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BACKGROUND AND AIMS: To improve Helicobacter pylori (H. pylori) eradication rate, enhanced patient instructions (EPI) such as telephone-based re-education, short-message service, and Wechat have been proposed with conflicting results. The aim of this meta-analysis was to evaluate the effect of EPI on H. pylori eradication. METHODS: The PROSPERO registered number of this study is CRD42021278536. PubMed, Embase, and CENTRAL database were searched to identify relevant randomized controlled trials (RCTs) from inception to September 2021. Meta-analysis was performed to estimate the pooled relative risk (RR) with 95% confidence intervals (CI) using a random-effects model. Trial sequential analysis (TSA) was conducted to determine the robustness of the H. pylori eradication rate. RESULTS: Nine RCTs were included. Compared with patients receiving only regular instructions, patients received EPI showed significantly higher H. pylori eradication rate (n = 8 RCTs, ITT analysis: RR = 1.20, 95% CI: 1.06-1.35; PP analysis: RR = 1.12, 95% CI:1.02-1.23) and better patient compliance (n = 8 RCTs, RR = 1.23, 95% CI: 1.09-1.39), as well as higher patient satisfaction (n = 3 RCTs, RR = 1.42, 95% CI: 1.14-1.76). However, there were no significant difference between groups in the incidence of total adverse events (n = 6 RCTs, RR = 0.66, 95%CI: 0.40-1.08) and symptom relief rates (n = 2 RCTs, RR = 1.17, 95% CI: 0.89-1.54). The TSA result indicated that the effect was robust. CONCLUSIONS: Evidence from our meta-analysis shows that EPI intervention may be a promising strategy to improve H. pylori eradication rate, patient compliance, and patient satisfaction.
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Infecções por Helicobacter , Helicobacter pylori , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-ß (TGF-ß) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. METHODS: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. RESULTS: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-ß2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-ß signaling pathway by down-regulation of TGF-ß2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-ß signaling increased ECM degradation. CONCLUSIONS: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.
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Células Estreladas do Fígado , MicroRNAs , Animais , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Fator de Crescimento Transformador beta2/metabolismoRESUMO
G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy.
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Aptâmeros de Nucleotídeos/farmacologia , DNA/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/síntese química , Aptâmeros de Nucleotídeos/química , Quadruplex G/efeitos dos fármacos , Humanos , Oligodesoxirribonucleotídeos/síntese química , Oligodesoxirribonucleotídeos/químicaRESUMO
BACKGROUND AND AIMS: Whether Saccharomyces boulardii (S boulardii) as an adjuvant therapy are beneficial to H pylori eradication remains controversial. The aim of the study was to update and determine the effects of S boulardii as an adjuvant therapy on H pylori eradication rates and adverse effects. METHODS: We searched PubMed, Embase, CENTRAL, and Web of Science to collect all randomized controlled trials assessing the effects of S boulardii as an adjuvant therapy for H pylori eradication from inception to February 2019. Quality of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluation system. Trial sequential analysis was performed to control the risk of type I and type II errors. RESULTS: Eighteen trials with 3592 patients were eligible for meta-analysis. Compared with standard eradication regimen, the S boulardii supplementation could significantly improve eradication rates [risk ratio (RR) = 1.09, 95% confidence interval (CI):1.05-1.13; moderate quality evidence] and reduce the incidence of total side effects (RR = 0.47, 95%CI:0.36-0.61; low quality evidence), as well as some gastrointestinal adverse effects, especially diarrhea (RR = 0.33, 95%CI:0.23-0.47; low quality evidence) and constipation (RR = 0.37, 95%CI:0.23-0.57; moderate quality evidence). In addition, the need for discontinuation rate in S boulardii supplementation group was significantly lower than in the control group (RR = 0.33, 95%CI:0.16-0.69, P = .003; moderate quality evidence). The TSA results for overall eradication rates and total side effects indicated that the effects were conclusive. CONCLUSIONS: Our meta-analysis shows that S boulardii supplementation on standard eradication therapy significantly increased H pylori eradication rates and reduced the incidence of total side effects and some gastrointestinal adverse effects during eradication therapy.
