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INTRODUCTION: We aimed to determine the diagnostic criteria of myosteatosis in a Chinese population and investigate the effect of skeletal muscle abnormalities on the outcomes of cirrhotic patients. METHODS: Totally 911 volunteers were recruited to determine the diagnostic criteria and impact factors of myosteatosis, and 480 cirrhotic patients were enrolled to verify the value of muscle alterations for prognosis prediction and establish new noninvasive prognostic strategies. RESULTS: Multivariate analysis showed age, sex, weight, waist circumference, and biceps circumference had a remarkable influence on the L3 skeletal muscle density (L3-SMD). Based on the cut-off of a mean - 1.28 × SD among adults aged < 60 years, the diagnostic criteria for myosteatosis was L3-SMD < 38.93 Hu in males and L3-SMD < 32.82 Hu in females. Myosteatosis rather than sarcopenia has a close correlation with portal hypertension. The concurrence of sarcopenia and myosteatosis not only is associated with poor liver function but also evidently reduced the overall and liver transplantation-free survival of cirrhotic patients (p < 0.001). According to the stepwise Cox regression hazard model analysis, we established nomograms including TBil, albumin, history of HE, ascites grade, sarcopenia, and myosteatosis for easily determining survival probabilities in cirrhotic patients. The AUC is 0.874 (95% CI 0.800-0.949) for 6-month survival, 0.831 (95% CI 0.764-0.898) for 1-year survival, and 0.813 (95% CI 0.756-0.871) for 2-year survival prediction, respectively. CONCLUSIONS: This study provides evidence of the significant correlation between skeletal muscle alterations and poor outcomes of cirrhosis, and establishes valid and convenient nomograms incorporating musculoskeletal disorders for the prognostic prediction of liver cirrhosis. Further large-scale prospective studies are necessary to verify the value of the nomograms.
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Sarcopenia , Masculino , Adulto , Femenino , Humanos , Sarcopenia/complicaciones , Sarcopenia/diagnóstico , Estudios Prospectivos , Músculo Esquelético/patología , Cirrosis Hepática/patología , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Information is limited regarding the prevalence and importance of hepatic histologic abnormalities in dogs with gallbladder mucocele (GBM). OBJECTIVES: To (a) report prevalence of hepatic histologic abnormalities in dogs with GBM (b) evaluate for association between hepatic abnormalities and outcome in dogs with GBM (c) evaluate whether neutrophil-to-lymphocyte ratio (NLR) differs in dogs with GBM with and without specific hepatic lesions. ANIMALS: Fifty-two dogs with grossly and histologically confirmed GBM. METHODS: Multicenter, retrospective study of dogs with GBM undergoing cholecystectomy with concurrent liver biopsy. Archived histological sections of gallbladder and liver evaluated by investigators blinded to data. Proportions of dogs with each histologic abnormality alive vs deceased at 1, 3, and 12 months post-cholecystectomy compared. Mann-Whitney U performed to determine if NLR differed in dogs with or without selected lesions. RESULTS: 51/52 (98%, 95% CI [89%, 99%]) dogs with GBM had at least 1 hepatic histologic abnormality. Hepatic fibrosis (37/51; 73%, 95% CI [59%, 83%]), biliary hyperplasia (29/52; 56%, 95% CI [42%, 68%]), and portal inflammation (25/52; 48%, 95% CI [35%, 61%]) were most common. The proportion of dogs alive vs dead differed based on the fibrosis score at 1, 3, and 12 (P ≤ .04) months post-cholecystectomy. Dogs with hepatic necrosis (P = .006) and cholangitis/cholangiohepatitis (P = .02) had higher NLRs compared to dogs without these lesions. CONCLUSIONS AND CLINICAL IMPORTANCE: Histologic abnormalities of the liver are common in dogs with GBM. A higher portal fibrosis score might be associated with shortened long-term survival after cholecystectomy for dogs with GBM. An increase in NLR might predict hepatic necrosis and cholangitis/cholangiohepatitis in dogs with GBM.
