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1.
Mod Pathol ; 32(12): 1795-1805, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300804

RESUMO

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

2.
Mol Cell ; 68(1): 185-197.e6, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28943315

RESUMO

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.


Assuntos
Inflamassomos/genética , Macrófagos/imunologia , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Choque Séptico/genética , Sequência de Aminoácidos , Animais , Enzimas Desubiquitinantes/genética , Enzimas Desubiquitinantes/imunologia , Escherichia coli/química , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase 8 Ativada por Mitógeno/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fosforilação , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Choque Séptico/induzido quimicamente , Choque Séptico/mortalidade , Choque Séptico/patologia , Transdução de Sinais , Análise de Sobrevida
3.
Int J Ophthalmol ; 10(4): 632-638, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28503439

RESUMO

AIM: To assess the corneal sensitivity and the incidences of dry eye after small incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK). METHODS: The Meta-analysis was performed using RevMan 5.3. We searched on PubMed from inception to March 2016. Summary weighted mean difference (WMD) and 95% confidence intervals (CIs) were used to analyze the datum. Random-effects or fixed-effects models were chosen up to between-study heterogeneity. The main outcomes were composed of the Ocular Surface Disease Index (OSDI) scores, tear film break-up time (TBUT), Schirmer Test and corneal sensitivity. RESULTS: Eight eligible studies including 772 eyes (386 in SMILE group and 386 in FS-LASIK group) were identified. The parameters have no significiant difference heterogeneity between SMILE and FS-LASIK group preoperatively. There were significant differences between the two groups in OSDI scores at one and three months postoperatively, in TBUT at one and three months postoperatively, in corneal sensitivity at one week, about one month and three months postoperatively. However, there was no significant difference observed in Schirmer Test at the follow-up periods. CONCLUSION: Compare to FS-LASIK, dry eye and the corneal sensitivity recover better in the SMILE group, in first three months after the surgery.

4.
Drug Des Devel Ther ; 9: 1393-400, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25834397

RESUMO

BACKGROUND: This meta-analysis was performed to determine the effectiveness of steroids as an adjunct following rhegmatogenous retinal detachment (RRD) surgery. METHODS: RRD patients with or without proliferative vitreoretinopathy (PVR) were included. The treatment group included patients in whom steroids were used as an adjunct and a control group in which placebo was used. Only randomized controlled trials were included. We searched the main electronic databases and included studies published until July 2014. PVR odds ratio, visual acuity, retinal reattachment rate, and complications were evaluated in three trials. RESULTS: Three randomized controlled trials were included in the meta-analysis. There was no significant difference in the incidence of postoperative PVR between groups (heterogeneity I (2)=48%, P=0.14). However, the incidence of postoperative PVR was lower in the treatment group (I (2)=0%, P<0.0001) than in the control group when a PVR grade C study was excluded. There was no statistically significant difference in postoperative visual acuity between the treatment and control groups (odds ratio -0.18; 95% confidence interval -0.38, 0.02; P=0.08). The two groups had similar results for primary/final retinal reattachment and reoperation rate. There was no significant difference in postoperative intraocular pressure. CONCLUSION: This systematic review demonstrates that steroids may significantly reduce the incidence of postoperative PVR grade B or lower following RRD surgery.


Assuntos
Descolamento Retiniano/complicações , Descolamento Retiniano/cirurgia , Esteroides/farmacologia , Vitreorretinopatia Proliferativa/complicações , Vitreorretinopatia Proliferativa/prevenção & controle , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Esteroides/administração & dosagem , Esteroides/uso terapêutico
5.
Cell Rep ; 7(6): 1982-93, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24882011

RESUMO

CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.


Assuntos
Proteínas de Transporte/metabolismo , Neoplasias do Colo/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Colite/genética , Colite/imunologia , Colite/metabolismo , Colite/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Feminino , Regulação da Expressão Gênica , Células HeLa , Humanos , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais
6.
Biochem Biophys Res Commun ; 448(4): 454-60, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24802396

RESUMO

Embryonic stem (ES) cells are pluripotent cells that are capable of giving rise to any type of cells in the body and possess unlimited self-renewal potential. However, the exact regulatory mechanisms that govern the self-renewal ability of ES cells remain elusive. To understand the immediate early events during ES cell differentiation, we performed a proteomics study and analyzed the proteomic difference in murine ES cells before and after a 6-h spontaneous differentiation. We found that the expression level of glutathione peroxidase-1 (GPx-1), an antioxidant enzyme, is dramatically decreased upon the differentiation. Both knockdown of GPx-1 expression with shRNA and inhibiting GPx-1 activity by inhibitor led to the differentiation of ES cells. Furthermore, we showed that during early differentiation, the quick degradation of GPx-1 was mediated by proteasome. Thus, our data indicated that GPx-1 is a key regulator of self-renewal of murine embryonic stem cells.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/enzimologia , Glutationa Peroxidase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Peroxidase/genética , Leupeptinas/farmacologia , Camundongos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , RNA Interferente Pequeno/genética , Tiomalatos/farmacologia
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