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1.
Liver Transpl ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482616

RESUMO

The aim is to explore the impact of the Kasai procedure (KP) and the length of native liver survival time (NLST) on outcomes of liver transplantation (LT). Patients with biliary atresia (BA), who underwent LT in Beijing Friendship Hospital from January 2017 to December 2019, were enrolled and divided into non-KP (N-KP) and post-KP (P-KP) groups. The patients in the P-KP group were further divided into early failure (KP-EF) defined by NLST <1 year, medium failure (KP-MF, NLST 1-5 years), and late failure (KP-LF, NLST >5 years) subgroups. Clinical data at baseline and during follow-up were collected. The inverse probability of treatment weighting method was used to evaluate the independent effect of KP and the length of NLST on clinical outcomes. Among 197 patients with BA, the N-KP group accounted for 43 (21.8%), KP-EF 71 (46.1%), KP-MF 59 (38.3%), and KP-LF 24 (15.6%) cases, respectively. The N-KP and KP-EF groups had significantly longer hospitalization and intensive care unit stays after LT. Graft and overall survival rates were 93.0% in the N-KP group and 97.4% in P-KP group, respectively. The mortality rate in the P-KP group were significantly lower compared with that of the N-KP group with a hazard ratio (HR) of 0.2 (P = 0.02). The risks of biliary and vascular complications and cytomegalovirus (CMV) infection after LT were significantly higher in KP-EF group than those in the KP-MF and KP-LF groups (HRs = 0.09, 0.2, and 0.3, respectively; all P < 0.001). The KP significantly improved after LT overall survival. Patients with early native liver failure after KP have significantly higher risks for biliary and vascular complications and CMV infection.

2.
Hepatobiliary Pancreat Dis Int ; 20(5): 409-415, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34420885

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a public health challenge and significant cause of morbidity and mortality worldwide. Early identification is crucial for disease intervention. We recently proposed a nomogram-based NAFLD prediction model from a large population cohort. We aimed to explore machine learning tools in predicting NAFLD. METHODS: A retrospective cross-sectional study was performed on 15 315 Chinese subjects (10 373 training and 4942 testing sets). Selected clinical and biochemical factors were evaluated by different types of machine learning algorithms to develop and validate seven predictive models. Nine evaluation indicators including area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), accuracy, positive predictive value, sensitivity, F1 score, Matthews correlation coefficient (MCC), specificity and negative prognostic value were applied to compare the performance among the models. The selected clinical and biochemical factors were ranked according to the importance in prediction ability. RESULTS: Totally 4018/10 373 (38.74%) and 1860/4942 (37.64%) subjects had ultrasound-proven NAFLD in the training and testing sets, respectively. Seven machine learning based models were developed and demonstrated good performance in predicting NAFLD. Among these models, the XGBoost model revealed the highest AUROC (0.873), AUPRC (0.810), accuracy (0.795), positive predictive value (0.806), F1 score (0.695), MCC (0.557), specificity (0.909), demonstrating the best prediction ability among the built models. Body mass index was the most valuable indicator to predict NAFLD according to the feature ranking scores. CONCLUSIONS: The XGBoost model has the best overall prediction ability for diagnosing NAFLD. The novel machine learning tools provide considerable beneficial potential in NAFLD screening.

3.
Ann Palliat Med ; 10(6): 6841-6849, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237981

RESUMO

BACKGROUND: The risk of cardiovascular and cerebrovascular events is the highest during the first several hours post-awakening in patients with hypertension. This is largely due to surges in morning blood pressure (BP). The current meta-analysis explored whether morning BP is affected by the timing of antihypertensive drug administration. METHODS: Four medical databases were searched for clinical trials that examined the relationship between the timing of antihypertensive drug administration and morning BP levels. This meta-analysis compared morning BP surges in patients administered medication at bedtime versus patients administered medication during the day. RESULTS: The random effects model demonstrated that bedtime administration of antihypertensive drugs reduced morning systolic blood pressure (SBP) by 1.17 mmHg [with 95% confidence interval (CI): -2.47 to 0.37; P=0.08), and reduced morning diastolic blood pressure (DBP) by 0.95 mmHg (95% CI: -2.03 to 0.13; P=0.08), compared with patients who were administered medication during the daytime hours. However, the results did not demonstrate statistical significance. There was strong heterogeneity in both morning SBP (I2 =77.9% >50%, and Q test >0.1) and morning DBP results (I2 =77.9% >50%, and Q test >0.1). The funnel plots showed no publication bias in this study. DISCUSSION: Studies have shown that a 1 mmHg change was sufficient to reduce the risk of cardiovascular-related deaths by 2.1%. Therefore, changing the time of taking antihypertensive medications may significantly reduce cardiovascular-associated mortality. There were certain limitations to this meta-analysis. First, the heterogeneity of the meta-analysis was strong, with undefined reasons. Second, the sample size was relatively small, and future studies involving larger cohorts are warranted to further assess the effects of bedtime antihypertensive medication on minimizing morning BP surges.


