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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 378-381, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018007

RESUMO

Inspired by the collaborative movements of the living cells in different natural biological processes, this paper highlights a self-regulated and co-ordinated targeting strategy to detect tumor in complex human vasculature. We show by computational experiments that simple and non-centralized nanoparticles with limited locomotive capability, when they collaborate and move in the form of groups, can be very robust in the tumor homing process. Once reaching tumor location, such nanoparticles (potential contrast agents) can deposit themselves on tumor through the enhanced permeability and retention (EPR) effect thereby making the malignant cancerous area more prominent. Hence, existing medical imaging techniques with limited resolution can be used to detect small malignant tumors. We believe that our work will help in early cancer detection through an independent, non-centralized and self-controlled system.Clinical Relevance:- With the help of target amplification through contrast agents such as self-regulated nanoparticles contrast enhanced medical imaging can detect the tumor at its initial stages when 90% of the cancers are curable.


Assuntos
Nanopartículas , Neoplasias , Detecção Precoce de Câncer , Humanos , Permeabilidade
2.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 34(9): 1163-1169, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-32929911

RESUMO

Objective: To explore the feasibility and mechanism of inhibiting miR-429 to improve the permeability of the blood spinal cord barrier (BSCB) in vitro, and provide a new gene therapy target for enhancing the spinal cord microenvironment. Methods: First, the immortalized human brain microvascular endothelial cell line (hCMEC/D3) was transfected with the anti-miR-429 antagonist (antagomiR-429) and its negative control (antagomiR-429-NC), respectively. The miR-429 expression of hCMEC/D3 cells was observed by fluorescence microscopy and real-time fluorescence quantitative PCR to verify the transfection efficiency of antagomiR-429. Then the effect of miR-429 on BSCB permeability was observed in vitro. The experiment was divided into 4 groups. The blank control group (group A) was constructed of normal hCMEC/D3 cells and Ha-sc cells to prepare the BSCB model, the hypoxia-induced group (group B), the hypoxia-induced+antagomiR-429-NC group (group C), and the hypoxia-induced+antagomiR-429 group (group D) were constructed of normal, antagomiR-429-NC transfected, and antagomiR-429 transfected hCMEC/D3 cells and Ha-sc cells to prepare the BSCB models and hypoxia treatment for 12 hours. The permeability of BSCB in vitro was measured by horseradish peroxidase (HRP) permeability. Real-time fluorescence quantitative PCR, Western blot, and immunofluorescence staining were used to observe the expressions of ZO-1, Occludin, and Claudin-5. Results: The antagomiR-429 and antagomiR-429-NC were successfully transfected into hCMEC/D3 cells under a fluorescence microscope, and the transfection efficiency was about 90%. Real-time fluorescence quantitative PCR results showed that the relative expression of miR-429 in antagomiR-429 group was 0.109±0.013, which was significantly lower than that of antagomiR-429-NC group (0.956±0.004, P<0.05). HRP permeability measurement, real-time fluorescence quantitative PCR, and Western blot results showed that the HRP permeability of groups B and C were significantly higher than those of groups A and D ( P<0.05), and the relative expressions of ZO-1, Occludin, and Claudin-5 proteins and mRNAs were significantly lower in groups B and C than in groups A and D ( P<0.05) and in group D than in group A ( P<0.05); there was no significant difference between groups B and C ( P>0.05). Immunofluorescence staining showed that the immunofluorescence of ZO-1, Occudin, and Claudin-5 at the cell membrane boundary in group D were stronger than those in groups B and C, but not as strong as that in group A. Conclusion: Inhibition of miR-429 expression can promote the expressions of ZO-1, Occludin, and Claudin-5 proteins in microvascular endothelial cells, thereby improving the increased permeability of BSCB due to hypoxia.


