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1.
Xenobiotica ; 51(10): 1101-1109, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34382487

RESUMO

miR-199a-5p is an important regulator of many biological processes. However, whether and how CYP enzymes are regulated by miR-199a-5p are unknown. Here, we aimed to investigate the potential role of mmu-miR-199a-5p in regulating CYP2 enzymes.Regulatory effects of mmu-miR-199a-5p on CYP expression were assessed in mouse AML-12 hepatocytes. The metabolic activity of CYP2B10 was probed using cyclophosphamide (CPA) as a specific substrate. The regulatory mechanism was investigated using combined luciferase reporter assays and chromatin immunoprecipitation.Of several important drug-metabolizing CYPs, mmu-miR-199a-5p significantly increased the mRNA levels of Cyp2a10, Cyp2c29, and Cyp2j5 in AML-12 cells with Cyp2a10 altered the most. Consistently, mmu-miR-199a-5p enhanced the expression of CYP2B10 protein and cellular metabolism of CPA. Based on database analysis, Cyp2b10 was not a direct target gene of mmu-miR-199a-5p. Thus, a mediator is necessary for the miRNA regulation of CYP2B10. We found that E4BP4 repressed Cyp2b10 transcription and expression through specific binding to a D-box element in the gene promoter. Moreover, mmu-miR-199a-5p inhibited the expression of E4bp4 at the posttranscriptional level by directly targeting the 59-65 nt segment in its 3'-UTR.In conclusion, mmu-miR-199a-5p positively regulates CYP2B10 expression through inhibiting its repressor E4BP4. Our findings may provide an increased understanding of the complex regulatory pathways for CYP2B10.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Regiões 3' não Traduzidas , Animais , Hepatócitos , Camundongos , MicroRNAs/genética , RNA Mensageiro
2.
Biomaterials ; 274: 120855, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33975276

RESUMO

Drug-loaded hydrogels can improve blood supply and inhibit extracellular matrix degradation after myocardial infarction. However, due to the continual dynamic motion of cardiac tissue, the hydrogel structure cannot be reconstructed in time, causing accelerated degradation and drug burst release. Here, a novel, superior, self-healing elastin-mimic peptide hydrogel (EMH) was fabricated for the local delivery of salvianolic acid B (SaB). The self-healing ability of EMH is enhanced by SaB-loaded polydopamine nanoparticles (SaB-PDA). In vitro, the pre-hydrogel (SaB-PDA/pre-EMH) is endowed with excellent biocompatibility and a low viscosity, making it suitable for intramyocardial injection. Once injected into the myocardial infarction (MI) region, SaB-PDA/pre-EMH can form SaB-PDA/EMH with great mechanical strength under the action of upregulated transglutaminase (TGase) in heart tissue post-MI. The superior self-healing ability of SaB-PDA/EMH allows for an increase in retention time in the beating ventricular wall. Therefore, with long-term release of SaB, SaB-PDA/EMH can inhibit ventricular remodeling and promote angiogenesis for MI treatment.


Assuntos
Hidrogéis , Infarto do Miocárdio , Benzofuranos , Humanos , Infarto do Miocárdio/tratamento farmacológico , Peptídeos , Remodelação Ventricular
3.
Theranostics ; 11(1): 426-444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391484

