Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.047
Filtrar
1.
Cells ; 10(12)2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34943969

RESUMO

Biliary atresia (BA) is an obstructive neonatal cholangiopathy leading to liver cirrhosis and end stage liver disease. A Kasai portoenterostomy may restore biliary drainage, but most patients ultimately require liver transplantation for survival. At diagnosis, immune cells within the liver of patients with BA demonstrate a T-helper 1 (Th1) inflammatory profile similar to rhesus rotavirus (RRV)-infected mice livers developing BA. The transcription factor Tbx21 (T-bet) is essential for induction of a Th1 immune response in both the adaptive and innate immune system. Here we used animals with targeted deletion of the T-bet gene to determine its role in the progression of BA. Infection of newborn T-bet knockout (KO) pups with RRV resulted in a decreased Th1 inflammatory chemokine/cytokine profile when compared to infected wild-type mice. Analysis of the mononuclear cells profile from T-bet KO mice revealed both a significant decrease in the total number of CD3, CD4, and CD8 T cells and their effector molecules granzyme A, perforin, and FasL. Even though the percentage of T-bet KO mice displaying symptoms of an obstructive cholangiopathy and overall mortality rate was not different compared to wild-type mice, the extrahepatic bile ducts of T-bet KO mice remained patent.


Assuntos
Atresia Biliar/genética , Fígado/metabolismo , Infecções por Rotavirus/genética , Proteínas com Domínio T/genética , Animais , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Atresia Biliar/patologia , Atresia Biliar/cirurgia , Atresia Biliar/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Humanos , Fígado/patologia , Fígado/virologia , Camundongos , Camundongos Knockout , Rotavirus/patogenicidade , Infecções por Rotavirus/complicações , Infecções por Rotavirus/virologia , Células Th1/imunologia , Células Th1/metabolismo
2.
Sci Rep ; 11(1): 11413, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075171

RESUMO

Accumulating studies suggest that senescent biliary epithelial cells (BECs) produce senescence-associated secretory phenotypes (SASPs) and play various roles in the pathogenesis of primary biliary cholangitis (PBC) and other cholangiopathies. We examined comprehensive profiles of senescent BECs and its contribution to the pathogenesis of PBC taking advantage of microarray analysis. cDNA microarray analysis revealed that 1841 genes including CCL2, IFIT3, CPQ were commonly up-regulated in senescent BECs cultured in serum depleted media or media with glycochenodeoxycholic acid. Knockdown of IFIT3 significantly suppressed cellular senescence (p < 0.01) and significantly increased apoptosis (p < 0.01) in BECs treated with serum depletion or glycochenodeoxycholic acid. Significantly increased expression of IFIT3 was seen in senescent BECs in small bile ducts showing cholangitis and in ductular reactions in PBC, compared to control livers (p < 0.01). An inadequate response to UDCA was inversely correlated to the increased expression of IFIT3 in small bile duct in PBC (p < 0.05). In conclusion, the expression of various genes related to immunity and inflammation including SASPs were increased in senescent BECs. Upregulated IFIT3 in senescent BECs may be associated with the pathogenesis of PBC and may be a possible therapeutic target in PBC.


Assuntos
Ductos Biliares , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Cirrose Hepática Biliar , Animais , Apoptose , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Proliferação de Células , Células Cultivadas , Senescência Celular , Células Epiteliais , Feminino , Humanos , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Camundongos , Camundongos Endogâmicos BALB C
3.
Cells ; 10(5)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-34062960

RESUMO

Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.