Assuntos
Células Endoteliais , MicroRNAs , Barreira Hematoencefálica , Hipóxia Celular , Claudina-5 , Humanos , Ocludina , Permeabilidade , Medula Espinal , Proteína da Zônula de Oclusão-1
3.
Am J Chin Med ; 48(6): 1315-1330, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907362

RESUMO

Critical care medicine is a medical specialty engaging the diagnosis and treatment of critically ill patients who have or are likely to have life-threatening organ failure. Sepsis, a life-threatening condition that arises when the body responds to infection, is currently the major cause of death in intensive care units (ICU). Although progress has been made in understanding the pathophysiology of sepsis, many drawbacks in sepsis treatment remains unresolved. For example, antimicrobial resistance, controversial of glucocorticoids use, prolonged duration of ICU care and the subsequent high cost of the treatment. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) in sepsis management. The TCM application emphasizes use of herbal formulation to balance immune responses to infection, which include clearing heat and toxin, promoting blood circulation and removing its stasis, enhancing gastrointestinal function, and strengthening body resistance. In this paper, we will provide an overview of the current status of Chinese herbal formulations, single herbs, and isolated compounds, as an add-on therapy to the standard Western treatment in the sepsis management. With the current trajectory of worldwide pandemic eruption of newly identified Coronavirus Disease-2019 (COVID-19), the adjuvant TCM therapy can be used in the ICU to treat critically ill patients infected with the novel coronavirus.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/tratamento farmacológico , Sepse/tratamento farmacológico , Artemisininas/uso terapêutico , Astragalus propinquus , Berberina/uso terapêutico , Betacoronavirus , Estado Terminal , Emodina/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Mucosa Intestinal , Microcirculação , Pandemias , Permeabilidade , Rheum , Salvia miltiorrhiza
4.
PLoS One ; 15(9): e0238301, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881954

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is a primary astrocytopathy driven by antibodies directed against the aquaporin-4 water channel located at the end-feet of the astrocyte. Although blood-brain barrier (BBB) breakdown is considered one of the key steps for the development and lesion formation, little is known about the molecular mechanisms involved. The aim of the study was to evaluate the effect of human immunoglobulins from NMOSD patients (NMO-IgG) on BBB properties. METHODS: Freshly isolated brain microvessels (IBMs) from rat brains were used as a study model. At first, analysis of the secretome profile from IBMs exposed to purified NMO-IgG, to healthy donor IgG (Control-IgG), or non-treated, was performed. Second, tight junction (TJ) proteins expression in fresh IBMs and primary cultures of brain microvascular endothelial cells (BMEC) was analysed by Western blotting (Wb) after exposition to NMO-IgG and Control-IgG. Finally, functional BBB properties were investigated evaluating the presence of rat-IgG in tissue lysate from brain using Wb in the rat-model, and the passage of NMO-IgG and sucrose in a bicameral model. RESULTS: We found that NMO-IgG induces functional and morphological BBB changes, including: 1) increase of pro-inflammatory cytokines production (CXCL-10 [IP-10], IL-6, IL-1RA, IL-1ß and CXCL-3) in IBMs when exposed to NMO-IgG; 2) decrease of Claudin-5 levels by 25.6% after treatment of fresh IBMs by NMO-IgG compared to Control-IgG (p = 0.002), and similarly, decrease of Claudin-5 by at least 20% when BMEC were cultured with NMO-IgG from five different patients; 3) a higher level of rat-IgG accumulated in periventricular regions of NMO-rats compared to Control-rats and an increase in the permeability of BBB after NMO-IgG treatment in the bicameral model. CONCLUSION: Human NMO-IgG induces both structural and functional alterations of BBB properties, suggesting a direct role of NMO-IgG on modulation of BBB permeability in NMOSD.


