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1.
Artigo em Inglês | MEDLINE | ID: mdl-32003925

RESUMO

Considerable efforts have been made to increase the topological complexity of mechanically interlocked molecules over the years. Three-dimensional catenated structures composed of two or several cages are one representative example, most of them being made up of symmetric cages. However, due to the lack of an efficient yet universal synthetic strategy, interlocked structures made up of dissymmetric cages are relatively rare. Considering the space volume of the inner cavity of interlocked structure is smaller than that of its outside, we developed a novel synthetic approach with voluminous reductant NaBH(OAc) 3 that discriminates this space difference, and therefore selectively reduce the outer surface of the catenated dimer composed of two symmetric cages, thus yielding the corresponding catenane of dissymmetric-cages. Insight into the catenation mechanism, i.e. the template effect that facilitates catenation of cages, was proved by computational and experimental techniques. We believe, our approach provides an efficient method for the synthesis of catenane of dissymmetric cages, which could potentially be utilized as synthons to engineer novel functional materials.

2.
J Pharm Sci ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32081720

RESUMO

Gold nanoparticles through nucleation of Au clusters have been extensively studied. However, due to low potency, prolonged tissue retention and irreversible accumulation, the safety considerations have limited their therapeutic and diagnostic applications. Novel gold nanostructures with retained physical properties and higher biodegradability could be prepared by alternative approaches. Previously, a lipid nanoparticle (LNP) platform carrying gadolinium (Gd3+) has been reported to eliminate through the biliary without accumulation in the liver or kidney within 24 hrs1. Inspired by this discovery, we investigated a new approach of forming gold nanoparticles using preformed LNPs grafting DTPA (diethylenetriamine-pentaacetic acid) as chelating agent. Tiny Au nanoparticles are formed by simply mixing Au3+ with preformed DTPA-LNP. The Au3+ associates stably to these LNPs after a systematic optimization. The Au-LNPs are scalable and showed excellent photothermal effects when subjected to near-infrared light irradiation. They exhibit enhanced light-induced tumor cell killing at higher efficiency, compared to that of classical gold nanoparticles (citrated reduced). Given an additional small dose (2 Gy) of gamma irradiation, Au-LNPs could produce synergistic photothermal and radiotherapeutic effects under reduced light dose. The simple and adaptive nanoparticle design may enhance the margin of safety of gold nanoparticles in the treatment of cancers and other diseases.

3.
Eur J Pharm Sci ; 144: 105213, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926941

RESUMO

Compared with the traditional treatment, photodynamic therapy (PDT) in the treatment of malignant tumors has the advantages of less damage to normal tissues, quick therapeutic effect, and ability to repeat treatments to the same site. However, most of the traditional photosensitizers (PSs) have severe skin photosensitization, poor tumor targeting, and low therapeutic effect in hypoxic tumor environment, which limit the application of PDT. Nanoparticle-based drug delivery systems can improve the targeting of PSs and release drugs with controllable photoactivity at predetermined locations, so as to achieve desired therapeutic effects with minimal side-effects. The present review summarizes the current nanoparticle platforms for PDT, and offers the description of different strategies including tumor-targeted delivery, controlled-release of PSs and the triggered photoactivity to achieve controllable PDT by nanoparticle-based drug delivery systems. The challenges and prospects for further development of intelligent PSs for PDT are also discussed.