RESUMO

Background: Understanding the molecular events and mechanisms underlying development and progression of nonalcoholic steatohepatitis is essential in an attempt to formulating a specific treatment. Here, we uncover Platr4 as an oscillating and NF-κB driven lncRNA that is critical to the pathological conditions in experimental steatohepatitis Methods: RNA-sequencing of liver samples was used to identify differentially expressed lncRNAs. RNA levels were analyzed by qPCR and FISH assays. Proteins were detected by immunoblotting and ELISA. Luciferase reporter, ChIP-sequencing and ChIP assays were used to investigate transcriptional gene regulation. Protein interactions were evaluated by Co-IP experiments. The protein-RNA interactions were studied using FISH, RNA pull-down and RNA immunoprecipitation analyses Results: Cyclic expression of Platr4 is generated by the core clock component Rev-erbα via two RevRE elements (i.e., -1354/-1345 and -462/-453 bp). NF-κB transcriptionally drives Platr4 through direct binding to two κB sites (i.e., -1066/-1056 and -526/-516 bp), potentially accounting for up-regulation of Platr4 in experimental steatohepatitis. Intriguingly, Platr4 serves as a circadian repressor of Nlrp3 inflammasome pathway by inhibiting NF-κB-dependent transcription of the inflammasome components Nlrp3 and Asc. Loss of Platr4 down-regulates Nlrp3 inflammasome activity in the liver, blunts its diurnal rhythm, and sensitizes mice to experimental steatohepatitis, whereas overexpression of Platr4 ameliorates the pathological conditions in an Nlrp3-dependent manner. Mechanistically, Platr4 prevents binding of the NF-κB/Rxrα complex to the κB sites via a physical interaction, thereby inhibiting the transactivation of Nlrp3 and Asc by NF-κB. Conclusions: Platr4 functions to inactivate Nlrp3 inflammasome via intercepting NF-κB signaling. This lncRNA might be an attractive target that can be modulated to ameliorate the pathological conditions of steatohepatitis.


Assuntos
Inflamassomos/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Hepatopatia Gordurosa não Alcoólica/genética , RNA Longo não Codificante/metabolismo , Animais , Ritmo Circadiano , Regulação da Expressão Gênica , Imunoprecipitação , Hibridização in Situ Fluorescente , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Receptor X Retinoide alfa/metabolismo
4.
Theranostics ; 10(18): 8162-8178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724464

RESUMO

Rationale: Both spatial accuracy and temporal persistence are crucial in drug delivery, especially for anti-tumor intravenous nanomedicines, which have limited persistence due to their small particle sizes and easy removal from tumors. The present study takes advantage of morphological transformation strategy to regulate intravenous nanomedicines to display different sizes in different areas, achieving high efficient enrichment and long retention in lesions. Methods: We designed and synthesized functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) consisting of self-assembled doxorubicin-peptide conjugates (DPCs) and an acidic-responsive shielding layer named the functional polylysine graft (FPG), which can regulate the assembly morphology of the DPCs from spherical DPC nanoparticles (DPC-NPs) to DPC-nanofibers (DPC-NFs) by preventing the assembly force from π-π stacking and hydrogen bond between the DPC-NPs. The morphology transformation and particle changes of FDPC-NPs in different environments were determined with DLS, TEM and SEM. We used FRET to explore the enhanced retention effect of FDPC-NPs in tumor site in vivo. HPLC-MS/MS analytical method was established to analyze the biodistribution of FDPC-NPs in H22 hepatoma xenograft mouse model. Finally, the antitumor effect and safety of FDPC-NPs was evaluated. Results: The FDPC-NPs were stable in blood circulation and responsively self-assembled into DPC-NFs when the FDPC-NPs underwent the acid-sensitive separation of the shielding layer in a mildly acidic microenvironment. The FDPC-NPs maintained a uniform spherical size of 80 nm and exhibited good morphological stability in neutral aqueous solution (pH 7.4) but aggregated into a long necklace-like chain structure or a crosslinked fiber structure over time in a weakly acidic solution (pH 6.5). These acidity-triggered transformable FDPC-NPs prolonged the accumulation in tumor tissue for more than 5 days after a single injection and improved the relative uptake rate of doxorubicin in tumors 31-fold. As a result, FDPC-NPs exhibited a preferable anti-tumor efficacy and a reduced side effect in vivo compared with free DOX solution and DOX liposomes. Conclusions: Morphology-transformable FDPC-NPs represent a promising therapeutic approach for prolonging the residence time of drugs at the target site to reduce side effect and enhance therapeutic efficacy. Our studies provide a new and simple idea for the design of long-term delivery systems for intravenous chemotherapeutic drugs.