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Enfermedades de los Conductos Biliares , Colangitis , Enfermedades de los Perros , Enfermedades de la Vesícula Biliar , Hepatopatías , Mucocele , Perros , Animales , Estudios Retrospectivos , Mucocele/complicaciones , Mucocele/veterinaria , Prevalencia , Enfermedades de la Vesícula Biliar/complicaciones , Enfermedades de la Vesícula Biliar/cirugía , Enfermedades de la Vesícula Biliar/veterinaria , Hepatopatías/veterinaria , Enfermedades de los Conductos Biliares/veterinaria , Colangitis/veterinaria , Fibrosis , Necrosis/veterinaria , Enfermedades de los Perros/patologíaRESUMEN
OBJECTIVES: Covert hepatic encephalopathy (CHE) negatively affects the health-related quality of life and increases the risk of overt HE (OHE) in patients with liver cirrhosis. However, the impact of CHE on long-term patient outcomes remains controversial. This study aimed to explore the association between CHE and disease progression and survival among cirrhotic patients. METHODS: This was a single-center prospective study that enrolled 132 hospitalized patients with cirrhosis, with an average follow-up period of 45.02 ± 23.06 months. CHE was diagnosed using the validated Chinese standardized psychometric hepatic encephalopathy score. RESULTS: CHE was detected in 35.61% cirrhotic patients. During the follow-up, patients with CHE had a higher risk of developing OHE (log-rank 5.840, P = 0.016), exacerbation of ascites (log-rank 4.789, P = 0.029), and portal vein thrombosis (PVT) (log-rank 8.738, P = 0.003). Cox multivariate regression analyses revealed that CHE was independently associated with the occurrence of OHE, exacerbation of ascites, and PVT. Furthermore, patients with progression of cirrhosis were more likely to be diagnosed as CHE (log-rank 4.462, P = 0.035). At the end of the follow-up, patients with CHE had a lower survival rate compared to those without CHE (log-rank 8.151, P = 0.004). CHE diagnosis (hazard ratio 2.530, P = 0.008), together with elder age and higher Child-Pugh score, were risk factors for impaired survival in cirrhotic patients. CONCLUSION: CHE is associated with disease progression and poor survival in patients with cirrhosis, indicating that CHE may serve as an independent predictor of poor prognosis among these patients.
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Encefalopatía Hepática , Humanos , Anciano , Encefalopatía Hepática/etiología , Estudios Prospectivos , Calidad de Vida , Ascitis/etiología , Cirrosis Hepática/complicaciones , Progresión de la EnfermedadRESUMEN
Wound infections with antibiotic-resistant bacteria, particularly the Gram-negative strains, pose a substantial health risk for patients with limited treatment options. Recently topical administration of gaseous ozone and its combination with antibiotics through portable systems has been demonstrated to be a promising approach to eradicate commonly found Gram-negative strains of bacteria in wound infections. However, despite the significant impact of ozone in treating the growing number of antibiotic-resistant infections, uncontrolled and high concentrations of ozone can cause damage to the surrounding tissue. Hence, before such treatments could advance into clinical usage, it is paramount to identify appropriate levels of topical ozone that are effective in treating bacterial infections and safe for use in topical administration. To address this concern, we have conducted a series of in vivo studies to evaluate the efficacy and safety of a portable and wearable adjunct ozone and antibiotic wound therapy system. The concurrent ozone and antibiotics are applied through a wound interfaced gas permeable dressing coated with water-soluble nanofibers containing vancomycin and linezolid (traditionally used to treat Gram-positive infections) and connected to a portable ozone delivery system. The bactericidal properties of the combination therapy were evaluated on an ex vivo wound model infected with Pseudomonas aeruginosa, a common Gram-negative strain of bacteria found in many skin infections with high resistance to a wide range of currently available antibiotics. The results indicated that the optimized combination delivery of ozone (4 mg h-1) and topical antibiotic (200 µg cm-2) provided complete bacteria eradication after 6 h of treatment while having minimum cytotoxicity to human fibroblast cells. Furthermore, in vivo local and systemic toxicity studies (e.g., skin monitoring, skin histopathology, and blood analysis) on pig models showed no signs of adverse effects of ozone and antibiotic combination therapy even after 5 days of continuous administration. The confirmed efficacy and biosafety profile of the adjunct ozone and antibiotic therapy places it as a strong candidate for treating wound infection with antimicrobial-resistant bacteria and further pursuing human clinical trials.
