RESUMO
BACKGROUND: Sarcopenia is a senile syndrome of age-related muscle loss. It is thought to affect the development of chronic kidney disease and has a serious impact on the quality of life of the elder adults. Little is known about the association between sarcopenia and new-onset chronic kidney disease in middle-aged and elder adults. Using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted a longitudinal analysis to investigate the association between sarcopenia status and new-onset chronic kidney disease in middle-aged and elder adults in China. METHODS: The study population consisted of 3676 participants aged 45 or older selected from 2011 CHARLS database who had no history of chronic kidney disease at the baseline and completed the follow-up in 2015. A multivariate cox regression model was employed to examine the association between sarcopenia and the incidence of new-onset chronic kidney disease. RESULTS: Followed up for 4 years, a total of 873 (22.5%) new cases of chronic kidney disease occurred. Among them, participants diagnosed with sarcopenia (HR1.45; 95% CI 1.15-1.83) were more likely to develop new-onset chronic kidney disease than those without sarcopenia. Similarly, patients with sarcopenia were more likely to develop new-onset chronic kidney disease than those with possible sarcopenia (HR 1.27; 95%CI 1.00-1.60). Subgroup analysis revealed that elder adults aged between 60 and 75 years old (HR 1.666; 95%CI 1.20-22.28), with hypertension (HR 1.57; 95%CI 1.02-2.40), people with sarcopenia had a significantly higher risk of developing new-onset chronic kidney disease than those without sarcopenia (all P < 0.05). CONCLUSION: Middle-aged and elder adults diagnosed with sarcopenia have a higher risk of developing new-onset chronic kidney disease.
Assuntos
Insuficiência Renal Crônica , Sarcopenia , Humanos , Pessoa de Meia-Idade , Idoso , Aposentadoria , Estudos Longitudinais , Qualidade de Vida , ChinaRESUMO
BACKGROUND: Pulmonary fibrosis is a chronic progressive fibrosis interstitial lung disease that is characterized by inflammatory infiltration and fibrotic changes. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation, immunomodulation, and fibrosis. The aim of this study was to investigate the role of 5-HT in bleomycin- (BLM-) induced pulmonary fibrosis through wild-type C57BL/6 (WT) and TPH1 knockout (KO) mouse experiments. METHODS: The mice were grouped as follows: WT control group, KO control group, WT BLM group, and KO BLM group. Mice were administrated bleomycin hydrochloride through intratracheal instillation to induce pulmonary fibrosis. Mice were sacrificed 0, 7, 14, and 21 days after modeling, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected to determine the severity of fibrotic changes. RESULTS: The results showed that the weight loss of mice in the WT BLM group was more severe than that in the KO BLM group. H&E and Sirius Red staining revealed that 5-HT markedly aggravated histological damage and fibrotic changes in the lung. Significantly lower levels of hydroxyproline, Ashcroft fibrosis score, total BALF protein and cells, BALF tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6, TNF-α and IL-6 mRNA, malondialdehyde (MDA), and myeloperoxidase- (MPO-) positive cells in the lung tissues, and fibrosis-associated proteins were discovered in the mice from the KO BLM group compared with the WT BLM group. CONCLUSION: 5-HT aggravated pulmonary fibrosis mainly by promoting the inflammation, exudation of proteins and cells, oxidative stress, and upregulation of fibrosis-associated genes in the lung tissues.
