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1.
Nanoscale ; 13(30): 12916-12928, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477775

RESUMO

One of the most realistic approaches for delivering actives (pharmaceuticals/cosmetics) deep into skin layers is encapsulation into nanoparticles (NPs). Nonetheless, molecular-level mechanisms related to active delivery from NPs to the skin have scarcely been studied despite the large number of synthesis and characterization studies. We herein report the underlying mechanism of active translocation and permeation through the outermost layer of skin, the stratum corneum (SC), via molecular dynamics (MD) simulations complemented by experimental studies. A SC molecular model is constructed using current state-of-the-art methodology via incorporating the three most abundant skin lipids: ceramides, free fatty acids, and cholesterol. As a potent antioxidant, ferulic acid (FA) is used as the model active, and it is loaded into Gelucire 50/13 NP. MD simulations elucidate that, first, FA-loaded NP approaches the skin surface quickly, followed by slight penetration and adsorption onto the upper skin surface; FA then translocates from the NP surface to the skin surface due to stronger NP-skin interactions compared to the FA-NP interactions; then, once FA is released onto the skin surface, it slowly permeates deep into the skin bilayer. Both the free energy and resistance to permeation not only indicate the spontaneous transfer of FA from the bulk to the skin surface, but they also reveal that the main barrier against permeation exists in the middle of the lipid hydrophobic tails. Significantly lower diffusion of FA is obtained in the main barrier region compared to the bulk. The estimated permeability coefficient (log P) values are found to be higher than the experimental values. Importantly, the permeation process evaluated via MD simulations perfectly matches with experiments. The study suggests a molecular simulation platform that provides various crucial insights relating to active delivery from loaded NP to skin, and it could facilitate the design and development of novel NP-based formulations for transdermal delivery and the topical application of drugs/cosmetics.


Assuntos
Simulação de Dinâmica Molecular , Nanopartículas , Administração Cutânea , Bicamadas Lipídicas , Lipídeos , Permeabilidade , Pele
2.
J Agric Food Chem ; 69(35): 10174-10183, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34449209

RESUMO

The intestinal tight junction (TJ) barrier plays a pivotal role in the regulation of intestinal homeostasis. This study investigated the effects of 3,5,7,3',4'-pentamethoxyflavone (PMF), a major polymethoxyflavone found in black ginger, on TJ barrier regulation using intestinal Caco-2 cells. PMF treatment enhanced the TJ barrier integrity in Caco-2 cells, indicated by increased transepithelial electrical resistance (control, 1261 ± 36 Ω·cm2; 100 µM PMF, 1383 ± 55 Ω·cm2 at 48 h, p < 0.05) and decreased permeability to fluorescein-conjugated dextran (control, 24.2 ± 1.8 pmol/(cm2 × h); 100 µM PMF, 18.6 ± 1.0 pmol/(cm2 × h), p < 0.05). Immunoblot analysis revealed that PMF increased the cytoskeletal association and cellular expression of the TJ proteins, zonula occludens-1, claudin-3, and claudin-4 (e.g., occludin; control, 1.00 ± 0.2; 100 µM PMF, 3.69 ± 0.86 at 48 h, p < 0.05). Quantitative reverse transcriptase-polymerase chain reaction analysis and a luciferase promoter assay showed that PMF enhanced the transcription of occludin, claudin-3, and claudin-4. The promoter assay with site-directed mutagenesis indicated that PMF-induced occludin and claudin-3 transcription was mediated by transcription factors, KLF5 and EGR1, respectively, while PMF activated claudin-4 transcription through GATA1 and AP1. Taken together, the transcriptional regulation of TJ proteins is involved in PMF-mediated promotion of the intestinal barrier in vitro.


Assuntos
Mucosa Intestinal , Junções Íntimas , Células CACO-2 , Flavonas , Humanos , Intestinos , Ocludina/genética , Permeabilidade
3.
Molecules ; 26(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34443336

RESUMO

We develop a suitable delivery system for niaouli essential oil (NEO) using a nanoemulsification method for acne vulgaris. Prepared nanoemulsions (NEs) were characterized for droplet dimension, rheology, surface charge, and stability. The ability of NEO formulations against Propionibacterium acnes and Staphylococcus epidermidis was investigated and all formulations showed antiacne potential in vitro. Ex vivo permeation studies indicated significant improvement in drug permeations and steady state flux of all NEO-NEs compared to the neat NEO (p < 0.05). On the basis of the studied pharmaceutical parameters, enhanced ex vivo skin permeation, and marked effect on acne pathogens, formulation NEO-NE4 was found to be the best (oil (NEO; 10% v/v); Kolliphor EL (9.25% v/v), Carbitol (27.75% v/v), and water (53% v/v)). Concisely, the in vitro and ex vivo results revealed that nanoemulsification improved the delivery as well as bioactivities of NEO significantly.