Assuntos
Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Peptídeos/farmacocinética , Animais , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Neoplasias/patologia , Tamanho da Partícula , Peptídeos/administração & dosagem , Peptídeos/química , Polilisina/química , Espectrometria de Massas em Tandem , Distribuição Tecidual
5.
Soft Matter ; 16(9): 2311-2320, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32051977

RESUMO

Inorganic-organic co-assembly of anionic polyoxometalates (POMs) with zwitterions provides a facile way to fabricate functional soft materials. In this paper, a translucent, photoluminescent polymer hydrogel was fabricated from Weakley-type POM Na9EuW10O36 (EuW10) and polymerizable imidazole-type zwitterion 3-(1-vinyl-3-imidazolio)propanesulfonate (VIPS) via a one-step synthesis method. Detailed characterization indicated that the polymerization of double bonds in VIPS and electrostatic interactions between EuW10 and VIPS play important roles in the formation of the hydrogels. Additionally, the introduction of non-polymerizable zwitterions 3-(1-methyl-3-imidazolio)propanesulfonate (MIPS) or 3-(1-decyl-3-imidazolio)propanesulfonate (C10IPS) can improve the mechanical and luminous performances of the hydrogels. Especially, C10IPS with a long alkyl chain would more significantly alter the coordination environment of EuW10, and consequently resulted in a more efficient energy transfer process. Further investigations revealed that the chemical environment around the Eu3+ can be highly influenced by organic solvents with stronger coordination abilities than water molecules, such as acetone. The translucency and luminescence intensity of the hydrogels can be reversibly transformed after alternately immersing in acetone or H2O for several minutes. Our results provided a useful strategy for the fabrication of luminescent hydrogels by regulating the noncovalent interactions between POMs and zwitterions.

6.
Chem Commun (Camb) ; 55(66): 9861-9864, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31364622

RESUMO

Single-tailed and gemini-type supra-gelators were facilely fabricated via the conjugation of the d- or l-enantiomeric dihydrazide TDH with single-tailed achiral aldehyde C12BAD through dynamic acylhydrazone bonding. Chirality transfer from small molecules to supramolecules was successfully achieved via the spontaneous assembly of the formed supra-gelators into supramolecular chiral hydrogels.

7.
Soft Matter ; 14(32): 6678-6683, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30067266

RESUMO

We report a new strategy for fabricating a smart low molecular weight hydrogel based on dynamic covalent chemistry from a bola-type supra-gelator, which was facilely fabricated in situ from two non-assembling building blocks, (3-(2-(4-formylphenoxy) ethyl)-1-methyl imidazolium bromide, MA) and (3,3'-dithiobis (propionohydrazide), DSPDZ), through dynamic acylhydrazone bonding. The obtained low molecular weight hydrogels exhibited redox-responsive and controllable self-healing properties. The role of dynamic covalent bonding in the formation of smart hydrogels is revealed in this study, which provides a simple and bottom-up method for constructing smart low molecular weight hydrogels.

