RESUMEN
Nasopharyngeal carcinoma, a malignant tumor prevalent in southeast Asia and north Africa, still lacks effective treatment. Esketamine, an N-methyl-D-aspartatic acid (NMDA) receptor (NMDAR) antagonist, is widely used in clinical anesthesia. Emerging evidence suggests that esketamine plays an important role in inhibiting tumor cell activity. However, the underlying mechanisms of esketamine on nasopharyngeal carcinoma remain unknown. In this study, we found that esketamine inhibited the proliferation and migration of nasopharyngeal carcinoma cells. Mechanically, transcriptome sequencing and subsequent verification experiments revealed that esketamine promoted the apoptosis of nasopharyngeal carcinoma cells through endoplasmic reticulum stress PERK/ATF4/CHOP signaling pathway mediated by NMDAR. Additionally, when combined with esketamine, the inhibitory effect of cisplatin on the proliferation of nasopharyngeal carcinoma cells was significantly enhanced. These findings provide new insights into future anti-nasopharyngeal carcinoma clinical strategies via targeting the NMDAR/PERK/CHOP axis alone or in combination with cisplatin.
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Ketamina , Neoplasias Nasofaríngeas , eIF-2 Quinasa , Humanos , eIF-2 Quinasa/metabolismo , Cisplatino/farmacología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Apoptosis , Neoplasias Nasofaríngeas/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción Activador 4/metabolismoRESUMEN
BACKGROUND: Curcumin has attracted much attention due to its wide range of therapeutic effects. In this study, we used serum collected from patients undergoing one-lung ventilation (OLV) to establish an in vitro acute lung injury (ALI) model to explore the potential protective mechanism of curcumin on ALI. Our study provides a new reference for the prevention and treatment of ALI induced by OLV. METHODS: A549 cells were treated with 20% serum from patients undergoing OLV to establish an in vitro ALI model. Curcumin, at a dose of 40 µg/ml, was administered two hours prior to this model. The levels of inflammation and oxidative stress markers were observed by Western blot, qRT-PCR, ELISA and reactive oxygen species assay. Additionally, the expression of peroxiredoxin 6 (Prdx6) and proteins involved in the NF-κB signaling pathway was evaluated. RESULTS: Twenty percent of serum collected from patients undergoing OLV downregulated the expression of Prdx6, leading to the activation of the NF-κB signaling pathway, which was associated with the subsequent overproduction of inflammatory cytokines and reactive oxygen species. Pretreatment with curcumin restored Prdx6 downregulation and inhibited NF-κB pathway activation by suppressing the nuclear translocation of P65, eventually reducing inflammation and oxidative stress damage in A549 cells. CONCLUSIONS: Prdx6 mediated the protective function of curcumin by inhibiting the activation of the NF-κB pathway in ALI in vitro.
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Lesión Pulmonar Aguda , Curcumina , Ventilación Unipulmonar , Lesión Pulmonar Aguda/inducido químicamente , Curcumina/efectos adversos , Humanos , Inflamación/etiología , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Ventilación Unipulmonar/efectos adversos , Peroxiredoxina VI/genética , Especies Reactivas de OxígenoRESUMEN
Postoperative pulmonary complications including acute lung injury (ALI) and acute respiratory distress syndrome have contributed to mortality and morbidity of orthotopic liver transplantation (OLT) with unclear mechanisms. Mast cells (MCs) and polymorphonuclear neutrophils (PMNs) are the main inflammatory cells and participants in the process of ALI. The present study was designed to investigate the role of MCs and PMNs and their potential relation to ALI following OLT. Rat orthotopic autologous liver transplantation (OALT) model was designed to determine lung injury at different time points after liver reperfusion. We also evaluated the function of MCs and the effect of tumor necrosis factor-α (TNF-α) and tryptase on ALI and PMN apoptosis in rats subjected to OALT. Histological scores and inflammatory factor levels as well as PMN apoptosis were measured. Rats suffered from ALI after OALT, which was demonstrated by a collapse of the pulmonary architecture, pulmonary edema, and infiltration of inflammatory cells in alveolar and interstitial spaces, as well as increased levels of proinflammatory cytokines. ALI maximized at 8 h after OALT. However, PMN apoptosis lagged behind the pulmonary injury and maximized at 16 h after OALT, when the acute inflammation resolution initiated. MC stabilization, and tryptase and TNF-α inhibitors could significantly decrease the lung pathophysiologic scores accompanied by an increase in PMN apoptosis. ALI after OALT was associated with MC activation and PMN apoptosis. ALI progression might be affected by delayed PMN apoptosis, which was related to MC activation. Induction of PMN apoptosis might alleviate ALI after OALT.
