RESUMEN

Background: Existing studies have shown that sacubitril-valsartan ameliorated atrial remodeling in atrial fibrillation (AF) and favored maintenance of sinus rhythm in patients with AF and heart failure. However, the effect of sacubitril-valsartan in patients with persistent AF is yet unknown. We aimed to evaluate the effect of sacubitril-valsartan on restoration and maintenance of sinus rhythm in patients with persistent AF who underwent electrical cardioversion (ECV). Method: Consecutive patients with persistent AF who underwent ECV between 1 January 2016 and 30 September 2020 were investigated in this retrospective cohort study. All eligible patients were categorized into sacubitril-valsartan users and sacubitril-valsartan non-users based on whether they received treatment with sacubitril-valsartan or not. The endpoint was ineffictive ECV, defined as the composite of failure to terminate AF or any recurrence of AF during 30 days follow-up. Results: A total of 76 patients were enrolled in this study, including 28 sacubitril-valsartan users and 48 non-users. Within a follow-up of 30 days after ECV, the endpoint had occurred in 7 (25%) of 28 sacubitril-valsartan users and 25 (52%) of 48 non-users. Significantly lower rate of ineffictive ECV in sacubitril-valsartan users compared with non-users was shown in Kaplan-Meier survival curves (P = 0.02; Log-rank test). Multivariate Cox regression analysis indicated that sacubitril-valsartan use (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.14-0.91), amiodarone use (HR, 0.32; 95% CI, 0.13-0.78), left atrial diameter ≤ 39 mm (HR, 0.21; 95% CI, 0.06-0.71) were independently associated with a decreased rate of ineffective electrical cardioversion.

RESUMEN

In this paper, an image-based visual servoing (IBVS) controller with a 6 degree-of-freedom robotic manipulator that tracks moving objects is investigated using the proposed Deep Q-Networks and proportional-integral-derivative (DQN-PID) controller. First, the classical IBVS controller and the problem of feature loss and large steady-state error for tracking moving targets are introduced. Then, a DQN-PID based IBVS method is proposed to solve the problem of feature loss and large steady-state error and improve the servo precision, as the existing methods are hard to use for solve the problems. Specifically, the IBVS method is inherited by our controller to build the tracking model, and a value-based reinforcement learning method is proposed as an adaptive law for dynamically tuning the PID parameters in the discrete space, which can track the moving target and keep the servo feature in the field of the camera. Finally, compared with the different existing methods, the DQN-PID based IBVS method has merits of higher accuracy and more stable tracking, or generalization.

RESUMEN

In this paper, a novel path planning algorithm with Reinforcement Learning is proposed based on the topological map. The proposed algorithm has a two-level structure. At the first level, the proposed method generates the topological area using the region dynamic growth algorithm based on the grid map. In the next level, the Multi-SARSA method divided into two layers is applied to find a near-optimal global planning path, in which the artificial potential field method, first of all, is used to initialize the first Q table for faster learning speed, and then the second Q table is initialized with the connected domain obtained by topological map, which provides the prior information. A combination of the two algorithms makes the algorithm easier to converge. Simulation experiments for path planning have been executed. The results indicate that the method proposed in this paper can find the optimal path with a shorter path length, which demonstrates the effectiveness of the presented method.

RESUMEN

Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus. Establishment of hepatotoxicity model of APAP in vitro and in vivo. In vitro, HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo, C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1ß and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils' damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1.

RESUMEN

Robot grasping has become a very hot research field so that the requirements for robot operation are getting higher and higher. In previous research studies, the use of traditional target detection algorithms for grasping is often very inefficient, and this article is dedicated to improving the deep reinforcement learning algorithm to improve the grasping efficiency and solve the problem of robots dealing with the impact of unknown disturbances on grasping. Using the characteristic that deep reinforcement learning actively explores the unknown environment, a Gaussian parameter Deep Deterministic Policy Gradient (Gaussian-DDPG) algorithm based on the Importance-Weighted Autoencoder (IWAE) is proposed to realize the robot's autonomous learning of the grasping task. Traditional coordinate positioning methods and deep learning methods have poor grasping effects for disturbed situations (such as the movement of the target object). The IWAE algorithm is used to compress the high-dimensional information of the original visual input to the hidden space and pass it to the deep reinforcement learning network as part of the state value. Based on the classic DDPG algorithm, it smoothly adds Gaussian parameters to improve the exploratory nature of the algorithm, dynamically sets the robot grasping space parameters to adapt to the workspace of multiple scales, and finally, realizes the accurate grasping of the robot. Relying on the possible position information deviation of the visual information, the control of the grasping position by the manipulator torque information is further optimized to improve the grasping efficiency of disturbed objects.