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Antibacterianos , Infección de Heridas , Humanos , Animales , Porcinos , Antibacterianos/efectos adversos , Linezolid/farmacología , Linezolid/uso terapéutico , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiologíaRESUMEN
Hepatocellular carcinoma progression is thought to be driven by cancer stem cells (CSCs). No clinical trial has, as yet, shown convincing long-term disease free survival results for the majority of patients in HCC. So it is important to discover new anti-cancer agents. In our study, we chose sophocarpine, which is derived from the foxtail-like sophora herb, for its efficacy to inhibit HCC including CSCs and potential mechanism study. Our results show that sophocarpine could not only reduce HCC cell viability, eliminate HCC and reverse hepatoma cells malignant phenotype, but also reduce the ratio of CSCs and inhibit the sphere formation of CSCs in vitro. In vivo, sophocarpine significantly displayed antitumor effects in subcutaneous xenograft HCC models and orthotopic transplantation tumor models. Further studies showed that sophocarpine could exert anti-tumor effects partly via downregulating the activity of the cancer stem cell related pathways and inhibiting EMT induced by TGF-ß.
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Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Cateninas/metabolismo , Diferenciación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/enzimología , Células Madre Neoplásicas/patología , Fenotipo , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To study the preventive effect of sophocarpine (Soc) on dextran sulfate sodium (DSS)-induced colitis in mice, in order to analyze the influence of Soc on toll like receptor 4 (TLR4)/mitogen-activated protein kinases (MAPKs) and janus tyrosine kinase 2 signal transducer and activator of transcription 3 (JAK2/STAT3) signal pathways in mice intestinal tissues. The mice was given 2.5% DSS for 6 days to induce the acute colitis model. The Soc-treated group was intraperitoneally injected with sophocarpine 30 mg · kg(-1) · d(-1) since the day before the experiment to the end. The disease activity index (DAI) was assessed everyday, and the colonic morphology and histological damage were observed with HE staining. The mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were detected by real-time RT-PCR. The changes in key protein kinase p38 mitogen-activated protein kinase (p38MAPK), c-Jun NH2-terminal protein kinase1/2 (JNK1/2), extracellular signal-regulated kinase1/2 (ERK1/2), JAK2, STAT3 in TLR4/MAPKs and JAK2/STAT3 signaling pathways were detected by western blot. The result showed that the model group showed statistical significance in body weight, DAI, colon length and histopathological changes compared with the normal group (P <0.05); however, the Soc-treated group showed significant improvements in the above indexes compared with the model group (P <0.05). TNF-α, IL-1ß and IL-6 in the model group was significantly higher than that in the normal group (P <0.05), but lowered in the Soc-treated group to varying degrees (P <0.05). In the normal group, the expressions of TLR4 and the phosphorylation of P38, JNK1/2, JAK2, STAT3 were at low levels; in the model group, the phosphorylation of P38, JNK1/2, JAK2, STAT3 increased; the Soc-treated group showed a decrease in TLR4 expression compared with the model group, with notable declines in the phosphorylation of TLR4, P38, JNK1/2, JAK2, STAT3. These findings indicate that Soc can inhibit TLR4/MAPKs, K2/STAT3 signaling pathway activation, reduce the expression of proinflammatory cytokines TNF-α, IL-1ß and IL-6 and relieve inflammatory reactions, so as to effectively prevent experimental colitis.
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Alcaloides/uso terapéutico , Colitis/tratamiento farmacológico , Alcaloides/farmacología , Animales , Colitis/inmunología , Colitis/patología , Citocinas/genética , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Fosforilación , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/fisiología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/fisiologíaRESUMEN
OBJECTIVE: To evaluate the efficacy, safety and tolerability of different doses of rifaximin in Chinese patients with liver cirrhosis. METHODS: This random prospective study included a screening visit, a 2-week treatment period and a subsequent 4-week observation phase. Patients with liver cirrhosis were randomly assigned to a low-dose rifaximin group, a high-dose rifaximin group and the control group in a ratio of 1:1:1. The low-dose and high-dose groups received 400 mg or 600 mg rifaximin per 12 h for 2 weeks, respectively. All other therapeutic strategies remained unchanged in the three groups as long as possible. RESULTS: In total, 60 patients with liver cirrhosis were screened and 43 of them met the eligibility criteria. After 2-week treatment serum endotoxin levels in the low-dose (1.1 ± 0.8 EU/mL) and high-dose rifaximin groups (1.0 ± 0.8 EU/mL) were significantly lower than that in the control group (2.5 ± 1.8 EU/mL), while no significant difference was found between the two rifaximin-treated groups. The effect of high-dose rifaximin on endotoxemia lasted for at least 4 weeks after drug withdrawal. A significant reduction in the abundance of the Veillonellaceae taxa and an increase in the abundance of Bacteroidaceae were shown after 2 weeks of rifaximin therapy. The incidence of adverse events and severe adverse events was similar among the three groups. CONCLUSION: Low-dose (800 mg/day) rifaximin could be analogous to high-dose (1200 mg/day) rifaximin to reduce the serum endotoxin level after 2 weeks of treatment.