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Lesión Pulmonar Aguda , Apoptosis , Trasplante de Hígado/efectos adversos , Neutrófilos , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Animales , Modelos Animales de Enfermedad , Masculino , Mastocitos/metabolismo , Mastocitos/patología , Neutrófilos/metabolismo , Neutrófilos/patología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND Effects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency. MATERIAL AND METHODS We assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 µg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software. RESULTS In the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained. CONCLUSIONS Propofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.
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Insuficiencia Hepática/metabolismo , Propofol/administración & dosificación , Propofol/farmacocinética , Adulto , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/farmacocinética , Pueblo Asiatico , China , Estudios de Cohortes , Femenino , Insuficiencia Hepática/sangre , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Propofol/sangreRESUMEN
BACKGROUND: Post-liver transplantation acute lung injury (ALI) severely affects patients' survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion-induced increased oxidative stress plays a critical role in mediating post-liver transplantation ALI and that induction of heme oxgenase-1 (HO-1), an enzyme with anti-oxidative stress properties, can confer effective protection of lung against ALI. METHODS: Male Sprague-Dawley rats underwent autologous orthotopic liver transplantation (OALT) in the absence or presence of treatments with the selective HO-1 inducer (Hemin) or HO-1 inhibitor (ZnPP). Lung tissues were collected at 8 h after OALT, pathological scores and lung water content were evaluated; survival rate of rats was analyzed; protein expression of HO-1 was determined by western blotting, and nuclear translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor(NF)-κB p65 were detected by Immunofluorescence staining. The inflammatory cytokines and oxidative indexes of lung tissue were determined. RESULTS: In lungs harvested at the early stage i.e. 8 h after OALT, Hemin treatment significantly increased superoxide dismutase activities, and reduced malondialdehyde, hydrogen peroxide, interleukin-6, myeloperoxidase, and tumor necrosis factor-α production,which were associated with increased HO-1 protein expression and lower pathological scores and increased survival rate of rats. The underline mechanisms might associate with activation of Nrf2 and inhibition of NF-κB p65 nuclear translocation. However, these changes were aggravated by ZnPP. CONCLUSIONS: Hemin pretreatment, by enhancing HO-1 induction, increased lung antioxidant capacity and reduced inflammatory stress,protected the lung from OALT-induced ALI at early stage of reperfusion.
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Lesión Pulmonar Aguda/enzimología , Lesión Pulmonar Aguda/prevención & control , Hemo-Oxigenasa 1/biosíntesis , Hemina/farmacología , Trasplante de Hígado/efectos adversos , Pulmón/enzimología , Pulmón/patología , Lesión Pulmonar Aguda/etiología , Animales , Inducción Enzimática/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Interleucina-6/metabolismo , Pulmón/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Oxígeno , Presión Parcial , Peroxidasa/metabolismo , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Análisis de Supervivencia , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Agua/metabolismoRESUMEN
BACKGROUND: Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which influences patient survival rate obviously. However, its mechanisms are unclear and effective therapies are still lacking. The current study focused on effects of propofol on liver transplantation-induced ALI and whether its underlying mechanism was relative with connexin43 (Cx43) alternation. The authors postulated that endotoxin induced enhancement of Cx43 gap junction (GJ) plays a critical role in mediating post liver transplantation ALI and that pretreatment with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. METHODS: Male Sprague-Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx43 inhibitor, enanthol (0.1 mg/kg) and propofol (50 mg/kg), a commonly used anesthetic in clinical anesthesia. In vitro study, BEAS-2B cells, a kind of lung epithelial cell line expressing Cx43, exposed to lipopolysaccharide (LPS), which mainly contributed to ALI. Function of Cx43 GJ was regulated by Cx43 specific inhibitors, gap26 (300 µM) or enhancer, retinoic acid (10 µM) and two specific siRNAs. RESULTS: Compared with the sham group, AOLT results in ALI obviously with plasma endotoxin increase. Cx43 inhibition decreased ALI through inflammatory reaction reduction. In vitro studies, LPS-induced BEAS-2B cells damage was attenuated by Cx43 function inhibition, but amplified by enhancement. Another important finding was propofol reduced Cx43 function and protected against LPS-mediated BEAS-2B cells damage or AOLT-induced ALI, mechanisms of which were also associated with inflammatory reaction decrease. CONCLUSION: Cx43 plays a vital role in liver transplantation-induced ALI. Propofol decreased Cx43 function and protected against ALI in vivo and in vitro. This finding provide a new basis for targeted intervention of organ protection in liver transplantation, even in other kinds of operations.
