Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35.837
Filtrar
1.
J Neurotrauma ; 39(1-2): 20-34, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33632026

RESUMO

Traumatic brain injury (TBI) is a leading cause of death and disability, especially in young persons, and constitutes a major socioeconomic burden worldwide. It is regarded as the leading cause of mortality and morbidity in previously healthy young persons. Most of the mechanisms underpinning the development of secondary brain injury are consequences of disruption of the complex relationship between the cells and proteins constituting the neurovascular unit or a direct result of loss of integrity of the tight junctions (TJ) in the blood-brain barrier (BBB). A number of changes have been described in the BBB after TBI, including loss of TJ proteins, pericyte loss and migration, and altered expressions of water channel proteins at astrocyte end-feet processes. There is a growing research interest in identifying optimal biological and radiological biomarkers of severity of BBB dysfunction and its effects on outcomes after TBI. This review explores the microscopic changes occurring at the neurovascular unit, after TBI, and current radiological adjuncts for its evaluation in pre-clinical and clinical practice.


Assuntos
Barreira Hematoencefálica , Lesões Encefálicas Traumáticas , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/complicações , Permeabilidade Capilar , Humanos , Permeabilidade , Junções Íntimas/metabolismo
2.
Mol Pharm ; 19(2): 520-531, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34936359

RESUMO

Mucus represents a strong barrier to tackle for oral or pulmonary administered drugs, especially in mucus-related disorders. This study uses a pathological cystic fibrosis (CF) mucus model to investigate how mucus impacts the passive diffusion of 45 ad hoc commercial drugs selected to maximize physicochemical variability. An in vitro mucosal surface was recreated by coupling the mucus model to a 96-well permeable support precoated with structured layers of phospholipids (parallel artificial membrane permeability assay, PAMPA). Results show that the mucus model was not a mere physical barrier but it behaves like an interactive filter. In nearly one-half of the investigated compounds, the diffusion was reduced by mucus, while other drugs were not sensitive to the mucus barriers. We also found that permeability can be enhanced when drug-calcium salts are formed. This was confirmed with cystic fibrosis sputum as a rough ex vivo model of CF mucus. Since the drug discovery process is characterized by a high rate of failure, the mucus platform is expected to provide an efficient support to early reduce the number of poor-performing drug candidates.


Assuntos
Fibrose Cística , Fibrose Cística/tratamento farmacológico , Difusão , Humanos , Muco , Permeabilidade , Escarro
3.
Sci Rep ; 12(1): 15094, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064964

RESUMO

A growing number of recent investigations on the human genome, gut microbiome, and proteomics suggests that the loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between the gut microbiome and the immune system. This cross-talk is highly influential in shaping the host immune system function and ultimately affecting the outcome of interventions. We hypothesized that the loss of mucosal barrier in the gut may be associatedto acute and chronic periprosthetic joint infections (PJI). Zonulin, soluble CD14 (sCD14), and lipopolysaccharide (LPS) were tested in plasma as part of a prospective cohort study of patients undergoing primary arthroplasty or revision arthroplasty because of an aseptic failure or PJI (as defined by the 2018 criteria). All blood samples were collected before antibiotic administration. Samples were tested using commercially available enzyme-linked immunosorbent assays as markers for gut permeability. A total of 134 patients were included in the study of which 44 patients had PJI (30 chronic and 14 acute), and the remaining 90 patients were categorized as non-infected that included 64 patients revised for aseptic failure, and 26 patients undergoing primary total joint arthroplasty. Both Zonulin (7.642 ± 6.077 ng/mL vs 4.560 ± 3.833 ng/mL; p < 0.001) and sCD14 levels (555.721 ± 216.659 ng/mL vs 396.872 ± 247.920 ng/mL; p = 0.003) were significantly elevated in the PJI group compared to non-infected cases. Higher levels of Zonulin were found in acute infections compared to chronic PJI (11.595 ± 6.722 ng/mL vs. 5.798 ± 4.841 ng/mL; p = 0.005). This prospective study reveals a possible link between gut permeability and the 'gut-immune-joint axis' in PJI. If this association continues to be borne out with a larger cohort and more in-depth analysis, it will have a clinically significant implication in managing patients with PJI. It may be that in addition to the administration of antimicrobials, patients with PJI and other orthopaedic infections may benefit from administration of gastrointestinal modulators such as pro and prebiotics.