Assuntos
Anti-Hipertensivos , Hipertensão , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Humanos , Hipertensão/tratamento farmacológico
4.
J Drug Target ; : 1-13, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34319831

RESUMO

Nanoparticles (NPs) with 'stealth' properties have been designed to decrease the phagocytosis of such particles by mononuclear phagocytes and to protect them from enzymatic degradation, thus improving circulation time and bioavailability after intravenous administration. Brain-targeting modifications endow NPs with the capacity to cross the blood-brain barrier, facilitating chemotherapy for brain diseases such as glioma. In this study, newly designed alkoxy cyanoacrylate (CA)-based NPs with stealth and brain-targeting properties were synthesised and evaluated. The monomers for NP core polymerisation were chemically modified to hydrophilic short alkoxy structure for stealth purposes and coated with polysorbate-80 for brain targeting. Two monomers (2-methoxyethyl CA and 2-(2-methoxyethyl)ethyl CA) were used to create NP2 and NP3, respectively. Both NPs were successfully loaded with anti-sense oligonucleotide (ASON) of transforming growth factor beta 2. Compared to traditional n-butyl CA-based ASON-NP1, ASON-NP3 was found to decrease phagocytosis by mononuclear macrophages (RAW264.7) and to increase cellular uptake by cancer cells. ASON-NP3 showed definite brain targeting and anti-cancer effects. This work provides a potential new strategy for preparing stealth NPs core, providing a new NP vehicle for clinical drug delivery that may be targeted to the brain and circulates in the blood for an extended period of time.

6.
Cells ; 10(2)2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494295

RESUMO

The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC-MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR's beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.


Assuntos
Berberina/uso terapêutico , Progressão da Doença , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais , Animais , Berberina/farmacologia , Ácidos e Sais Biliares/metabolismo , Dieta Ocidental , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos Endogâmicos C57BL , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
7.
Clin Gastroenterol Hepatol ; 19(5): 1009-1019.e11, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32634627

RESUMO

BACKGROUND & AIMS: Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 (ABCB11) gene and expression of its product, ABCB11 (also called BSEP). METHODS: We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n = 100; healthy controls) and patients with chronic hepatitis B (n = 105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP was analyzed by immunohistochemistry in liver biopsy specimens. RESULTS: Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71-0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids. CONCLUSIONS: In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids.

8.
Hepatobiliary Pancreat Dis Int ; 19(4): 349-357, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32622826

RESUMO

BACKGROUND: The downstaging of hepatocellular carcinoma (HCC) has been confirmed to benefit liver transplantation (LT) patients whose tumors are beyond the transplantation criteria. Milan criteria (MC), a tumor size and number-based assessment, is currently used as the endpoint in these patients. However, many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy. Hence, this study aimed to explore the feasibility of Hangzhou criteria (HC), which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number, as an endpoint of downstaging. METHODS: We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy (LRT) as downstaging/bridge treatment prior to LT in three centers of China. RESULTS: Recipients were divided into four groups: failed downstaging to the HC (group A, n = 46), successful downstaging to the HC (group B, n = 30), remained within the HC all the time (group C, n = 113), and tumor progressed (group D, n = 17). The 3-year HCC recurrence probabilities of groups B and C were not significantly different (10.3% vs. 11.6%, P = 0.87). The HCC recurrent rate was significantly higher in group A (52.3%) compared with that in group B/C (P < 0.05). Seven patients (7/76, 9.2%) whose tumor exceeded the the HC were successfully downstaged to the MC, and 39.5% (30/76) to the the HC. In group B, 23 patients remained beyond the MC and their survivals were as well as those of patients within the MC. CONCLUSIONS: Compared to the MC, HC downstaging criteria can give more HCC patients access to LT and furthermore, the outcome of these patients is the same as those matching MC downstaging criteria. Hangzhou downstaging criteria therefore is applicable in clinical practice.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado , Seleção de Pacientes , Adulto , Idoso , Carcinoma Hepatocelular/cirurgia , China , Feminino , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
9.
Hepatol Int ; 14(5): 808-816, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32572817