Assuntos
Colestase Intra-Hepática/metabolismo , Transdução de Sinais , Animais , Ductos Biliares/citologia , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Colestase Intra-Hepática/patologia , Fibrose , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia
4.
Molecules ; 26(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066903

RESUMO

The effect of effective microorganisms (EM) on internal organ morphology, intestinal morphometry, and serum biochemical activity in Japanese quails under Clostridium perfringens challenge was determined. After 30 days of EM addition, one group of quails was orally inoculated with Clostridium perfringens. The second group did not receive EM and was inoculated with C. perfringens. In the gut, EM supplementation reduced the number of lesions, enhanced gut health, and protected the mucosa from pathogenic bacteria. EM showed an anti-inflammatory effect and fewer necrotic lesions in villi. In the internal organs, EM showed a protective effect against a typical lesion of C. perfringens infection. Necrosis and degeneration of the hepatocytes, necrosis of bile ducts, and bile duct proliferation were more severe in the infected group without EM. Morphometric evaluation showed significantly higher villi in the jejunum after EM addition. A greater crypt depth was observed in the C. perfringens group. Biochemical analysis of the blood indicated lower cholesterol on the 12th day of the experiment and between-group differences in total protein, lactate dehydrogenase (LDH), and albumin levels in the EM group. Further studies are needed to improve EM activity against pathologic bacteria as a potential alternative to antibiotics and to develop future natural production systems.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças das Aves/sangue , Doenças das Aves/dietoterapia , Infecções por Clostridium/sangue , Infecções por Clostridium/dietoterapia , Clostridium perfringens , Enterite/sangue , Enterite/dietoterapia , Mucosa Intestinal/microbiologia , Probióticos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Codorniz/sangue , Codorniz/microbiologia , Ração Animal/microbiologia , Animais , Ductos Biliares/patologia , Doenças das Aves/microbiologia , Colesterol/sangue , Infecções por Clostridium/microbiologia , Enterite/microbiologia , Feminino , Hepatócitos/patologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , L-Lactato Desidrogenase/sangue , Necrose , Albumina Sérica/análise , Resultado do Tratamento
5.
Dis Mon ; 67(12): 101225, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34176572

RESUMO

Chronic pancreatitis is characterized by irreversible destruction of pancreatic parenchyma and its ductal system resulting from longstanding inflammation, leading to fibrosis and scarring due to genetic, environmental, and other risk factors. The diagnosis of chronic pancreatitis is made based on a combination of clinical features and characteristic findings on computed tomography or magnetic resonance imaging. Abdominal pain is the most common symptom of chronic pancreatitis. The main aim of treatment is to relieve symptoms, prevent disease progression, and manage complications related to chronic pancreatitis. Patients who do not respond to medical treatment or not a candidate for surgical treatment are usually managed with endoscopic therapies. Endoscopic therapies help with symptoms such as abdominal pain and jaundice by decompression of pancreatic and biliary ducts. This review summarizes the risk factors, pathophysiology, diagnostic evaluation, endoscopic treatment of chronic pancreatitis, and complications. We have also reviewed recent advances in endoscopic retrograde cholangiopancreatography and endoscopic ultrasound-guided therapies for pancreatic duct obstruction due to stones, strictures, pancreatic divisum, and biliary strictures.


Assuntos
Endoscopia/métodos , Pâncreas/patologia , Pancreatite Crônica/terapia , Dor Abdominal/etiologia , Dor Abdominal/terapia , Ductos Biliares/patologia , Colangiopancreatografia Retrógrada Endoscópica , Drenagem , Humanos , Ductos Pancreáticos/patologia , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/patologia , Ultrassonografia
6.
Toxicol Lett ; 349: 134-144, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153406

RESUMO

Recent epidemiological studies reported cases of cholangiocarcinoma in workers exposed to 1,2-dichloropropane (1,2-DCP) in an offset proof printing factory in Japan. The present study investigated the effects of 1,2-DCP on the expression of histone family member X (H2AX) phosphorylated on Ser 139 (γ-H2AX), a marker of DNA double strand break, in human immortalized cholangiocytes MMNK-1 cells. Mono-cultures of MMNK-1 cells and co-cultures of MMNK-1 cells with THP-1 macrophages were exposed to 1,2-DCP at concentrations of 100 and 500 µM for 24 h. Expression of γ-H2AX was visualized by immunofluorescence staining. Exposure to 1,2-DCP had no effect on the expression of γ-H2AX in mono-cultured MMNK-1 cells, but significantly increased the number of nuclear foci stained by γ-H2AX in MMNK-1 cells co-cultured with THP-1 macrophages. Exposure to 1,2-DCP also significantly increased the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in co-cultured MMNK-1 cells. The results suggest that macrophages play a critical role by producing cytokines in 1,2-DCP-induced DNA double strand break in MMNK-1 cells.