Assuntos
Artrite Infecciosa , Artroplastia de Quadril , Artroplastia do Joelho , Infecções Relacionadas à Prótese , Artrite Infecciosa/etiologia , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Humanos , Receptores de Lipopolissacarídeos , Permeabilidade , Estudos Prospectivos , Infecções Relacionadas à Prótese/cirurgia , Reoperação/efeitos adversos , Estudos Retrospectivos
4.
Fluids Barriers CNS ; 19(1): 70, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068542

RESUMO

Neurovascular coupling is a precise mechanism that induces increased blood flow to activated brain regions, thereby providing oxygen and glucose. In this study, we hypothesized that N-methyl-D-aspartate (NMDA) receptor signaling, the most well characterized neurotransmitter signaling system which regulates delivery of essential molecules through the blood-brain barrier (BBB). Upon application of NMDA in both in vitro and in vivo models, increased delivery of bioactive molecules that was mediated through modulation of molecules involved in molecular delivery, including clathrin and caveolin were observed. Also, NMDA activation induced structural changes in the BBB and increased transcellular permeability that showed regional heterogeneity in its responses. Moreover, NMDA receptor activation increased endosomal trafficking and facilitated inactivation of lysosomal pathways and consequently increased molecular delivery mediated by activation of calmodulin-dependent protein kinase II (CaMKII) and RhoA/protein kinase C (PKC). Subsequent in vivo experiments using mice specifically lacking NMDA receptor subunit 1 in endothelial cells showed decreased neuronal density in the brain cortex, suggesting that a deficiency in NMDA receptor signaling in brain endothelial cells induces neuronal losses. Together, these results highlight the importance of NMDA-receptor-mediated signaling in the regulation of BBB permeability that surprisingly also affected CD31 staining.


Assuntos
N-Metilaspartato , Receptores de N-Metil-D-Aspartato , Animais , Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Endoteliais/metabolismo , Camundongos , N-Metilaspartato/farmacologia , Permeabilidade , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Eur J Dermatol ; 32(3): 334-337, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36065544

RESUMO

Background: Exposome factors originating from the surrounding environment influence skin structure and physiology. Climate conditions (cold, high air humidity), solar radiation, and air pollutants induce epidermal barrier breakdown, and stimulate oxidative stress effects on the skin. It is currently unclear how skin barrier permeability, as well as skin pigmentation and inflammation, is affected by environmental factors in Antarctica. Objectives: The aim of this study was to evaluate the effect of short (four days) and longer (30 days) exposure to climate conditions of Antarctica on skin physiology parameters. Materials & Methods: Nineteen Caucasian healthy subjects were enrolled into two groups: Group 1 comprised nine subjects exposed to climate conditions of Antarctica for a short period (four days), and Group 2 comprised 10 subjects who spent 30 days under the same conditions. Skin physiological parameters, namely transepidermal water loss (TEWL), stratum corneum hydration, and erythema and melanin indices, were evaluated non-invasively at two locations­the cheek and volar forearm. In vivo skin carotenoid levels were assessed using a non-invasive, reflectance spectroscopy-based device. Results: Facial skin displayed increased TEWL, erythema and melanin levels, while no such difference between groups could be disclosed for volar forearm skin. In addition, no significant differences were observed for hydration and skin carotenoid levels. Conclusion: We disclose differences in skin physiology between the two groups, mainly affecting environment-exposed facial skin. Prolonged contact to exposome factors resulted in epidermal barrier impairment and an inflammatory response, while the increased melanin content may be a defensive mechanism of adaptation.