Assuntos
Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Serotonina/uso terapêutico , Triptofano Hidroxilase/metabolismo , Animais , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triptofano Hidroxilase/genéticaRESUMO
Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Piroptose , Humanos , Acetaminofen/toxicidade , Caspases Iniciadoras/metabolismo , Caspases/metabolismo , Ácido LácticoRESUMO
Background: NSAIDs are one of the most frequently used medications and a risk factor for AKI. However, the optimal time of NSAIDs in patients with AKI is unknown. Methods: A secondary analysis of a multicenter, randomized clinical trial including adult inpatients with acute kidney injury was performed. Univariate, multivariate, and subgroup analyses were used to explore the impact of NSAIDs during the early onset of AKI on the outcome of patients with AKI. Results: A total of 6,030 patients with AKI were enrolled in the study. Following are the findings of the multi-factor analysis: NSAID treatments within 72 and 24 h before the onset of AKI were not associated with AKI progression, dialysis, or discharge from dialysis; only NSAID treatment within the 24-h onset of AKI was associated with these outcomes, and their OR values were independently 1.50 (95% CI: 1.02-2.19, p = 0.037), 4.20 (95% CI: 1.47-11.97, p = 0.007), and 0.71 (95% CI: 0.54-0.92, p = 0.011); only NSAID treatment within the 24-h onset of AKI would decrease the 14-day mortality, and the OR value was 0.52 (95% CI: 0.33-0.82, p = 0.005). The subgroup analysis revealed that in patients with age ≥65 years, CKD (chronic kidney disease), congestive heart failure, hypertension, and liver disease, NSAID treatments within the 24-h onset of AKI would deteriorate the outcome of patients with AKI. Conclusion: Before an early onset of AKI, NSAID treatment might be safe, but during the onset of AKI, even early NSAID treatment would deteriorate the outcome of patients with AKI.
RESUMO
Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts anti-inflammatory and antioxidative properties. To investigate the potential effects of PPARγ on sepsis-induced liver injury and determine the related mechanisms, C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to create a sepsis model which was treated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulation of PPARγ decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and liver pathological damage and improved the 5-day survival rate. Increased expression of PPARγ also decreased sepsis-induced reactive oxygen species (ROS) by promoting the expression of Nrf2. In addition, upregulated PPARγ inhibited the expression of the TXNIP/NLRP3 signaling pathway by reducing ROS-induced injury in the liver during sepsis, which further reduced NLRP3-mediated pyroptosis and the inflammatory response. The role of PPARγ was further examined in in vitro experiments, where lipopolysaccharide- (LPS-) treated HepG2 and Hep3B cells were incubated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulated PPARγ ameliorated LDH release and improved cell viability. Our results indicated that increased expression of PPARγ reduced ROS levels and inhibited the TXNIP/NLRP3 signaling pathway, resulting in decreased pyroptosis and reduced liver dysfunction during sepsis.
Assuntos
Proteínas de Transporte/metabolismo , Hepatócitos/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Tiorredoxinas/metabolismo , Anilidas/administração & dosagem , Animais , Benzofenonas/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Hepatopatias/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Resultado do Tratamento , Tirosina/administração & dosagem , Tirosina/análogos & derivados , Regulação para Cima/efeitos dos fármacosRESUMO
Acetaminophen (APAP) overdose has been considered responsible for the drug-induced liver injury for many years. Ferroptosis is defined as an iron-dependent form of cell death associated with lipid peroxide accumulation. Ferroptosis is involved in APAP-induced acute liver failure, and UTI is an effective drug treatment for acute liver failure. Thus, we aimed to determine whether UTI protects the liver against APAP-induced acute liver failure by decreasing ferroptosis-induced lipid peroxide accumulation. C57BL/6 mice and LO2 cell line were treated with UTI before and after the exposure to APAP. Liver tissues and LO2 cells were collected for biochemical assessment of molecular parameters. APAP-induced upregulation of ferroptotic events (iron content), lipid hydroperoxides (ROS production, MDA, and 4-HNE), and depletion of GSH were effectively relieved by ferrostatin-1 (Fer-1), a ferroptosis inhibitor, and UTI. UTI blocked ferroptosis-induced lipid peroxide accumulation by promoting nuclear translocation of NRF2 to activate its downstream targets (HO-1). An increased expression or knockdown of of SIRT1 influenced the UTI effect on the NRF2 pathway and had an impact on lipid accumulation. Overall, UTI plays a role in mitigation of APAP-induced acute liver injury by inhibiting ferroptosis-induced lipid peroxide accumulation, and the effect of UT1 was mediated by the NRF2/HO-1 pathway and SIRT1 expression.