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Antibacterianos/administración & dosificación , Endotoxemia/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Rifamicinas/administración & dosificación , Adolescente , Adulto , Anciano , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Endotoxemia/sangre , Endotoxemia/etiología , Femenino , Humanos , Masculino , Microbiota/efectos de los fármacos , Persona de Mediana Edad , Estudios Prospectivos , Rifamicinas/efectos adversos , Rifamicinas/uso terapéutico , Rifaximina , Receptores Toll-Like/sangre , Adulto JovenRESUMEN
Hepatocytes are critical for the maintenance of liver homeostasis, but its involvement in hepatic fibrogenesis remains elusive. Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that plays a key role in hepatocyte function. Our previous study revealed a significant inhibitory effect of HNF1α on hepatocellular carcinoma. In this study, we report that the expression of HNF1α is significantly repressed in both human and rat fibrotic liver. Knockdown of HNF1α in the liver significantly aggravates hepatic fibrogenesis in either dimethylnitrosamine (DMN) or bile duct ligation (BDL) model in rats. In contrast, forced expression of HNF1α markedly alleviates hepatic fibrosis. HNF1α regulates the transcriptional expression of SH2 domain-containing phosphatase-1 (SHP-1) via directly binding to SHP-1 promoter in hepatocytes. Inhibition of SHP-1 expression abrogates the anti-fibrotic effect of HNF1α in DMN-treated rats. Moreover, HNF1α repression in primary hepatocytes leads to the activation of NF-κB and JAK/STAT pathways and initiates an inflammatory feedback circuit consisting of HNF1α, SHP-1, STAT3, p65, miR-21 and miR-146a, which sustains the deregulation of HNF1α in hepatocytes. More interestingly, a coordinated crosstalk between hepatocytes and hepatic stellate cells (HSCs) participates in this positive feedback circuit and facilitates the progression of hepatocellular damage. Our findings demonstrate that impaired hepatocytes play an active role in hepatic fibrogenesis. Early intervention of HNF1α-regulated inflammatory feedback loop in hepatocytes may have beneficial effects in the treatment of chronic liver diseases.
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Células Estrelladas Hepáticas/metabolismo , Factor Nuclear 1-alfa del Hepatocito/biosíntesis , Hepatocitos/metabolismo , Hígado/patología , Animales , Comunicación Celular , Retroalimentación Fisiológica , Fibrosis , Humanos , Quinasas Janus/metabolismo , Hígado/metabolismo , FN-kappa B/metabolismo , Ratas , Factores de Transcripción STAT/metabolismoRESUMEN
BACKGROUND AND AIM: Sophocarpine, a tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L., has been documented that it can suppress pro-inflammatory cytokines synthesis in alleviating nonalcoholic steatohepatitis (NASH) in vivo. Toll-like receptor 4 (TLR4) is a pattern recognition receptor whose activation results in the production of several pro-inflammatory cytokines. It has been reported that TLR4 is upregulated in nonalcoholic fatty liver disease and plays an important role in the pathogenesis of NASH. This study aimed to examine the changes of TLR4 and its signaling pathways in sophocarpine's anti-inflammatory process on experimental NASHâ in vitro. METHODS: Primary hepatocytes were isolated, and oleic acid-induced steatosis model was established. Cell Counting Kit-8 assay was used to detect the number of metabolically active mitochondria and viable cells. Immunocytochemistry analysis was applied to evaluating pro-inflammatory cytokines synthesis. Total RNA and protein were extracted for real-time polymerase chain reaction and Western blot detection. RESULTS: Enhanced expression of TLR4 was observed in oleic acid-induced steatotic hepatocytes. Sophocarpine suppressed pro-inflammatory cytokines synthesis and reduced the expression of TLR4 in steatotic hepatocytes. Expression of TLR4 and pro-inflammatory cytokines recovered after sophocarpine was removed. Moreover, sophocarpine restrained the activation of nuclear factor-kappaB (NF-κB), c-Jun-N-terminal kinase (JNK), and Extracellular regulated protein kinases (ERK) signaling pathways in the anti-inflammatory process. CONCLUSION: Sophocarpine could decrease the expression of TLR4 in steatotic hepatocytes and suppress pro-inflammatory cytokines synthesis. NF-κB, JNK, and ERK signaling pathways were important workable downstream pathways.