Assuntos
Eritema , Melaninas , Regiões Antárticas , Carotenoides , Eritema/etiologia , Humanos , Permeabilidade , Pigmentação da Pele , Água
6.
Biol Pharm Bull ; 45(9): 1246-1253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36047192

RESUMO

Microfluidic devices are attracting attention for their ability to provide a biomimetic microenvironment wherein cells are arranged in a particular pattern and provided fluidic and mechanical forces. In this study, we evaluated drug transport across Caco-2 cell layers in microfluidic devices and investigated the effects of fluid flow on drug transport and metabolism. We designed a microfluidic device that comprises two blocks of polydimethylsiloxane and a sandwiched polyethylene terephthalate membrane with pores 3.0 µm in diameter. When cultured in a dynamic fluid environment, Caco-2 cells were multilayered and developed microvilli on the surface as compared with a static environment. Drugs with higher lipophilicity exhibited higher permeability across the Caco-2 layers, as well as in the conventional method using Transwells, and the fluidic conditions had little effect on permeability. In the Caco-2 cell layers cultured in Transwells and microfluidic devices, the basal-to-apical transport of rhodamine 123, a substrate of P-glycoprotein, was greater than the apical-to-basal transport, and the presence of tariquidar, an inhibitor of P-glycoprotein, completely diminished asymmetric transport. Furthermore, fluidic conditions promoted the metabolism of temocapril by carboxylesterases. On the other hand, we showed that fluidic conditions have little effect on gene expression of several transporters and metabolic enzymes. These results provide useful information regarding the application of microfluidic devices in drug transport and metabolism studies.


Assuntos
Intestinos , Dispositivos Lab-On-A-Chip , Subfamília B de Transportador de Cassetes de Ligação de ATP , Células CACO-2 , Humanos , Absorção Intestinal , Permeabilidade
7.
Clin Immunol ; 242: 109107, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36049603

RESUMO

Systemic lupus erythematosus (SLE) is characterized by the production of anti-nuclear autoantibodies. Here, for the first time, we show that the abundances of gut permeability marker Zonulin and IgA1- and IgA2- subclasses are significantly higher in the fecal samples of SLE patients compared to HCs. Importantly, IgA-total, and IgA1- and IgA2-subclasses from SLE patients showed higher nAg reactivity titers. Notably, we found that not only the nuclear antigen (nAg) reactive fecal IgA1:IgA2 ratio is higher in SLE patients, but also the abundance and nAg reactivity of fecal IgA and subclasses, IgA1 particularly, correlate with the fecal levels of Zonulin, which is produced primarily in the small intestine. These observations that higher amounts of nAg-reactive IgA and gut permeability marker are produced, particularly, in the proximal gut suggest a compromised epithelial barrier function and pro-inflammatory characteristics of small intestine in SLE patients.


Assuntos
Imunoglobulina A , Lúpus Eritematoso Sistêmico , Antígenos Nucleares , Biomarcadores , Fezes , Humanos , Permeabilidade
8.
Fluids Barriers CNS ; 19(1): 72, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076213

RESUMO

BACKGROUND: Systemic drug delivery to the central nervous system is limited by presence of the blood-brain barrier (BBB). Low intensity focused ultrasound (LiFUS) is a non-invasive technique to disrupt the BBB, though there is a lack of understanding of the relationship between LiFUS parameters, such as cavitation dose, time of sonication, microbubble dose, and the time course and magnitude of BBB disruption. Discrepancies in these data arise from experimentation with modified, clinically untranslatable transducers and inconsistent parameters for sonication. In this report, we characterize microbubble and cavitation doses as LiFUS variables as they pertain to the time course and size of BBB opening with a clinical Insightec FUS system. METHODS: Female Nu/Nu athymic mice were exposed to LiFUS using the ExAblate Neuro system (v7.4, Insightec, Haifa, Israel) following target verification with magnetic resonance imaging (MRI). Microbubble and cavitation doses ranged from 4-400 µL/kg, and 0.1-1.5 cavitation dose, respectively. The time course and magnitude of BBB opening was evaluated using fluorescent tracers, ranging in size from 105-10,000 Da, administered intravenously at different times pre- or post-LiFUS. Quantitative autoradiography and fluorescence microscopy were used to quantify tracer accumulation in brain. RESULTS: We observed a microbubble and cavitation dose dependent increase in tracer uptake within brain after LiFUS. Tracer accumulation was size dependent, with 14C-AIB (100 Da) accumulating to a greater degree than larger markers (~ 625 Da-10 kDa). Our data suggest opening of the BBB via LiFUS is time dependent and biphasic. Accumulation of solutes was highest when administered prior to LiFUS mediated disruption (2-fivefold increases), but was also significantly elevated at 6 h post treatment for both 14C-AIB and Texas Red. CONCLUSION: The magnitude of LiFUS mediated BBB opening correlates with concentration of microbubbles, cavitation dose as well as time of tracer administration post-sonication. These data help define the window of maximal BBB opening and applicable sonication parameters on a clinically translatable and commercially available FUS system that can be used to improve passive permeability and accumulation of therapeutics targeting the brain.