RESUMO
Introduction: COVID-19 has overloaded worldwide medical facilities, leaving some potentially high-risk patients trapped in outpatient clinics without sufficient treatment. However, there is still a lack of a simple and effective tool to identify these patients early. Methods: A retrospective cohort study was conducted to develop an early warning model for predicting the death risk of COVID-19. Seventy-five percent of the cases were used to construct the prediction model, and the remaining 25% were used to verify the prediction model based on data immediately available on admission. Results: From March 1, 2020, to April 16, 2020, a total of 4,711 COVID-19 patients were included in our study. The average age was 63.37 ± 16.70 years, of which 1,148 (24.37%) died. Finally, age, SpO2, body temperature (T), and mean arterial pressure (MAP) were selected for constructing the model by univariate analysis, multivariate analysis, and a review of the literature. We used five common methods for constructing the model and finally found that the full model had the best specificity and higher accuracy. The area under the ROC curve (AUC), specificity, sensitivity, and accuracy of full model in train cohort were, respectively, 0.798 (0.779, 0.816), 0.804, 0.656, and 0.768, and in the validation cohort were, respectively, 0.783 (0.751, 0.815), 0.800, 0.616, and 0.755. Visualization tools of the prediction model included a nomogram and an online dynamic nomogram (https://wanghai.shinyapps.io/dynnomapp/). Conclusion: We developed a prediction model that might aid in the early identification of COVID-19 patients with a high probability of mortality on admission. However, further research is required to determine whether this tool can be applied for outpatient or home-based COVID-19 patients.
RESUMO
Sepsis-associated coagulation dysfunction greatly increases the mortality of sepsis. Irregular clinical time-series data remains a major challenge for AI medical applications. To early detect and manage sepsis-induced coagulopathy (SIC) and sepsis-associated disseminated intravascular coagulation (DIC), we developed an interpretable real-time sequential warning model toward real-world irregular data. Eight machine learning models including novel algorithms were devised to detect SIC and sepsis-associated DIC 8n (1 ≤ n ≤ 6) hours prior to its onset. Models were developed on Xi'an Jiaotong University Medical College (XJTUMC) and verified on Beth Israel Deaconess Medical Center (BIDMC). A total of 12,154 SIC and 7,878 International Society on Thrombosis and Haemostasis (ISTH) overt-DIC labels were annotated according to the SIC and ISTH overt-DIC scoring systems in train set. The area under the receiver operating characteristic curve (AUROC) were used as model evaluation metrics. The eXtreme Gradient Boosting (XGBoost) model can predict SIC and sepsis-associated DIC events up to 48 h earlier with an AUROC of 0.929 and 0.910, respectively, and even reached 0.973 and 0.955 at 8 h earlier, achieving the highest performance to date. The novel ODE-RNN model achieved continuous prediction at arbitrary time points, and with an AUROC of 0.962 and 0.936 for SIC and DIC predicted 8 h earlier, respectively. In conclusion, our model can predict the sepsis-associated SIC and DIC onset up to 48 h in advance, which helps maximize the time window for early management by physicians.
RESUMO
Brain injury induced by cardiac arrest/cardiopulmonary resuscitation (CA/CPR) is the leading cause of death among patients who have recovery of spontaneous circulation (ROSC). Inflammatory response, apoptosis, and oxidative stress are proven pathological mechanisms implicated in neuronal damage. Methane-rich saline (MRS) has been proven that exerts a beneficial protectiveness impact in several models of ischemia-reperfusion injury. The goal of this paper is to ascertain the role of MRS in CA/CPR-induced brain injury and its potential mechanisms. The tracheal intubation of Sprague-Dawley (SD) rats was clamped for 6 min to establish an asphyxiating cardiac arrest model. After that, chest compressions were applied; then, MRS or saline was administered immediately post-ROSC, the rats were sacrificed, and brain tissue was collected at the end of 6 hours. We observed that MRS treatment attenuated neuronal damage in the hippocampal CA1 region by inhibiting microglial activation, leading to a decrease in the overexpression of proinflammatory cytokines such as TNF-α, IL-6, and iNOS. The results also illustrated that MRS treatment diminished apoptosis in the hippocampal CA1 region , reduced the expression of apoptosis-associated proteins Bax and cleaved caspase9, and increased Bcl-2 expression, as well as inhibited the expression of endoplasmic reticulum (ER) stress pathway-related proteins GRP78, ATF4, and CHOP. Further findings showed that MRS treatment significantly attenuated hippocampal ROS and MDA levels and increased GSH and SOD antioxidant factor levels, which indicated that MRS treatment could inhibit oxidative stress. Our results suggest that MRS exerts a protective effect against CA/CPR brain injury, by inhibiting oxidative stress, microglial activation-induced inflammatory responses, and ER stress-mediated apoptosis.