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Antibacterianos/uso terapêutico , Infecções por Helicobacter/terapia , Probióticos/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Saccharomyces boulardii/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Terapia Combinada , Quimioterapia Combinada/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: As 'chemical antibodies', aptamers have some advantages, such as lack of immunogenicity, rapid tissue penetration, cell internalization and so on. Consequently, more and more aptamers have been screened out by the systematic evolution of ligands through exponential enrichment for the desired cells or membrane receptors. On the basis of the result, researchers use aptamers to guide drug targeting to the desired cells and internalization in vivo. AREAS COVERED: In this review, we explore the mechanisms of cargo- or aptamer-mediated internalization, and then briefly summarize five strategies for exploring the mechanism of aptamer internalization. Finally, we focus on four types of applications involving aptamer internalization: aptamers as drugs, aptamers as chemical drug-delivery systems, aptamer-based chimeras and aptamer-conjugated nanoparticles or block copolymer micelles. EXPERT OPINION: Two aptamer-internalization mechanisms are known, namely receptor-mediated endocytosis and macropinocytosis. The latter mechanism, which is has only been verified in the internalization of nucleolin aptamer shuttles between the nucleus and cytoplasm, may be important for nuclear internalization and cargo molecule escape from the endosomal compartment. Thus, it is feasible to use some strategies to further explore the macropinocytosis internalization mechanism and then to screen for aptamers similar to the nucleolin aptamer for use with the desired cell types as a targeted delivery tool.
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Aptâmeros de Nucleotídeos/química , Sistemas de Liberação de Medicamentos , Nanopartículas , Endocitose , Humanos , Ligantes , Micelas , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , NucleolinaRESUMO
Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate gene or protein expression; however, their function in the progression of hepatic fibrosis remains unclear. Hepatic fibrosis is a continuous wound-healing process caused by numerous chronic hepatic diseases, and the activation of hepatic stellate cells (HSCs) is generally considered to be a pivotal step in hepatic fibrosis. In the process of hepatic fibrosis, some lncRNAs regulates diverse cellular processes. Here are several examples: the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and liver fibrosis-associated lncRNA1 (lnc-LFAR1) promote HSC activation in the progression of hepatic fibrosis via the transforming growth factor-ß signaling pathway; the lncRNA HIF 1 alpha-antisense RNA 1 (HIF1A-AS1) and Maternally expressed gene 3 reduce HSC activation which are associated with DNA methylation; the lncRNA plasmacytoma variant translocation 1, Homeobox (HOX) transcript antisense RNA and MALAT1 promote HSC activation as competing endogenous RNAs (ceRNAs); the long intergenic non-coding RNA-p21 (lncRNA-p21) and Growth arrest-specific transcript 5 reduce HSC activation as ceRNAs. As we get to know more about the function of lncRNAs in hepatic fibrosis, more and more ideas for the molecular targeted therapy in hepatic fibrosis will be put forward.
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Increasing evidence indicates that embryonic stem cell specific microRNAs (miRNAs) play an essential role in the early development of embryo. Among them, the miR-290-295 cluster is the most highly expressed in the mouse embryonic stem cells and involved in various biological processes. In this paper, we reviewed the research progress of the function of the miR-290-295 cluster in embryonic stem cells. The miR-290-295 cluster is involved in regulating embryonic stem cell pluripotency maintenance, self-renewal, and reprogramming somatic cells to an embryonic stem cell-like state. Moreover, the miR-290-295 cluster has a latent pro-survival function in embryonic stem cells and involved in tumourigenesis and senescence with a great significance. Elucidating the interaction between the miR-290-295 cluster and other modes of gene regulation will provide us new ideas on the biology of pluripotent stem cells. In the near future, the broad prospects of the miRNA cluster will be shown in the stem cell field, such as altering cell identities with high efficiency through the transient introduction of tissue-specific miRNA cluster.