Assuntos
Barreira Hematoencefálica , Microbolhas , Animais , Barreira Hematoencefálica/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Imageamento por Ressonância Magnética , Camundongos , Permeabilidade , Sonicação/métodos
9.
BMC Microbiol ; 22(1): 220, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36117157

RESUMO

BACKGROUND: The widespread use of antibiotics has led to the emergence of many drug-resistant strains; thus, the development of new antibacterial drugs is essential with antimicrobial peptides becoming the focus of research. This study assessed the antibacterial effect of a novel antimicrobial peptide, named LL-1 on Escherichia coli (E.coli) by determining the minimum inhibitory concentration (MIC) and the antibacterial curve. The interaction between LL-1 and E. coli DNA was then detected by nucleic acid gel electrophoresis. The effect of LL-1 on the E. coli cell membrane was assessed by detecting the leakage of ß-galactosidase, nucleic acid and protein. The influence of LL-1 on the intracellular ATP of E. coli was analysed by determining the concentration of intracellular ATP. Finally, the bacteria and colonies of E. coli treated with LL-1 were observed using scanning and transmission electron microscopy. RESULTS: The results suggested that the MIC value was 3.125 µg/ml, and the antibacterial effect was dose-dependent. LL-1 dose-dependently combined with E. coli DNA. LL-1 resulted in the leakage of intracellular ß-galactosidase, nucleic acid and protein, and decreased intracellular ATP concentrations of E. coli. Two MIC of LL-1 caused E. coli to shrink, resulting in a rough surface, plasmolysis, and bacterial adhesion. CONCLUSION: This study indicated that LL-1 had a good bactericidal effect on E. coli by mainly increasing the permeability of the cell membrane, leading to leakage of the intracellular content. This will lay the foundation for an in-depth study on the antibacterial mechanism of LL-1 against E. coli and its clinical application.


Assuntos
Infecções por Escherichia coli , Ácidos Nucleicos , Trifosfato de Adenosina/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Escherichia coli/genética , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Ácidos Nucleicos/metabolismo , Ácidos Nucleicos/farmacologia , Permeabilidade , beta-Galactosidase/metabolismo
10.
Sci Rep ; 12(1): 15531, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109537

RESUMO

Community acquired pneumonia, mainly caused by Streptococcus pneumoniae (S.pn.), is a common cause of death worldwide. Despite adequate antibiotic therapy, pneumococcal pneumonia can induce pulmonary endothelial hyperpermeability leading to acute lung injury, which often requires mechanical ventilation (MV) causing ventilator-induced lung injury (VILI). Endothelial stabilization is mediated by angiopoietin-1 induced Tie2 activation. PEGylated (polyethylene glycol) Tie2-agonist Vasculotide (VT) mimics Angiopietin-1 effects. Recently, VT has been shown to reduce pulmonary hyperpermeability in murine pneumococcal pneumonia. The aim of this study was to determine whether VT reduces lung damage in S.pn. infected and mechanically ventilated mice. Pulmonary hyperpermeability, immune response and bacterial load were quantified in S.pn. infected mice treated with Ampicillin + /-VT and undergoing six hours of MV 24 h post infection. Histopathological lung changes, Tie2-expression and -phosphorylation were evaluated. VT did not alter immune response or bacterial burden, but interestingly combination treatment with ampicillin significantly reduced pulmonary hyperpermeability, histological lung damage and edema formation. Tie2-mRNA expression was reduced by S.pn. infection and/or MV but not restored by VT. Moreover, Tie2 phosphorylation was not affected by VT. These findings indicate that VT may be a promising adjunctive treatment option for prevention of VILI in severe pneumococcal pneumonia.