Assuntos
Aquaporina 4/imunologia , Barreira Hematoencefálica/metabolismo , Imunoglobulina G/farmacologia , Neuromielite Óptica/patologia , Permeabilidade/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Quimiocinas/metabolismo , Claudina-5/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Imunoglobulina G/isolamento & purificação , Microvasos/citologia , Microvasos/metabolismo , Neuromielite Óptica/metabolismo , Ratos
5.
Int J Nanomedicine ; 15: 5671-5685, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821096

RESUMO

Aim: The aim of the current work was to develop vardenafil hydrochloride (VRD)-loaded ethosome-derived invasomes as a possible transdermal system which could be used for patients suffering from pulmonary arterial hypertension. Methods: VRD-loaded ethosomes were developed at three concentrations of phosphatidylcholine (5, 10 and 15 mg/mL) and three percentages of ethanol (20%, 30% and 40%, v/v). The best achieved VRD-loaded ethosomes (ETH9) were optimized to invasomes via incorporation of terpenes (limonene, cineole and a 1:1 mixture) at three concentrations (0.5%, 1% and 2%, v/v). All systems were evaluated for vesicle size, zeta potential, drug entrapment efficiency (EE%), cumulative drug permeated percentages after 0.5hrs (Q0.5h) and 12hrs (Q12h) and steady-state flux (Jss). The optimized system (ETH9-INV8) was further characterized for morphology, histopathology and confocal laser scanning microscopy (CLSM). Physiologically based pharmacokinetic (PBPK) modeling was employed to estimate VRD pharmacokinetic parameters from the optimized transdermal system and an oral aqueous drug dispersion, in adults and geriatrics. Results: The optimized invasomal system (ETH9-INV8) was characterized with spherical vesicles (159.9 nm) possessing negative zeta potential (-20.3 mV), promising EE% (81.3%), low Q0.5h (25.4%), high Q12h (85.3%) and the largest steady-state flux (6.4 µg.cm-2h-1). Following a leave-on period of 12hrs in rats, it showed minor histopathologic changes. CLSM studies proved its ability to deeply permeate rat skin. Lower Cmax values, delayed Tmax estimates and greater AUC0-24h folds in adults and geriatrics (≈ 2.18 and 1.69, respectively) were estimated following the transdermal application of ETH9-INV8 system. Conclusion: ETH9-INV8 is a promising transdermal system for VRD.


Assuntos
Sistemas de Liberação de Medicamentos , Etanol/química , Geriatria , Modelos Biológicos , Dicloridrato de Vardenafila/administração & dosagem , Dicloridrato de Vardenafila/farmacocinética , Administração Cutânea , Animais , Lipossomos , Masculino , Microscopia Confocal , Tamanho da Partícula , Permeabilidade , Ratos Wistar , Absorção Cutânea , Eletricidade Estática
7.
J Chromatogr A ; 1627: 461415, 2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32823113

RESUMO

A molecularly imprinted polymeric monolith was synthesized in an aqueous environment in 15 min via UV-irradiation. The imprinted monolith was composed of hydroxyethyl methacrylate as monomer, dimethyl amino ethyl methacrylate as functional monomer, methylene bisacrylamide and piperazine diacrylamide as crosslinkers and human serum albumin as template molecule. The synthesis took place in a PDMS-based device (2.5 cm long) yielding a micro-solid phase extraction column (3 × 5 mm) with two built-in fingertight connectors for an infusion pump and fraction collector. The imprinted monolith displayed the characteristic features of a porous polymeric monolith, had dimethyl amino ethyl methacrylate and human serum albumin as functional groups within the monolith and showed high permeability (0.51 × 10-13 m2). 85% of the imprinted cavities were readily available for rebinding of human serum albumin with an imprinting factor of 1.3. In comparison to a non-imprinted monolith, molecular imprinting increased human serum albumin adsorption by > 30%. Imprinted monolith displayed selectivity for human serum albumin over other competing proteins (human transferrin, ovalbumin and carbonic anhydrase) with similar or different isoelectric points and size. Human serum albumin was adsorbed (in dynamic mode) with > 98% selectivity from diluted human plasma using the imprinted monolith device. Device to device reproducibility and reusability of the device for 5 cycles showcase the imprinted monolith micro-device efficiency.