Assuntos
Portadores de Fármacos/química , Melaleuca/química , Nanoestruturas/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Emulsões , Óleos Voláteis/metabolismo , Permeabilidade , Pele/metabolismo , Staphylococcus epidermidis/efeitos dos fármacos
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360835

RESUMO

Defective intestinal tight junction (TJ) barrier is a hallmark in the pathogenesis of inflammatory bowel disease (IBD). To date, there are no effective therapies that specifically target the intestinal TJ barrier. Among the various probiotic bacteria, Bifidobacterium, is one of the most widely studied to have beneficial effects on the intestinal TJ barrier. The main purpose of this study was to identify Bifidobacterium species that cause a sustained enhancement in the intestinal epithelial TJ barrier and can be used therapeutically to target the intestinal TJ barrier and to protect against or treat intestinal inflammation. Our results showed that Bifidobacterium bifidum caused a marked, sustained enhancement in the intestinal TJ barrier in Caco-2 monolayers. The Bifidobacterium bifidum effect on TJ barrier was strain-specific, and only the strain designated as BB1 caused a maximal enhancement in TJ barrier function. The mechanism of BB1 enhancement of intestinal TJ barrier required live bacterial cell/enterocyte interaction and was mediated by the BB1 attachment to Toll-like receptor-2 (TLR-2) at the apical membrane surface. The BB1 enhancement of the intestinal epithelial TJ barrier function was mediated by the activation of the p38 kinase pathway, but not the NF-κB signaling pathway. Moreover, the BB1 caused a marked enhancement in mouse intestinal TJ barrier in a TLR-2-dependent manner and protected against dextran sodium sulfate (DSS)-induced increase in mouse colonic permeability, and treated the DSS-induced colitis in a TJ barrier-dependent manner. These studies show that probiotic bacteria BB1 causes a strain-specific enhancement of the intestinal TJ barrier through a novel mechanism involving BB1 attachment to the enterocyte TLR-2 receptor complex and activation of p38 kinase pathway.


Assuntos
Bifidobacterium bifidum/fisiologia , Colite/microbiologia , Mucosa Intestinal/microbiologia , Transdução de Sinais , Junções Íntimas , Receptor 2 Toll-Like/metabolismo , Animais , Células CACO-2 , Colite/prevenção & controle , Humanos , Mucosa Intestinal/metabolismo , Camundongos , NF-kappa B , Permeabilidade , Probióticos
5.
Chem Pharm Bull (Tokyo) ; 69(8): 727-733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334516

RESUMO

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.


Assuntos
Cafeína/farmacologia , Umidificadores , Pele/efeitos dos fármacos , Administração Cutânea , Ar , Animais , Cafeína/administração & dosagem , Cafeína/química , Umidade , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Pelados , Absorção Cutânea/efeitos dos fármacos , Temperatura , Água/química
6.
Chem Pharm Bull (Tokyo) ; 69(8): 806-810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334526

RESUMO

Effect of rubbing application on the skin permeation of a hydrophilic drug caffeine (CAF) and lipophilic drug rhododendrol (RD) from lotion and cream were investigated. Skin permeation of CAF was markedly increased by rubbing action independent of the formulation type. In addition, the skin penetration-enhancement effect was affected by the rubbing direction: rubbing application against the direction of hair growth showed the highest permeation compared with rubbing applications along the direction of hair growth and in a circular pattern on the skin. On the other hand, no enhancement effect was observed by the rubbing actions on the skin permeation of RD, regardless of formulation type. Change in the infundibula orifice size of hair follicles by the rubbing and following skin stretching may be related to the higher skin permeation for CAF. In contrast, high RD distribution into the stratum corneum may be a reason why no enhancement effect was observed by the rubbing action. These results can be helpful to predict safety and effectiveness of topically applied formulations.


Assuntos
Butanóis/farmacologia , Cafeína/farmacologia , Pomadas/farmacologia , Creme para a Pele/farmacologia , Pele/efeitos dos fármacos , Animais , Butanóis/química , Cafeína/química , Interações Hidrofóbicas e Hidrofílicas , Pomadas/química , Permeabilidade/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Creme para a Pele/química , Suínos
7.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360633

RESUMO

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.


Assuntos
Glucuronidase/metabolismo , Hiperglicemia/metabolismo , Podócitos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Glicólise , Masculino , Permeabilidade , Ratos Wistar
8.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360634

RESUMO

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.