Assuntos
Apoptose , Reanimação Cardiopulmonar , Estresse do Retículo Endoplasmático , Parada Cardíaca/complicações , Inflamação/patologia , Microglia/patologia , Estresse Oxidativo , Solução Salina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Parada Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Metano/química , Microglia/efeitos dos fármacos , Modelos Biológicos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Retorno da Circulação EspontâneaRESUMO
Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has anti-oxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.
Assuntos
Metformina , Traumatismo por Reperfusão , Animais , Células CACO-2 , Proteínas de Transporte/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Metformina/farmacologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Neoplasias , Proteínas de Ligação a Fosfato , Piroptose , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , TiorredoxinasRESUMO
BACKGROUND: Due to the special clinical features and biologic characteristics of adolescent and young adult (AYA) cancers, AYA cancers are different from cancers in children and elderly individuals. However, there are few reports on AYA hepatocellular carcinoma (HCC). AIM: To investigate the overall survival (OS) of AYA (15-39 years) and elderly (40-74 years) patients with HCC. METHODS: The data of all the HCC cases were extracted from the Surveillance, Epidemiology, and End Results database from 2004 to 2015 and were then divided into two groups based on age: AYA group (15-39 years) and older group (40-74 years). Kaplan-Meier curves and log-rank tests were used to compare the OS of the two groups. Propensity score matching (PSM) was employed to analyze the OS difference between the two groups. The Cox proportional hazards regression model was used to perform multivariate analysis to explore the risk factors for OS of HCC patients. RESULTS: Compared to elderly cancer patients, AYA patients with HCC had a worse Surveillance, Epidemiology, and End Results stage, including the distant stage (22.1% vs 15.4%, P < 0.001), and a more advanced American Joint Committee on Cancer (AJCC) stage, including AJCC III and IV (49.2% vs 38.3%, P < 0.001), and were more likely to receive surgery (64.5% vs 47.5%, P < 0.001). Before PSM, the AYA group had a longer survival in months (median: 20.00, interquartile range [IQR]: 5.00-62.50) than the older group (median: 15.00, IQR: 4.00-40.00) (P < 0.001). After PSM, the AYA group still had a longer survival in months (median: 21.00, IQR: 5.00-64.50) than the older group (median: 18.00, IQR: 6.00-53.00) (P < 0.001). The Cox proportional hazards regression model showed that advanced age (hazard ratio [HR] = 1.405, 95%CI: 1.218-1.621, P < 0.001) was a risk factor for OS of HCC patients. In the subgroup analysis, the Cox proportional hazards regression model showed that in AJCC I/II HCC patients, advanced age (HR = 1.749, 95%CI: 1.352-2.263, P < 0.001) was a risk factor for OS, while it was not a risk factor in AJCC III/IV HCC patients (HR = 1.186, 95%CI: 0.997-1.410, P = 0.054) before PSM. After PSM, advanced age (HR = 1.891, 95%CI: 1.356-2.637, P < 0.001) was still a risk factor for OS in AJCC I/II HCC patients, but was not a risk factor for OS in AJCC III/IV HCC patients (HR = 1.192, 95%CI: 0.934-1.521, P = 0.157) after PSM. CONCLUSION: AYA patients with HCC have different clinical characteristics from older adults. In different AJCC stages, the two groups of patients have different OS: In AJCC I/II HCC patients, advanced age is a risk factor for OS, but it is not a risk factor for OS in the AJCC III/IV HCC patient group.