Assuntos
Ductos Biliares/efeitos dos fármacos , Histonas/metabolismo , Macrófagos/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Propano/análogos & derivados , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Técnicas de Cocultura , Quebras de DNA de Cadeia Dupla , Humanos , Interleucina-6/metabolismo , Macrófagos/metabolismo , Propano/toxicidade , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
7.
Sci Rep ; 11(1): 10895, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035351

RESUMO

We aim to evaluate the safety and feasibility of novel elbow biopsy forceps with a prebent head for sampling biliary strictures in our institution. A total of 24 patients (15 males and 9 females) with biliary stricture who underwent biliary biopsy during endoscopic retrograde cholangiopancreatography (ERCP) using novel elbow biopsy forceps from June 2019 to August 2020 were retrospectively included. The novel biopsy forceps had a head angulation of 30 degrees and were able to cannulate the bile duct and approach the biliary strictures easily to obtain adequate samples. The technical success rate, incidence of adverse events, and consistency of pathological and surgical specimens were assessed. This device was used successfully in all patients. A total of 52 biopsy specimens were obtained from 24 patients, and all specimens could be used for histopathological examination. Seventeen patients were diagnosed with malignancy based on biopsies, and all of them underwent surgical treatment. The histopathological findings of the biopsy specimens were in accordance with the postoperative pathology diagnoses. One of the seven patients was diagnosed with a benign lesion that was proven to be malignant during surgical treatment in the follow-up period. Two patients experienced a single episode of acute pancreatitis and recovered shortly after appropriate treatment. No patients experienced biliary perforation or biliary bleeding. Biopsy using novel elbow forceps in patients with biliary stenosis is feasible and safe. The novel device and related biopsy technique may be widely applied for biliary disease differentiation.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Ductos Biliares/patologia , Colangiopancreatografia Retrógrada Endoscópica/instrumentação , Idoso , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/diagnóstico por imagem , Constrição Patológica , Estudos de Viabilidade , Feminino , Humanos , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
J Immunol Res ; 2021: 6890423, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977112

RESUMO

Background and Aims: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. We found microRNA-34a (miR-34a), as the downstream gene of p53, was overexpressed in some of fibrogenic diseases. In this study, we sought to explore whether miR-34a plays a role in the fibrosis of PBC. Methods: The peripheral blood of PBC patients and controls was collected to analyze the level of miR-34a. Human intrahepatic biliary epithelial cells (HIBEC) were cultured. The expression of miR-34a was regulated by miR-34a mimics and inhibitor. The biomarkers of epithelium-mesenchymal transition (EMT), fibrogenesis, inflammation, and transforming growth factor- (TGF-) ß1/smad pathway were analyzed. Results: We found that miR-34a was overexpressed in the peripheral blood in PBC patients. In vitro, overexpressed miR-34a increased the EMT and fibrogenesis activity of HIBEC. Transforming growth factor-beta type 1 receptor (TßR1), TGF-ß1, and p-smad2/3 were upregulated by miR-34a. Inflammatory factors such as IL-6 and IL-17 were also upregulated. Finally, we showed that miR-34a promoted EMT and liver fibrosis in PBC by targeting the TGF-ß1/smad pathway antagonist transforming growth factor-beta-induced factor homeobox 2 (TGIF2). Conclusions: Our findings show that miR-34a plays an important role in the EMT and fibrosis of PBC through the TGF-ß1/smad pathway by targeting TGIF2. This study suggests that miR-34a may be a new marker of fibrogenesis in PBC. Inhibition of miR-34a may be a promising strategy in treating PBC and improving the prognosis of the disease.