Assuntos
Autofagia , Dermatopatias/etiologia , Humanos , Terapia de Alvo Molecular , Permeabilidade , Pele/metabolismo , Dermatopatias/metabolismo , Dermatopatias/terapia
9.
Nat Commun ; 12(1): 5042, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413297

RESUMO

Food production must increase significantly to sustain a growing global population. Reducing plant water loss may help achieve this goal and is especially relevant in a time of climate change. The plant cuticle defends leaves against drought, and so understanding water movement through the cuticle could help future proof our crops and better understand native ecology. Here, via mathematical modelling, we identify mechanistic properties of water movement in cuticles. We model water sorption in astomatous isolated cuticles, utilising three separate pathways of cellulose, aqueous pores and lipophilic. The model compares well to data both over time and humidity gradients. Sensitivity analysis shows that the grouping of parameters influencing plant species variations has the largest effect on sorption, those influencing cellulose are very influential, and aqueous pores less so but still relevant. Cellulose plays a significant role in diffusion and adsorption in the cuticle and the cuticle surfaces.


Assuntos
Celulose/metabolismo , Plantas/metabolismo , Água/metabolismo , Adsorção , Transporte Biológico , Difusão , Secas , Umidade , Modelos Biológicos , Permeabilidade , Epiderme Vegetal/metabolismo , Folhas de Planta/metabolismo
10.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443489

RESUMO

Hydrogel formulations (masks or patches, without tissue support) represent the new frontier for customizable skin beauty and health. The employment of these materials is becoming popular in wound dressing, to speed up the healing process while protecting the affected area, as well as to provide a moisturizing reservoir, control the inflammatory process and the onset of bacterial development. Most of these hydrogels are acrylic-based at present, not biodegradable and potentially toxic, due to acrylic monomers residues. In this work, we selected a new class of cellulose-derived and biodegradable hydrogel films to incorporate and convey an active compound for dermatological issues. Films were obtained from a combination of different polysaccharides and clays, and berberine hydrochloride, a polyphenolic molecule showing anti-inflammatory, immunomodulatory, antibacterial and antioxidant properties, was chosen and then embedded in the hydrogel films. These innovative hydrogel-based systems were characterized in terms of water uptake profile, in vitro cytocompatibility and skin permeation kinetics by Franz diffusion cell. Berberine permeation fitted well to Korsmeyer-Peppas kinetic model and achieved a release higher than 100 µg/cm2 within 24 h. The latter study, exploiting a reliable skin model membrane, together with the biological assessment, gained insights into the most promising formulation for future investigations.


Assuntos
Berberina/administração & dosagem , Sistemas de Liberação de Medicamentos , Metilgalactosídeos/química , Pele/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células HaCaT , Humanos , Cinética , Permeabilidade , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Difração de Raios X
11.
Eur J Pharm Sci ; 166: 105975, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34391880

RESUMO

Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm2 for 20 min were optimal. In vitro, EN-US showed a considerable enhancement of the permeation of GA, and the enhancement effect was stronger than that with the use of EN or US alone. In vivo antitumor study showed that the tumor growth was significantly inhibited after percutaneous administration of GA by EN-US, more than in the intravenous injection group. The penetration enhancement mechanism revealed that EN-US not only altered the structure of lipid bilayers and keratins to reduce the barrier effect of the stratum corneum but also produced diffusion channels in the skin under the cavitation effect of US, thereby promoting the skin penetration of GA. In addition, there was no observable skin irritation in mice after treatment with EN-US. Our study demonstrated that the combination of EN and US improved the skin permeation and retention of GA to enhance the anti-melanoma activity. This method also provides technical guidance for the future development of topical and transdermal therapeutic system of GA.


Assuntos
Melanoma , Neoplasias Cutâneas , Administração Cutânea , Animais , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Permeabilidade , Pele/metabolismo , Absorção Cutânea , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Xantonas
12.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445284

RESUMO

TMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca2+-dependent phospholipid scramblase and a Ca2+-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca2+-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na+ and Cl¯ (PNa/PCl) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, PNa/PCl was approximately 0.5, indicating a slight preference for Cl¯ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na+ with PNa/PCl reaching 3.7. Our results demonstrate that the time dependence of Ca2+ activation and the ion selectivity of TMEM16F depend on the recording configuration.