4.
Redox Biol ; 28: 101356, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704583

RESUMO

Airway remodeling is one of the characteristics for chronic obstructive pulmonary disease (COPD). The mechanism underlying airway remodeling is associated with epithelial-mesenchymal transition (EMT) in the small airways of smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to reduce oxidative stress, and to modulate EMT. Here, we investigated the effects and mechanisms of hydrogen sulfide (H2S) on pulmonary EMT in vitro and in vivo. We found that H2S donor NaHS inhibited cigarette smoke (CS)-induced airway remodeling, EMT and collagen deposition in mouse lungs. In human bronchial epithelial 16HBE cells, NaHS treatment also reduced CS extract (CSE)-induced EMT, collagen deposition and oxidative stress. Mechanistically, NaHS upregulated SIRT1 expression, but inhibited activation of TGF-ß1/Smad3 signaling in vivo and in vitro. SIRT1 inhibition by a specific inhibitor EX527 significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress. SIRT1 inhibition also abolished the protection of NaHS against CSE-induced EMT. Moreover, SIRT1 activation attenuated CSE-induced EMT by modifying TGF-ß1-mediated Smad3 transactivation. In conclusion, H2S prevented CS-induced airway remodeling in mice by reversing oxidative stress and EMT, which was partially ameliorated by SIRT1 activation. These findings suggest that H2S may have therapeutic potential for the prevention and treatment of COPD.

5.
Aging (Albany NY) ; 11(24): 11844-11864, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31881011

RESUMO

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 (SIRT1) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H2S attenuates senescence and apoptosis of alveolar epithelial cells via a SIRT1-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H2S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with SIRT1 upregulation. SIRT1 activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While SIRT1 inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, SIRT1 inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H2S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a SIRT1-dependent manner. These findings provide novel mechanisms underlying the protection of H2S against cigarette smoke-induced COPD.

6.
Int Immunopharmacol ; : 105979, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771816

RESUMO

Chronic obstructive pulmonary fibrosis (COPD) is a chronic and fatal lung disease with few treatment options. Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S), was found to alleviate cigarette smoke (CS)-induced emphysema in mice, however, the underlying mechanisms have not yet been clarified. In this study, we investigated its effects on COPD in a CS-induced mouse model in vivo and in cigarette smoke extract (CSE)-stimulated alveolar epithelial A549 cells in vitro. The results showed that NaHS not only relieved emphysema, but also improved pulmonary function in CS-exposed mice. NaHS significantly increased the expressions of tight junction proteins (i.e., ZO-1, Occludin and claudin-1), and reduced apoptosis and secretion of pro-inflammatory cytokines (i.e., TNF-α, IL-6 and IL-1ß) in CS-exposed mouse lungs and CSE-incubated A549 cells, indicating H2S inhibits CS-induced inflammation, injury and apoptosis in alveolar epithelial cells. NaHS also upregulated prolyl hydroxylase (PHD)2, and suppressed hypoxia-inducible factor (HIF)-1α expression in vivo and in vitro, suggesting H2S inhibits CS-induced activation of PHD2/HIF-1α axis. Moreover, NaHS inhibited CS-induced phosphorylation of ERK, JNK and p38 MAPK in vivo and in vitro, and treatment with their inhibitors reversed CSE-induced ZO-1 expression and inflammation in A549 cells. These results suggest that NaHS may prevent emphysema via the suppression of PHD2/HIF-1α/MAPK signaling pathway, and subsequently inhibition of inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD.

7.
Beilstein J Nanotechnol ; 10: 1933-1942, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598460

RESUMO

Diosgenin (Di), a steroidal sapogenin derived from plants, has been shown to exert anticancer effects in preclinical studies. Using Di as a starting material, various Di derivatives were designed and synthesized, aiming to discover new steroid-based antitumor agents. In this work, we synthesized several Di derivatives and screened FZU-0021-194-P2 (P2), which showed more potent cytotoxic activities against human non-small-cell lung cancer A549 and PC9 cells. Considering that Di has a unique sterol structure similarly to cholesterol, P2 phytosomes (P2Ps) were prepared to further improve the water solubility of P2. The P2Ps exhibited a particle size of 53.6 ± 0.3 nm with oval shape and a zeta potential of -4.0 ± 0.7 mV. P2Ps could inhibit the proliferation of lung cancer cells more efficiently than Di phytosomes after 72 h of incubation time by inducing cell cycle arrest and apoptosis. The results indicated that P2Ps could be a promising anticancer formulation for non-small-cell lung cancer.

