RESUMO
BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.
Assuntos
Pancreatite , Humanos , Pancreatite/complicações , Pancreatite/tratamento farmacológico , Pancreatite/prevenção & controle , Octreotida/uso terapêutico , Inibidores de Ciclo-Oxigenase 2 , Estudos Retrospectivos , Doença Aguda , Ciclo-Oxigenase 2/uso terapêutico , Somatostatina/uso terapêutico , CitocinasRESUMO
B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
Assuntos
Cirrose Hepática , Transdução de Sinais , Camundongos , Animais , Humanos , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Celecoxib/metabolismo , Ciclo-Oxigenase 2 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Células Epiteliais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores CXCR4/genética , Proliferação de CélulasRESUMO
BACKGROUND: Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study. MATERIALS AND METHODS: Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified. RESULTS: A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA. CONCLUSIONS: Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.
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Cirrose Hepática , Esplenomegalia , Ratos , Animais , Celecoxib/farmacologia , Esplenomegalia/tratamento farmacológico , Esplenomegalia/etiologia , Esplenomegalia/patologia , Antígeno Ki-67 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Colágeno , Inflamação/tratamento farmacológico , Perfilação da Expressão GênicaRESUMO
PURPOSE: To compare the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation versus portal vein stent placement (PVS) in patients with noncirrhotic cavernous transformation of the portal vein (CTPV). MATERIALS AND METHODS: In this retrospective study, clinical data from patients with noncirrhotic CTPV who underwent TIPS creation or PVS were compared. A total of 54 patients (mean age, 43.8 years ± 15.8; 31 men and 23 women) were included from January 2013 to January 2021; 29 patients underwent TIPS creation, and 25 patients underwent PVS. Stent occlusion, variceal rebleeding, survival, and postprocedural complications were compared between the 2 groups. RESULTS: The mean follow-up time was 40.2 months ± 26.2 in the TIPS group and 35.3 months ± 21.1 in the PVS group. The stent occlusion rate in the PVS group (16%, 4 of 25) was significantly lower than that in the TIPS group (41.4%, 12 of 29) during the follow-up (P = .042). The cumulative variceal rebleeding rates in the TIPS group were significantly higher than those in the PVS group (28% vs 4%; P = .027). The procedural success rate was 69% in the TIPS group and 86% in the PVS group (P = .156). There was a higher number of severe adverse events after TIPS than after PVS (0% vs 24%; P = .012). CONCLUSIONS: Portal vein recanalization with PVS may be a preferable alternative to TIPS creation in the treatment of noncirrhotic CTPV because of higher stent patency rates, lower risk of variceal rebleeding, and fewer adverse events.
Assuntos
Varizes Esofágicas e Gástricas , Derivação Portossistêmica Transjugular Intra-Hepática , Masculino , Humanos , Feminino , Adulto , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Estudos Retrospectivos , Stents/efeitos adversos , Resultado do Tratamento , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Varizes Esofágicas e Gástricas/diagnóstico por imagem , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/cirurgiaRESUMO
BACKGROUND: This study was aimed to develop a computer-aided diagnosis (CAD) system with deep-learning technique and to validate its efficiency on detecting the four categories of lesions such as polyps, advanced cancer, erosion/ulcer and varices at endoscopy. METHODS: A deep convolutional neural network (CNN) that consists of more than 50 layers were trained with a big dataset containing 327,121 white light images (WLI) of endoscopy from 117,005 cases collected from 2012 to 2017. Two CAD models were developed using images with or without annotation of the training dataset. The efficiency of the CAD system detecting the four categories of lesions was validated by another dataset containing consecutive cases from 2018 to 2019. RESULTS: A total of 1734 cases with 33,959 images were included in the validation datasets which containing lesions of polyps 1265, advanced cancer 500, erosion/ulcer 486, and varices 248. The CAD system developed in this study may detect polyps, advanced cancer, erosion/ulcer and varices as abnormality with the sensitivity of 88.3% and specificity of 90.3%, respectively, in 0.05 s. The training datasets with annotation may enhance either sensitivity or specificity about 20%, p = 0.000. The sensitivities and specificities for polyps, advanced cancer, erosion/ulcer and varices reached about 90%, respectively. The detect efficiency for the four categories of lesions reached to 89.7%. CONCLUSION: The CAD model for detection of multiple lesions in gastrointestinal lumen would be potentially developed into a double check along with real-time assessment and interpretation of the findings encountered by the endoscopists and may be a benefit to reduce the events of missing lesions.