RESUMO
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Methane has been reported to have anti-oxidative, anti-apoptotic and anti-inï¬ammatory properties. We investigated the potential protective effects of methane on sepsis-induced injury and determined the related mechanisms. C57BL/6 mice received laparotomy with cecal ligation and puncture (CLP) to create a septic model, followed by methane-rich saline (MRS) treatment after CLP. MRS treatment improved the 5-day survival rate and organ functions and alleviated pathological damage of the mice, as well as reduced excessive inflammatory mediators, such as tumor necrosis factor-α and interleukin-6. MRS treatment also decreased the levels of oxidative stress index proteins, decreased the apoptosis of cells and inhibited nod-liker receptor protein (NLRP)3-mediated pyroptosis in the lung and intestine. In in vitro experiments, RAW264.7 and primary peritoneal macrophages were treated with lipopolysaccharide (LPS) plus adenosine-triphosphate (ATP) to induce inflammation and pyroptosis. Consistent with the in vivo results, methane-rich medium (MRM) treatment also reduced the levels of excessive inflammatory mediators, and decreased the levels of ROS, inhibited apoptosis and pyroptosis. Our results indicate that methane offers a protective effect for septic mice via its anti-inflammation, anti-oxidation, anti-pyroptosis and anti-apoptosis properties.
Assuntos
Apoptose/efeitos dos fármacos , Metano/administração & dosagem , Piroptose/efeitos dos fármacos , Solução Salina/administração & dosagem , Solução Salina/química , Sepse/terapia , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/complicações , Células RAW 264.7 , Sepse/etiologiaRESUMO
Sepsis, a life-threatening organ dysfunction due to a dysregulated response to infection, is a common complication of major surgery. Previous studies have shown that methane possesses protective properties. This study aims to investigate the protective effect of methane-rich saline (MRS) on sepsis-induced liver injury. In an in vivo experiment, C57BL/6 mice received cecal ligation and puncture to create a septic model followed by MRS treatment (10âmL/kg, ip treatment) 30âmin and 12âh after the operation. We found that methane effectively decreased the serum aspartate aminotransferase, alanine aminotransferase and liver index, as well as the liver pathological damage, and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the toll-like receptor 4/nuclear factor-kappa B (NF-κB) signaling pathway and stimulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) during sepsis, which inhibited the activation of NF-κB and decreased the level of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1ß. Moreover, we found that MRS treatment relieved reactive oxygen species (ROS) damage by upregulating heme oxygenase-1, superoxide dismutase and glutathione, and downregulating malondialdehyde, which was consistent with the results of dihydroethidium fluorescent staining. MRS treatment also regulated apoptosis-related proteins, such as Bax, Bcl-2, and caspase-3. In the in vitro experiment, HepG2 cells received inflammatory stimulation induced by LPS followed by methane-rich medium (MRM) treatment. We found that MRM alleviated the inflammatory damage, ROS damage and regulated the expression of PPAR-γ/NF-κB. Our data indicated that methane treatment prevented liver damage in sepsis via anti-inflammatory, anti-oxidative, and anti-apoptotic properties that involved the PPAR-γ/ NF-κB signaling pathway.
Assuntos
Hepatopatias , Metano/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Solução Salina/farmacologia , Sepse , Transdução de Sinais/efeitos dos fármacos , Animais , Células Hep G2 , Humanos , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Hepatopatias/prevenção & controle , Masculino , Camundongos , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologiaRESUMO
Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF-κB pathway and further reduced the levels of proinflammatory factors. Downregulation of NF-κB subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF-κB/NLRP3 signaling pathway.