RESUMO

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease in China. The early identification and management of patients at risk are essential. We aimed to develop a novel clinical and laboratory-based nomogram (CLN) model to predict NAFLD with high accuracy. METHODS: We designed a retrospective cross-sectional study and enrolled 21,468 participants (16,468 testing and 5000 validation). Clinical information and laboratory/imaging results were retrieved. Significant variables independently associated with NAFLD were identified by a logistic regression model, and a NAFLD prediction CLN was constructed. The CLN was then compared with four existing NAFLD-related prediction models: the fatty liver index (FLI), the hepatic steatosis index (HSI), the visceral adiposity index (VAI) and the triglycerides and glucose (TyG) index. Area under the receiver operator characteristic curve (AUROC) and decision curve analysis (DCA) were performed. RESULTS: A total of 6261/16,468 (38.02%) and 1759/5000 (35.18%) participants in the testing and validation datasets, respectively, had ultrasound-proven NAFLD. Six variables were selected to build the CLN: body mass index (BMI), diastolic blood pressure (DBP), uric acid (UA), fasting blood glucose (FBG), triglyceride (TG), and alanine aminotransferase (ALT). The diagnostic accuracy of the CLN for NAFLD (AUROC 0.857, 95% CI 0.852-0.863) was significantly superior to that of the FLI (AUROC 0.849, 95% CI 0.843-0.855), the VAI (AUROC 0.752, 95% CI 0.745-0.760), the HSI (AUROC 0.828, 95% CI 0.822-0.834), and the TyG index (AUROC 0.774, 95% CI 0.767-0.781) (all p < 0.001). DCA confirmed the clinical utility of the CLN. CONCLUSIONS: This physical examination and laboratory test-based, nonimage-assisted novel nomogram has better performance in predicting NAFLD than the FLI, the VAI, the HSI and the TyG index alone. This model can be used as a quick screening tool to assess NAFLD in the general population.

10.
Can J Gastroenterol Hepatol ; 2020: 8219536, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32377514

RESUMO

Background: Chronic HCV infection affects 80 million people globally and may progress to advanced liver disease. The present study aims to investigate the present epidemiology of HCV infection in a southeastern Chinese surgical patient cohort. Methods: Blood samples obtained from 78,484 surgical patients from 18 different city and county hospitals were enrolled. The incidence of serum HCV antibody positivity, HCV RNA load, and HCV genotyping, as well as demographics and relevant clinical history, were investigated. Data were stratified using the multistage cluster random sampling method and further analyzed using the SPSS-20 package. Results: HCV antibody positivity was detected in 0.15% of the population (95% confidence interval (CI): 0.12%-0.18%). Genotype 1b (55.74%) was the dominant type. The HCV infection peaked in the age groups of 16-20, 41-50, and 61-65 years, and it was higher in males than in females (0.19% vs. 0.13%, P < 0.05). The geographical distribution of infection rates differed: 0.19% (95% CI: 0.14%-0.24%), 0.18% (95% CI: 0.13%-0.23%), and 0.06% (95% CI: 0.03-0.09%) in plain areas, islands, and valley regions, respectively. Patients with transfusion history and urban residence were associated with high HCV RNA levels (adjusted odds ratio = 11.24 and 6.20, P < 0.05). Conclusion: The prevalence of HCV infection in this cohort from southeast China was 0.17%, which is lower than the reported 0.43% infection rate in China in 2006. This result can be (partially) explained by the improvement of blood donor screening and the successful campaign for the use of disposable syringes and needles.