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: As the largest genus of Gentianaceae family, the Gentiana genus harbors over 400 species, widely distributed in the alpine areas of temperate regions worldwide. Plants from Gentiana genus are traditionally used to treat a wide variety of diseases including easing pain dispelling rheumatism, and treating liver jaundice, chronic pharyngitis and arthritis in China since ancient times. In this review, a systematic and constructive overview of the traditional uses, phytochemistry, molecular mechanisms, toxicology and pharmacological activities of the researched species of genus Gentiana is provided. MATERIALS AND METHODS: The used information in this review is based on various databases (PubMed, Science Direct, Wiley online library, Wanfang Data, Web of Science) through a search using the keyword "Gentiana" in the period of 1981-2019. Besides, other ethnopharmacological information was acquired from Chinese herbal classic books and Chinese pharmacopoeia 2015 edition. RESULTS: The plants from Gentiana genus have a long tradition of various medicinal uses in Europe and Asia. Phytochemical studies showed that the main bioactive components isolated from this genus includes iridoids xanthones and flavonoids. These compounds and extracts isolated from this genus show a wide range of protective activities including hepatic protection, gastrointestinal protection, cardiovascular protection, immunomodulation, joint protection, pulmonary protection, bone protection and reproductive protection. Molecular mechanism studies also indicated several potential therapeutic targets in the treatment of certain diseases by plants from this genus. Besides, natural products from this plant show no significant animal toxicity, cytotoxicity or genotoxicity. CONCLUSION: This review summarized the traditional medicinal uses, phytochemistry, pharmacology, toxicology and molecular mechanism of genus Gentiana, providing references and research tendency for plant-based drug development and further clinical studies.

Asunto(s)

Medicamentos Herbarios Chinos/uso terapéutico , Etnofarmacología/métodos , Gentiana , Fitoquímicos/uso terapéutico , Animales , Fármacos Cardiovasculares/aislamiento & purificación , Fármacos Cardiovasculares/uso terapéutico , Medicamentos Herbarios Chinos/aislamiento & purificación , Etnofarmacología/tendencias , Fármacos Gastrointestinales/aislamiento & purificación , Fármacos Gastrointestinales/uso terapéutico , Humanos , Fitoquímicos/aislamiento & purificación

RESUMEN

HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-ß-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1ß secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Receptores Purinérgicos P2X7/metabolismo , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Retroalimentación Fisiológica , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Humanos , Cirrosis Hepática/patología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Tetrazoles/farmacología , Tioacetamida/toxicidad

RESUMEN

BACKGROUND AND PURPOSE: Regulating macrophage-hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis. EXPERIMENTAL APPROACH: A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7 receptors. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation. Western blots, RT-PCR and immunohistochemical analysis were used, along with over-expression and silencing of P2X7 receptors. KEY RESULTS: Knockdown or overexpression of P2X7 receptors in THP-1 macrophages affected release of mature IL-1ß and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB-AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1-AMPK-SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL-1ß release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase-1 and NF-κB, release of IL-1ß, calcium influx and PI uptake were reduced by 2354glu. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP-activated THP-1 macrophages pretreated with 2354glu. CONCLUSION AND IMPLICATIONS: Modulation of P2X7 receptors in macrophages regulated lipid accumulation in hepatocytes during alcoholic hepatosteatosis. 2354glu might be a promising candidate that targets P2X7 receptors in macrophages interacting with hepatocytes during alcoholic hepatosteatosis.

Asunto(s)

Macrófagos , Receptores Purinérgicos P2X7 , Adenosina Trifosfato , Animales , Glucósidos , Hepatocitos/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Estilbenos

RESUMEN

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 µM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-ß-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.

Asunto(s)

Diseño de Fármacos , Fibrosis/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Fibrosis/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Relación Estructura-Actividad

RESUMEN

Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 ß release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.