Assuntos
Colestase/complicações , Inflamassomos/efeitos dos fármacos , Hepatopatias/prevenção & controle , Metano/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cloreto de Sódio/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Ductos Biliares , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Ligadura , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genéticaRESUMO
Acetaminophen- (APAP-) induced hepatic injury is an important clinical challenge. Oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress (ERS) contribute to the pathogenesis. Methane has potential anti-inflammatory, antioxidant, and antiapoptotic properties. This project was aimed at studying the protective effects and relative mechanisms of methane in APAP-induced liver injury. In the in vivo experiment, C57BL/6 mice were treated with APAP (400 mg/kg) to induce hepatic injury followed by methane-rich saline (MRS) 10 ml/kg i.p. after 12 and 24 h. We observed that MRS alleviated the histopathological lesions in the liver, decreased serum aminotransferase levels, reduced the levels of inflammatory cytokines, suppressed the nuclear factor-κB expression. Further, we found that MRS relieved oxidative stress by regulating the Nrf2/HO-1/NQO1 signaling pathway and their downstream products after APAP challenge. MRS also regulated proteins associated with ERS-induced apoptosis. In the in vitro experiment, the L-02 cell line was treated with APAP (10 mM) to induce hepatic injury. We found that a methane-rich medium decreased the levels of reactive oxygen species (DHE fluorescent staining), inhibited apoptosis (cell flow test), and regulated the Nrf2/HO-1/NQO1 signaling pathway. Our data indicated that MRS prevented APAP-induced hepatic injury via anti-inflammatory, antioxidant, anti-ERS, and antiapoptotic properties involving the Nrf2/HO-1/NQO1 signaling pathway.
Assuntos
Acetaminofen/efeitos adversos , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metano/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acetaminofen/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Proteínas de Membrana/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
BACKGROUND & AIMS: Accumulating evidence showed platelets were closely related to hepatocellular carcinoma (HCC) prognosis. We here aimed to develop two simple-to-use nomograms based on the PLT-associated modified models to refine prognostic prediction of Asian HCC. METHODS: The nomograms were established using 684 eligible Asian patients who received curative resection for HCC, among which 456 and 228 were randomly assigned to the derivation and validation cohorts, respectively. Univariate and multivariate Cox analyses in the derivation set were used to identify the independent prognostic factors of the hepatectomy patients as the nomogram variables. We evaluated the discrimination and calibration of the nomograms by concordance indexes (C-index), calibration plots and Kaplan-Meier curves. The discrimination ability of the PLT-based nomograms was compared with the conventional staging systems using time-dependent receiver operating characteristic (ROC) curves. RESULTS: The nomogram for overall survival (OS) estimation was comprised of MPV/PC [mean platelet volume/platelet count], SII [systemic immune-inflammation index], NPS [neutrophil-platelet score], PAPAS [platelet count/age/ALP/AFP/AST index] and S index. And the nomogram for recurrence-free survival (RFS) prediction was of NPS, PAPAS and S index. The C-indexes of the OS nomogram in the derivation and validation sets were 0.704 and 0.707, and those of the RFS nomogram were 0.668 and 0.703. The calibration plots fitted well. The survival curves showed great discriminatory powers. The area under the curve (AUC) of our nomograms were significantly larger than that of the three conventional models (Pâ¯<â¯0.05). CONCLUSIONS: The two PLT-based nomograms were accurate in predicting the OS and RFS of Asian HCC patients after hepatectomy.