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Lesión Pulmonar Aguda/etiología , Conexina 43/metabolismo , Uniones Comunicantes/metabolismo , Trasplante de Hígado/efectos adversos , Propofol/farmacología , Animales , Línea Celular , Conexinas/metabolismo , Uniones Comunicantes/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Lipopolisacáridos , Masculino , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , Trasplante Autólogo , Proteína beta1 de Unión ComunicanteRESUMEN
Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α2-adrenoceptor antagonists including atipamezole (a nonselective α2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1ß and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Hígado/efectos de los fármacos , FN-kappa B/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Receptor Toll-Like 4/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Dexmedetomidina/administración & dosificación , Dexmedetomidina/uso terapéutico , Interleucina-1beta/metabolismo , Hígado/irrigación sanguínea , Hígado/metabolismo , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: To investigate whether pretreatment with dexmedetomidine (Dex) has a protective effect against acute lung injury (ALI) in an orthotopic autologous liver transplantation (OALT) rat model and to explore the mechanisms responsible for the protective effect of Dex against lung injury. METHODS: Forty-eight rats underwent OALT and were randomly divided into six groups (n = 8 in each group) that received 10 µg/kg Dex, 50 µg/kg Dex, 50 µg/kg Dex + nonspecific α2-adrenergic receptor (AR) antagonist atipamezole, 50 µg/kg Dex + specific α2B/C-AR antagonist ARC-239, 50 µg/kg Dex + specific α2A-AR antagonist BRL-44408, or the same amount of normal saline. The sham rats (n = 8) underwent anesthesia induction, laparotomy, and separation of the portal vein without liver ischemia and reperfusion. Lung tissue sections were stained with hematoxylin and eosin (HE) to visualize the damage. The expression of Toll-like receptor 4 (TLR4) and the phospho-nuclear factor (NF)-κB p65 subunit as well as inflammatory cytokines was measured. RESULTS: Rats exhibited increased histological lung injury scores and pulmonary edema following OALT. Pretreatment with 50 µg/kg Dex attenuated OALT-induced lung injury in rats, probably by inhibiting the activation of the TLR4-NF-κB signaling pathway. The protective effect of Dex could be blocked by atipamezole or BRL-44408, but not by ARC-239, suggesting these effects of Dex were mediated, at least in part, by the α2A-AR. CONCLUSIONS: Dex exerts protective effects against ALI following OALT, and this protection is associated with the suppression of TLR4-NF-κB signaling. Thus, pretreatment with Dex may be a useful method for reducing lung damage caused by liver transplantation.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Dexmedetomidina/uso terapéutico , Trasplante de Hígado , FN-kappa B/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Dexmedetomidina/farmacología , Interleucina-1beta/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Peroxidasa/metabolismo , Fosforilación/efectos de los fármacos , Subunidades de Proteína/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Trasplante Autólogo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Postliver transplantation acute kidney injury (AKI) severely affects patient survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion induced enhancement of connexin32 (Cx32) gap junction plays a critical role in mediating postliver transplantation AKI and that pretreatment/precondition with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. METHODS: Male Sprague-Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol (50 mg/kg) (n = 8 per group). Also, kidney tubular epithelial (NRK-52E) cells were subjected to hypoxia-reoxygenation and the function of Cx32 was manipulated by three distinct mechanisms: cell culture in different density; pretreatment with Cx32 inhibitors or enhancer; Cx32 gene knock-down (n = 4 to 5). RESULTS: AOLT resulted in significant increases of renal Cx32 protein expression and gap junction, which were coincident with increases in oxidative stress and impairment in renal function and tissue injury as compared to sham group. Similarly, hypoxia-reoxygenation resulted in significant cellular injury manifested as reduced cell growth and increased lactate dehydrogenase release, which was significantly attenuated by Cx32 gene knock-down but exacerbated by Cx32 enhancement. Propofol inhibited Cx32 function and attenuated post-AOLT AKI. In NRK-52E cells, propofol reduced posthypoxic reactive oxygen species production and attenuated cellular injury, and the cellular protective effects of propofol were reinforced by Cx32 inhibition but cancelled by Cx32 enhancement. CONCLUSION: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.
