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Nutritional status is an essential factor in the occurrence of complications in patients with esophageal cancer. We sought to assess the relationship between malnutrition and complications using various nutritional assessment indicators. We conducted a comprehensive literature search of medical databases for articles published up to July 2023. The primary outcome indicator is the occurrence of complications, for which we combined 95% confidence intervals (CIs) and odds ratios (ORs) for postoperative complications and analyzed them using a random effects model. The analysis was carried out using STATA15.0 software. A total of 33 study groups from 22 publications with 5,675 subjects were included. Pooled results show that nutritional indicators are strongly correlated with the occurrence of postoperative complications (OR = 1.45, 95% CI: 1.30-1.62). In the subgroup analyses, comprehensive indicators and the skeletal muscle index were significantly associated with complications, whereas laboratory indicators were not associated with complications (comprehensive indicators OR = 2.68, 95% CI: 1.80-4.00; skeletal muscle index OR = 2.93, 95% CI: 1.44-5.99; laboratory indicators OR = 1.05, 95% CI: 0.96-1.16). Patients with normal body mass index and hospitalized patients were more likely to develop complications. Malnutrition is strongly associated with the development of complications. Nutritional indicators and patient characteristics influenced this relationship.
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Neoplasias Esofágicas , Desnutrición , Estado Nutricional , Complicaciones Posoperatorias , Humanos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/complicaciones , Desnutrición/etiología , Evaluación Nutricional , Periodo Preoperatorio , Índice de Masa CorporalRESUMEN
AIM: To assess early postoperative core symptoms in oesophageal cancer patients and their relationship with resilience. BACKGROUND: Patients with oesophageal cancer face a high number of severe symptoms in the early post-operative period and require the development of an effective symptom management programme. Identifying core symptoms through network analysis helps in accurate patient care. DESIGN: A multicentre cross-sectional study. METHODS: A cross-sectional survey was conducted from August 2022 to August 2023 at three hospitals in Anhui Province, China. A total of 469 patients were recruited for this study and 418 (89.1%) patients completed this investigation. Using network analysis to find early post-operative core symptoms in oesophageal cancer patients. Multiple linear regression was used to analyse resilience factors affecting core symptoms. RESULTS: Sadness was the most core symptom in oesophageal cancer patients in the early post-operative period (rs = 1.41), followed by incision pain and difficulty breathing while resting (rs = 1.20, rs = 1.08). Resilience was significantly associated with patients' feelings of sadness, with optimism having the greatest impact on sadness (p < .01). CONCLUSION: Sadness is the most core symptom in patients in the early post-operative period and special attention should be paid to improving their level of resilience. Local symptoms and dysfunction in the early post-operative period should be treated in a synergistic manner. IMPACT: This study identifies core symptoms and their relationship to resilience in patients with oesophageal cancer in the early post-operative period. Symptoms as the main core symptom in patients in the early post-operative period, which was sadness and was significantly associated with resilience. Precise interventions can be made to target patients' core post-operative symptoms, which can help improve the effectiveness of symptom management. REPORTING METHOD: We have complied with the relevant EQUATOR research reporting checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution in the study.
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BACKGROUND: Oxidative stress and neurocyte apoptosis are crucial pathophysiological process in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Geniposide (GNP) has been reported to exert neuroprotective effects by reducing oxidative injury and neurocyte apoptosis. However, the effect of GNP has not been clarified in EBI after SAH. The study was performed to evaluate the neuroprotective effects and mechanisms of GNP in EBI after SAH. METHODS AND RESULTS: A total of 60 male Wistar rats were randomly divided into five groups. The prechiasmatic cistern SAH model was used in this study. SAH grade was evaluated using a grading system. Neurological function was evaluated using the Garcia scores. Brain edema was measured by the wet-dry method. Blood-brain barrier (BBB) permeability was measured by the extravasation of Evans Blue (EB). The neurocyte apoptosis was observed using TUNEL assay. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD), as well as the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), glutathione S-transferase (GST) and quinone oxidoreductase-1 (NQO-1) were performed. The results showed that GNP reduced brain edema, attenuated BBB permeability, inhibited neurocyte apoptosis and improved neurological function. Moreover, GNP also decreased the levels of ROS and MDA, elevated Nrf2 expression in the temporal cortex and up-regulated the expression of NQO-1, HO-1 and GST after SAH. CONCLUSIONS: GNP could ameliorate oxidative stress and neurocyte apoptosis to exert neuroprotective effects by Nrf2 pathway.
