via miR-181a-5p/PPARα pathway.


Assuntos
Injúria Renal Aguda/genética , Rim/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Sepse/genética , Injúria Renal Aguda/metabolismo , Animais , Apoptose , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Células HEK293 , Humanos , Interleucina-1beta/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Biochem Biophys Res Commun ; 519(3): 525-532, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537384

RESUMO

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 1 (IGF2BP1) mediates lipopolysaccharide (LPS)-induced NFκB activation and pro-inflammatory cytokines production in human macrophages. Recent studies have identified a novel IGF2BP1-binding LncRNA LIN28B-AS1. In the present study we show that LPS induced LIN28B-AS1-IGF2BP1 association in THP-1 macrophages, required for LPS-induced IGF2BP1-p65-p52 association and NFκB activation. LIN28B-AS1 silencing, by targeted shRNAs, potently inhibited LPS-induced activation of NFκB, as well as expression and productions of key pro-inflammatory cytokines, inducing IL-1ß, IL-6 and TNF-α. Conversely, ectopic overexpression of LIN28B-AS1 in THP-1 macrophages potentiated NFκB activation and pro-inflammatory cytokines production by LPS. Significantly, LIN28B-AS1 shRNA was ineffective on LPS-induced pro-inflammatory responses in IGF2BP1-knockout THP-1 macrophages. In ex vivo cultured primary human peripheral blood mononuclear cells (PBMCs), LPS-induced IL-1ß expression and production were attenuated by LIN28B-AS1 shRNA, but augmented with forced LIN28B-AS1 overexpression. Collectively, we show that LIN28B-AS1, binding to IGF2BP1, is required for LPS-induced NFκB activation and pro-inflammatory responses in human macrophages.


Assuntos
Inflamação/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , RNA Antissenso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células Cultivadas , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Células THP-1
8.
Int J Mol Med ; 43(1): 276-284, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431066

RESUMO

The objectives of the present study comprised the recognition of major genes related to pulmonary thromboembolism (PTE) and the evaluation of their functional enrichment levels, in addition to the identification of small chemical molecules that may offer potential for use in PTE treatment. The RNA expression profiling of GSE84738 was obtained from the Gene Expression Omnibus database. Following data preprocessing, the differently expressed genes (DEGs) between the PTE group and the control group were identified using the Linear Models for Microarray package. Subsequently, the protein­protein interaction (PPI) network of these DEGs was examined using the Search Tool for the Retrieval of Interacting Genes/Proteins database, visualized via Cytoscape. The most significantly clustered modules in the network were identified using Multi Contrast Delayed Enhancement, a plugin of Cytoscape. Subsequently, functional enrichment analysis of the DEGs was performed, using the Database for Annotation Visualization and Integrated Discovery tool. Furthermore, the chemical­target interaction networks were investigated using the Comparative Toxicogenomics Database as visualized via Cytoscape. A total of 548 DEGs (262 upregulated and 286 downregulated) were identified in the PTE group, compared with the control group. The upregulated and downregulated genes were enriched in Gene Ontology terms related to inflammation and eye sarcolemma, respectively. Tumor necrosis factor (TNF) and erb­b2 receptor tyrosine kinase 2 (ERBB2) were upregulated genes that ranked higher in the PPI network (47 and 40 degrees, respectively) whereas C­JUN was the most downregulated gene (46). Small chemical molecules ethinyl (135), cyclosporine (126), thrombomodulin precursor (113) and tretinoin (111) had >100 degrees in the DEG­chemical interaction network. In addition, ethinyl targeted to TNF, whereas TNF and ERBB2 were targeted by cyclosporine, and tretinoin was a targeted chemical of ERBB2. Therefore, cyclosporine, ethinyl, and tretinoin may be potential targets for PTE treatment.


Assuntos
Biologia Computacional , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/genética , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Ontologia Genética , Genoma , Mapas de Interação de Proteínas/genética , Coelhos , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação para Cima/genética
9.
Colloids Surf B Biointerfaces ; 172: 414-422, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30195159

RESUMO

The prodrug strategy serves well in drug formulation and delivery. Two disulfide-based PEGylated prodrugs were developed and the drug reconversion upon different conditions were studied in detail. The reconversion-induced oversaturation phenomenon was firstly reported here. We found the prodrug can co-assemble with parent drug via π-π stacking into well-defined nanoparticles. The PEG layer of the self-assembled nanoparticles improved the stability of the PEGylated prodrug by reducing the contact with biological enzymes. The nanoparticles also show favorable antitumor efficacy, both in vitro and in vivo.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Polietilenoglicóis/química , Pró-Fármacos/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/síntese química , Feminino , Humanos , Cinética , Camundongos Nus , Polietilenoglicóis/síntese química , Suínos
10.
Biochem Biophys Res Commun ; 503(3): 1874-1879, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30064910

RESUMO

Antibody-dependent cell-mediated cytotoxicity bridges humoral immunity and cellular immunity. Thus vaccine candidates which can elicit both broadly neutralizing antibodies and potent antibody-dependent cell-mediated cytotoxicity (ADCC) are recommended. Previously, a panel of functional epitopes that can elicit ADCC effects is isolated and characterized on the H1N1 Influenza Virus. Based on these identified epitopes, an epitope vaccine against H1N1 infection has been designed. The serum of vaccine immunized mice show potent ADCC activities in comparison with vector control group and HA ecto domain vaccinated group. However, the release of IL-6 and TNFα is higher in lung of epitope vaccine immunized mice. The viral load is also higher in epitope vaccine immunized mice. In addition, the epitope vaccine immunized mice showed lower survive rate than both empty vector immunized mice and HA ectodomain immunized mice. Passive transfer of serum from epitope vaccine immunized mice to healthy adult mice can decrease the survival rate of recipients after viral challenge. Our data suggested that ADCC epitope based vaccine has a mortality promoting effect rather than protective effect after H1N1 viral challenge. This result provides indications in future vaccine design with a consideration of balancing humoral immune response and cellular immune response.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Epitopos/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/imunologia , Vacinação/efeitos adversos , Animais , Linhagem Celular , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Taxa de Sobrevida
11.
PLoS One ; 12(3): e0173252, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28334043

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related human mortalities. Over-activation of mammalian target of rapamycin (mTOR) is important for HCC tumorigenesis and progression. The current study assessed the potential anti-HCC activity by a novel mTOR kinase inhibitor, CC-223. We demonstrate that CC-223, at nM concentrations, induced profound cytotoxic and anti-proliferative activities against established HCC cell lines (HepG2, KYN-2 and Huh-7) and primary human HCC cells. Meanwhile, CC-223 activated caspase-3/-9 and apoptosis in the above HCC cells. CC-223 concurrently blocked mTORC1 and mTORC2 activation, and its cytotoxicity against HCC cells was much more potent than the traditional mTORC1 inhibitors (RAD001 and rapamycin). Further studies demonstrated that CC-223 disrupted mitochondrial function, and induced mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. On the other hand, ROS scavengers and mPTP blockers (cyclosporin A or sanglifehrin A) largely attenuated CC-223-induced HepG2 cell apoptosis. In vivo studies showed that oral administration of CC-223 dramatically inhibited growth of HepG2 xenografts in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation was also blocked in xenografts with CC-223 administration. Together, CC-223 simultaneously blocks mTORC1/2 and efficiently inhibits human HCC cells.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Complexos Multiproteicos/metabolismo , Pirazinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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