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Lesión Renal Aguda/prevención & control , Conexinas/efectos de los fármacos , Uniones Comunicantes/efectos de los fármacos , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/prevención & control , Propofol/farmacología , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Anestésicos Intravenosos/metabolismo , Anestésicos Intravenosos/farmacología , Animales , Western Blotting/métodos , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Conexinas/genética , Conexinas/metabolismo , Modelos Animales de Enfermedad , Uniones Comunicantes/genética , Uniones Comunicantes/metabolismo , Expresión Génica/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Trasplante de Hígado/métodos , Masculino , Estrés Oxidativo/efectos de los fármacos , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/metabolismo , Propofol/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína beta1 de Unión ComunicanteRESUMEN
BACKGROUND: Nuclear factor-E2-related factor 2 (Nrf2)-mediated antioxidant response is the main protective system of graft-liver against ischemia-reperfusion injury after liver transplantation. Propofol is considered to confer protective effects on different organs; thus, we explored the possibility that whether propofol could attenuate graft-liver injury in a rat autologous orthotopic liver transplantation (AOLT) model and mechanisms were associated with activation of Nrf2 pathway. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham-operated group, saline-treated AOLT group, low-dose propofol intervention group, and high-dose propofol intervention group. Liver injury was determined, and concentration of hydroxyl free radical (â¢OH), superoxide anion (O2(â¢-)), and malondialdehyde in the liver tissue were detected. The expression of Keap1, Nrf2, HO-1, and NQO1 were explored by Western blotting, and also the change of Nrf2 and keap1 was assessed by immunofluorescence. RESULTS: Compared with sham group, pathologic damage of graft-livers was in a time-dependent manner, accompanied with the increased level of oxidative stress in the AOLT group, and nuclear Nrf2 expression and its downstream antioxidant enzyme, HO-1 and NQO1, were also increased in this group. However, in propofol pretreatment groups especially in the high-dose group, the pathologic score was significantly decreased, accompanied with a lower level of â¢OH, O2(â¢-), and malondialdehyde than that of the AOLT group. The change of oxidative stress might be related to the Nrf2 pathway, evidenced as the elevation of protein expression level of NQO1, HO-1, and nuclear Nrf2. CONCLUSIONS: Protective effects of propofol against liver transplantation-induced graft-liver injury may be related with Keap1-Nrf2 signal pathway activation.
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Anestésicos Intravenosos/uso terapéutico , Hepatopatías/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , Propofol/uso terapéutico , Daño por Reperfusión/prevención & control , Anestésicos Intravenosos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/etiología , Hepatopatías/metabolismo , Trasplante de Hígado/efectos adversos , Masculino , Estrés Oxidativo/efectos de los fármacos , Propofol/farmacología , Distribución Aleatoria , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismoRESUMEN
Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-α and IL-ß level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-α and IL-ß, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats' survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.