Assuntos
Pneumonia Pneumocócica , Lesão Pulmonar Induzida por Ventilação Mecânica , Ampicilina/farmacologia , Angiopoietina-1/farmacologia , Animais , Antibacterianos/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Permeabilidade , Pneumonia Pneumocócica/tratamento farmacológico , Polietilenoglicóis/farmacologia , RNA Mensageiro/farmacologia , Respiração Artificial/efeitos adversos , Streptococcus pneumoniae , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle
11.
Commun Biol ; 5(1): 908, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064747

RESUMO

The blood-tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood-brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.


Assuntos
Neoplasias Encefálicas , Glioma , Metiltransferases , Proteínas de Ligação a RNA , Fatores de Processamento de Serina-Arginina , Animais , Astrócitos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Células Endoteliais/metabolismo , Epigênese Genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Humanos , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Microvasos/metabolismo , Permeabilidade , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
12.
J Agric Food Chem ; 70(36): 11301-11313, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36066018

RESUMO

The effectiveness of resveratrol (RES) on intestinal barrier dysfunction and colitis has been extensively studied. However, the specific effects of its microbial metabolites on gut barrier function remain unclear. Hence, we compared the protective effects of RES and its microbial metabolites dihydroresveratrol (DHR) and 3-(4-hydroxyphenyl)-propionic acid (4HPP) against intestinal barrier injury and colitis. Only 4HPP and RES significantly reduced paracellular permeability and the secretion of proinflammatory cytokines in lipopolysaccharides (LPS)-treated intestinal Caco-2 cells, which was consistent with the upregulation in tight junction (TJ) proteins. Furthermore, RES and 4HPP ameliorated intestinal barrier dysfunction and colonic inflammation in colitis mice, while DHR did not. In particular, the expressions of intestinal TJ proteins and Muc2 were restored by RES and 4HPP. The molecular mechanism involved the adenosine monophosphate-activated protein kinase (AMPK)-mediated activation of CDX2 and the regulation of the SIRT1/NF-κB pathway. These findings provide new insights into understanding the protective effects of RES against intestinal barrier damage and colitis.


Assuntos
Colite , Junções Íntimas , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células CACO-2 , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Permeabilidade , Resveratrol/farmacologia , Estilbenos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
13.
Crit Care ; 26(1): 273, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36096866

RESUMO

Preclinical studies in animals and human clinical trials question whether the endothelial glycocalyx layer is a clinically important permeability barrier. Glycocalyx breakdown products in plasma mostly originate from 99.6-99.8% of the endothelial surface not involved in transendothelial passage of water and proteins. Fragment concentrations correlate poorly with in vivo imaging of glycocalyx thickness, and calculations of expected glycocalyx resistance are incompatible with measured hydraulic conductivity values. Increases in plasma breakdown products in rats did not correlate with vascular permeability. Clinically, three studies in humans show inverse correlations between glycocalyx degradation products and the capillary leakage of albumin and fluid.