Assuntos
Transição Epitelial-Mesenquimal/genética , Cirrose Hepática Biliar/complicações , Cirrose Hepática/genética , MicroRNAs/metabolismo , Ductos Biliares/citologia , Ductos Biliares/patologia , Estudos de Casos e Controles , Células Epiteliais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células HEK293 , Humanos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/imunologia , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
9.
Am J Gastroenterol ; 116(7): 1414-1425, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33993134

RESUMO

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS: We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS: Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION: Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.


Assuntos
COVID-19/complicações , Colangite Esclerosante/epidemiologia , Doença Hepática Terminal/epidemiologia , Icterícia/epidemiologia , Adulto , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Ductos Biliares/diagnóstico por imagem , Ductos Biliares/imunologia , Ductos Biliares/patologia , Biópsia , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19 , Colangiopancreatografia por Ressonância Magnética , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/imunologia , Colangite Esclerosante/terapia , Progressão da Doença , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/cirurgia , Feminino , Humanos , Icterícia/diagnóstico , Icterícia/imunologia , Icterícia/terapia , Testes de Função Hepática , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
10.
Transplant Proc ; 53(5): 1726-1730, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33993996

RESUMO

BACKGROUND: Biliary stricture (BS) is a severe complication after liver transplantation. It is difficult to treat, especially after living donor liver transplantation (LDLT). We successfully treated 4 patients for intractable BS after LDLT. All patients had developed cholangitis with stenosis of bile ducts anastomosis. CASE 1: . A 65-year-old woman underwent LDLT with right lobe graft and duct-to-duct biliary reconstruction. Internal plastic stents inserted by endoscopic retrograde cholangiography (ERC) were changed quarterly for the next 2 years. CASE 2: A 55-year-old man underwent LDLT with right lobe graft and duct-to-duct biliary reconstruction. Insertion of internal plastic stents by ERC was attempted; however, the posterior bile duct branch showed complete obstruction. After percutaneous transhepatic biliary drainage (PTCD), the stents were inserted using the rendezvous technique of ERC and were changed by ERC quarterly for the next 3 years. CASE 3: A 22-year-old man underwent LDLT with left lobe graft and hepaticojejunostomy. An external drainage tube was inserted by PTCD, and stents were changed quarterly for the next 2 years. CASE 4: A 60-year-old man underwent LDLT with right lobe graft and hepaticojejunostomy. An external drainage tube was inserted by PTCD, and changed to a metallic stent after 1 year. Three months later the stent was extracted using the rendezvous technique of double balloon enteroscopy. CONCLUSION: BS of complete obstruction type after LDLT is difficult to treat. Appropriate procedures should be chosen based on the types of strictures and biliary reconstruction methods.


Assuntos
Ductos Biliares/patologia , Constrição Patológica/diagnóstico , Transplante de Fígado/efeitos adversos , Idoso , Colangiopancreatografia Retrógrada Endoscópica , Colangite/diagnóstico , Colangite/etiologia , Constrição Patológica/etiologia , Drenagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Stents , Adulto Jovem
11.
Can J Gastroenterol Hepatol ; 2021: 6610434, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954154

RESUMO

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs ∗ 31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Ductos Biliares/patologia , Adulto , Pré-Escolar , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
12.
Br J Surg ; 108(4): 419-426, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33793726

RESUMO

BACKGROUND: The relevance of laparoscopic resection of intrahepatic cholangiocarcinoma (ICC) remains debated. The aim of this study was to compare laparoscopic (LLR) and open (OLR) liver resection for ICC, with specific focus on textbook outcome and lymph node dissection (LND). METHODS: Patients undergoing LLR or OLR for ICC were included from two French, nationwide hepatopancreatobiliary surveys undertaken between 2000 and 2017. Patients with negative margins, and without transfusion, severe complications, prolonged hospital stay, readmission or death were considered to have a textbook outcome. Patients who achieved both a textbook outcome and LND were deemed to have an adjusted textbook outcome. OLR and LLR were compared after propensity score matching. RESULTS: In total, 548 patients with ICC (127 LLR, 421 OLR) were included. Textbook-outcome and LND completion rates were 22.1 and 48.2 per cent respectively. LLR was independently associated with a decreased rate of LND (odds ratio 0.37, 95 per cent c.i. 0.20 to 0.69). After matching, 109 patients remained in each group. LLR was associated with a decreased rate of transfusion (7.3 versus 21.1 per cent; P = 0.001) and shorter hospital stay (median 7 versus 14 days; P = 0.001), but lower rate of LND (33.9 versus 73.4 per cent; P = 0.001). Patients who underwent LLR had lower rate of adjusted TO completion than patients who had OLR (6.5 versus 17.4 per cent; P = 0.012). CONCLUSION: The laparoscopic approach did not substantially improve quality of care of patients with resectable ICC.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Laparoscopia , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Transfusão de Sangue/estatística & dados numéricos , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Feminino , França , Humanos , Laparoscopia/métodos , Tempo de Internação/estatística & dados numéricos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
13.
Oncol Rep ; 45(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846801