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When hepatocytes are damaged severely, a variety of signaling pathways will be triggered by inflammatory factors and cytokines involving in the process of hepatic fibrosis. The microRNA (miRNA) family consists of several miRNAs which have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of miRNA family as a whole in hepatic fibrosis. Increasing studies have suggested several miRNA families are related with activation of hepatic stellate cells and hepatic fibrosis through cooperatively regulating certain signaling pathways. During the process of hepatic fibrosis, miR-29 family primarily induces cell apoptosis by modulating phosphatidylinositol 3-kinase/AKT signaling pathway and regulates extracellular matrix accumulation. miR-34 family promotes the progression of hepatic fibrosis by inducing activation of hepatic stellate cells, while miR-378 family suppresses the process in Glis dependent manner. miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and miR-200 family are responsible for extracellular matrix deposition and the release of pro-fibrotic cytokines. These miRNA family members play pro-fibrotic or anti-fibrotic roles by targeting genes collectively or respectively which involve in hepatic fibrosis related signaling pathways and hepatic stellate cell activation. Thus, good understandings of molecular mechanisms which are based on miRNA families may provide new ideas for the molecular targeted therapy of hepatic fibrosis in the future.
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In this work, a novel type of block copolymer micelles with K+ -responsive characteristics for targeted intracellular drug delivery is developed. The proposed smart micelles are prepared by self-assembly of poly(ethylene glycol)-b-poly(N-isopropylacry-lamide-co-benzo-18-crown-6-acrylamide) (PEG-b-P(NIPAM-co-B18C6Am)) block copolymers. Prednisolone acetate (PA) is successfully loaded into the micelles as the model drug, with loading content of 4.7 wt%. The PA-loaded micelles display a significantly boosted drug release in simulated intracellular fluid with a high K+ concentration of 150 × 10-3 m, as compared with that in simulated extracellular fluid. Moreover, the in vitro cell experiments indicate that the fluorescent molecules encapsulated in the micelles can be delivered and specifically released inside the HSC-T6 and HepG2 cells responding to the increase of K+ concentration in intracellular compartments, which confirms the successful endocytosis and efficient K+ -induced intracellular release. Such K+ -responsive block copolymer micelles are highly potential as new-generation of smart nanocarriers for targeted intracellular delivery of drugs.
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Acrilamidas/química , Portadores de Fármacos/química , Micelas , Polietilenoglicóis/química , Polímeros/química , Prednisolona/análogos & derivados , Animais , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Prednisolona/administração & dosagem , Prednisolona/farmacocinética , RatosRESUMO
Gremlin1, the antagonist of bone morphogenetic protein-7 and one of the target genes of transforming growth factor (TGF)-ß signal pathway, plays an important role in embryonic development and its expression decreases along with aging. To explore the expression of gremlin1 in liver fibrosis and the causal link between gremlin1 and hepatic stellate cell (HSC) activation, we detected the expression of gremlin1 in mice with hepatic fibrosis induced by porcine serum using real time quantitative PCR (RT-qPCR) and immunohistochemical staining. The hepatic fibrosis mice were evaluated by the external feature of the liver, histology, hepatic function, collagen deposition, and the expression of fibrosis-related genes (genes COLIα2 and COLIVα2) in the liver. In the HSC-T6, western blotting was used to analyze the expression of α-smooth muscle actin (α-SMA), COL1α, and TGF-ß1 in conditions of overexpression of gremlin1 or gremlin1 being knocked down by specific siRNA, respectively. The results showed that the mRNA expression of the gremlin1 gene was significantly increased consistent with increased expression of COLIα2 and COLIVα2 in the liver tissue of the hepatic fibrosis mice. Increased expression of gremlin1 coincided with the same area of the collagen deposition. Furthermore, the results also showed that the expression of α-SMA, COLIα1, and TGF-ß1 was consistent with the expression of gremlin1 not only in the HSC-T6 overexpressing gremlin1 but also in the HSC-T6 that gremlin1 is knocked down by specific siRNA. The findings suggest that gremlin1 might play an important role in the progression of hepatic fibrosis and that it modulates HSC activation.