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Edema Encefálico , Lesiones Encefálicas , Fármacos Neuroprotectores , Hemorragia Subaracnoidea , Animales , Apoptosis , Encéfalo/metabolismo , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Glutatión Transferasa/metabolismo , Iridoides , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismoRESUMEN
Bovine mastitis is one of the most prevalent and costly diseases, and can be caused by a variety of bacterial pathogens including enterococci. Unfortunately, comprehensive studies about the prevalence and antimicrobial resistance profiles of entercocci are scarcely reported. This study aimed to investigate the occurrence of enterococci associated with bovine clinical mastitis and subclinical mastitis, to assess their antimicrobial resistance profiles, and to detect the distribution of integrons and gene cassette arrays in Liaoning of China. Our results indicated subclinical mastitis occurred in 34.3% of bovine, and 21.4% of bovine were positive for clinical mastitis, meanwhile Enterococcus faecium is the predominant pathogen in both clinical mastitis and subclinical mastitis. More than 50% of the total isolates were resistant to penicillin, ceftiofur, tylosin, lincomycin, and oxytetracycline. Class I integrons was detected in enterococcal isolates from both clinical and subclinical mastitis with 57.1% and 45.3%, respectively. Meanwhile, class II integrons only were observed in enterococcal isolates from subclinical mastitis. Multidrug resistance has become prevalent in enterococci isolated from clinical mastitis and subclinical mastitis in Liaoning, northeast of China. This study revealed that enterococcal isolates had shown resistant to ß-lactam antibiotics including penicillin, and different therapeutic programs should be carried out in Liaoning of China.
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Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Enterococcus/aislamiento & purificación , Infecciones por Bacterias Grampositivas/veterinaria , Integrones , Mastitis Bovina/epidemiología , Mastitis Bovina/microbiología , Animales , Bovinos , China/epidemiología , Enterococcus/clasificación , Enterococcus/efectos de los fármacos , Enterococcus/genética , Femenino , Infecciones por Bacterias Grampositivas/epidemiología , Infecciones por Bacterias Grampositivas/microbiología , PrevalenciaRESUMEN
BACKGROUND: Cases with brain tumor and subdural hematoma are rare; surgical management of the elderly patients with a glioblastoma multiform (GBM) and a chronic subdural hematoma (CSDH) can be intractable. CASE DESCRIPTION: We report a 77-year-old patient, who had a left front lobe GBM and a giant, calcified, left frontoparietaloccipitotemporal CSDH. The patient recovered well from anesthesia after removal of the GBM and CSDH. However, the patient developed severe hemiplegia and aphasia because of the in-situ hemorrhage 1 day later. Laboratory tests indicated disseminated intravascular coagulation (DIC) leading to the postoperative hemorrhage. The patient was left with hemiparesis and alalia after the in-situ hematoma evacuation. CONCLUSIONS: We presume elderly patients have a higher incidence of postoperative hemorrhage in residual intracranial cavity owing to higher possibility to get DIC. A less aggressive surgical management could be a more appropriate choice.