8.
J Biomater Appl ; 33(9): 1195-1201, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30646803

RESUMO

Cerebral thrombosis disease is a worldwide problem, with high rates of morbidity, disability, and mortality. Magnetic resonance imaging diffusion-weighted imaging was used as an important early diagnostic method for cerebral thrombotic diseases; however, its diagnosis time is 2 h after onset. In this study, we designed EGFP-EGF1-NP-Fe3O4 for earlier diagnosis of cerebral thrombosis by taking advantage of EGFP-EGF1 fusion protein, in which EGF1 can bind with tissue factor and enhanced green fluorescent protein has previously been widely used as a fluorescent protein marker. EGFP-EGF1-NP-Fe3O4 or NP-Fe3O4 reaches the highest concentration in the infarction areas in 1 h. To evaluate the targeting ability of EGFP-EGF1-NP-Fe3O4, a fluorochrome dye, Dir, was loaded into the nanoparticle. As shown by the in vivo organ multispectral fluorescence imaging, Dir-loaded EGFP-EGF1-NP-Fe3O4 exhibited higher fluorescence than those of model rats treated with Dir-loaded NP-Fe3O4. Coronal frozen sections and transmission electron microscope further showed that EGFP-EGF1-NP-Fe3O4 was mainly accumulated in the tissue factor exposure region of brain. The data indicated that the EGFP-EGF1-NP-Fe3O4 targeted cerebral thrombosis and might be applied in the early diagnosis of intracranial thrombosis.

9.
Curr Cancer Drug Targets ; 19(4): 257-276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29956629

RESUMO

BACKGROUND: Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment. OBJECTIVE: Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers. METHODS: We collected related information and data from articles. RESULTS: In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment. CONCLUSION: The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.

10.
Mol Pharm ; 15(11): 5146-5161, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30296375

RESUMO

The outcome of molecular targeted therapies is restricted by the ambiguous molecular subtypes of nonsmall cell lung cancer (NSCLC), which are difficult to be defined with druggable mutations, and the inevitable emergence of drug-resistance. Here we used the Cu-catalyzed click chemistry to synthesize a chitosan-based self-assembled nanotheranostics (CE7Ns) composed of a near-infrared (NIR) fluorescent photosensitizer Cy7 and molecular targeted drug erlotinib. The well-characterized CE7Ns can release erlotinib and Cy7 fast under acidic condition in the presence of lysozyme, distinguish three molecular subtypes of NSCLC, and specifically bind to the erlotinib-sensitive epidermal growth factor receptor (EGFR)-mutated PC-9 cells. The uptake of CE7Ns is much more in PC-9 cells than in other NSCLC cells, thus generating a notable fluorescence signal in PC-9 cells. Upon NIR irradiation, Cy7 in CE7Ns produces high reactive oxygen species in PC-9 cells. The synergistic effect between erlotinib-targeted therapy and photodynamic therapy significantly up-regulates cancer suppressor p53 and inhibits Survivin, which results in more apoptosis and cell cycle arrest. Upon intravenous administration, the erlotinib-guided CE7Ns significantly accumulate in PC-9-seeded mouse lungs and produce strong fluorescence. Upon NIR irradiation, CE7Ns significantly inhibit the subcutaneously implanted PC-9 tumor growth. This study provides, for the first time, a novel strategy to synthesize a multifunctional theranostic entity to simultaneously distinguish and image druggable mutations and combine targeted therapy with photodynamic therapy to overcome drug resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carbocianinas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/terapia , Nanomedicina Teranóstica/métodos , Administração Intravenosa , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Química Click , Cobre/química , Liberação Controlada de Fármacos/efeitos da radiação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Receptores ErbB/genética , Feminino , Humanos , Raios Infravermelhos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Microscopia Confocal , Microscopia de Fluorescência , Terapia de Alvo Molecular/métodos , Mutação , Fotoquimioterapia/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Exp Physiol ; 103(11): 1532-1542, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30070749