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Actinas/genética , Colágeno Tipo I/genética , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Cirrose Hepática/genética , Fator de Crescimento Transformador beta1/genética , Actinas/agonistas , Actinas/metabolismo , Animais , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Colágeno Tipo I/agonistas , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Feminino , Células Estreladas do Fígado/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Soro/química , Transdução de Sinais , Suínos/sangue , Fator de Crescimento Transformador beta1/agonistas , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The imbalance between transforming growth factor ß and bone morphogenetic protein 7 signaling pathways is a critical step in promoting hepatic stellate cell activation during hepatic fibrogenesis. Gremlin1 may impair the balance. Something remains unclear about the regulatory mechanisms of gremlin1 action on hepatic stellate cell activation and hepatic fibrosis. In the current study, gremlin1 overexpression promotes activation of hepatic stellate cells. Knockdown of gremlin1 with siRNAs suppresses hepatic stellate cell activation and attenuates hepatic fibrosis in rat model. Our results also show that miR-23b/27b cluster members bind to 3'-untranslated region of gremlin1 resulting in reduction of transforming growth factor ß, α-smooth muscle actin and collagenI α1/2 gene expression. Our findings suggest that gremlin1 promotes hepatic stellate cell activation and hepatic fibrogenesis through impairment of the balance between transforming growth factor ß and bone morphogenetic protein 7 signaling pathways. The miR-23b/27b cluster suppresses activation of hepatic stellate cells through binding gremlin1 to rectify the imbalance.
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Células Estreladas do Fígado/fisiologia , MicroRNAs/fisiologia , Proteínas/genética , Animais , Proteína Morfogenética Óssea 7/fisiologia , Citocinas , Regulação para Baixo , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologiaRESUMO
Hepatic fibrosis is a reversible process involving plenty of transcription factors and pathways. Vitamin D receptor (VDR) as a member of ligand-induced transcription factors can interact with 9-cis retinoid X receptor (RXR) and VDR-interacting repressor (VDIR) to mediate transactivation or transrepression in the absence or in the presence of VDR ligand to regulate the expression of VDR target genes. The active form of vitamin D [1α,25(OH)2D3] can downregulate the expression of type I collagen both α1 and α2 (COLIα1 and COLIα2) in hepatic stellate cells (HSC-T6) in a time-dependent fashion, which provides a new direction for hepatic fibrosis therapy. As one of VDR target genes, rat COLIα1 gene contains 1αnVDRE (E-box1 and E-box2) in its promoter, and unliganded VDR/RXR may bind to 1αnVDRE through VDIR to mediate transactivation, whereas liganded VDR/RXR may bind to 1αnVDRE through VDIR for transrepression. The results suggested a sort of relying on each other relationship between VDR/RXR and VDIR in regulating the expression of COLIα1 gene in HSC-T6 cells, which established VDR as a potential target for blocking and even reversing hepatic fibrosis.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Colágeno Tipo I/genética , Células Estreladas do Fígado/metabolismo , Receptores de Calcitriol/genética , Receptores X de Retinoides/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Linhagem Celular , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Regulação da Expressão Gênica , Células Estreladas do Fígado/citologia , Ligantes , Regiões Promotoras Genéticas , Ligação Proteica , Ratos , Receptores de Calcitriol/metabolismo , Receptores X de Retinoides/metabolismo , Transdução de Sinais , Vitamina D/metabolismoRESUMO
Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily. Whereas the structure of the ligand binding domain (LBD) of VDR has been determined in great detail, the role of its amino acid residues in stabilizing the structure and ligand triggering conformational change is still under debate. There are 13 α-helices and one ß-sheet in the VDR LBD and they form a three-layer sandwich structure stabilized by 10 residues. Thirty-six amino acid residues line the ligand binding pocket (LBP) and six of these residues have hydrogen-bonds linking with the ligand. In 1α,25-dihydroxyvitamin D3 signaling, H3 and H12 play an important role in the course of conformational change resulting in the provision of interfaces for dimerization, coactivator (CoA), corepressor (CoR), and hTAFII 28. In this paper we provide a detailed description of the amino acid residues stabilizing the structure and taking part in conformational change of VDR LBD according to functional domains.