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Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Trasplante de Hígado/efectos adversos , Receptor Toll-Like 4/metabolismo , Lesión Pulmonar Aguda/prevención & control , Adulto , Animales , Femenino , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Interleucina-1beta/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Acute lung injury (ALI) is a serious complication that commonly occurs during orthotopic liver transplantation (OLT). Toll-like receptor 2/4 (TLR2/4) are the main membrane receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signal pathway. We previously showed that TLR2/4 expression on monocytes and serum cytokine levels were increased in patients with ALI induced by OLT. Myeloid differentiation protein-2 (MD-2) expresses the functional domains that combines TLRs and play a key regulatory role in TLRs activation. Therefore, we hypothesized that blocking MD-2 would inhibit the TLR2/4-mediated inflammatory response and lessen ALI induced by liver transplantation. METHOD: Thirty-two Sprague Dawley (SD) rats were randomly divided into four groups. One group received a sham operation (Group S), and the other three groups underwent orthotopic autologous liver transplantation (OALT) 48 h after intratracheal administration of saline (Model group; Group M), non-targeting siRNA (negative siRNA control group; Group NC) or siRNA against MD-2 (intervention group; Group RNAi). Lung pathology, lung water content, PaO2, and expression levels of MD-2, TLR2/4, NF-κB, TNF-α, IL-1ß and IL-6 were assessed 8 h after OALT. RESULTS: In Groups M and NC, OALT produced marked lung pathology with decreased PaO2 levels and increased MD-2, TLR2/4 gene and protein expression levels. Furthermore, the nuclear translocation of the NF-κB P65 subunit, was increased, as were lung concentrations of TNF-α, IL-1ß and IL-6. The pathology of ALI and the severity of the above biochemical changes induced by OALT were significantly reduced in the group treated with MD-2 siRNA. CONCLUSION: MD-2 gene knock-down attenuated the increase in TLR2/4 activation and reduced ALI after OALT.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/fisiopatología , Trasplante de Hígado/efectos adversos , Antígeno 96 de los Linfocitos/farmacología , Animales , Modelos Animales de Enfermedad , Agua Pulmonar Extravascular/metabolismo , Expresión Génica , Inflamación/metabolismo , Inflamación/patología , Interleucinas/biosíntesis , Pulmón/patología , Masculino , FN-kappa B/biosíntesis , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Toll-Like 2/biosíntesis , Receptor Toll-Like 4/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn from the journal "Combinatorial Chemistry & High Throughput Screening".Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.
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Cyclodextrins (CyDs) in nano drug delivery systems have received much attention in pursuit of good compatibility, negligible toxicity, and improved pharmacokinetics of drugs. Their unique internal cavity has widened the application of CyDs in drug delivery based on its advantages. Besides this, the polyhydroxy structure has further extended the functions of CyDs by inter- and intramolecular interactions and chemical modification. Furthermore, the versatile functions of the complex contribute to alteration of the physicochemical characteristics of the drugs, significant therapeutic promise, a stimulus-responsive switch, a self-assembly capability, and fiber formation. This review attempts to list recent interesting strategies regarding CyDs and discusses their roles in nanoplatforms, and may act as a guideline for developing novel nanoplatforms. Future perspectives on the construction of CyD-based nanoplatforms are also discussed at the end of this review, which may provide possible direction for the construction of more rational and cost-effective delivery vehicles.
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Background: Insomnia has become increasingly prevalent in modern society and is notoriously difficult to treat. Many patients exhibit a poor response to pharmacological interventions. Stellate ganglion block (SGB) has emerged as an effective method for managing insomnia; however, its efficacy may be compromised in some patients, primarily due to a variant vertebral artery anatomy. Case presentation: This case report describes a patient with severe insomnia accompanied by anxiety. Through cervical ultrasound scanning, we identified richly branched cervical arteries at the C6-C7 segment of the vertebral artery, along with anatomical variations, which could pose a heightened risk for the traditional SGB procedure. Therefore, after carefully adjusting the patient's positioning, we proceeded with ultrasound-guided SGB using a lateral paravein out-of-plane approach. Clinical signs of successful insomnia symptoms alleviation were consistently observed after each block utilizing this alternative technique multiple times in a single patient. Conclusion: Our report reveals a new lateral paravein out-of-plane approach for ultrasound-guided SGB to treat insomnia, which might be considered an alternative method. More studies should be carried out to confirm the efficacy of this new approach.