Assuntos
Impressão Molecular , Proteínas/isolamento & purificação , Microextração em Fase Sólida/instrumentação , Adsorção , Etilaminas/química , Humanos , Metacrilatos/química , Permeabilidade , Polímeros/química , Porosidade , Reprodutibilidade dos Testes , Albumina Sérica Humana/isolamento & purificação , Espectroscopia de Infravermelho com Transformada de Fourier
8.
Yakugaku Zasshi ; 140(8): 1007-1012, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741858

RESUMO

We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Leucócitos , Lipossomos/metabolismo , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Humanos , Permeabilidade , Transporte Proteico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
9.
Int J Nanomedicine ; 15: 5113-5129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764940

RESUMO

Background: Low bioavailability and poor permeability of the blood-brain barrier are problematic when delivering therapeutic agents and particularly anti-human immunodeficiency virus therapy to the central nervous system. The intranasal route offers an alternative for central nervous system delivery. Cubosomes have been reported as helpful vehicles for intranasal delivery of therapeutics to enable brain targeting. Objective: In this study, we aimed to develop the intranasal cubosomal thermogelling dispersion of saquinavir mesylate for central nervous system delivery. Methods: The Box-Behnken design was applied to study the effect of monoolein, Poloxamer 407, and polyvinyl alcohol as independent factors and the particle size, entrapment efficiency, gelation temperature, and stability index as responses. The optimized cubosomes were evaluated using transmission electron microscopy, ex vivo permeation, and in vivo pharmacokinetics. Results: The optimized formula consisting of monoolein (8.96%), Poloxamer 407 (17.45%), and polyvinyl alcohol (7.5%) was prepared and evaluated. Higher values for the steady-state flux, permeability coefficient, and enhancement factor were observed for the cubosomal thermogelling dispersion of saquinavir during ex vivo permeation in comparison with an aqueous suspension of saquinavir. From the pharmacokinetic profile, the relative bioavailability for the intranasal optimized formula was approximately 12-fold higher when compared with oral aqueous suspension and 2.5-fold greater when compared to the intranasal aqueous suspension of saquinavir. Conclusion: Overall, the saquinavir-loaded cubosomal thermogelling formulation is promising for central nervous system delivery by intranasal administration.


Assuntos
Portadores de Fármacos/química , Cristais Líquidos/química , Nanoestruturas/química , Saquinavir/farmacologia , Temperatura , Administração Intranasal , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Géis , Glicerídeos/química , Masculino , Tamanho da Partícula , Permeabilidade , Poloxâmero/química , Álcool de Polivinil/química , Saquinavir/administração & dosagem , Saquinavir/metabolismo
10.
Vascul Pharmacol ; 133-134: 106783, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32835836

RESUMO

BACKGROUND: Low-molecular-weight heparins (LMWHs) influence the fibrin network structure in in vitro models. There have been no reports on LMWH-induced modifications of fibrin clot characteristics and their determinants in acute pulmonary embolism (PE). AIM: We investigated how enoxaparin alters fibrin clot properties in acute PE patients. METHODS: Clots were generated from plasma of 46 acute PE patients, aged 47-77 years treated with enoxaparin 1 mg/kg bid. Fibrin clot permeability (Ks) and clot lysis time (CLT), along with coagulation and fibrinolysis proteins were determined. Plasma fibrin clot nanostructure was assessed using scanning electron microscopy (SEM). RESULTS: Both Ks and CLT were associated with anti-factor (F)Xa activity (r = 0.75, p < 0.0001 and r = -0.37, p = 0.011). Anti-FXa was positively associated with fibrin fiber diameter and the pore area, and inversely with fibrin fiber density on SEM images. Multiple regression analysis adjusted for age, body-mass index, and fibrinogen levels showed that anti-FXa activity, antithrombin activity, and FVIII activity determined Ks, while anti-FXa activity, plasminogen activator inhibitor-1 level, and presence of right ventricular dysfunction determined CLT. CONCLUSIONS: We identified new laboratory and clinical factors contributing to prothrombotic plasma fibrin clot characteristics during enoxaparin treatment, which might help elucidate mechanisms underlying therapy failure in patients with acute PE.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Enoxaparina/uso terapêutico , Fibrina/metabolismo , Fibrinolíticos/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Adulto , Idoso , Feminino , Fibrina/ultraestrutura , Tempo de Lise do Coágulo de Fibrina , Humanos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Porosidade , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Falha de Tratamento
11.
Int J Nanomedicine ; 15: 5629-5643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801706