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Glioblastoma/complicaciones , Hematoma Subdural Crónico/complicaciones , Hemorragia Posoperatoria/etiología , Anciano , Glioblastoma/patología , Glioblastoma/cirugía , Hematoma Subdural Crónico/patología , Hematoma Subdural Crónico/cirugía , Humanos , Masculino , Hemorragia Posoperatoria/patología , Hemorragia Posoperatoria/cirugía , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
Attempting to improve the anticancer activity and solubility of evodiamine in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions, thirty-eight N13-substituted evodiamine derivatives were designed, synthesized and tested for antitumor activities against six kinds of human cancer cell lines, namely prostate cancer (DU-145 and PC-3), lung cancer (H460), breast cancer (MCF-7), colon cancer (HCT-5) and glioblastoma (SF-268). The solubility of these compounds in SGF and SIF solutions was evaluated, and apoptosis induced by 2-2, 2-3, 2-16 and 3-2 was determined. The results showed: (1) among all compounds examined, 2-16 showed the highest antitumor activity and a broader spectrum of activity, with IC50 values ranging from 1-2 µM; (2) their solubility was obviously improved; (3) 2-3, 2-16 and 3-2 had a significant impact inducing apoptosis in some cancer cell lines. The preliminary structure-activity relationships of these derivatives were discussed.
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Antineoplásicos/química , Antineoplásicos/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Células MCF-7 , Modelos Moleculares , Conformación Molecular , Quinazolinas/síntesis químicaRESUMEN
BACKGROUND: Drug coated balloon (DCB) angioplasty can provide sustained anti-restenotic efficacy without the limitations of permanent vascular implantation and is presumably ideal for treating intracranial atherosclerotic disease. However, the safety of paclitaxel in the neurovasculature remains a concern. METHODS: 242 patients with angiographically verified symptomatic stenosis >70% in intracranial arteries treated with DCB angioplasty were reviewed divided into two groups: group A, patients with stenotic intracranial arteries; and group B, patients with acute, subacute, or chronic occluded intracranial arteries. The primary endpoint was any stroke or death within 30 days. The secondary endpoint was arterial restenosis of >50% during follow-up. RESULTS: 16 major and 12 minor complications occurred among 245 procedures (6.5% and 4.9%, respectively). Five patients died within 30 days after the procedure (2.1%, 5/242). 12 major and 12 minor complications occurred among 211 procedures in group A (5.7% and 5.7%). In group B, four major complications occurred among 34 procedures (11.8%). Hyperperfusion and perforator stroke accounted for half of all complications (53.6%, 15/28). Restenosis >50% was present in eight lesions during the follow-up period (4.8%, 8/167). CONCLUSIONS: After treatment with DCB angioplasty, complications were no different from those after standard balloon angioplasty or stenting. This study suggests that DCB angioplasty may be a safe and effective procedure for intracranial arterial stenosis.
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Angioplastia de Balón , Arteriosclerosis Intracraneal , Enfermedad Arterial Periférica , Accidente Cerebrovascular , Humanos , Constricción Patológica , Resultado del Tratamiento , Enfermedad Arterial Periférica/cirugía , Angioplastia de Balón/efectos adversos , Angioplastia de Balón/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/cirugía , Materiales Biocompatibles Revestidos , Arteria Femoral , Arteria Poplítea/cirugía , Grado de Desobstrucción VascularRESUMEN
BACKGROUND: The optimal choice of dialysis modality for diabetic patients remains controversial. This study aimed to compare mortality between peritoneal dialysis (PD) and hemodialysis (HD) in end-stage renal disease (ESRD) patients with type 2 diabetes (T2D). METHODS: Our observational, longitudinal cohort consisted of all incident ESRD patients with T2D who received either PD or HD in our center from January 2012 to December 2017 and were followed until December 2019. Propensity scores were used to select a 1:1 matched cohort. Mortality was compared between dialysis modalities using Kaplan-Meier survival analysis, and risk factors for mortality were estimated using multivariate Cox regression analyses. RESULTS: The median follow-up times were 35.5 months in the PD group (n = 134) and 41.6 months in the HD group (n = 134, p = 0.0381). The 1-, 2-, 3-, 5-, and 7-year patient survival rates were 98%, 91%, 77%, 61%, and 35% for diabetic PD patients and 96%, 88%, 81%, 60%, and 57% for diabetic HD patients. Kaplan-Meier survival analysis showed that overall mortality did not significantly differ between modalities (log-rank = 0.9473, p = 0.6575). Using a multivariate Cox regression model, advanced age and increased cholesterol at the initiation of PD treatment were independent risk factors associated with mortality, whereas under HD therapy, the risk factors associated with mortality were lower BMI and higher HbA1c. CONCLUSIONS: These results suggest that in patients with T2D, mortality is comparable between PD and HD irrespective of whether there are the first 2 years or over the 2-year period, and that different mortality predictor patterns exist between patients treated with PD versus HD.