Asunto(s)

Proteínas Quinasas Activadas por AMP/metabolismo , Acetaminofén/administración & dosificación , Acetaminofén/efectos adversos , Benzoquinonas/farmacología , Benzoquinonas/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Sobredosis de Droga/complicaciones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fitoterapia , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Modelos Animales de Enfermedad , Hepatocitos/efectos de los fármacos , Humanos , Inflamación , Masculino , Ratones

RESUMEN

Inspired by cocktails, we designed a medium term (2-20 weeks) male contraceptive strategy. Through a sequential injection process of four reagents (calcium alginate hydrogel, PEG-Au nanoparticles (PEG-AuNps), EDTA, and PEG-AuNps), physical clogging of the vas deferens and chemical inhibition of the sperm motility were realized simultaneously. The contraceptive period could be directly preset by adjusting the injection ratio of each reagent. More interesting, the embolism area could be readily dredged through a short-time noninvasive near-infrared irradiation. The present study offered an effective and reversible manner to fill the gap of current medium-term contraceptive strategy. In addition, the proposed in vivo pipeline plugging technology, with a flexible noninvasive self-cleared characteristic, might also provide a convenient and reliable strategy for some other biomedical engineering researches.

Asunto(s)

Anticonceptivos Masculinos/química , Alginatos/química , Ácido Edético/química , Oro/química , Humanos , Hidrogeles/química , Masculino , Nanopartículas del Metal/química , Polietilenglicoles/química

RESUMEN

Pleurotus citrinopileatus (golden oyster mushroom) is a widely used edible mushroom. We investigated the inhibitory effect of P. citrinopileatus aqueous extract against alcoholic steatohepatitis and its underlying mechanism. Acute and chronic ethanol-feeding murine models were established by intragastrically administering ethanol or feeding an ethanol-containing Lieber-DeCarli liquid diet to male C57BL/6 mice. In both models, P. citrinopileatus decreased serum alanine aminotransferase (ALT), aspartate transaminase (AST), triglyceride (TG), and hepatic TG levels. Hematoxylin and eosin (HE) and Oil Red O staining confirmed that P. citrinopileatus ameliorated both acute and chronic alcoholic hepatosteatosis, characterized by regulation of lipid-metabolism-related proteins, including sirtuin 1 (SIRT1), AMP-activated kinase (AMPK), and sterol regulatory element-binding protein (SREBP1). P. citrinopileatus reversed inflammatory response via modulating purinergic receptor P2X ligand-gated ion channel 7 (P2X7R)-NOD-like receptor pyrin domain 3 (NLRP3) inflammasome. P. citrinopileatus restored the expressions of those proteins to a normal level. In addition, HepG2 cells were incubated with P. citrinopileatus prior to ethanol stimulation. P. citrinopileatus reduced ethanol exposure-induced lipid deposition. Concomitantly, P. citrinopileatus increased AMPK and SIRT1 expressions, which were reduced by ethanol treatment. P. citrinopileatus ameliorated alcoholic hepatic steatosis and accompanied inflammatory response via regulating SIRT1-AMPK and P2X7R-NLRP3 inflammasome activation, highlighting a promising strategy and utility of P. citrinopileatus for alcoholic steatohepatitis as dietary health supplements.

Asunto(s)

Hígado Graso Alcohólico/tratamiento farmacológico , Inflamasomas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Pleurotus/química , Receptores Purinérgicos P2X7/inmunología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/inmunología , Animales , Hígado Graso Alcohólico/genética , Hígado Graso Alcohólico/inmunología , Hígado Graso Alcohólico/metabolismo , Células Hep G2 , Humanos , Inflamasomas/genética , Hígado/efectos de los fármacos , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptores Purinérgicos P2X7/genética , Sirtuina 1/genética , Sirtuina 1/inmunología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/inmunología , Triglicéridos/metabolismo

RESUMEN

The current study was aimed to reveal that leucodin, a sesquiterpene lactone from Artemisia capillaris could inhibit the inflammatory response in macrophages and the lipid accumulation in hepatocytes via P2x7R-NLRP3 inflammasome activation. Several types of macrophages including mouse peritoneal macrophages, mouse bone marrow-derived macrophages and human macrophages THP-1 cells were pretreated with different concentrations of leucodin for 1 h and then stimulated with LPS and ATP. LPS plus ATP initiated IL-1ß cleavage and release in mouse peritoneal macrophages and peaked at 4 h. Leucodin did not show significant toxicity within 200 µM and effectively inhibited pro-IL-1ß cleavage and release of mature-IL-1ß in macrophages. Also, P2x7R antagonist and caspase-1 inhibitor also decreased IL-1ß release and cleavage. Additionally, leucodin suppressed P2x7R, TLR4 and NLRP3 expression in LPS/ATP-stimulated macrophages. HepG2 cells were pretreated with different concentrations of leucodin for 1 h and then exposed to ethanol for 24 h. Leucodin suppressed lipid accumulation and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells exposed to ethanol. In addition, leucodin inhibited the expression of sterol regulatory element binding protein-1 (SREBP1) and ACC in ethanol-treated HepG2 cells. Leucodin possessed the capacity for inhibiting inflammatory response in macrophages and suppressing lipid accumulation in hepatocytes, suggesting a promising therapeutic potential targeting inflammation and lipid metabolism in alcoholic liver disease.