RESUMO

Purpose: Lecithin/chitosan nanoparticles have shown great promise in the transdermal delivery of therapeutic agents. Baicalein, a natural bioactive flavonoid, possesses multiple biological activities against dermatosis. However, its topical application is limited due to its inherently poor hydrophilicity and lipophilicity. In this study, the baicalein-phospholipid complex was prepared to enhance the lipophilicity of baicalein and then lecithin/chitosan nanoparticles loaded with the baicalein-phospholipid complex were developed to improve the transdermal retention and permeability of baicalein. Methods: Lecithin/chitosan nanoparticles were prepared by the solvent-injection method and characterized in terms of particle size distribution, zeta potential, and morphology. The in vitro release, the ex vivo and in vivo permeation studies, and safety evaluation of lecithin/chitosan nanoparticles were performed to evaluate the effectiveness in enhancing transdermal retention and permeability of baicalein. Results: The lecithin/chitosan nanoparticles obtained by the self-assembled interaction of chitosan and lecithin not only efficiently encapsulated the drug with high entrapment efficiency (84.5%) but also provided sustained release of baicalein without initial burst release. Importantly, analysis of the permeation profile ex vivo and in vivo demonstrated that lecithin/chitosan nanoparticles prolonged the retention of baicalein in the skin and efficiently penetrated the barrier of stratum corneum without displaying skin irritation. Conclusion: These results indicate the potential of drug-phospholipid complexes in enhancing the entrapment efficiency and self-assembled lecithin/chitosan nanoparticles based on phospholipid complexes in the design of a rational transdermal delivery platform to improve the efficiency of transdermal therapy by enhancing its percutaneous retention and penetration in the skin.


Assuntos
Flavanonas/administração & dosagem , Nanopartículas/administração & dosagem , Fosfolipídeos/química , Administração Cutânea , Animais , Quitosana/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Flavanonas/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Lecitinas/química , Masculino , Nanopartículas/efeitos adversos , Nanopartículas/química , Permeabilidade , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele
12.
Ecotoxicol Environ Saf ; 204: 111072, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758694

RESUMO

Zearalenone (ZEN) is a mycotoxin that causes serious health problems in humans and animals. However, few studies have focused on the destruction of the intestinal barrier caused by ZEN. In this study, rats were exposed to different dosages of ZEN (0, 0.2, 1.0 and 5.0 mg/kg bw) by gavage for 4 weeks. The results showed that 1.0 and 5.0 mg/kg ZEN impaired gut morphology, induced the inflammatory response, reduced mucin expression, increased intestinal permeability, decreased the expression of TJ proteins and activated the RhoA/ROCK pathway. However, 0.2 mg/kg ZEN had no significant effect on intestinal barrier except for reducing the expression of some TJ proteins and mucins. Moreover, exposure to ZEN led to slight imbalance in microbiota. In conclusion, ZEN exposure resulted in intestinal barrier dysfunction by inducing intestinal microbiota dysbiosis, decreasing the expression of TJ proteins, activating the RhoA/ROCK pathway, and inducing the inflammatory response.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Relação Dose-Resposta a Droga , Disbiose/induzido quimicamente , Feminino , Microbioma Gastrointestinal/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , Masculino , Mucinas/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
13.
Int J Nanomedicine ; 15: 4001-4020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606661