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Diabetes Mellitus Tipo 2 , Fallo Renal Crónico , Diálisis Peritoneal , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Diálisis Peritoneal/efectos adversos , Modelos de Riesgos Proporcionales , Diálisis Renal/métodos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Although percutaneous transluminal angioplasty and stenting (PTAS) was an effective and safe alternative treatment for severe intracranial atherosclerosis disease (ICAD), the high rate of restenosis remained a major issue for this endovascular procedure. Recently, the application of drug-coated balloons (DCB) in ICAD was developed to reduce restenosis. This systematic review aimed to evaluate the efficacy and safety of DCB angioplasty for ICAD. METHODS: We searched relevant databases for eligible studies enrolling ICAD patients treated with DCB. The event rates of restenosis and periprocedural complications in the follow-up period were pooled with random-/fixed-effect models using Freeman-Tukey double arcsine transformation. Heterogeneity tests and publication bias tests were performed. RESULTS: Two hundred and twenty-four ICAD patients treated with DCB from 9 eligible studies were included. Rate of stenosis in the DCB arm before treatment was ranged from 62% to 90% and reported median follow-up was ranged from 3 to 10.7 months. The pooled incidence of restenosis were 5.7% (95% confidence interval [CI] 2.6%-9.7%; I2 = 0%, p = 0.516) and 5.9% for periprocedural complications (95% CI: 2.5-10.3%; I2 = 0%, p = 0.649) in follow-up term. CONCLUSION: With the limitation of the low quality of the available evidence, angioplasty with DCB appears to be effective and safe in severe ICAD. Further larger randomized trials are needed to provide more definitive evidence and to address the ideal clinical context for their application.
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Angioplastia de Balón , Arteriosclerosis Intracraneal , Angioplastia , Angioplastia de Balón/métodos , Materiales Biocompatibles Revestidos/uso terapéutico , Constricción Patológica/etiología , Constricción Patológica/cirugía , Humanos , Arteriosclerosis Intracraneal/etiología , Arteriosclerosis Intracraneal/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Progressive supranuclear palsy is a neurodegenerative condition that worsens over time. Given the lack of targeted treatments, patients with severe progressive supranuclear palsy have very low life expectancy. CASE PRESENTATION: We present a case of a 61-year-old Chinese man with severe progressive supranuclear palsy and treated with umbilical cord blood stem cells transplantation. After the umbilical cord blood stem cells therapy, his neurologic symptoms stopped deteriorating, his muscle rigidity was mildly improved, and he remains alive for more than 8 years. CONCLUSIONS: Umbilical cord blood stem cells transplantation may be an alternative therapy for patients with severe progressive supranuclear palsy.
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Parálisis Supranuclear Progresiva , Sangre Fetal , Humanos , Masculino , Persona de Mediana Edad , Células Madre , Parálisis Supranuclear Progresiva/terapiaRESUMEN
This study was to test the hypothesis that tetramethylpyrazine (TMP) protected against early brain injury after subarachnoid hemorrhage (SAH) by affecting the mitochondrial-dependent caspase-3 apoptotic pathway. TMP was administrated after the rats' prechiasmatic SAH mode. Animal neurobehavioral functions were assessed and the mitochondrial morphology, mitochondrial and cytoplasmic calcium, and mitochondrial membrane potential changes (Δψm) of the brain tissues were measured. The expressions of cytoplasmic cytochrome c (cyt c), second mitochondria-derived activator of caspases (Smac), and cleaved caspase-3 B-cell lymphoma 2 (bcl-2) in cells were determined and cellular apoptosis was detected. The treatment of TMP resulted in less apoptotic cells and milder mitochondrial injury and potentially performed better in the neurobehavioral outcome compared to those with saline. Also, TMP ameliorated calcium overload in mitochondria and cytoplasm and alleviated the decrease of Δψm. In addition, TMP inhibited the expression of cytoplasmic cyt c, Smac, and cleaved caspase-3, yet it upregulated the expression of bcl-2. These findings suggest that TMP exerts an antiapoptosis property in the SAH rat model and this is probably mediated by the caspase-3 apoptotic pathway triggered by mitochondrial calcium overload. The finding offers a new therapeutic candidate for early brain injury after SAH.