Assuntos
Permeabilidade Capilar , Glicocálix , Albuminas , Animais , Capilares , Glicocálix/metabolismo , Humanos , Permeabilidade , Ratos
14.
Nutrients ; 14(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36079905

RESUMO

Altered intestinal barrier permeability has been associated with obesity and its metabolic and inflammatory complications in animal models. The purpose of this systematic review is to assess the evidence regarding the association between obesity with or without Metabolic Syndrome (MetS) and alteration of the intestinal barrier permeability in humans. A systematic search of the studies published up until April 2022 in Latin America & Caribbean Health Sciences Literature (LILACS), PubMed, Scopus, Embase, and ScienceDirect databases was conducted. The methodological quality of the studies was assessed using the Newcastle-Ottawa scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) checklist. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to assess the quality of the evidence. Eight studies were included and classified as moderate to high quality. Alteration of intestinal barrier permeability was evaluated by zonulin, lactulose/mannitol, sucralose, sucrose, lactulose/L-rhamnose, and sucralose/erythritol. Impaired intestinal barrier permeability measured by serum and plasma zonulin concentration was positively associated with obesity with MetS. Nonetheless, the GRADE assessment indicated a very low to low level of evidence for the outcomes. Thus, clear evidence about the relationship between alteration of human intestinal barrier permeability, obesity, and MetS was not found.


Assuntos
Síndrome Metabólica , Humanos , Mucosa Intestinal/metabolismo , Intestinos , Lactulose/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Permeabilidade
15.
J Tradit Chin Med ; 42(5): 707-714, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36083477

RESUMO

OBJECTIVE: To investigate the protective effect of Yajieshaba (YJSB) on the intestinal barrier dysfunction induced by lipopolysaccharide (LPS). METHODS: C57BL/6 mice and rat intestinal epithelial cells were treated with LPS. Thiazolyl Blue Tetrazolium Bromide assay were used to detect cell viability. D-Lactate, diamine oxidase and myeloperoxidase and cytokines were determined by enzyme-linked immunosorbent assay. Western blot was used to detect apoptosis-related proteins and tight junction (TJ) proteins. Real-time quantitative polymerase chain reaction was used to quantify the levels of mRNA expression of cytokines. Histological analysis was performed by hematoxylin and eosin staining. An immunofluorescence staining assay was performed to determine the expression level of TJ protein. RESULTS: YJSB increased cell viability and decreased apoptosis, maintained intestinal permeability after LPS-induced. YJSB inhibited LPS-induced decrease of TJ protein expression, pro-inflammatory cytokine levels and neutrophil infiltration. CONCLUSION: YJSB protect against LPS-induced intestinal barrier dysfunction anti-inflammatory and anti-apoptosis, suggesting its therapeutic potential against intestinal barrier injury-related diseases.


Assuntos
Mucosa Intestinal , Lipopolissacarídeos , Animais , Citocinas/genética , Citocinas/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Ratos
16.
Annu Int Conf IEEE Eng Med Biol Soc ; 2022: 1346-1349, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36085687

RESUMO

In this work, an attempt has been made to discriminate drug with blood brain barrier (BBB) permeability using clinical phenotypes and extreme gradient boosting (XGBoost) methods. For this, the drug name and their clinical phenotypes namely side effects and indications are obtained from public available database. Prominent clinical phenotypes are selected using genetic algorithm (GA) and binary particle swarm optimization (BPSO). Four machine algorithms namely k-Nearest Neighbours, support vector machines, rotation forest and XGBoost are used for classification of BBB drugs. The result show that the proposed clinical phenotypes based features are able to distinguish drugs with BBB permeability. The maximum number of clinical phenotypes (69%) is reduced by BPSO and GA for classification. The XGBoost method is found to be most accurate [Formula: see text] is discriminating drugs with BBB permeability. The proposed approach are found to be capable of handling multi-parametric characteristics of the drugs. Particularly, the combination of XGBoost with combination of side effects and indications could be used for precision medicine applications. Clinical relevance- This establishes XGBoost approach for improved BBB permeability based drug classification with F1 =98.7% using exclusively clinical phenotypes.


Assuntos
Barreira Hematoencefálica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Algoritmos , Bases de Dados Factuais , Humanos , Permeabilidade , Fenótipo
17.
Molecules ; 27(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36014405

RESUMO

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).