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Aberrant expression of G-protein-coupled receptor 158 (GPR158) has been reported to be inextricably linked to a variety of diseases affecting the central nervous system, including Alzheimer's disease (AD), depression, intraocular pressure, and glioma, but the underlying mechanism remains elusive due to a lack of biological and pharmacological tools to elaborate its preferential cellular distribution and molecular interaction network. To assess the cellular localization, expression, and function of GPR158, we generated an epitope-tagged GPR158 mouse model (GPR158Tag) that exhibited normal motor, cognitive, and social behavior, no deficiencies in social memory, and no anxiety-like behavior compared to C57BL/6J control mice at P60. Using immunofluorescence, we found that GPR158+ cells were distributed in several brain regions including the cerebral cortex, hippocampus, cerebellum, and caudate putamen. Next, using the cerebral cortex of the adult GPR158Tag mice as a representative region, we found that GPR158 was only expressed in neurons, and not in microglia, oligodendrocytes, or astrocytes. Remarkably, the majority of GPR158 was enriched in Camk2a+ neurons whilst limited expression was found in PV+ interneurons. Concomitant 3D co-localization analysis revealed that GPR158 was mainly distributed in the postsynaptic membrane, but with a small portion in the presynaptic membrane. Lastly, via mass spectrometry analysis, we identified proteins that may interact with GPR158, and the relevant enrichment pathways were consistent with the immunofluorescence findings. RNA-seq analysis of the cerebral cortex of the GPR158-/- mice showed that GPR158 and its putative interacting proteins are involved in the chloride channel complex and synaptic vesicle membrane composition. Using these GPR158Tag mice, we were able to accurately label GPR158 and uncover its fundamental function in synaptic vesicle function and memory. Thus, this model will be a useful tool for subsequent biological, pharmacological, and electrophysiological studies related to GPR158.
Asunto(s)
Encéfalo , Receptores Acoplados a Proteínas G , Ratones , Animales , Ratones Transgénicos , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Encéfalo/metabolismo , Comunicación CelularRESUMEN
The mortality rate of sepsis remains high despite improvements in the diagnosis and treatment of sepsis using symptomatic and supportive therapies, such as anti-infection therapy and fluid resuscitation. Nucleic acid-based drugs have therapeutic potential, although their poor stability and low delivery efficiency have hindered their widespread use. Herein, it is confirmed that miR-223 can polarize proinflammation M1 macrophages to anti-inflammation M2 macrophages. A pH-sensitive nano-drug delivery system comprising ß-cyclodextrin-poly(2-(diisopropylamino)ethyl methacrylate)/distearoyl phosphoethanolamine-polyethylene glycol (ß-CD-PDPA/DSPE-PEG) is synthesized and developed to target M1 macrophages and miR-223 is encapsulated into nanoparticles (NPs) for sepsis treatment. NPs/miR-223 demonstrated in vitro pH responsiveness with favorable biosafety, stability, and high delivery efficiency. In vivo studies demonstrate that NPs/miR-223 are preferentially accumulated and retained in the inflammation site, thereby reducing inflammation and improving the survival rate of mice with sepsis while exhibiting ideal biosafety. Mechanically, NPs/miR-223 regulates macrophage polarization by targeting Pknox1 and inhibiting the activation of the NF-κB signaling pathway, thereby achieving an anti-inflammatory effect. Collectively, it is demonstrated that the miRNA delivery vector described here provides a new approach for sepsis treatment and accelerates the advancement of nucleic acid drug therapy.