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INTRODUCTION: Some micro arteriovenous malformations (AVMs) located in deep brain are undetectable. How to choose a proper timing to detect these AVMs remains unclear. CASE DESCRIPTION: A 21-year-old male patient was admitted to our center for intraventricular haematoma. Digital subtraction angiographies (DSAs) were performed one week and one month respectively after his haemorrhage, but no positive results were obtained. The patient was hospitalized for re-haemorrhage six years later. A micro AVM with two diffused niduses was detected and embolised three months after his re-haemorrhage. The patient recovered without any neurological deficit. DISCUSSION AND EVALUATION: Compressive effects of haematoma and spontaneous obliteration of AVMs might play pivotal roles in negative DSA results. CONCLUSIONS: Strategic and timely use of DSA could identify some dormant re-haemorrhagic AVMs.
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Swertianlarin, isolated from Swertia mussotii Franch and Enicostemma axillare, has hepatoprotective effects against cholestasis in rat models of hepatotoxicity. However, the underlying molecular mechanism is not clear. We then treated rats with swertianlarin for 7 d and then measured serum liver injury markers, lipids, and bile salts, as well as the expression of bile acid synthesis and detoxification enzymes (e.g. Cyp7a1 and Cyp3a), membrane influx and efflux transporters (e.g. Ntcp and Mrp3), nuclear receptors (e.g. Pxr and Fxr/Shp) and transcriptional factors (e.g. Nrf2 and Hnf3ß) in the liver. We found a significant induction of the expression of the basolateral efflux transporters Mrp3 and Mrp4 and canalicular transporter Mdr1 in rats treated with swertianlarin, compared with the controls (1.9-fold and 2.2-fold, P < 0.005, and 3.4-fold, P < 0.05, respectively). The expression of detoxification enzymes Cyp3a, Ugt2b, Sult2a1 and Gsta1 in rats treated with swertianlarin was significantly higher than that in controls (3.7-fold, 2.8-fold, 2.1-fold, and 1.7-fold, respectively, all P < 0.05). Expression of the synthetic enzyme, Cyp8b1, was higher in rats treated with swertianlarin than that in controls (1.8-fold at mRNA level and 3.4-flod at protein level, P < 0.05). Elevated serum levels of the conjugated bile acids, taurocholic acid and taurodeoxycholic acid, and a reduction in levels of serum ALP, unconjugated bile acid αMCA, and TG were observed (all P < 0.05). In conclusion, swertianlarin significantly up-regulates hepatic bile acid detoxification enzymes and efflux transporters in rats, which can increase the water solubility of hydrophobic bile acids and elimination of conjugated bile acids.
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Ácidos y Sales Biliares/metabolismo , Colestasis/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Extractos Vegetales/farmacología , Swertia/química , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL). Serum alanine aminotransferase (ATL) and aspartate aminotransferase (AST) levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P < 0.05). The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα) were decreased by swertianlarin in BDL rats for 3 and 7 days (P < 0.05). Moreover, reductions in serum interleukins IL-1ß and IL-6 levels were also observed in BDL rats treated with swertianlarin (P < 0.05). In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)) in cholestatic rats were decreased by swertianlarin (P < 0.05). In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.