Asunto(s)

Hígado Graso/patología , Hepatocitos/metabolismo , Inflamación/patología , Metabolismo de los Lípidos , Hepatopatías Alcohólicas/patología , Macrófagos Peritoneales/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sesquiterpenos/farmacología , Adenosina Trifosfato/farmacología , Animales , Línea Celular , Etanol , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Interleucina-1beta/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipopolisacáridos/farmacología , Hepatopatías Alcohólicas/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo

RESUMEN

Dihydroquercetin (TAX) is the most abundant dihydroflavone found in onions, milk thistle, and Douglas fir bark. We investigated whether TAX could inhibit lipid accumulation in alcoholic liver steatosis in vivo and in vitro. An in vivo model was established by intragastrically treating mice with ethanol, and an in vitro model was created by treating HepG2 cells with ethanol. TAX regulated SREBP1 and ACC expression by elevating LKB1 and AMPK phosphorylation. Also, TAX upregulated SIRT1 expression, which was suppressed by ethanol intake. Decreased expression of P2X7R and NLRP3 and suppressed cleavage of caspase-1 by TAX resulted in the inhibition of IL-1ß production and release. Additionally, TAX reduced lipogenesis and promoted lipid oxidation via the regulation of AMPK and ACC in ethanol-treated steatotic HepG2 cells. TAX downregulated IL-1ß cleavage responses to LPS and ATP stimulation in HepG2 cells. P2X7R deficiency attenuated lipid accumulation, characterized by increased AMPK activity and decreased SREBP1 expression in ethanol-treated HepG2 cells. Our data showed that TAX exhibited the ability to inhibit lipogenesis and a hepatoprotective capacity, indicating that TAX has therapeutic potential for preventing alcoholic liver steatosis.

Asunto(s)

Proteínas Quinasas Activadas por AMP/metabolismo , Hígado Graso Alcohólico/tratamiento farmacológico , Inflamasomas/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Quercetina/análogos & derivados , Receptores Purinérgicos P2X7/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Hígado Graso Alcohólico/genética , Hígado Graso Alcohólico/metabolismo , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Quercetina/administración & dosificación , Receptores Purinérgicos P2X7/genética

RESUMEN

BACKGROUND AND PURPOSE: Regulating P2X7 receptor-mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa. EXPERIMENTAL APPROACH: In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP. KEY RESULTS: In both the acute and chronic alcohol-induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up-regulated SREBP1, down-regulated PPARα and phosphorylated acetyl-CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor-NLRP3 activation by gentiopicroside inhibited IL-1ß production. In ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1ß from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside. CONCLUSIONS AND IMPLICATIONS: Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.

Asunto(s)

Proteínas Quinasas Activadas por AMP/metabolismo , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/prevención & control , Glucósidos Iridoides/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adenosina Trifosfato , Animales , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Etanol/antagonistas & inhibidores , Etanol/farmacología , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipopolisacáridos , Macrófagos/metabolismo , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , PPAR alfa/metabolismo , Fosforilación/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X7/efectos de los fármacos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Transaminasas/sangre , Triglicéridos/sangre , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

In current study, we aimed to reveal the potential antifibrotic effects of oligomeric proanthocyanidin (OPC) from grape seeds on lipopolysaccharide (LPS)-activated, HSC-T6, a rat hepatic stellate cell line. HSC-T6 cells were treated with OPC 1h prior to LPS, and then incubated for indicated time. OPC inhibited cells viability of HSC-T6 cells and decrease protein expression of collagen I, α-smooth muscle actin (α-SMA), tissue inhibitors of metalloproteinases I (TIMP-1) on LPS-induced HSC-T6 cells. OPC also significantly inhibited phosphorylation of LPS-stimulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Furthermore, OPC pretreatment blocked LPS-triggered nuclear factor-kappa B (NF-κB) translocation from cytosol to nuclear. OPC, as well as specific inhibitors of NF-κB, PI3K and JNK could effectively inhibited α-SMA and collagen I expression. In conclusion, we demonstrated that the anti-fibrotic mechanism of OPC might be involved the inhibition of HSC activation and transdifferentiation by suppressing NF-κB activation through JNK/ERK MAPK and PI3K/Akt phosphorylation. Thus, OPC possesses the potential inhibitory property of HSC activation through NF-κB modulation involving MAPK-PI3K/AKT pathways.