RESUMO

NEW FINDINGS: What is the central question of this study? In this study, by using motor vehicle exhaust (MVE) exposure with or without lipopolysaccharide (LPS) instillation, we established, evaluated and compared MVE, LPS and MVE+LPS treatment-induced chronic obstructive pulmonary disease (COPD) models in mice. What is the main finding and its importance? Our study demonstrated that the combination of chronic exposure to MVE with early LPS instillation can establish a mouse model with some features of COPD, which will allow researchers to investigate the underlying molecular mechanisms linking air pollution and COPD pathogenesis. ABSTRACT: Although it is well established that motor vehicle exhaust (MVE) has a close association with the occurrence and exacerbation of chronic obstructive pulmonary disease (COPD), very little is known about the combined effects of MVE and intermittent or chronic subclinical inflammation on COPD pathogenesis. Therefore, given the crucial role of inflammation in the development of COPD, we wanted to establish an animal model of COPD using both MVE exposure and airway inflammation, which could mimic the clinical pathological changes observed in COPD patients and greatly benefit the study of the molecular mechanisms of COPD. In the present study, we report that mice undergoing chronic exposure to MVE and intratracheal instillation of lipopolysaccharide (LPS) successfully established COPD, as characterized by persistent air flow limitation, airway inflammation, inflammatory cytokine production, emphysema and small airway remodelling. Moreover, the mice showed significant changes in ventricular and vascular pathology, including an increase in right ventricular pressure, right ventricular hypertrophy and remodelling of pulmonary arterial walls. We have thus established a new mouse COPD model by combining chronic MVE exposure with early intratracheal instillation of LPS, which will allow us to study the relationship between air pollution and the development of COPD and to investigate the underlying molecular mechanisms.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Animais , Modelos Animais de Doenças , Camundongos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
12.
Acta Biomater ; 76: 257-274, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29960010

RESUMO

Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation-positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability, controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo. This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC. STATEMENT OF SIGNIFICANCE: NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.


Assuntos
Aptâmeros de Nucleotídeos , Carcinoma Pulmonar de Células não Pequenas , Cloroquina , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib , Neoplasias Pulmonares , Mutação , Nanopartículas , Proteínas de Neoplasias/genética , RNA Interferente Pequeno , Survivina , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacocinética , Aptâmeros de Nucleotídeos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cloroquina/química , Cloroquina/farmacocinética , Cloroquina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacocinética , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Front Pharmacol ; 9: 263, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29765317

RESUMO

Aberrant activation of hypoxia-inducible factor (HIF)-1α is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1α-induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1α expression in vivo and in vitro, and pretreatment with HIF-1α siRNA reduced CSE-induced elevation of TNF-α, IL-1ß, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1α expression. It indicated that STS inhibits CSE-induced HIF-1α expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1α protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1α signaling, and may be a novel strategy for the treatment of COPD.

14.
Sci Rep ; 8(1): 376, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321495

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by abnormal inflammation, persistent and progressive lung function decline. The anti-inflammatory actions of tanshinone IIA, which is the most important active component from Chinese herbal medicine Danshen, have been well studied. However, it remains unknown whether sodium tanshinone IIA sulfonate (STS) protects against the development of COPD. Here we found that STS inhalation (5 mg/kg, 30 min per session, twice a day) significantly attenuated lung function decline, airspace enlargement, mucus production, bronchial collagen deposition, inflammatory responses and oxidative stress caused by cigarette smoke (CS) and lipopolysaccharide (LPS) exposures in mice. Moreover, treatment with STS (10 µg/ml) reduced CS extract (CSE)-induced IL-6 and IL-8 secretion in human bronchial epithelial (16HBE) cells. The anti-inflammatory actions of STS were associated with inhibition of ERK1/2 and NF-κB activations. Interestingly, STS inhibited CS-induced reduction of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse lungs and in 16HBE cells. Treatment with a specific CFTR inhibitor CFTR-Inh172 augmented CSE-induced ERK1/2 and NF-κB-dependent inflammatory responses, but abolished the inhibitory action of STS on IL-6 and IL-8 secretion in 16HBE cells. These results demonstrate that CS-induced COPD and down-regulation of CFTR are prevented by STS.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fenantrenos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Linhagem Celular , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Camundongos , Fenantrenos/farmacologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/metabolismo , Testes de Função Respiratória
15.
Mol Genet Genomics ; 293(3): 649-655, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29285564