RESUMO

Cholangiocarcinoma (CCA) is the second most common type of hepatocellular carcinoma characterized by high aggressiveness and extremely poor patient prognosis. The germ cell­specific gene 2 protein (GSG2) is a histone H3 threonine­3 kinase required for normal mitosis. Nevertheless, the role and mechanism of GSG2 in the progression and development of CCA remain elusive. In the present study, the association between GSG2 and CCA was elucidated. Firstly, we demonstrated that GSG2 was overexpressed in CCA specimens and HCCC­9810 and QBC939 cells by immunohistochemical (IHC) staining. It was further revealed that high expression of GSG2 in CCA had significant clinical significance in predicting disease deterioration. Subsequently, cell proliferation, apoptosis, cell cycle distribution and migration were measured by MTT, flow cytometry, and wound healing assays, respectively in vitro. The results demonstrated that downregulation of GSG2 decreased proliferation, promoted apoptosis, arrested the cell cycle and weakened migration in the G2 phase of CCA cells. Additionally, GSG2 knockdown inhibited CCA cell migration by suppressing epithelial­mesenchymal transition (EMT)­related proteins, such as N­cadherin and vimentin. Mechanistically, GSG2 exerted effects on CCA cells by modulating the PI3K/Akt, CCND1/CDK6 and MAPK9 signaling pathways. In vivo experiments further demonstrated that GSG2 knockdown suppressed tumor growth. In summary, GSG2 was involved in the progression of CCA, suggesting that GSG2 may be a potential therapeutic target for CCA patients.


Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , /metabolismo , Animais , Apoptose/genética , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672682

RESUMO

Hexapeptide WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met), a ligand of formyl peptide receptor 2, exhibits anti-inflammatory and angiogenic properties in disease models. However, the therapeutic effects of WKYMVm on hepatic fibrosis have not been evaluated to date. Therefore, we investigated whether WKYMVm exerts antifibrotic effects and induces vascular regeneration in a rat model of bile duct ligation (BDL). The antifibrotic and angiogenic effects of WKYMVm on liver regeneration in the BDL rat model were analyzed using biochemical assays, qRT-PCR, western blotting, immunofluorescence, and immunohistochemistry. To determine the effects of WKYMVm on hepatic fibrosis and angiogenesis in vitro, we measured the expression levels of fibrotic factors in hepatic stellate cells (HSCs) and angiogenic factors in human umbilical vein endothelial cells (HUVECs). WKYMVm attenuated the expression of collagen type I (Col I) and α-smooth muscle actin (α-SMA) and significantly increased the levels of angiogenetic factors in the BDL model (p < 0.05). WKYMVm reduced fibrotic marker expression in transforming growth factor (TGF)-ß-induced HSCs and promoted angiogenic activity through tube formation in 5-Fluorouracil (FU)-treated HUVECs (p < 0.05). Also, WKYMVm administration enhanced hepatocyte proliferation in BDL rats (p < 0.05). The WKYMVm alleviates hepatic fibrosis by inhibiting HSC activation and promotes hepatic regeneration via vascular remodeling. These data suggest that the WKYMVm may be a new therapeutic agent for liver fibrosis.