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Alcaloides/farmacología , Citocinas/biosíntesis , Hepatocitos/metabolismo , Mediadores de Inflamación , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Ácido Oléico , Reacción en Cadena de la Polimerasa , Ratas Sprague-Dawley , Transducción de Señal/genética , Transducción de Señal/fisiología , Sophora/química , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance. METHODS: Stomach Age was determined by FISH examination of telomere length in stomach biopsies. Δψm was also determined by flow cytometry. Sixty volunteers were used to confirm the linear relationship between telomere length and age while 120 subjects were used to build a mathematical model by a multivariate analysis. Overall, 146 subjects were used to evaluate the validity of the model, and 1,007 subjects were used to evaluate the relationship between prognosis and Δage (calculated from the mathematical model). ROC curves were used to evaluate the relationship between prognosis and Δage and to determine the cut-off point for Δage. RESULTS: We established that a tight linear relationship between the telomere length and the age. The telomere length was obvious different between patients with and without CAG even in the same age. Δψm decreased in individuals whose Stomach Age was greater than real age, especially in younger adults. A mathematical model of Stomach Age (real age + Δage) was successfully constructed which was easy to apply in clinical work. A higher Δage was correlated with a worse outcome. The criterion of Δage >3.11 should be considered as the cut-off to select the subgroup of patients who require endoscopic surveillance. CONCLUSION: Variation in Stomach Age between individuals of the same biological age was confirmed. Attention should be paid to those with a greater Stomach Age, especially in younger adults. The Δage in the Simple Model can be used as a criterion to select CAG patients for gastric cancer surveillance.
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AIM: To explore the effect of sophocarpine on experimental liver fibrosis and the potential mechanism involved. METHODS: Sophocarpine was injected intraperitoneally in two distinct rat hepatic fibrosis models induced either by dimethylnitrosamine or bile duct ligation. Masson's trichrome staining, Sirius red staining and hepatic hydroxyproline level were used for collagen determination. Primary hepatic stellate cells (HSCs) were isolated and treated with different concentrations of sophocarpine. Real-time reverse transcription-polymerase chain reaction was used to detect the mRNA levels of fibrotic markers and cytokines. The expression of pathway proteins was measured by Western blot. The Cell Counting Kit-8 test was used to detect the proliferation rate of activated HSCs treated with a gradient concentration of sophocarpine. RESULTS: Sophocarpine decreased serum levels of aminotransferases and total bilirubin in rats under chronic insult. Moreover, administration of sophocarpine suppressed extracellular matrix deposition and prevented the development of hepatic fibrosis. Furthermore, sophocarpine inhibited the expression of α-smooth muscle actin (SMA), interleukin (IL)-6, transforming growth factor-ß1 (TGF-ß1), Toll-like receptor 4 (TLR4), and extracellular-related kinase (ERK) in rats. Sophocarpine also down-regulated the mRNA expression of α-SMA, collagenâ I, collagen III, TGF-ß1, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1, and decreased protein levels of TLR4, p-ERK, p-JNK, p-P38 and p-IKK in vitro after Lipopolysaccharide induction. In addition, sophocarpine inhibited the proliferation of HSCs accompanied by a decrease in the expression of Cyclin D1. The protein level of proliferating cell nuclear antigen was decreased in activated HSCs following a gradient concentration of sophocarpine. CONCLUSION: Sophocarpine can alleviate liver fibrosis mainly by inhibiting the TLR4 pathway. Sophocarpine may be a potential chemotherapeutic agent for chronic liver diseases.
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Alcaloides/farmacología , Cirrosis Hepática/patología , Receptor Toll-Like 4/metabolismo , Animales , Conductos Biliares/cirugía , Proliferación Celular , Células Cultivadas , Colágeno/metabolismo , Colorantes/química , Dimetilnitrosamina/química , Hidroxiprolina/metabolismo , Hígado/metabolismo , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de SeñalRESUMEN
UNLABELLED: MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer-associated genomic region. However, the role of miR-370 in malignances remains controversial. Here, we report that miR-370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated that miR-370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR-370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA-binding protein, LIN28A, was identified as a direct functional target of miR-370, which, in turn, blocked the biogenesis of miR-370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR-370 on migration and invasion of HCC cells by post-transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF-κB) pathway. Interleukin-6 (IL-6), a well-known NF-κB downstream inflammatory molecule, reduced miR-370 but increased LIN28A levels in HCC. Furthermore, miR-370 levels were inversely correlated with LIN28A and IL-6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL-6 expression in human HCC samples. Interestingly, reduction of miR-370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. CONCLUSIONS: These data demonstrate the involvement of a novel regulatory circuit consisting of miR-370, LIN28A, RelA/p65 and IL-6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment.