Asunto(s)
Ciclodextrinas , MicroARNs , Sepsis , Animales , Ratones , MicroARNs/genética , Macrófagos/metabolismo , Inflamación/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Concentración de Iones de Hidrógeno , Proteínas de Homeodominio/metabolismoRESUMEN
BACKGROUND: Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein-coupled receptor 158 (GPR158) in modulating sensitivity to the sedative-hypnotic effect of ethanol has not been investigated. METHODS: Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158-/- mice and wild-type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open-field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158-/- mice (n = 6/genotype). We also tested CamK2A-Cre;Gpr158fl/fl (n = 9) and Vgat-Cre;Gpr158fl/fl mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). RESULTS: Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = -5.241, p = 0.0001, without altering spontaneous activity, t(14) = -0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin-dependent protein kinase II alpha-positive (CamK2A+ ) neurons, t(16) = -2.914, p = 0.01, and by 92% in the vesicular GABA transporter-positive (Vgat+ ) neurons, t(9.802) = -2.519, p = 0.023. Locomotion was not altered in Camk2A-Cre;Gpr158fl/fl , t(16) = 0.49, p = 0.631 or Vgat-Cre;Gpr158fl/fl mice, t(16) = 0.035, p = 0.972. CONCLUSIONS: This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative-hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.
RESUMEN
Depression is a common recurrent psychiatric disorder with a high lifetime prevalence and suicide rate. At present, although several traditional clinical drugs such as fluoxetine and ketamine, are widely used, medications with a high efficiency and reduced side effects are of urgent need. Our group has recently reported that a single administration of salmon calcitonin (sCT) could ameliorate a depressive-like phenotype via the amylin signaling pathway in a mouse model established by chronic restraint stress (CRS). However, the molecular mechanism underlying the antidepressant effect needs to be addressed. In this study, we investigated the antidepressant potential of sCT applied chronically and its underlying mechanism. In addition, using transcriptomics, we found the MAPK signaling pathway was upregulated in the hippocampus of CRS-treated mice. Further phosphorylation levels of ERK/p38/JNK kinases were also enhanced, and sCT treatment was able only to downregulate the phosphorylation level of p38/JNK, with phosphorylated ERK level unaffected. Finally, we found that the antidepressant effect of sCT was blocked by p38 agonists rather than JNK agonists. These results provide a mechanistic explanation of the antidepressant effect of sCT, suggesting its potential for treating the depressive disorder in the clinic.
RESUMEN
BACKGROUND: The aim of this study was to investigate the effects of small volume resuscitation with 7.5% hypertonic sodium chloride (HSS), hydroxyethyl starch 130/0.4 solution (HES), and hypertonic sodium chloride hydroxyethyl starch 40 injection (HSH) on endotoxin shock rat lung. METHODS: Thirty Sprague-Dawley (SD) rats were divided randomly into 5 groups ï¼Group C (negative control group), Group E (lipopolysaccharide, LPS +4 ml/kg saline), Group HSS (LPS +4 ml/kg HSS), Group HES (LPS +4 ml/kg HES) and Group HSH (LPS +4 ml/kg HSH). Endotoxin shock model of rat was produced by injection with LPS. Then small volume resuscitation with different fluids was implemented in each group, respectively. RESULTS: Compared to Group C(negative control groupï¼, lung injury in the other four groups was increased. Compared to Group E(LPS +4 ml/kg normal saline), lung injury of Group HSS(LPS +4 ml/kg HSS), HES(LPS +4 ml/kg HES), and HSH (LPS +4 ml/kg HSH)was lessened. Compared to Group C, oxygenation index in Groups E, HSS, HES, and HSH were decreased (P < 0.01). Compared to Group E, oxygenation indexes in Groups HSS, HES, and HSH were significantly increased (P < 0.01). Data of tumor necrosis factor (TNF)-α of lung tissue had similar results. However, protein concentration of bronchoalveolar lavage fluid and hydrogen sulfide (H(2)S) concentration indicated contrary results. CONCLUSION: Small volume resuscitation with 7.5% hypertonic sodium chloride, hydroxyethyl starch 130/0.4 solution, and hypertonic sodium chloride hydroxyethyl starch 40 injection could lessen lung injury caused by lipopolysaccharide. And this effect had relation to change of TNF-α and H(2)S.