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Inteligência Artificial , Redes Neurais de Computação , Endoscopia Gastrointestinal , Trato Gastrointestinal , Humanos , Projetos PilotoRESUMO
OBJECTIVES: Severe acute pancreatitis (SAP) is still a big challenge. Accumulated data showed that overexpression of cyclooxygenase-2 (COX-2) in acute pancreatitis and experimental pancreatitis could be attenuated with COX-2 inhibitors. This study was aimed to evaluate whether the occurrence of SAP could be prevented by selective COX-2 inhibitors. METHODS: A total of 190 patients with predicted SAP were randomized into convention group or convention plus COX-2 inhibitors (C+COX-2-Is) group. Besides conventional treatment to all patients in 2 groups, parecoxib (40 mg/d intravenous injection for 3 days) and celecoxib (200 mg oral or tube feeding twice daily for 7 days) were sequentially administrated to the patients in the C+COX-2-Is group. The primary outcome was predefined as the occurrence of SAP. The serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) for all of the patients were measured. RESULTS: The occurrence of SAP in the C+COX-2-Is group was decreased 47.08% compared with the convention group, 21.05% (20/95) vs 39.78% (37/93), P = 0.005. A reduction of late local complications was also shown in the C+COX-2-Is group, 18.95% (18/93) vs 34.41% (32/95), P = 0.016. The serum levels of IL-6 and TNF-α were significantly lower in the C+COX-2-Is group than those in the convention group, P < 0.05. Parecoxib relieved abdominal pain more rapidly and decreased the consumption of meperidine. An incremental reduction of cost for 1% decrease of SAP occurrence was RMB475. DISCUSSION: Sequential administration of parecoxib and celecoxib in patients with predicted SAP obtained about half-reduction of SAP occurrence through decreasing serum levels of TNF-α and IL-6. This regimen presented good cost-effectiveness.
Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Isoxazóis/uso terapêutico , Pancreatite/prevenção & controle , Administração Oral , Adolescente , Adulto , Idoso , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Long intergenic non-coding RNA for kinase activation (Linc-A) has been reported to enhance the occurrence and progression of breast cancer. Nevertheless, whether Linc-A is related to the tumorigenesis of colorectal cancer (CRC) remains unknown. In this study, we aimed to evaluate the expression of Linc-A in colon adenocarcinoma and explore the correlation between Linc-A and prognosis of CRC. The expression of Linc-A in human colon tissues was evaluated by qRT-PCR, which contained 15 pairs of human colon adenocarcinoma and paracancerous tissues and other 65 colon adenocarcinoma tissues. A total of 80 patients were divided into low and high expression groups according to the Linc-A levels. The levels of Linc-A in colon adenocarcinoma was higher than that in paracancerous tissues (p = 0.047). Furthermore, high expression of Linc-A was associated with advanced TNM stage (p = 0.013), positive lymph nodes (p = 0.024), low 5-year survival rate (p = 0.024) and even 10-year survival rate (p = 0.007). Besides, Linc-A, advanced age, advanced TNM stage, deep infiltration degree and positive lymph nodes were also found to be positively related to poor overall 5-year survival by Kaplan-Meier survival analysis(p < 0.05). Then, multivariable Cox regression analysis revealed that Linc-A was an independent risk factor for prognosis of colon adenocarcinoma (p = 0.047). In conclusion, high expression of Linc-A is associated with advanced TNM stage, lymphatic metastasis and poor survival in patients with CRC. Linc-A may be served as a candidate prognostic biomarker for CRC.
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Adenocarcinoma , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante , RNA Neoplásico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Taxa de SobrevidaRESUMO
BACKGROUND/OBJECTIVES: Obesity is an independent risk factor for severe acute pancreatitis (AP). Leptin plays an important role in energy homeostasis. It has been reported that leptin might also participate in the regulation of the intestinal mucosal barrier and inflammatory response. This study aimed to evaluate the effects of leptin on the intestinal mucosal barrier and inflammatory injury in obese mice with AP. SUBJECTS/METHODS: AP was induced in leptin-deficient (ob/ob) or wild type (WT) mice by peritoneal injection of caerulein. The animals were divided into 4 groups: WT mice with or without exogenous leptin injection and ob/ob mice with or without leptin treatment. The inflammatory scoring of the pancreas and intestine were evaluated. Intestinal permeability, ileal interleukin (IL)-6 and IL-1ß, proliferation, apoptosis and intestinal expression levels of claudin-1 and occludin were measured. RESULTS: Pancreatic pathologic scores (8.50 ± 0.96 vs. 3.78 ± 1.35, p < 0.001), pancreatic levels of IL-6 (8.34 ± 3.21 ng/mg vs. 4.99 ± 0.53 ng/mg, p = 0.022), intestinal oedema scores (2.25 ± 0.46 vs. 1.14 ± 0.69, p = 0.001) and intestinal permeability to FD4 (0.78 ± 0.06 µg/ml vs. 0.53 ± 0.11 µg/ml, p < 0.001) were significantly higher in ob/ob mice than those in WT mice. Leptin replacement in ob/ob mice greatly improved the intestinal permeability (FD4 0.66 ± 0.03 µg/ml, vs. 0.78 ± 0.06 µg/ml, p = 0.012), increased the ileal expression of claudin-1(1.07 ± 0.08 vs. 0.83 ± 0.07 relative densitometry, p = 0.001) and reduced intestinal IL-6 and IL-1ß to levels comparable to those in WT mice. The pancreatic level of IL-6 in ob/ob mice treated with leptin was also significantly decreased relative to that of untreated ob/ob mice (4.45 ± 1.71 ng/mg vs. 8.34 ± 3.21 ng/mg, p = 0.010). CONCLUSIONS: Obesity may aggravate intestinal inflammation and increase intestinal permeability under the condition of acute pancreatitis. Exogenous leptin supplementation was in favour of anti-inflammation and improvement of intestinal mucosal barrier.