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Carcinoma Hepatocelular/patología , Proteínas de Unión al ADN/metabolismo , Neoplasias Hepáticas/patología , MicroARNs/fisiología , FN-kappa B/metabolismo , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , Interleucina-6/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Ratones , Proteínas de Unión al ARN , Factor de Transcripción ReIA/fisiologíaRESUMEN
Sophocarpine, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 µmol/L oleic acid for 24h to induce steatotic model, then treated with sophocarpine for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While sophocarpine treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, sophocarpine could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that sophocarpine could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK.
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Proteínas Quinasas Activadas por AMP/metabolismo , Alcaloides/farmacología , Antiinflamatorios/farmacología , Hígado Graso/tratamiento farmacológico , Adipoquinas/metabolismo , Adiponectina/metabolismo , Alcaloides/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Hígado Graso/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: The aim of this study was to determine whether cirrhosis could be reversed after treated with hepatocyte nuclear factor 4α (HNF4α), a key transcriptional regulator of hepatocyte differentiation and function. METHODS: Early and advanced stages of liver cirrhosis were induced by thioacetamide (TAA) administration. The adenovirus carrying HNF4α gene was injected into cirrhotic rats via the tail vein. The effect of HNF4α on cirrhosis was evaluated by histological and immunohistochemical examination. RESULTS: Early stage of cirrhosis was remarkably resolved by HNF4α to a nearly-normal extent and advanced cirrhosis was partially ameliorated in vivo. The enforced expression of HNF4α downregulated profibrogenic factors remarkably including α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-ß1, fibroblast-specific protein (FSP)-1, collagen I and III.â In vivo and in vitro studies revealed that HNF4α administration inhibited extracellular signal-regulated kinase (ERK) signaling pathway through the downregulation of phosphorated ERK and phosphorated JunD. In addition, HNF4α readjusted the balance between extracellular matrix deposition and degradation through the upregulation of matrix metalloproteinase and downregulation of its inhibitors. Moreover, HNF4α treatment inhibited angiogenesis as determined by CD31 and CD34 immunostaining. CONCLUSIONS: Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis.
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Factor Nuclear 4 del Hepatocito/uso terapéutico , Cirrosis Hepática Experimental/tratamiento farmacológico , Animales , Células Cultivadas , Matriz Extracelular/metabolismo , Cirrosis Hepática Experimental/inducido químicamente , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neovascularización Patológica/prevención & control , Ratas , Ratas Sprague-Dawley , TioacetamidaRESUMEN
BACKGROUND: The use of a colonic stent as a bridge to surgery aims to provide patients with elective one-stage surgical resection while reducing stoma creation and postoperative complications. This study used meta-analytic techniques to compare the outcomes of stent use as a bridge to surgery and emergency surgery in the management of obstructive colorectal cancer. METHODS: A literature search of Medline, Embase, Cochrane controlled trials registry, and the Chinese Biomedical Literature Database was performed on all studies comparing stent as a bridge to surgery and emergency surgery for obstructive colorectal cancer. A meta-analysis of the included studies was carried out to identify the differences in outcomes between the two procedures. RESULTS: Eight studies matched the criteria for inclusion and reported on the outcomes of 601 patients, of whom 232 (38.6%) underwent stent insertion and 369 (61.4%) underwent emergency surgery. Fewer patients in the stent group needed intensive care (risk ratio [RR], 0.42; 95% confidence interval [CI], 0.19-0.93; p = 0.03) and stoma creation (RR, 0.70; 95% CI, 0.50-0.99; p = 0.04). The primary anastomosis rate in the stent group was higher (RR, 1.62; 95% CI, 1.21-2.16; p = 0.001). Overall complications (RR, 0.42; 95% CI, 0.24-0.71; p = 0.001), including anastomotic leakage (RR, 0.31; 95% CI, 0.14-0.69; p = 0.004), were reduced by stent insertion. Stent placement before elective surgery did not adversely affect mortality and long-term survival. CONCLUSIONS: The use of a stent as a bridge to surgery for obstructive left-sided colorectal cancer could increase the chance of primary anastomosis and reduce the need for stoma creation and postprocedural complications. Stent insertion before subsequent surgery has no effect on perioperative mortality and long-term survival.