Assuntos
Hepacivirus , Hepatite C Crônica/epidemiologia , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Adolescente , Adulto , Idoso , China/epidemiologia , Feminino , Genótipo , Hepacivirus/genética , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prevalência , RNA Viral/sangue , Carga Viral , Adulto Jovem
11.
Ann Transl Med ; 8(5): 221, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32309368

RESUMO

Background: Liver transplantation (LT) is the most effective treatment for patients with end-stage liver diseases, but acute rejection is still a major concern. However, the mechanisms underlying rejection remain unclear. Biomarkers are lacking for predicting rejection and long-term survival after LT. Methods: Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics was performed between acute cellular rejection (ACR) and non-rejection recipients. The molecular signature differences and potential biomarkers were identified by comprehensive bioinformatics. Heme oxygenase-1 (HO-1) expression and its association with clinical outcomes were investigated by tissue microarrays consisted of liver specimens from recipients with (n=80) and without ACR (n=57). Results: A total of 287 differentially expressed proteins (DEPs) were identified. Pathway analysis revealed that T/B cell activation, integrin/inflammation signaling pathway, etc. were significantly correlated with ACR. Through comprehensive bioinformatics, HO-1 was identified as a candidate potential biomarker for ACR. In tissue microarray (TMA) analysis, HO-1 expression was significantly higher in ACR group than in non-rejection group (P<0.01). Preoperative Child-Pugh and Meld scores were significantly higher in recipients with high HO-1 expression (P<0.01). In a mean 5-year follow-up, recipients with high HO-1 expression were associated with a shorter overall survival (P<0.05). Further multivariate analyses indicated that HO-1 could be an independent adverse prognostic factor for post-transplant survival (P=0.005). Conclusions: A total of 287 DEPs were identified, providing a set of targets for further research. Recipients with high preoperative HO-1 expression were associated with ACR. HO-1 may be used as a potential biomarker for predicting the development of post-transplant allograft ACR and recipient's survival.

12.
Pak J Pharm Sci ; 33(1(Special)): 437-440, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32173640

RESUMO

The aim of this study is to observe and analyze the clinical efficacy of simvastatin combined with exercise training in the treatment of stationary chronic obstructive pulmonary disease complicated with metabolic syndrome. In this study, 180 patients who had been treated for stable chronic obstructive pulmonary disease (COPD) complicated with metabolic syndrome in our hospital were enrolled as research objects. The selected patients were randomly divided into research group receiving simvastatin combined with exercise training and control group accepting routine therapy, each containing 90 cases. The therapeutic effects of the two groups were compared. The CAT score, insulin resistance index and 6 min walking distance of the two groups were compared. The results showed that compared with the control group, the improvement effect of the research group was more obvious, and the effect was better than that of the control group, p<0.05. The levels of IL-6 (interleukin-6), IL-8 (interleukin-8) and other inflammatory factors were significantly lower in the research group than those in the control group, p<0.05. Simvastatin combined with exercise training in the treatment of stationary chronic obstructive pulmonary disease with metabolic syndrome is an effective treatment, which can significantly improve the treatment effect and help patients to achieve a higher quality of life.


Assuntos
Exercício Físico , Síndrome Metabólica/terapia , Doença Pulmonar Obstrutiva Crônica/terapia , Sinvastatina/uso terapêutico , Idoso , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Síndrome Metabólica/imunologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
13.
Genes (Basel) ; 11(2)2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013248

RESUMO

Diachasmimoorpha longicaudata (Ashmead, D. longicaudata) (Hymenoptera: Braconidae) is a solitary species of parasitoid wasp and widely used in integrated pest management (IPM) programs as a biological control agent in order to suppress tephritid fruit flies of economic importance. Although many studies have investigated the behaviors in the detection of their hosts, little is known of the molecular information of their chemosensory system. We assembled the first transcriptome of D. longgicaudata using transcriptome sequencing and identified 162,621 unigenes for the Ashmead insects in response to fruit flies fed with different fruits (guava, mango, and carambola). We annotated these transcripts on both the gene and protein levels by aligning them to databases (e.g., NR, NT, KEGG, GO, PFAM, UniProt/SwissProt) and prediction software (e.g., SignalP, RNAMMER, TMHMM Sever). CPC2 and MIREAP were used to predict the potential noncoding RNAs and microRNAs, respectively. Based on these annotations, we found 43, 69, 60, 689, 26 and 14 transcripts encoding odorant-binding protein (OBP), chemosensory proteins (CSPs), gustatory receptor (GR), odorant receptor (OR), odorant ionotropic receptor (IR), and sensory neuron membrane protein (SNMP), respectively. Sequence analysis identified the conserved six Cys in OBP sequences and phylogenetic analysis further supported the identification of OBPs and CSPs. Furthermore, 9 OBPs, 13 CSPs, 3 GRs, 4IRs, 25 ORs, and 4 SNMPs were differentially expressed in the insects in response to fruit flies with different scents. These results support that the olfactory genes of the parasitoid wasps were specifically expressed in response to their hosts with different scents. Our findings improve our understanding of the behaviors of insects in the detection of their hosts on the molecular level. More importantly, it provides a valuable resource for D. longicaudata research and will benefit the IPM programs and other researchers in this filed.