RESUMO

The polymorphisms of cytokine genes has been reported to modulate the individual's susceptibility to environmental stimuli in COPD development. C-X-C motif chemokine 10 (CXCL10) mediates recruitment inflammatory cells such as monocytes. Therefore, it may play a key role in COPD. Here, a case-control study was conducted to evaluate the association between CXCL10 tag-SNPs and COPD risk. Four tag-SNPs including rs4256246, rs4508917, rs56061981, and rs56316945 were identified based on the linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between these four tag-SNPs and COPD risk were further evaluated in 480 COPD cases and 488 controls. We found that the "T" allele of rs56061981 was significantly associated with reducing risk of COPD, while "G" allele of rs56316945 was significantly associated with increasing risk of COPD. SNP rs56316945 was significantly associated with increasing risk of COPD under different models except recessive model after adjusting the sex, age, pack year, and biomass. SNP rs56061981 was significantly associated with decreasing COPD risk under different models except recessive model after adjusting the sex, age, pack year, and biomass. Stratified analysis of smoking status and biomass with SNPs supported rs56061981 may interact with biomass and smoking thus modulate COPD susceptibility and rs56216945 was apparently associated with the severity of pulmonary function of COPD patients. This study suggests that rs56061981 and rs56216945 in CXCL10 gene promoter contribute COPD susceptibility.


Assuntos
Quimiocina CXCL10/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
16.
Biomacromolecules ; 18(7): 2146-2160, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28628303

RESUMO

Folate (FA) and heptamethine cyanine (Cy7)-modified chitosan (CF7) was synthesized by click chemistry and its self-assembled nanoparticles (CF7Ns) were developed for tumor-specific imaging and photodynamic therapy. The characterization spectrum confirmed CF7 had a good FA and Cy7 conjugation efficacy. The diameter of CF7Ns measured by DLS was about 291.6 nm, and the morphology observed with AFM showed filamentous clusters of particles. The results of targeting ability of CF7Ns demonstrated enhanced targeting behaviors of CF7Ns compared with non-FA-modified nanoparticles C7Ns in FA receptor-positive HeLa cells. The cytotoxicity and cell apoptosis assay showed that CF7Ns under near-infrared light irradiation led to more apoptotic cell death in HeLa cells to improve the therapeutic efficacy. The mechanisms of the photodynamic effects of CF7Ns were demonstrated through measurement of intracellular reactive oxygen species and the apoptosis-related cytokines. These results suggested that CF7Ns are promising tumor targeting carriers for simultaneous fluorescence imaging and photodynamic therapy.


Assuntos
Carbocianinas , Quitosana , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Nanomedicina Teranóstica/métodos , Carbocianinas/química , Carbocianinas/farmacologia , Quitosana/química , Quitosana/farmacologia , Fluorescência , Ácido Fólico , Células HeLa , Células Hep G2 , Humanos , Raios Infravermelhos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/patologia
17.
Mater Sci Eng C Mater Biol Appl ; 75: 182-190, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28415453