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Modelos Moleculares , Conformação Molecular , Domínios e Motivos de Interação entre Proteínas , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Vitamina D/análogos & derivados , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Dados de Sequência Molecular , Ligação Proteica , Alinhamento de Sequência , Relação Estrutura-Atividade , Vitamina D/química , Vitamina D/metabolismoRESUMO
While the structure of the DNA-binding domain (DBD) of the vitamin D receptor (VDR) has been determined in great detail, the roles of its domains and how to bind the motif of its target genes are still under debate. The VDR DBD consists of two zinc finger modules and a C-terminal extension (CTE), at the end of the C-terminal of each structure presenting α-helix. For the first zinc finger structure, N37 and S-box take part in forming a dimer with 9-cis retinoid X receptor (RXR), while V26, R50, P-box and S-box participate in binding with VDR response elements (VDRE). For the second zinc finger structure, P61, F62 and H75 are essential in the structure of the VDR homodimer with the residues N37, E92 and F93 of the downstream of partner VDR, which form the inter-DBD interface. T-box of the CTE, especially the F93 and I94, plays a critical role in heterodimerization and heterodimers-VDRE binding. Six essential residues (R102, K103, M106, I107, K109, and R110) of the CTE α-helix of VDR construct one interaction face, which packs against the DBD core of the adjacent symmetry mate. In 1,25(OH)2D3-activated signaling, the VDR-RXR heterodimer may bind to DR3-type VDRE and ER9-type VDREs of its target gene directly resulting in transactivation and also bind to DR3-liked nVDRE of its target gene directly resulting in transrepression. Except for this, 1α,25(OH)2D3 ligand VDR-RXR may bind to 1αnVDRE indirectly through VDIR, resulting in transrepression of the target gene. Upon binding of 1α,25(OH)2D3, VDR can transactivate and transrepress its target genes depending on the DNA motif that DBD binds.
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Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Sequência de Aminoácidos , Animais , DNA/química , DNA/metabolismo , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Dedos de ZincoRESUMO
INTRODUCTION: In the therapy of clinical diseases such as cancer, it is important to deliver drugs directly to tumor sites in order to maximize local drug concentration and reduce side effects. This objective may be realized by using 'smart' nanoparticles (NPs) as drug delivery systems, because they enable dramatic conformational changes in response to specific physical/chemical stimuli from the diseased cells for targeted and controlled drug release. AREAS COVERED: In this review, we first briefly summarize the characteristics of 'smart' NPs as drug delivery systems in medical therapy, and then discuss their targeting transport, transmembrane and endosomal escape behaviors. Lastly, we focus on the applications of 'smart' NPs as drug delivery systems for tumor therapy. EXPERT OPINION: Biodegradable 'smart' NPs have the potential to achieve maximum efficacy and drug availability at the desired sites, and reduce the harmful side effects for healthy tissues in tumor therapy. It is necessary to select appropriate NPs and modify their characteristics according to treatment strategies of tumor therapy.
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Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Preparações de Ação Retardada/administração & dosagem , HumanosRESUMO
AIM: To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells (HSCs) and whether Hes1 is regulated by transforming growth factor (TGF)/bone morphogenetic protein (BMP) signaling. METHODS: Immunofluorescence staining was used to detect the expression of desmin, glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin (α-SMA) after freshly isolated, normal rat HSCs had been activated in culture for different numbers of days (0, 1, 3, 7 and 10 d). The expression of α-SMA, collagen1α2 (COL1α2), Notch receptors (Notch1-4), and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction. Luciferase reporter assays and Western blot were used to study the regulation of α-SMA, COL1α1, COL1α2 and Hes1 by NICD1, Hes1, CA-ALK3, and CA-ALK5 in HSC-T6 cells. Moreover, the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated. RESULTS: The expression of Notch1 and Hes1 mRNAs was significantly down-regulated during the culture of freshly isolated HSCs. In HSC-T6 cells, Notch1 inhibited the promoter activities of α-SMA, COL1α1 and COL1α2. On the other hand, Hes1 enhanced the promoter activities of α-SMA and COL1α2, and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy. Furthermore, co-transfection of pcDNA3-CA-ALK3 (BMP signaling activin receptor-like kinase 3) and pcDNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells, while pcDNA3-CA-ALK5 (TGF-ß signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression. CONCLUSION: Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2, and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.