Assuntos
Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Pancreatite/metabolismo , Doença Aguda , Animais , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Leptina/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Pâncreas/química , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
OBJECTIVE: To evaluate the effect of proton pump inhibitors (PPIs) therapy on severe acute pancreatitis (SAP) patients. METHODS: Forty five patients with SAP recruited in our center from October 2015 to October 2016,were randomly assigned into two groups: convention group (C group,n=21) and convention+esomeprazole group (C+E group,n=24). C+E group received esomeprazole 40 mg/d intravenously for 1 week,whereas C group only received baseline treatment. Serum C-reactive protein (CRP),interleukin-6 (IL-6) and interleukin-8 (IL-8),tumor necrosis factor-α (TNF-α) and procalcitonin (PCT) were detected by ELISA on the first day (baseline) and the seventh day. Acute physiology and chronic health evaluation â ¡ scores (APACHE â ¡),systemic inflammatory response syndrome scores (SIRS) and modified Marshall scoring system (Marshall) were obtained at 1 d (baseline),3 d and 7 d. Upper gastrointestinal manifestation (peptic ulcer) and gastric pH were detected by endoscopic examination at 7 d. Fecal occult blood test was performed at 7 d. RESULTS: No significant difference was found in CRP,IL-6,IL-8,TNF-α and PCT between the two groups ( P>0.05),also no difference in APACHE â ¡,SIRS and Marshall scores ( P>0.05). The gastric pH was remarkably higher in C+E group when compared to C group (5.02±1.61 vs.2.83±1.08, P<0.001). There was no significant difference in the incidence of peptic ulcer and the rate of positive fecal occult blood between the two groups. CONCLUSION: PPIs therapy did not show benefit on alleviating systemic inflammatory response and clinical scores in SAP patients,and didn't improve the prevention of peptic ulcer and gastrointestinal hemorrhage.
Assuntos
Esomeprazol/uso terapêutico , Pancreatite/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Doença Aguda , Proteína C-Reativa/análise , Calcitonina/sangue , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Estudos Prospectivos , Fator de Necrose Tumoral alfa/sangueRESUMO
Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Celecoxib/administração & dosagem , Hipertensão Portal/prevenção & controle , Cirrose Hepática Experimental/complicações , Cirrose Hepática Experimental/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Octreotida/administração & dosagem , Animais , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Sinergismo Farmacológico , Hipertensão Portal/patologia , Hipertensão Portal/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/patologia , Pressão na Veia Porta/efeitos dos fármacos , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/toxicidade , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis.
Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Jejuno/metabolismo , Cirrose Hepática/tratamento farmacológico , Fígado/metabolismo , Animais , Células CACO-2 , Caderinas/metabolismo , Celecoxib/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/metabolismo , Absorção Intestinal , Jejuno/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cirrose Hepática/metabolismo , Ratos , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
BACKGROUND AND AIM: The epithelial-mesenchymal transition (EMT) of hepatocytes is a key step for hepatic fibrosis and cirrhosis. Long-term administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can ameliorate hepatic fibrosis. This research aimed to examine the effect of celecoxib on the EMT of hepatocytes during the development of liver cirrhosis. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). Thirty-six rats were randomly assigned to control, TAA, and TAA + celecoxib groups. Hepatic expressions of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), COX-2, prostaglandin E2 (PGE2 ), matrix metalloproteinase (MMP)-2 and -9, transforming growth factor-ß1 (TGF-ß1), Phospho-Smad2/3, Snail1, α-smooth muscle actin (α-SMA), vimentin, collagen I, fibroblast-specific protein (FSP-1), E-cadherin and N-cadherin were quantitated. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and Ishak's scoring system. RESULTS: Exposed to TAA treatment, hepatocytes underwent the process of EMT during hepatic fibrosis. Compared with those in TAA group, celecoxib significantly downregulated the hepatic expressions of TNF-α, IL-6, COX-2, PGE2 , MMP-2, MMP-9, TGF-ß1, Phospho-Smad2/3, Snail1, α-SMA, FSP-1, and vimentin while greatly restoring the levels of E-cadherin. The fibrotic areas and collagen I levels of TAA + celecoxib group were much lower than those in TAA group. CONCLUSIONS: Celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA-rat model through suppression of the mesenchymal biomarkers in the hepatocytes while restoring the levels of their epithelial biomarkers. The inhibitory effect of celecoxib on the EMT of hepatocytes is associated with reduction of intrahepatic inflammation, preservation of normal basement matrix, and inhibition of TGF-ß1/Smad pathway.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hepatócitos/fisiologia , Cirrose Hepática Experimental , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Animais , Celecoxib , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad , Tioacetamida , Fator de Crescimento Transformador beta1RESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.