Assuntos
Anoctaminas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Animais , Ânions/metabolismo , Anoctaminas/genética , Cátions/metabolismo , Cloretos/metabolismo , Células HEK293 , Humanos , Transporte de Íons , Camundongos , Permeabilidade , Proteínas de Transferência de Fosfolipídeos/genética , Sódio/metabolismo
13.
Chem Biol Interact ; 347: 109615, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34363819

RESUMO

It has been reported that Dendrobium officinale polysaccharides (DOPS) could alleviate colitis in animal model and suppress the activation of NLRP3 inflammasome and ß-arrestin1 in vitro. However, it remains unclear whether DOPS has effect on protecting against colitis-induced pulmonary injury. The purpose of this study was to explore the protective effect and mechanism of DOPS on colitis-induced lung injury. A dextran sodium sulfate (DSS)-induced mice colitis model and lipopolysaccharide (LPS)-stimulated BEAS-2B cells model were applied in this study. The results showed that DOPS treatment restored histopathological changes, reduced inflammatory cells infiltration, pro-inflammatory cytokines levels, reactive oxygen species (ROS) formation and MDA generation, and increased anti-oxidative enzymes activities including SOD and GSH-Px in colitis mice. Further investigation showed that DOPS significantly inhibited the protein expression of TLR4, and apparently up-regulated proteins expressions of nuclear-Nrf2, HO-1 and NQO-1 in lung tissues of colitis mice and in BEAS-2B cells. These results indicated that DOPS significantly inhibited inflammation and oxidative stress to alleviate colitis-induced secondary lung injury, and its mechanisms are closely related to the inhibition of TLR4 signaling pathway and the activation of Nrf2 signaling pathway. DOPS may be a promising drug for alleviating colitis-induced lung injury.


Assuntos
Colite/complicações , Inflamação/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Linhagem Celular , Dendrobium/química , Humanos , Inflamação/patologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
14.
Zool Res ; 42(5): 562-573, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34355875

RESUMO

Inositol requiring mutant 80 (INO80) is a chromatin remodeler that regulates pluripotency maintenance of embryonic stem cells and reprogramming of somatic cells into pluripotent stem cells. However, the roles and mechanisms of INO80 in porcine pre-implantation embryonic development remain largely unknown. Here, we show that INO80 modulates trophectoderm epithelium permeability to promote porcine blastocyst development. The INO80 protein is highly expressed in the nuclei during morula-to-blastocyst transition. Functional studies revealed that RNA interference (RNAi)-mediated knockdown of INO80 severely blocks blastocyst formation and disrupts lineage allocation between the inner cell mass and trophectoderm. Mechanistically, single-embryo RNA sequencing revealed that INO80 regulates multiple genes, which are important for lineage specification, tight junction assembly, and fluid accumulation. Consistent with the altered expression of key genes required for tight junction assembly, a permeability assay showed that paracellular sealing is defective in the trophectoderm epithelium of INO80 knockdown blastocysts. Importantly, aggregation of 8-cell embryos from the control and INO80 knockdown groups restores blastocyst development and lineage allocation via direct complementation of the defective trophectoderm epithelium. Taken together, these results demonstrate that INO80 promotes blastocyst development by regulating the expression of key genes required for lineage specification, tight junction assembly, and fluid accumulation.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Blastocisto/fisiologia , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mórula/fisiologia , Suínos , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Proteínas de Ligação a DNA/genética , Técnicas de Cultura Embrionária/veterinária , Fertilização In Vitro , Regulação da Expressão Gênica/fisiologia , Oócitos/fisiologia , Permeabilidade
15.
Sci Total Environ ; 796: 149066, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34328883

RESUMO

Carbon dioxide (CO2) geological storage (CGS) is an effective way for reducing greenhouse emissions. The injection of CO2 into the deep formation changes the pore pressure and effective stresses in the reservoir, thus leading to changes in stress-dependent porosity and permeability. These changes give feedback to the injection rate, migration, storage amount of CO2 in the target reservoir. In this study, we focus on the Liujiagou reservoir, one of the first demonstration CGS project in saline aquifers in the Ordos Basin, China. The mathematical model that defines the relationship between the permeability and the injection pressure (or effective stress) was obtained by laboratory experiments. On this basis, the permeability-stress law was successfully integrated into the thermo-hydro-mechanical (THM) coupled simulator TOUGH2Biot to simulate the feedback between the flow and mechanical response. The improved simulator was used to analyze the effects of reservoir mechanical response on CO2 geological storage efficiency. The modeling results indicated that the mechanical response of the reservoir had little effect on reservoir pore pressure and porosity, but it had a significant effect on reservoir permeability and the migration distance, injection rate, and total storage amount of CO2. The maximum increases in the lateral migration distance of CO2 caused by the reservoir mechanical response reached 13.1% using 5 MPa injection pressure. In addition, the total CO2 storage amount increased by 11.6% after 5 years of continuous CO2 injection. Furthermore, when the injection pressure was greater, the reservoir mechanical response had stronger enhancement effects on CGS. Overall, the results suggested that the reservoir mechanical response during CO2 injection was beneficial for increasing CGS efficiency and emphasized the importance of considering the mechanical response in CGS.