RESUMO

Background: Simvastatin (SMV), a hypocholesterolemic agent, suffers from very low bioavailability due to its poor aqueous solubility and extensive first-pass metabolism. Methods: Two SMV carrier systems, namely, polymeric drug inclusion complex (IC) and mixed micelles (MM) nanoparticles, were developed and loaded into mucoadhesive buccal films to enhance SMV bioavailability. The two carrier systems were characterized and their permeation across human oral epithelial cells (OEC) was studied. The effect of IC to MM ratio (X1) and the mucoadhesive polymer concentration (X2) on the cumulative percent of drug released, elongation percent and the mucoadhesive strength, from the prepared mucoadhesive films, were optimized. Ex vivo permeation across bovine mucosal tissue was investigated. The permeation parameters for the in vitro and ex vivo release data were calculated. Results: Complexation of SMV with hydroxypropyl beta-cyclodextrin (HP ß-CD) was superior to all other polymers as revealed by the equilibrium saturation solubility, stability constant, complexation efficiency and thermodynamic potential. SMV-HP ß-CD IC was utilized to develop a saturated polymeric drug solution. Both carrier systems showed enhanced permeation across OEC when compared to pure drug. X1 and X2 were significantly affecting the characteristics of the prepared films. The optimized mucoadhesive buccal film formulation loaded with SMV IC and drug MM nanoparticles demonstrated superior ex vivo permeation when compared to the corresponding pure drug buccal film, and the calculated permeation parameters confirmed this finding. Conclusion: Mucoadhesive buccal films containing SMV IC and drug MM can be used to improve drug bioavailability; however, additional pharmacokinetic and pharmacodynamic studies are required.


Assuntos
Portadores de Fármacos/química , Liberação Controlada de Fármacos , Mucosa Bucal/efeitos dos fármacos , Muco/química , Sinvastatina/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/química , Adesividade , Animais , Varredura Diferencial de Calorimetria , Bovinos , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura , Permeabilidade , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
14.
PLoS Pathog ; 16(7): e1008654, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673372

RESUMO

Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes.


Assuntos
Cálcio/metabolismo , Neurônios/metabolismo , Proteínas PrPSc/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Morte Celular/fisiologia , Camundongos , Permeabilidade , Transporte Proteico/fisiologia
15.
Am J Gastroenterol ; 115(7): 1055-1065, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32618656

RESUMO

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome. The gut microbiome plays a role in metabolism and maintaining gut barrier integrity. Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD. Fecal microbiota transplantation (FMT) can be used to alter the gut microbiome. It was hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability. METHODS: Twenty-one patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum. IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test. Additional markers of metabolic syndrome and the gut microbiota were examined. Patient visits occurred at baseline, 2, 6 weeks, and 6 months post-FMT. RESULTS: There were no significant changes in HOMA-IR or hepatic PDFF in patients who received the allogenic or autologous FMT. Allogenic FMT patients with elevated small intestinal permeability (>0.025 lactulose:mannitol, n = 7) at baseline had a significant reduction 6 weeks after allogenic FMT. DISCUSSION: FMT did not improve IR as measured by HOMA-IR or hepatic PDFF but did have the potential to reduce small intestinal permeability in patients with NAFLD.


Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Intestino Delgado , Hepatopatia Gordurosa não Alcoólica/terapia , Método Duplo-Cego , Duodenoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Permeabilidade
17.
PLoS One ; 15(7): e0233252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701962

RESUMO

Phthiocerol dimycocerosates (PDIMs) are a class of mycobacterial lipids that promote virulence in Mycobacterium tuberculosis and Mycobacterium marinum. It has recently been shown that PDIMs work in concert with the M. tuberculosis Type VII secretion system ESX-1 to permeabilize the phagosomal membranes of infected macrophages. As the zebrafish-M. marinum model of infection has revealed the critical role of PDIM at the host-pathogen interface, we set to determine if PDIMs contributed to phagosomal permeabilization in M. marinum. Using an ΔmmpL7 mutant defective in PDIM transport, we find the PDIM-ESX-1 interaction to be conserved in an M. marinum macrophage infection model. However, we find PDIM and ESX-1 mutants differ in their degree of defect, with the PDIM mutant retaining more membrane damaging activity. Using an in vitro hemolysis assay-a common surrogate for cytolytic activity, we find that PDIM and ESX-1 differ in their contributions: the ESX-1 mutant loses hemolytic activity while PDIM retains it. Our observations confirm the involvement of PDIMs in phagosomal permeabilization in M. marinum infection and suggest that PDIM enhances the membrane disrupting activity of pathogenic mycobacteria and indicates that the role they play in damaging phagosomal and red blood cell membranes may differ.