Assuntos
Perfilação da Expressão Gênica/métodos , Himenópteros/fisiologia , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Ração Animal/classificação , Animais , Evolução Molecular , Feminino , Regulação da Expressão Gênica , Himenópteros/genética , Himenópteros/metabolismo , Masculino , MicroRNAs/genética , Filogenia , RNA não Traduzido/genética , Receptores Odorantes/genética , Análise de Sequência de RNA , Olfato
14.
Gut ; 69(7): 1322-1334, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31776228

RESUMO

OBJECTIVE: We aimed to elucidate the mutual regulation mechanism of ubiquitin-specific protease 22 (USP22) and hypoxia inducible factor-1α (HIF1α), and the mechanism they promote the stemness of hepatocellular carcinoma (HCC) cells under hypoxic conditions. DESIGN: Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were established to detect the stemness of HCC cells. Immunoprecipitation, ubiquitination assay and chromatin immunoprecipitation assay were used to elucidate the mutual regulation mechanism of USP22 and HIF1α. HCC patient samples and The Cancer Genome Atlas data were used to demonstrate the clinical significance. In vivo USP22-targeting experiment was performed in mice bearing HCC. RESULTS: USP22 promotes hypoxia-induced HCC stemness and glycolysis by deubiquitinating and stabilising HIF1α. As direct target genes of HIF1α, USP22 and TP53 can be transcriptionally upregulated by HIF1α under hypoxic conditions. In TP53 wild-type HCC cells, HIF1α induced TP53-mediated inhibition of HIF1α-induced USP22 upregulation. In TP53-mutant HCC cells, USP22 and HIF1α formed a positive feedback loop and promote the stemness of HCC. HCC patients with a loss-of-function mutation at TP53 and high USP22 and/or HIF1α expression tend to have a worse prognosis. The USP22-targeting lipopolyplexes caused high tumour inhibition and high sorafenib sensitivity in mice bearing HCC. CONCLUSION: USP22 promotes hypoxia-induced HCC stemness by a HIF1α/USP22 positive feedback loop on TP53 inactivation. USP22 is a promising target for the HCC therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Glicólise , Neoplasias Hepáticas/patologia , Camundongos , Células-Tronco Neoplásicas/patologia , Sorafenibe/farmacologia
15.
Hepatol Int ; 13(6): 715-725, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31531761

RESUMO

BACKGROUND: Approximately 50% hepatocellular carcinoma (HCC) patients die within 5 year after surgical resection. The present staging systems do not fully allow to accurately predict the HCC prognosis and recurrence. This study aimed to identify clinicopathological characteristics and molecular markers to establish classifiers to predict the 5-year overall survival (OS) and the 3-year recurrence in HCC patients post-operatively. METHODS: We enrolled 647 HCC patients from two institutions, underwent surgical resection and divided the patients into one training and two validation cohorts. Clinicopathologic characteristics and tumor protein expression of 29 biomarkers by immunohistochemical (IHC) analysis were used to develop and validate a prognostic and a recurrent classifier, using the maximum relevance minimum redundancy algorithm jointly with the multivariable regression method. RESULTS: The prognostic classifier distinguished HCC patients into high- and low-probability survival groups with significant differences in 5-year OS rate in all three cohorts (training cohort: 57.36% vs. 22.97%; p < 0.0001; internal validation cohort: 61.90% vs. 28.85%; p < 0.0001; independent validation cohort: 64.28% vs. 22.45%; p < 0.0001). The recurrent classifier also demonstrated good discrimination in all three cohorts. CONCLUSION: This study presented a prognostic classifier and a recurrent classifier using clinicopathologic and IHC characteristics. The developed classifiers stratified HCC patients into high- and low-probability survival or recurrent groups, which can help clinicians judge whether adjuvant therapy is beneficial post-operatively.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , China , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Adulto Jovem
16.
Dig Liver Dis ; 51(8): 1154-1163, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31003959

RESUMO

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2-/-) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnfα, F4/80, Il-1ß). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2-/- mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases.