Assuntos
Dióxido de Carbono , Água Subterrânea , Dióxido de Carbono/análise , Geologia , Laboratórios , Permeabilidade
16.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299013

RESUMO

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.


Assuntos
Colite/metabolismo , Interleucina-10/genética , Mucosa Intestinal/efeitos dos fármacos , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Piroxicam/farmacologia , Receptores Opioides/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naloxona/farmacologia , Permeabilidade/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Índice de Gravidade de Doença
17.
J Chem Inf Model ; 61(7): 3681-3695, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34236179

RESUMO

Membrane permeability is a significant obstacle facing the development of cyclic peptide drugs. However, membrane permeation mechanisms are poorly understood. To investigate common features of permeable (and nonpermeable) designs, it is necessary to reproduce the membrane permeation process of cyclic peptides through the lipid bilayer. We simulated the membrane permeation process of 100 six-residue cyclic peptides across the lipid bilayer based on steered molecular dynamics (MD) and replica-exchange umbrella sampling simulations and predicted membrane permeability using the inhomogeneous solubility-diffusion model and a modified version of it. Furthermore, we confirmed the effectiveness of this protocol by predicting the membrane permeability of 56 eight-residue cyclic peptides with diverse chemical structures, including some confidential designs from a pharmaceutical company. As a result, a reasonable correlation between experimentally assessed and calculated membrane permeability of cyclic peptides was observed for the peptide libraries, except for strongly hydrophobic peptides. Our analysis of the MD trajectory demonstrated that most peptides were stabilized in the boundary region between bulk water and membrane and that for most peptides, the process of crossing the center of the membrane is the main obstacle to membrane permeation. The height of this barrier is well correlated with the electrostatic interaction between the peptide and the surrounding media. The structural and energetic features of the representative peptide at each vertical position within the membrane were also analyzed, revealing that peptides permeate the membrane by changing their orientation and conformation according to the surrounding environment.


Assuntos
Bicamadas Lipídicas , Simulação de Dinâmica Molecular , Conformação Molecular , Peptídeos Cíclicos , Permeabilidade
18.
Langmuir ; 37(30): 8971-8977, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34242506

RESUMO

The stratum corneum (SC) covers the outer surface of the skin and prevents the permeation of unwanted materials; however, the SC barrier also inhibits the desired permeation of active pharmaceutical ingredients (APIs). Therefore, the development of a novel method to enhance the permeation of APIs through the skin has been the focus of significant attention. Palmitoyl-glycine-histidine (Pal-GH)-comprising palmitic acid, glycine, and histidine-can be co-assembled with various additives to form a thixotropic hydrogel. Self-assembled Pal-GH enhances the permeation of ivermectin through the skin; however, the permeation mechanism is unclear and has not yet been discussed in detail. In the present study, the self-assembled structure of Pal-GH was analyzed using X-rays and infrared, and its permeation enhancement effect was verified. There was a correlation between the amount of Pal-GH in the skin and permeation enhancement, suggesting the involvement of the Pal-GH molecule. The presence of Pal-GH in the skin was confirmed by liquid chromatography-mass spectrometry and fluorescence labeling (labeling with Thioflavin T, a fluorescent dye that responds to ß-sheets). The self-assembled Pal-GH permeated the SC without disrupting its organization. However, the structure of the Pal-GH caused changes to the lipid organization of the SC. The findings indicated that self-assembled Pal-GH is an effective permeation enhancer for transdermal delivery and does not induce skin irritation.


Assuntos
Histidina , Absorção Cutânea , Administração Cutânea , Glicina , Permeabilidade , Pele/metabolismo
19.
Int J Pharm ; 606: 120898, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34310952

RESUMO

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment's pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies.


Assuntos
Atropina , Organofosfatos , Administração Sublingual , Animais , Humanos , Concentração de Íons de Hidrogênio , Permeabilidade , Suínos , Comprimidos
20.
Arterioscler Thromb Vasc Biol ; 41(9): 2357-2369, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34196216

RESUMO

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) ß influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Transição Epitelial-Mesenquimal , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Movimento Celular , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Permeabilidade , Fenótipo , Transdução de Sinais
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