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The cathodic oxygen reduction reaction (ORR) has been continuously attracting worldwide interest due to the increasing popularity of proton exchange membrane (PEM) fuel cells. So far, various Pt-group metal (PGM) or PGM-free catalysts have been developed to facilitate the ORR. However, there is still a gap to achieve the expected goals as proposed by the U.S. Department of Energy (DoE). Recently, PGM-free@PGM hybrid catalysts, such as the M/N/C@PtM catalyst, have achieved the milestones of oxygen reduction, as reviewed in our recent work. It is, nevertheless, still challenging to unravel the underlying structure-property relationships. Here, by applying different Pt/Co ratios, a series of Co/N/C@PtxCo catalysts are synthesized. Interestingly, the ORR activity and stability are not linear with the Pt content, but show a volcano-like curve with increased Pt usage. This relationship has been deeply unraveled to be closely related to the contents of pyrrolic N, pyridinic N, and graphitized carbon in catalysts. This work provides guidelines to rationally design the coupled PGM-free@PGM catalysts toward the ORR by appropriate surface engineering.
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Pithiness is one of the physiological diseases of radishes, which is accompanied by the accumulation of reactive oxygen species (ROS) during the sponging of parenchyma tissue in the fleshy roots. A respiratory burst oxidase homolog (Rboh, also known as NADPH oxidase) is a key enzyme that catalyzes the production of ROS in plants. To understand the role of Rboh genes in radish pithiness, herein, 10 RsRboh gene families were identified in the genome of Raphanus sativus using Blastp and Hmmer searching methods and were subjected to basic functional analyses such as phylogenetic tree construction, chromosomal localization, conserved structural domain analysis, and promoter element prediction. The expression profiles of RsRbohs in five stages (Pithiness grade = 0, 1, 2, 3, 4, respectively) of radish pithiness were analyzed. The results showed that 10 RsRbohs expressed different levels during the development of radish pithiness. Except for RsRbohB and RsRbohE, the expression of other members increased and reached the peak at the P2 (Pithiness grade = 2) stage, among which RsRbohD1 showed the highest transcripts. Then, the expression of 40 genes related to RsRbohD1 and pithiness were analyzed. These results can provide a theoretical basis for improving pithiness tolerance in radishes.
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PURPOSE: To prospectively evaluate the efficacy of a transjugular intrahepatic portosystemic shunt (TIPS) alone and TIPS in association with embolotherapy (TIPS+E) in the variceal coronary vein to prevent recurrent variceal bleeding and stent dysfunction after TIPS creation. MATERIALS AND METHODS: Institutional review board approval was obtained; all participants provided informed consent. A total of 106 patients (66 men, 40 women; age range, 18-70 years) with recurrent variceal bleeding due to hepatic cirrhosis were assigned randomly to the TIPS+E (n = 54) or TIPS (n = 52) group from May 2007 to July 2011. The TIPS was created by using covered stents. Patients in the TIPS+E group underwent embolotherapy via the jugular vein before TIPS implantation. Rates of recurrent variceal bleeding, stent patency, and survival were evaluated. Scores for liver function and life quality were calculated. RESULTS: TIPS placement was successful in all patients. Recurrent variceal bleeding ranked second among causes of death after TIPS placement. Although the 3-year cumulative rates of shunt patency, recurrent variceal bleeding, and survival in the two groups were not significantly different (P > .05), the 6-month overall rate of shunt patency in the TIPS+E group was significantly higher than that in the TIPS group (96.2% vs 82.0%, P = .019), and the 6-month overall rate of recurrent variceal bleeding was also significantly lower than that in the TIPS group (5.7% vs 20.0%, P = .029). CONCLUSION: The TIPS+E regimen may reduce the risk of recurrent variceal bleeding during the first 6 months after the TIPS procedure by preventing shunt dysfunction, which may improve liver function and quality of life. © RSNA, 2013.