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Neoplasias Colorrectales/cirugía , Tratamiento de Urgencia/instrumentación , Obstrucción Intestinal/cirugía , Stents , Colectomía/mortalidad , Colectomía/estadística & datos numéricos , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/mortalidad , Colostomía/mortalidad , Colostomía/estadística & datos numéricos , Urgencias Médicas , Tratamiento de Urgencia/métodos , Tratamiento de Urgencia/mortalidad , Humanos , Obstrucción Intestinal/etiología , Obstrucción Intestinal/mortalidad , Laparoscopía/mortalidad , Laparoscopía/estadística & datos numéricos , Tiempo de Internación , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Sesgo de Publicación , Ensayos Clínicos Controlados Aleatorios como Asunto , Tamaño de la MuestraRESUMEN
UNLABELLED: Hepatocyte nuclear factor-1alpha (HNF1α) is one of the key transcription factors of the HNF family, which plays a critical role in hepatocyte differentiation. Substantial evidence has suggested that down-regulation of HNF1α may contribute to the development of hepatocellular carcinoma (HCC). Herein, human cancer cells and tumor-associated fibroblasts (TAFs) were isolated from human HCC tissues, respectively. A recombinant adenovirus carrying the HNF1α gene (AdHNF1α) was constructed to determine its effect on HCC in vitro and in vivo. Our results demonstrated that HCC cells and HCC tissues revealed reduced expression of HNF1α. Forced reexpression of HNF1α significantly suppressed the proliferation of HCC cells and TAFs and inhibited the clonogenic growth of hepatoma cells in vitro. In parallel, HNF1α overexpression reestablished the expression of certain liver-specific genes and microRNA 192 and 194 levels, with a resultant increase in p21 levels and induction of G(2)/M arrest. Additionally, AdHNF1α inhibited the expression of cluster of differentiation 133 and epithelial cell adhesion molecule and the signal pathways of the mammalian target of rapamycin and transforming growth factor beta/Smads. Furthermore, HNF1α abolished the tumorigenicity of hepatoma cells in vivo. Most interestingly, intratumoral injection of AdHNF1α significantly inhibited the growth of subcutaneous HCC xenografts in nude mice. Systemic delivery of AdHNF1α could eradicate the orthotopic liver HCC nodules in nonobese diabetic/severe combined immunodeficiency mice. CONCLUSION: These results suggest that the potent inhibitive effect of HNF1α on HCC is attained by inducing the differentiation of hepatoma cells into mature hepatocytes and G(2)/M arrest. HNF1α might represent a novel, promising therapeutic agent for human HCC treatment. Our findings also encourage the evaluation of differentiation therapy for tumors of organs other than liver using their corresponding differentiation-determining transcription factor.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Factor Nuclear 1-alfa del Hepatocito/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Antígeno AC133 , Adenoviridae/genética , Animales , Antígenos CD/biosíntesis , Antígenos de Neoplasias/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Molécula de Adhesión Celular Epitelial , Glicoproteínas/biosíntesis , Humanos , Masculino , Ratones , MicroARNs/fisiología , Trasplante de Neoplasias , Péptidos , Trasplante Heterólogo , Quinasas p21 Activadas/metabolismoRESUMEN
AIMS: Whether gemcitabine based chemoradiotherapy (GEM-based CRT) is superior to 5-fluorouracil based chemoradiotherapy (5-FU-based CRT) for locally advanced pancreatic cancer (LAPC) remains uncertain. The aim of the present study was to evaluate the effect of GEM-based CRT compared with 5-FU-based CRT. METHODS: Electronic database including Medline, Embase, Cochrane controlled trials register, PubMed (update to December 2010) and manual bibliography searches were carried out. A meta-analysis of all randomized clinical trials (RCTs) or other comparative studies comparing GEM-based CRT and 5-FU-based CRT were performed. RESULTS: Three RCTs and one retrospective comparative study including 229 patients were assessed. Meta-analysis showed survival advantage of GEM-based CRT compared with 5-FU-based CRT for 12-month (12-mo) survival rates (SRs) (RR=1.54, 95% CI 1.05-2.26, p=0.03). Moreover, there were also trends of benefit for SR after 6-months (RR 1.13, 95% CI 0.98-1.30, p=0.09) and 24-months (24-mo: RR 2.41, 95% CI 0.90-6.48, p=0.08), though the trends did not reach statistical significance. More frequent severe acute hematologic toxicities were found in the GEM-based CRT group. CONCLUSIONS: The meta-analysis found that GEM-based CRT was better than 5-FU-based CRT in the treatment of LAPC, especially for 12-mo SRs. However, the acute toxicity should be carefully regarded.