Asunto(s)

Células Estrelladas Hepáticas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proantocianidinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Semillas/química , Vitis/química , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Transdiferenciación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas , Transducción de Señal/efectos de los fármacos

RESUMEN

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, µ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, µ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, µ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the µ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for µ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional µ-agonist analgesics. These findings suggest that the development of δ>µâˆ¼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

Asunto(s)

Analgesia , Analgésicos Opioides/farmacología , Dolor/tratamiento farmacológico , Piperazinas/farmacología , Insuficiencia Respiratoria/tratamiento farmacológico , Tiofenos/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/química , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Conformación Molecular , Dimensión del Dolor , Piperazinas/administración & dosificación , Piperazinas/química , Ratas , Ratas Wistar , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Relación Estructura-Actividad , Tiofenos/administración & dosificación , Tiofenos/química

RESUMEN

OBJECTIVE: The aim of this study was to evaluate the microstructure and mechanical behavior of polymer-infiltrated zirconia ceramics as a function of pre-sintering temperature (1000-1150°C). METHODS: Polymer-infiltrated zirconia ceramics were prepared by combining the porous zirconia networks and polymer through infiltration and polymerization. XRD was employed to determine phase structure. The microstructure and fracture mechanism were observed by SEM. Flexural strength and fracture toughness were measured by three-point bending method and single-edge-notched beam method, respectively. A nanoindentation system was employed to determine elastic modulus and hardness. RESULTS: Different porosities and polymer contents can be obtained by tuning the pre-sintered temperature of zirconia ceramic precursors. Zirconia network porosity varies from 46.3% to 34.7% and the relevant polymer content ranges from 18.4wt.% to 12.3wt.% when the pre-sintered temperature is set from 1000°C to 1150°C. The flexural strength, fracture toughness, hardness, and elastic modulus values of the specimen pre-sintered at 1150°C are 240.9MPa, 3.69MPam1/2, 3.1GPa, and 58.8GPa, respectively. CONCLUSION: The pre-sintering temperature has a significant effect on the microstructure and mechanical properties of polymer-infiltrated zirconia ceramics and the optimal pre-sintering temperature is 1150°C. CLINICAL SIGNIFICANCE: Specimen pre-sintered at 1150°C shows tooth-like mechanical properties, suggesting a promising restorative material in dental clinic. Moreover, the synthesis process is simple and can be easily performed in a prosthesis laboratory.

Asunto(s)

Cerámica/química , Materiales Dentales/química , Porcelana Dental/química , Polímeros/química , Circonio/química , Óxido de Aluminio/química , Bisfenol A Glicidil Metacrilato/química , Módulo de Elasticidad , Dureza , Calor , Ensayo de Materiales , Fenómenos Mecánicos , Nanocompuestos , Docilidad , Porosidad , Estrés Mecánico , Resistencia a la Tracción

RESUMEN

OBJECTIVE: To evaluate the microstructure and mechanical behavior of polymer-infiltrated zirconia ceramics as a function of Fe2O3 concentration (0-0.3mol%). METHODS: Polymer-infiltrated zirconia ceramics with different concentrations of Fe2O3 were prepared by infiltration and polymerization. XRD was employed to determine phase structure. The microstructure and fracture mechanism was observed by SEM. Flexural strength and fracture toughness were measured by three-point bending method and single-edge-notched beam method, respectively. Data were analyzed by Weibull distribution. A nanoindentation system was employed to determine elastic modulus and hardness. RESULTS: With increasing content of Fe2O3, the flexural strength, fracture toughness, elastic modulus and hardness are all greatly enhanced and the chromatic behavior also improves significantly. As a tradeoff made between strength and elastic modulus, specimen containing 0.2mol% Fe2O3 is found to be the better one, with flexural strength and fracture toughness values being 336.8MPa and 3.91MPam1/2, respectively. Moreover, it maintains a relatively low elastic modulus of 88.2GPa and a moderate hardness of 4.8GPa, close to those of natural enamel. SIGNIFICANCE: This polymer-infiltrated zirconia ceramic material is a dental material of biomimetic chromatic and mechanical properties.

Asunto(s)

Porcelana Dental , Polímeros , Circonio , Cerámica , Compuestos Férricos , Dureza , Ensayo de Materiales , Docilidad