Assuntos
Cirrose Hepática/fisiopatologia , Receptores de Lipoxinas/metabolismo , Remodelação Vascular , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/patologia , Ductos Biliares/fisiopatologia , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ligadura , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/patologia , Regeneração Hepática/efeitos dos fármacos , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Oligopeptídeos/farmacologia , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/metabolismo , Remodelação Vascular/efeitos dos fármacos
15.
J Gastrointest Cancer ; 52(2): 814-818, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33683644

RESUMO

PURPOSE: Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy and overall prognosis remains poor, with a median survival of less than 24 months. Sequencing studies have revealed a high prevalence of genomic alterations in CCA, with multiple potential therapeutic targets. Next-generation sequencing (NGS) can identify actionable mutations such as FGFR, IDH, BRAF, ERBB2, ROS1, or microsatellite instability (MSI-H), among others. METHODS: We conducted a retrospective multicenter study in Spain in 2019. Thirty consecutive patients from 15 centers were included. All patients were diagnosed with advanced CCA and underwent NGS (FoundationOne®) in 2019. Twenty-four patients underwent tissue-based NGS (FoundationOne® CDx), and 6 patients underwent blood-based NGS (FoundationOne®Liquid) with sequencing panels of 324 and 70 genes, respectively RESULTS: We identified 12 patients (40%) with an actionable genetic alteration in tissue: 2 FGFR2 fusions, 6 IDH1 mutations, 1 ERBB2 mutation, 1 ROS1 fusion, 1 PIK3CA mutation, and 1 MSI-H. CONCLUSION: Comprehensive genomic profiling (CGP) in cholangiocarcinoma can identify, in a high proportion of patients, clinically relevant genomic alterations that can lead to targeted therapies, expanding treatment options.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Biomarcadores Tumorais/genética , Colangiocarcinoma/tratamento farmacológico , Medicina de Precisão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares/patologia , Biomarcadores Tumorais/antagonistas & inibidores , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Prognóstico , Estudos Retrospectivos , Espanha
16.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671269

RESUMO

Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats.


Assuntos
Ductos Biliares/patologia , Eletroacupuntura , Fígado/patologia , Inflamação Neurogênica/terapia , Dor Referida/terapia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Condutividade Elétrica , Hiperalgesia/complicações , Ligadura , Inflamação Neurogênica/complicações , Dor Referida/complicações , Ratos Sprague-Dawley , Pele/patologia , Substância P/metabolismo
17.
J Vis Exp ; (168)2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33720138

RESUMO

Chronic pancreatitis (CP) is a complex disease involving pancreatic inflammation and fibrosis, glandular atrophy, abdominal pain and other symptoms. Several rodent models have been developed to study CP, of which the bile duct 2,4,6 -trinitrobenzene sulfonic acid (TNBS) infusion model replicates the features of neuropathic pain seen in CP. However, bile duct drug infusion in mice is technically challenging. This protocol demonstrates the procedure of bile duct TNBS infusion for generation of a CP mouse model. TNBS was infused into the pancreas through the ampulla of Vater in the duodenum. This protocol optimized drug volume, surgical techniques, and drug handling during the procedure. TNBS-treated mice showed features of CP as reflected by bodyweight and pancreas weight reductions, changes in pain-associated behaviors, and abnormal pancreatic morphology. With these improvements, mortality associated with TNBS injection was minimal. This procedure is not only critical in generating pancreatic disease models but is also useful in local pancreatic drug delivery.