Assuntos
Hepatopatias Alcoólicas/enzimologia , Fígado/enzimologia , Fígado/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Células Cultivadas , Feminino , Hepatócitos/enzimologia , Humanos , Intestinos/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Esteroide Hidroxilases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
17.
Int J Clin Exp Pathol ; 12(1): 389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32256931

RESUMO

[This corrects the article on p. 1674 in vol. 11, PMID: 31938268.].

18.
Hepatobiliary Pancreat Dis Int ; 17(4): 310-315, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30108018

RESUMO

BACKGROUND: New-onset hyperglycemia (NOH) is a common phenomenon after liver transplantation (LT), but its impact on clinical outcomes has not yet been fully assessed. We aimed to evaluate the etiology and prognosis of NOH within 1 month after LT. METHODS: The data of 3339 adult patients who underwent primary LT from donation after citizen death between January 2010 and June 2016 were extracted from China Liver Transplant Registry database and analyzed. NOH was defined as fasting blood glucose ≥7.0 mmol/L confirmed on at least two occasions within the first post-transplant month with or without hypoglycemic agent. RESULTS: Of 3339 liver recipients, 1416 (42.4%) developed NOH. Recipients with NOH had higher incidence of post-transplant complications such as graft and kidney failure, infection, biliary stricture, cholangitis, and tumor recurrence in a glucose concentration-dependent manner as compared to non-NOH recipients (P < 0.05). The independent risk factors of NOH were donor warm ischemic time >10 min, cold ischemic time >10 h, anhepatic time >60 min, recipient model for end-stage liver disease score >30, moderate ascites and corticosteroid usage (P < 0.05). Liver enzymes (alanine aminotransferase and gamma-glutamyltranspeptidase) on post-transplant day 7 significantly correlated with NOH (P < 0.001). CONCLUSIONS: NOH leads to increased morbidity and mortality in liver recipients. Close surveillance and tight control of blood glucose are desiderated immediately following LT particularly in those with delayed graft function and receiving corticosteroid. Strategic targeting graft ischemic injury may help maintain glucose homeostasis.


Assuntos
Hiperglicemia/epidemiologia , Transplante de Fígado/efeitos adversos , Corticosteroides/efeitos adversos , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , China/epidemiologia , Função Retardada do Enxerto/epidemiologia , Feminino , Sobrevivência de Enxerto , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/mortalidade , Hipoglicemiantes/uso terapêutico , Imunossupressores/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Surgery ; 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29709370

RESUMO

BACKGROUND: Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. METHODS: Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. RESULTS: Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and α-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. CONCLUSION: The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk assessment. The identification of donor risks can further help understand the mechanism of different patterns of recurrence.

20.
Cell Death Dis ; 8(11): e3159, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29095437

RESUMO

Arsenic trioxide (ATO) is a well-accepted chemotherapy agent in managing promyelocytic leukemia. ATO often causes severe health hazards such as hepatotoxicity, dermatosis, neurotoxicity, nephrotoxicity and cardiotoxicity. The production of reactive oxygen species, (ROS) play a significant role in ATO-induced hepatotoxicity. The oral hypoglycemic drug, metformin, is considered to be a potential novel agent for chemoprevention in the treatment of cancer. Moreover, metformin has also been shown to have hepatoprotective effects. In the present study, we demonstrated that metformin protected normal hepatocytes from ATO-induced apoptotic cell death in vitro and in vivo. Gene expression screening revealed that glucose metabolism might be related to the metformin-induced protective effect on ATO-treated AML12 cells. The metformin-promoted or induced glycolysis was not responsible for the protection of AML12 cells from ATO-induced apoptotic cell death. Instead, metformin increased the intracellular NADH/NAD+ ratio by inhibiting mitochondrial respiratory chain complex I, further decreasing the intracellular ROS induced by ATO. Treatment with low glucose or rotenone, a mitochondrial respiratory chain complex I inhibitor, also protected AML12 cells from ATO-induced apoptotic cell death. We show for the first time that metformin protects the hepatocyte from ATO by regulating the mitochondrial function. With its properties of chemoprevention, chemosensitization and the amelioration of liver damage, metformin has great prospects for clinical application other than type 2 diabetes mellitus (T2DM).


Assuntos
Antineoplásicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Complexo I de Transporte de Elétrons/metabolismo , Metformina/farmacologia , Óxidos/toxicidade , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/uso terapêutico , Linhagem Celular , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Humanos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Masculino , Camundongos , NAD/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Óxidos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia
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