RESUMO

Baicalin (BAI) has been reported to exert antitumor effects. However, BAI has limited water solubility, non-specific tumor targeting, and low bioavailability, which severely limited its clinical application. The aim of this study was to develop folic acid (FA) covalently conjugated-polyamidoamine (PAMAM) dendrimers (PAMAM-FA) as carrier systems for improvement of water solubility and tumor-specificity of BAI, and study the role of generation on the physiochemical properties and biological effects of PAMAM-FA/BAI complexes. In this work, four generations of PAMAM-FA were synthesized to entrap BAI. The average sizes of G3-FA/BAI, G4-FA/BAI, G5-FA/BAI, and G6-FA/BAI complexes were 174.4nm, 184.5nm, 258.8nm, and 247.5nm, respectively, and the zeta potentials of four PAMAM-FA/BAI complexes were -2.9mV, -6.6mV, -9.3mV, -9.0mV, respectively. The entrapment efficiencies of four PAMAM-FA/BAI complexes were 91.1%, 53.5%, 80.3%, and 91.9%, respectively, and the drug loading of PAMAM-FA/BAI complexes were about 22%. The formed PAMAM-FA/BAI complexes allowed sustained release of BAI in acidic PBS (pH5.4). In cellular uptake assay, PAMAM-FA/BAI complexes demonstrated increased drug uptake level in folate receptor (FR)-positive Hela cancer cells than FR-negative A549 cells, and the cellular uptake efficiency of PAMAM-FA is closely related with the generation of PAMAM. The MTT assay results showed that PAMAM-FA/BAI complexes demonstrated enhanced toxicity against Hela cells than non-FA-modified PAMAM/BAI complexes, and the G6-FA/BAI demonstrated the best inhibition efficiency. The cell cycle and cell apoptosis analysis further demonstrated the tumor-specific therapeutic efficacy of PAMAM-FA/BAI. These results suggested that the PAMAM-FA have the potential for targeted delivery of BAI into cancer cells to enhance its anti-tumor efficacy.


Assuntos
Dendrímeros , Sistemas de Liberação de Medicamentos/métodos , Flavonoides , Ácido Fólico , Neoplasias/tratamento farmacológico , Poliaminas , Células A549 , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Flavonoides/química , Flavonoides/farmacocinética , Flavonoides/farmacologia , Ácido Fólico/química , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Células HeLa , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Poliaminas/química , Poliaminas/farmacocinética , Poliaminas/farmacologia
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 13(3): 512-3, 2005 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-15972155

RESUMO

To investigate the efficaciousness of recombinant human granulocyte colony-stimulating factor (G-CSF) combined with recombinant human erythropoietin (EPO) in the treatment of patients with myelodysplastic syndrome (MDS), the hematological changes in the blood and bone marrow along with clinical features after treatment with G-CSF and EPO in 15 patients were observed. Patients were subcutaneously injected with G-CSF 300 microg/d for 10 days, then injected with EPO 100 U/(kg x d) for 10 days. The results showed that the obvious improvements in granulocytes of blood were found in 10 patients with MDS, improvements in erythrocytes of blood were observed in 7 patients with MDS. No serious side effects occured is all treated patients. In conclusion, treatment of G-CSF in combination with EPO is effective for patients with MDS.


Assuntos
Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Quimioterapia Combinada , Contagem de Eritrócitos , Eritropoetina/administração & dosagem , Eritropoetina/efeitos adversos , Feminino , Febre/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Cefaleia/induzido quimicamente , Humanos , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Proteínas Recombinantes , Resultado do Tratamento
19.
World J Gastroenterol ; 4(2): 162-164, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11819264

RESUMO

AIM:To investigate the effects of TRH in DVC on motility of the gallbladder in rabbits.METHODS:fter fasted for 15h-18h, rabbits were anesthetized with urethane (1.0g/kg).Gallbladder pressure (GP) was measured by a frog bladder perfused with normal saline.RESULTS:After microinjection of TRH (8.8nmol,1&mgr;l) into DVC,GP was raised and the frequency of phasic contraction of gallbladder (FPCGB) increased. All the doses of TRH (0.13, 0.25, 0.50, 0.80, 1.30nmol, 1&mgr;l) injected into DVC could excite the motility of gallblader. As the dose of TRH was enlarged, the amplitude and duration of the reaction increased. Effects of TRH in DVC on motility of the gallbladder could be completely abolished by atropine (0.2mg/g, i.v.) or vagotomy, but could not be inhibited by phentolamine iv (1.5mg/g) or propranolol iv (1.5mg/g)or by transecting the spinal cord.CONCLUSION: Thyrotropin-releasing hormone in DVC can excite motility of gallbladder. This effect was mediated by vagus nerves and peripheral M receptor. Its physiological significance may be related to maintaining the phasic contraction of gallbladder in interdigestive period.

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