Assuntos
Povo Asiático/estatística & dados numéricos , Carcinoma Hepatocelular/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Nomogramas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVES: We aimed to confirm the clinical effectiveness of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with hepatocellular carcinoma after liver resection, and further identify the patients who could benefit most from PA-TACE. PATIENTS AND METHODS: Propensity score matching at a ratio of 1 : 2 was used between hepatectomy patients with and without receiving PA-TACE. Kaplan-Meier analysis was performed to compare overall survival and recurrence-free survival between two groups. Univariate COX regression and stratified analyses were performed to screen and identify survival predictors for PA-TACE patients. The identified predictive markers were validated in an external cohort. RESULTS: The propensity analysis matched 116 patients in PA-TACE group to 232 in the control group. Visible protective effect of PA-TACE was shown by survival curves in matched series (log-rank P=0.009 and 0.008), with hazard ratio of being 0.599 (95% confidence interval: 0.420-0.855) and 0.623 (95% confidence interval: 0.449-0.866), respectively, for overall survival and recurrence-free survival. The identified prognostic predictors for PA-TACE included TNM stage, tumor size and number, hepatitis B infection, spleen diameter, preoperative serum α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase and monocyte, and three risk signatures (aspartate aminotransferase-to-alanine aminotransferase ratio, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation index). CONCLUSION: The treatment effectiveness of adjuvant transcatheter arterial chemoembolization for patients with hepatocellular carcinoma after surgery was validated in this study, and the best candidates for PA-TACE were identified as well, including patients with late-stage tumor, portal hypertension, and high preoperative serum levels of α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase, and monocytes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Hepatectomia , Neoplasias Hepáticas/terapia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Hepatite B Crônica/epidemiologia , Humanos , Hipertensão Portal/epidemiologia , Contagem de Leucócitos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos , Estadiamento de Neoplasias , Neutrófilos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral , alfa-Fetoproteínas/metabolismo , gama-Glutamiltransferase/sangueRESUMO
The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72â¯h before and 24â¯h or 72â¯h after APAP challenge (i.p., 400â¯mg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200â¯mg/kg/day) as in the APAP group. After 24â¯h or 72â¯h of APAP challenge, blood and liver samples were collected to detect hepatic injury and liver regeneration. The results showed that low doses of simvastatin (10 and 20â¯mg/kg) could significantly reverse the histological change and decrease hepatic injury. Simvastatin also reduced the serum cytokine levels and transcriptional levels of tumor necrosis factor-α and interleukin-6 in the liver. The malonyldialdehyde and myeloperoxidase levels significantly decreased in the simvastatin treatment groups compared with the APAP group. Simvastatin restored the decrease in superoxide dismutase, catalase, glutathione and glutathione peroxidase activities induced by APAP hepatotoxicity. In addition, simvastatin inhibited hepatic C/EBP-homologous protein expression and hepatocyte apoptosis. However, simvastatin had no effect on liver regeneration after APAP hepatotoxicity. Moreover, high doses could aggravate APAP-induced liver injury. In conclusion, low doses of simvastatin had a significant therapeutic effect in APAP-induced liver injury by inhibiting oxidative stress, inflammation and apoptosis. However, high doses of simvastatin had adverse hepatotoxicity.
Assuntos
Acetaminofen/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Substâncias Protetoras/farmacologia , Sinvastatina/farmacologia , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: The objective of this study was to investigate the prognostic significance of several inflammation-based models in hepatitis B-associated hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively reviewed 470 cases of hepatitis B-associated HCC. Preoperative data were collected to calculate the inflammation-based markers, including systemic immune-inflammation index (neutrophil×platelets/lymphocyte), platelets-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio (NLR). Overall survival and recurrence-free survival were estimated by the Kaplan-Meier method and Cox analysis. RESULTS: During a median follow-up time of 29 months, 34.0% (160/470) of patients died and 36.0% (169/470) experienced recurrence. Compared with patients with lower scores of inflammation models, patients in the higher group had larger tumor diameter and higher risk of vascular invasion (both P<0.05). Multivariate analysis revealed that age, tumor size, platelets-to-lymphocyte ratio, NLR, and systemic immune-inflammation index were the independent predictors for both overall survival and recurrence-free survival. Furthermore, the combination of tumor size and NLR showed a significantly better discrimination ability for survival (C-index=0.716, 95% confidence interval: 0.664-0.768) than both Barcelona Clinic Liver Cancer and Cancer of Liver Italian Program. CONCLUSION: The inflammation-based markers, in particular the combination of NLR with tumor size, are effective tools for assessing prognosis in hepatitis B-associated HCC.