Assuntos
Antimaláricos , Mycobacterium tuberculosis , Antimaláricos/farmacologia , HEPES , Mefloquina/farmacologia , Permeabilidade , Sais , Solubilidade
18.
Sci Rep ; 12(1): 14578, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028741

RESUMO

The small intestinal mucosa constitutes a physical barrier separating the gut lumen from sterile internal tissues. Junctional complexes between cells regulate transport across the barrier, preventing water loss and the entry of noxious molecules or pathogens. Inflammatory diseases in cattle disrupt this barrier; nonetheless, mechanisms of barrier disruption in cattle are poorly understood. We investigated the direct effects of three inflammatory cytokines, TNFα, IFNγ, and IL-18, on the bovine intestinal barrier utilizing intestinal organoids. Flux of fluorescein isothiocyanate (FITC)-labeled dextran was used to investigate barrier permeability. Immunocytochemistry and transmission electron microscopy were used to investigate junctional morphology, specifically tortuosity and length/width, respectively. Immunocytochemistry and flow cytometry was used to investigate cellular turnover via proliferation and apoptosis. Our study shows that 24-h cytokine treatment with TNFα or IFNγ significantly increased dextran permeability and tight junctional tortuosity, and reduced cellular proliferation. TNFα reduced the percentage of G2/M phase cells, and IFNγ treatment increased cell apoptotic rate. IL-18 did not directly induce significant changes to barrier permeability or cellular turnover. Our study concludes that the inflammatory cytokines, TNFα and IFNγ, directly induce intestinal epithelial barrier dysfunction and alter the tight junctional morphology and rate of cellular turnover in bovine intestinal epithelial cells.


Assuntos
Citocinas , Enteropatias , Animais , Bovinos , Dextranos , Células Epiteliais , Interleucina-18 , Mucosa Intestinal , Permeabilidade , Junções Íntimas , Fator de Necrose Tumoral alfa
19.
Mediators Inflamm ; 2022: 3855698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032782

RESUMO

Background: Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability. Methods: Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins. Results: Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins. Conclusion: NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.


Assuntos
Isquemia Encefálica , Armadilhas Extracelulares , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Barreira Hematoencefálica , Desoxirribonuclease I , Edaravone , Humanos , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade
20.
Planta ; 256(3): 60, 2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-35988126

RESUMO

MAIN CONCLUSION: The efficiency of suberized plant/environment interfaces as transpiration barriers is not established by the suberin polymer but by the wax molecules sorbed to the suberin polymer. Suberized cell walls formed as barriers at the plant/soil or plant/atmosphere interface in various plant organs (soil-grown roots, aerial roots, tubers, and bark) were enzymatically isolated from five different plant species (Clivia miniata, Monstera deliciosa, Solanum tuberosum, Manihot esculenta, and Malus domestica). Anatomy, chemical composition and efficiency as transpiration barriers (water loss in m s-1) of the different suberized cell wall samples were quantified. Results clearly indicated that there was no correlation between barrier properties of the suberized interfaces and the number of suberized cell layers, the amount of soluble wax and the amounts of suberin. Suberized interfaces of C. miniata roots, M. esculenta roots, and M. domestica bark periderms formed poor or hardly any transpiration barrier. Permeances varying between 1.1 and 5.1 × 10-8 m s-1 were very close to the permeance of water (7.4 × 10-8 m s-1) evaporating from a water/atmosphere interface. Suberized interfaces of aerial roots of M. deliciosa and tubers of S. tuberosum formed reasonable transpiration barriers with permeances varying between 7.4 × 10-10 and 4.2 × 10-9 m s-1, which were similar to the upper range of permeances measured with isolated cuticles (about 10-9 m s-1). Upon wax extraction, permeances of M. deliciosa and S. tuberosum increased nearly tenfold, which proves the importance of wax establishing a transpiration barrier. Finally, highly opposite results obtained with M. esculenta and S. tuberosum periderms are discussed in relation to their agronomical importance for postharvest losses and tuber storage.


Assuntos
Solanum tuberosum , Água , Permeabilidade , Plantas , Polímeros , Solo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...