Assuntos
Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Lipídeos/farmacologia , Macrófagos/citologia , Mycobacterium marinum/metabolismo , Fagossomos/efeitos dos fármacos , Linhagem Celular , Humanos , Macrófagos/efeitos dos fármacos , Mycobacterium marinum/fisiologia , Permeabilidade/efeitos dos fármacos , Fagossomos/metabolismo
18.
Neuron ; 107(2): 205-207, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32702343

RESUMO

How circulating signals enter the median eminence to trigger homeostatic hypothalamic responses is not well understood. Jiang et al. describe a neural mechanism that increases endothelial fenestrations and enhances the hypothalamic response to the circulating hormone leptin, suggesting a novel way to regulate brain entry through vascular wall remodeling.


Assuntos
Barreira Hematoencefálica , Eminência Mediana , Hipotálamo , Neurônios , Permeabilidade
19.
PLoS One ; 15(7): e0236175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697798

RESUMO

Adenoviruses cause upper respiratory infections, conjunctivitis, keratitis, and gastrointestinal illness. These can be fatal in immunocompromised individuals. Adenoviruses have also been engineered into viral vectors to deliver therapeutic genes or induce immunity as vaccine carriers. The success of ocular gene therapy is driven partly by the immunologic and biochemical influences of the intraocular environment. We have shown that versican and hyaluronan modulate adenoviral vector transgene expression through CD44 signaling. Herein we explored the role of these pathways on virus replication and viral protein expression of wild type adenovirus. We report that the addition of vitreous humor (which contains both versican and hyaluronan) increases viral hexon protein levels. Vitreous humor also increased wild type adenovirus DNA replication in vitro. Metalloproteinase and γ-secretase inhibitors, which inhibit CD44 proteolytic activation, blocked adenoviral replication in vitro. Similarly, protein kinase C and RhoA kinase inhibitors, both proteins associated with CD44 mediated pathways, also inhibited wild type adenoviral replication in vitro. Application of metalloproteinase and γ-secretase inhibitors to human conjunctival explants sharply decreased adenoviral vector gene expression. Our results demonstrate that pharmacologic delivery of these inhibitors is easily achievable. The inhibition of these enzymes should be explored as potential therapies of wild type adenoviral infections.


Assuntos
Infecções por Adenoviridae/tratamento farmacológico , Adenoviridae/efeitos dos fármacos , Antivirais/farmacologia , Vetores Genéticos/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adenoviridae/fisiologia , Infecções por Adenoviridae/virologia , Administração Oftálmica , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/uso terapêutico , Túnica Conjuntiva/metabolismo , DNA Viral/genética , DNA Viral/isolamento & purificação , Diaminas/farmacologia , Diaminas/uso terapêutico , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/fisiologia , Células HeLa , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Maleimidas/farmacologia , Maleimidas/uso terapêutico , Metaloproteases/antagonistas & inibidores , Metaloproteases/metabolismo , Permeabilidade , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteólise/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Versicanas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Corpo Vítreo/metabolismo , Quinases Associadas a rho/metabolismo
20.
MMW Fortschr Med ; 162(Suppl 5): 3-6, 2020 07.
Artigo em Alemão | MEDLINE | ID: mdl-32661894

RESUMO

Different mechanisms have a negative impact on the course of inflammatory bowel disease. Important mechanisms include amongst others an increased release of pro-inflammatory cytokines, intestinal dysbiosis, increased permeability of the intestinal barrier, increased release of corticotropin-releasing factor (CRF) in the brain, activation of mast cells in the intestinal mucosa and inadequate central pain processing with the consequences of anxiety and depression. All of these factors can increase the inflammatory response in the intestine and lead to acute flare-ups. For this reason, appropriate stress management is extremely important for the success of therapy.


Assuntos
Hormônio Liberador da Corticotropina , Doenças Inflamatórias Intestinais , Estresse Psicológico , Humanos , Doenças Inflamatórias Intestinais/psicologia , Mucosa Intestinal , Mastócitos , Permeabilidade
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