Assuntos
Ductos Biliares/patologia , Pancreatite Crônica/patologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Humanos , Injeções , Masculino , Camundongos Endogâmicos C57BL , Soluções , Ácido Trinitrobenzenossulfônico
18.
Ann Diagn Pathol ; 52: 151723, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33725666

RESUMO

Intracholecystic papillary neoplasm (ICPN) is a recently proposed gallbladder neoplasm. Its prevalence and pathologies remain to be clarified. A total of 38 ICPN cases (28 ICPNs identified among 1904 cholecystectomies (1.5%) and in 100 surgically resected primary gallbladder neoplasms (28%) in Fukui Prefecture Saiseikai Hospital, Japan, and other 10 ICPNs) were examined pathologically and immunohistochemically. They were composed of 21 males and 17 females with a mean age of 75 years old, and presented intraluminal growth of papillary lesions with fine fibrovascular stalks. ICPNs were relatively frequent in the fundus (n = 11) and body (n = 9). Grossly, the conglomerated sessile type (n = 30) was more frequent than the isolated polypoid type (n = 8). All cases were classified as high-grade dysplasia, and they were further divided into 22 cases presenting irregular structures and 16 cases presenting regular structures. The former showed frequent complicated lesions and stromal invasion (54.5%) compared to the latter (12.5%). Twenty-four cases showed predominantly either of four subtypes (11 gastric, 7 intestinal, 4 biliary and 2 oncocytic subtype), while the remaining14 cases showed mixture of more than two subtypes. In conclusion, ICPN presented unique preinvasive neoplasm with characteristic histopathologies. Irregular histologies and complicated lesions of ICPN were related to stromal invasion.


Assuntos
Adenocarcinoma Papilar/diagnóstico , Ductos Biliares/patologia , Carcinoma in Situ/patologia , Neoplasias da Vesícula Biliar/patologia , Adenocarcinoma Papilar/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ductos Biliares/cirurgia , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/epidemiologia , Colecistectomia/métodos , Colecistectomia/estatística & dados numéricos , Feminino , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Imuno-Histoquímica/métodos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Prevalência
19.
Khirurgiia (Mosk) ; (2): 5-13, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33570348

RESUMO

OBJECTIVE: To determine the incidence of AS after right lobe living donor liver transplantation with various biliary reconstructions and to identify the predictors of this complication. MATERIAL AND METHODS: A retrospective and prospective analysis included 245 RLLDLTs for the period 2011-2018 at the Burnazjan Federal Medical Biophysical Center. The results of transplantations in 207 patients aged 19-68 years (median 43 years) were assessed. There were 82 men and 125 women. Follow-up period ranged from 10 to 98 months (median 35 months). We analyzed the relationship between surgical characteristics (preoperative data of recipients and donors, graft parameters, technical features of biliary reconstruction and features of post-transplantation period) and incidence of anastomotic strictures. A total of 58 parameters were analyzed. RESULTS: AS occurred in 20 (9.7%) recipients. Median AS-free period was 5 months (range 1-44). In 17 (85%) patients, AC developed within a year after surgery. Cumulative 1-, 2- and 5-year incidence of AS was 8.3%, 8.9%, and 11%, respectively. Significant predictors of AS were impaired arterial blood supply to the graft (HR 7.8, 95% CI 2.3-26.0, p<0.001), biliary leakage ISGLS class B or C (HR 5.0, 95% CI 2.0-12.8, p<0.001), early allograft dysfunction (HR 4.2, 95% CI 1.5-11.6, p=0.006) and female recipient (HR 3.2, 95% CI 1.1-9.9, p=0.04). In our sample, variant biliary anatomy of the graft and recipient liver, as well as technical features of biliary reconstruction did not affect the risk of AS. CONCLUSION: Variant biliary anatomy of potential donor alone should not be considered as a contraindication for organ donation and right liver lobe transplantation. Precise surgical technique, high transplantation activity, as well as experience of reconstructive interventions on the bile ducts during other operations can significantly reduce the incidence of AS after RLLDLT up to 9.7%.


Assuntos
Ductos Biliares/cirurgia , Constrição Patológica , Transplante de Fígado , Doadores Vivos , Adulto , Idoso , Anastomose Cirúrgica/efeitos adversos , Ductos Biliares/patologia , Constrição Patológica/diagnóstico , Constrição Patológica/epidemiologia , Constrição Patológica/etiologia , Feminino , Humanos , Fígado/cirurgia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
20.
Cell Death Dis ; 12(1): 16, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414436

RESUMO

Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1-/- mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Animais , Ductos Biliares/enzimologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Diferenciação Celular/fisiologia , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...