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BACKGROUND & AIMS: Oleanolic acid is abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb for the treatment of jaundice. However, the hepatoprotective role of oleanolic acid in obstructive cholestasis and its underlying molecular mechanism are unclear. METHODS: Normal rats and bile duct-ligated (BDL) rats were given oleanolic acid and serum biochemistry, bile salts, and pro-inflammatory factors were measured, as well as the expression levels of liver bile acid synthesis and detoxification enzymes, membrane transporters, nuclear receptors, and transcriptional factors. RESULTS: Oral administration of oleanolic acid at 100 mg/kg did not cause rat liver injury. However, it significantly reduced the serum levels of alanine aminotransferase (ALT) on days 7 and 14, aspartate aminotransferase (AST) and TNF-α on day 14, and alkaline phosphatase (ALP) and IL-1ß on days 3, 7, and 14 in the BDL rats. Furthermore, the serum levels of total bile acid (TBA) and bile acids, including CDCA, CA, DCA, and Tα/ßMCA were significantly reduced by oleanolic acid on day 3 in the BDL rats. In addition, the expression levels of detoxification enzymes Cyp3a, Ugt2b, Sult2a1, Gsta1-2, and Gstm1-3, membrane transporters Mrp3, Mrp4, Ostß, Mdr1, Mdr2, and Bsep, nuclear receptors Pxr, Vdr, Hnf4α, Rxrα, Rarα, Lxr, and Lrh-1, and transcriptional factors Nrf2, Hnf3ß, and Ahr were significantly increased in oleanolic acid-treated rats. CONCLUSION: We demonstrated that the oral administration of oleanolic acid attenuates liver injury, inflammation, and cholestasis in BDL rats. The anti-cholestatic effect may be associated with the induction of hepatic detoxification enzymes and efflux transporters mediated by nuclear receptors and transcriptional factors.
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Multidrug resistance-associated protein 2 (MRP2) plays an important role in bile acid metabolism by transporting toxic organic anion conjugates, including conjugated bilirubin, glutathione, sulfate, and multifarious drugs. MRP2 expression is reduced in cholestatic patients and rodents. However, the molecular mechanism of MRP2 down-regulation remains elusive. In this report, we treated human hepatoma HepG2 cells with interleukin-18 (IL-18) and measured the expression of MRP2, nuclear factor kappa B (NF-κB), farnesoid X receptor (FXR), and the transcription factor Yin Yang 1 (YY1) by quantitative real-time quantitative polymerase chain reaction (PCR) and western blotting. We found that expression of MRP2 was repressed by IL-18 at both the mRNA and protein levels in a dose- and time-dependent manner. Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR. These changes were all attenuated in HepG2 cells with knockdown of the NF-κB subunit, p65. The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown. We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers. Chromatin immunoprecipitation assays also showed that FXR bound to the promoter region in MRP2 was less abundant in liver extracts from bile duct-ligated rats than sham-operated rats. Our findings indicate that IL-18 down-regulates MRP2 expression through the nuclear receptor FXR in HepG2 cells, and may be mediated by NF-κB and YY1.
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Carcinoma Hepatocelular/genética , Interleucina-18/inmunología , Neoplasias Hepáticas/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , FN-kappa B/genética , Receptores Citoplasmáticos y Nucleares/genética , Factor de Transcripción YY1/genética , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/inmunología , FN-kappa B/inmunología , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/inmunología , Transducción de Señal , Factor de Transcripción YY1/inmunologíaRESUMEN
The beta-carboline alkaloids have been characterized as a class of potential antitumor agents. To further enhance the cytotoxic potency and improve water solubility of beta-carboline, a series of new beta-carboline amino acid ester, beta-carboline amino acid and N(2)-benzylated quaternary beta-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were evaluated using a panel of human tumor cell lines. The N(2)-benzylated quaternary beta-carboline amino acid ester conjugates represented the most interesting cytotoxic activities. Particularly, compounds 8b and 8g were found to be the most potent compounds with IC(50) values lower than 20 microM against all human tumor cell lines investigated. These results confirmed that the N(2)-benzyl substituent on the beta-carboline ring played an important role in the modulation of the cytotoxic potencies.