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Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Neoplasias Pancreáticas/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , GemcitabinaRESUMEN
BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is one entity in the spectrum of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to explore the prevention and therapeutic effect of sophocarpine on experimental rat NASH. METHODS: Sophocarpine with the dosage of 20 mg/kg/day was injected into NASH rats. At the end of 12 weeks, all rats were killed to detect the degree of fatty degeneration, inflammation and fibrosis. RESULTS: Sophocarpine intervention (in the pro-treated and treated groups) resulted in a significant decrease of liver weight, liver index, serum transaminase and serum lipids. Messenger RNA expressions of leptin, interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, procollagen-I and α-smooth muscle actin (SMA) and deposition of IL-6, TNF-α and TGF-ß1 in liver decreased, whereas the messenger RNA expression of adiponectin increased significantly compared with that in the model group. Moreover, histological improvement was also observed in the sophocarpine intervention group. In addition, there was no significant difference in any detected indicator between the pro-treated and treated group. CONCLUSIONS: Sophocarpine could decrease the level of serum transaminase, improve lipid metabolism, reduce synthesis of inflammatory cytokines TNF-α, TGF-ß1 and IL-6, activate protective adipocytokine adiponectin, and might be selected as a promising agent for the clinical prevention and therapy of NASH.
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Alcaloides/farmacología , Antiinflamatorios/farmacología , Hígado/efectos de los fármacos , Adipoquinas/sangre , Adipoquinas/genética , Animales , Citocinas/sangre , Citocinas/genética , Citoprotección , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hígado Graso/inmunología , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/prevención & control , Mediadores de Inflamación/sangre , Lípidos/sangre , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Factores de Tiempo , Transaminasas/sangreRESUMEN
Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of ß-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of ß-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas.
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Carcinoma Hepatocelular/metabolismo , Factor Nuclear 4 del Hepatocito/biosíntesis , Neoplasias Hepáticas/metabolismo , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Células Epiteliales/patología , Humanos , Inmunohistoquímica , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Mesodermo/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Ratas , beta Catenina/metabolismoRESUMEN
UNLABELLED: Extracellular signal-regulated kinase 1 (ERK1) is a critical part of the mitogen-activated protein kinase signal transduction pathway, which is involved in hepatic fibrosis. However, the effect of down-regulation of ERK1 on hepatic fibrosis has not been reported. Here, we induced hepatic fibrosis in rats with dimethylnitrosamine administration or bile duct ligation. An adenovirus carrying small interfering RNA targeting ERK1 (AdshERK1) was constructed to determine its effect on hepatic fibrosis, as evaluated by histological and immunohistochemical examination. Our results demonstrated that AdshERK1 significantly reduced the expression of ERK1 and suppressed proliferation and levels of fibrosis-related genes in hepatic stellate cells in vitro. More importantly, selective inhibition of ERK1 remarkably attenuated the deposition of the extracellular matrix in fibrotic liver in both fibrosis models. In addition, both hepatocytes and biliary epithelial cells were proven to exert the ability to generate the myofibroblasts depending on the insults of the liver, which were remarkably reduced by AdshERK1. Furthermore, up-regulation of ERK1 paralleled the increased expression of transforming growth factor beta1 (TGF-beta1), vimentin, snail, platelet-derived growth factor-BB (PDGF-BB), bone morphogenetic protein 4 (BMP4), and small mothers against decapentaplegic-1 (p-Smad1), and was in reverse correlation with E-cadherin in the fibrotic liver. Nevertheless, inhibition of ERK1 resulted in the increased level of E-cadherin in parallel with suppression of TGF-beta1, vimentin, snail, PDGF-BB, BMP4, and p-Smad1. Interestingly, AdshERK1 treatment promoted hepatocellular proliferation. CONCLUSION: Our study provides the first evidence for AdshERK1 suppression of hepatic fibrosis through the reversal of epithelial-mesenchymal transition of both hepatocytes and biliary epithelial cells without interference of hepatocellular proliferation. This suggests that ERK1 is implicated in hepatic fibrogenesis and selective inhibition of ERK1 by small interfering RNA may present a novel option for hepatic fibrosis treatment.