8.
J Cardiovasc Pharmacol ; 58(4): 432-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21709582

RESUMO

INTRODUCTION: Some studies have shown that the defibrillation threshold (DFT) differs between short-duration ventricular fibrillation (SDVF, <1 minute) and long-duration ventricular fibrillation (LDVF > 1 minute). The goal of this study is to evaluate the effects of acute intravenous amiodarone on SDVF-DFT and LDVF-DFT and its possible mechanism as well. METHODS: Twelve open-chest dogs were randomly divided into 2 groups (control group, normal saline, 10 mL·kg·h maintenance, n = 6; amiodarone group, loading dose 10 mg/kg over 10 minutes, maintenance dose 5 mg·kg·h, n = 6). VF was electrically induced and recorded with a 12 × 12 unipolar electrode plaque (2-mm spacing) sutured on the left ventricular epicardium and a plunge needle (6 unipolar electrode) inserted in the left ventricular apex. The DFTs of SDVF and LDVF were determined 20 seconds and 3 minutes after VF induction, respectively. Restitution was estimated from activation recovery intervals during pacing from the plaque and plunge needle electrodes. The activation rate was estimated by Fast Fourier Transform analysis of VF at same electrodes. The VF cycle length was defined as the reciprocal of the activation rate. The epicardial and transmural dispersion of the maximal slope of the restitution curve and VF cycle length of SDVF and LDVF were calculated, respectively. RESULTS: : In controls, LDVF-DFT was higher than SDVF-DFT (645 ± 61 vs. 520 ± 63 V, P < 0.01). Amiodarone did not significantly alter SDVF-DFTs (496 ± 49 vs. 552 ± 69 V, P > 0.05) but decreased LDVF-DFT by 31% (P < 0.01). Compared with control, amiodarone significantly reduced the maximum slope of the restitution curve (1.12 ± 0.35 vs. 0.81 ± 0.25, P = 0.03) and its epicardial dispersion (0.32 ± 0.07 vs. 0.24 ± 0.04,coefficient of variation, P = 0.017). Amiodarone significantly increased the SDVF-CL (92 ± 8 vs. 99 ± 10 milliseconds, P < 0.01) and epicardial dispersion 0.14 ± 0.06 vs. 0.18 ± 0.05, P < 0.01. Amiodarone did not change the LDVF-CL (228 ± 12 vs. 226 ± 10 milliseconds, P > 0.05) or epicardial dispersion (0.17 ± 0.03 vs. 0.15 ± 0.02, P > 0.05) compared with control. However, the drug significantly decreased the transmural dispersion of LDVF-CL (68 ± 28 vs. 39 ± 14 milliseconds, P < 0.01) without changing the transmural dispersion of SDVF-CL (29 ± 22 vs. 32 ± 30 milliseconds, P > 0.05). CONCLUSIONS: Acute amiodarone significantly decreased the LDVF-DFT. The decreased transmural dispersion of LDVF-CL by amiodarone might contribute to the decreased LDVF-DFT.


Assuntos
Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Fibrilação Ventricular/tratamento farmacológico , Amiodarona/administração & dosagem , Animais , Antiarrítmicos/administração & dosagem , Modelos Animais de Doenças , Cães , Cardioversão Elétrica , Análise de Fourier , Infusões Intravenosas , Distribuição Aleatória , Fatores de Tempo , Fibrilação Ventricular/fisiopatologia
9.
J Interv Card Electrophysiol ; 32(2): 81-6, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21671072

RESUMO

PURPOSE: This study evaluated the effects of shock energy on the dispersion of regional ventricular repolarization (DRVR), post-shock rhythm and sinus recovery time (SRT), and the relationship between DRVR and post-shock ventricular arrhythmias. MATERIALS AND METHODS: Ten open-chest dogs were anesthetized. Ventricular fibrillation (VF) was electrically induced and recorded from a 6 × 6 unipolar electrode plaque (4 mm spacing) sutured on the left ventricular epicardium. Defibrillation threshold (DFT) was determined after 20 s of VF. DRVR was measured before VF, during the earliest post-shock sinus rhythm, and during sinus rhythm 30 s following shocks. Post-shock rhythm and SRT were evaluated after energies of 100% DFT, 125% DFT, 175% DFT, and 250% DFT. RESULTS: In the100% DFT group, the DRVR of the earliest sinus rhythm and 30 s after successful defibrillation was not significantly different than that before VF. But the DRVRs were significantly increased in 125% DFT, 175% DFT, and 250% DFT group. DRVR after defibrillation in the 250% DFT group was higher than those in the 100% DFT and 125% DFT groups. SRT in the 250% DFT group was significantly longer than that in the other groups .The incidence of post-shock ventricular tachycardia was increased when a high-shock energy was applied (P = 0.041). CONCLUSION: DRVR was increased by application of high-energy defibrillation associated with SRT prolongation. The increased DRVR may play an important role in the onset of post-shock ventricular tachycardia.


Assuntos
Desfibriladores Implantáveis/efeitos adversos , Cardioversão Elétrica/efeitos adversos , Frequência Cardíaca/fisiologia , Taquicardia Ventricular/terapia , Fibrilação Ventricular/terapia , Animais , Limiar Diferencial , Modelos Animais de Doenças , Cães , Cardioversão Elétrica/métodos , Eletrocardiografia , Masculino , Distribuição Aleatória , Recuperação de Função Fisiológica , Valores de Referência , Medição de Risco , Taquicardia Ventricular/diagnóstico , Fatores de Tempo , Fibrilação Ventricular/diagnóstico
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