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BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis. CASE PRESENTATION: A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years. CONCLUSION: Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
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Enterite , Infecções por Vírus Epstein-Barr , Adulto , Doença Crônica , Enterite/complicações , Enterite/diagnóstico , Enterite/tratamento farmacológico , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Herpesvirus Humano 4/genética , Humanos , Estudos Retrospectivos , Úlcera/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes. METHODS: Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs). RESULTS: OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment. CONCLUSIONS: ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.
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Antagonistas de Receptores de Angiotensina/farmacologia , Transformação Celular Neoplásica/induzido quimicamente , Dietilnitrosamina/efeitos adversos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/prevenção & controle , Substâncias Protetoras/farmacologia , Tretinoína/análogos & derivados , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos OLETF , Tretinoína/farmacologiaRESUMO
A woman in her 70s with fever and abdominal distension was referred to our hospital for investigation. She had just finished a course of pegylated interferon and ribavirin combination therapy for chronic hepatitis C. Abdominal computed tomography revealed peritoneal thickening and ascites. QuantiFERON(®)-TB Gold was positive, ascitic adenosine deaminase was high, and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed diffuse accumulation in the peritoneum. Although these findings suggested tuberculous peritonitis, we did not detect Mycobacterium tuberculosis in any bacterial cultures, ascites, or other specimens. However, laparoscopic peritoneal biopsy demonstrated a large number of miliary white nodules in the parietal and visceral peritonea. Pathological examination of these nodules revealed epidermoid granuloma with giant Langhans' cells and caseous necrosis. Finally, the diagnosed of tuberculous peritonitis was established. It is important to consider tuberculosis in patients presenting with new symptoms while receiving interferon therapy.
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Hepatite C Crônica/tratamento farmacológico , Interferons/efeitos adversos , Peritonite Tuberculosa/etiologia , Ribavirina/efeitos adversos , Idoso , Antituberculosos/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Interferons/uso terapêutico , Imagem Multimodal , Peritonite Tuberculosa/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Ribavirina/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
AIM: Both angiotensin-II (AT-II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT-II and Ald with angiotensin-converting enzyme inhibitor (ACE-I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE-I and SAB in the progression of a non-diabetic rat model of steatohepatitis, and the possible mechanisms involved. METHODS: In the choline-deficient L-amino acid-defined (CDAA) diet-induced model, the effects of ACE-I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization. RESULTS: Treatment with both ACE-I and SAB suppressed the development of liver fibrosis and glutathione-S-transferase placental form (GST-P) positive pre-neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT-II type 1 receptor blocker (ARB) and SAB inhibited Ac-HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies. CONCLUSION: Dual blockade of AT-II and Ald suppresses the progression of a non-diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.
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AIM: Renin is a rate-limiting enzyme of the renin-angiotensin system (RAS), and several reports have shown that renin plays an important role in several pathological processes. Although RAS is known to play a pivotal role in the progression of non-alcoholic steatohepatitis (NASH), the role of renin is still obscure. The aim of the current study was to examine the effect of the clinically used direct renin inhibitor (DRI), aliskiren, on the progression of NASH in a rat model. METHODS: The effects of DRI on the choline-deficient L-amino acid-defined (CDAA) diet-induced rat NASH model was examined in conjunction with the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which are known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. RESULTS: DRI exerted a marked inhibitory effect against liver fibrosis development and glutathione-S-transferase placental form (GST-P) positive preneoplastic lesions along with suppression of the Ac-HSC and neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of transforming growth factor-beta 1 (TGF-beta 1), angiotensin-II (AT-II) and vascular endothelial growth factor (VEGF). These results indicated that renin played a pivotal role in the liver fibrosis development and hepatocarcinogenesis of NASH. CONCLUSION: Because DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the progression of NASH in the future.
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BACKGROUND AND AIM: The innate immune system, including toll-like receptor-4 (TLR4) signaling cascade and angiotensin-II (AT-II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT-II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT-II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT-II in the rat model of non-alcoholic steatohepatitis. METHODS: Fischer 344 rats were fed a choline-deficient, L-amino-acid-defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac-HSC) activation, TLR4, nuclear factor-κB (NF-κB), and transforming growth factor-ß (TGF-ß) expressions. In vitro study was carried out to elucidate the effect of AT-II on several indices including TLR4, myeloid differentiation factor 88, NF-κB, and TGF-ß expressions in the rat HSC. RESULTS: ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac-HSC and TGF-ß. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF-κB expressions. This in vitro study showed that AT-II significantly augmented the TLR4 expression in a dose- and time-dependent manner via AT-II type 1 receptor in the Ac-HSC. AT-II also augmented the lipopolysaccharide-induced myeloid differentiation factor 88 (MyD88), NF-κB, and TGF-ß and these increments were attenuated by treatment with ARB. CONCLUSIONS: These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.
Assuntos
Angiotensina II/metabolismo , Comunicação Celular/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Cirrose Hepática/prevenção & controle , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Primers do DNA/química , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Fígado Gorduroso/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Losartan/farmacologia , Masculino , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismoRESUMO
AIM: We evaluated real-world efficacy and toxicity of lenvatinib in 142 patients with advanced hepatocellular carcinoma (HCC) at six tertiary referral centres. PATIENTS AND METHODS: The patients with advanced HCC treated with lenvatinib were grouped into two categories based on REFLECT criteria for analysis of efficacy and safety. The primary endpoint was progression-free survival (PFS). RESULTS: The objective response rate (ORR) at week 12 of therapy was 41.5%, with a median PFS of 176 days. Child-Pugh score of 5 points, the presence of extrahepatic metastasis and adverse effects grade 2 or higher were considered independent factors associated with both better PFS and ORR. The ORR for patients who fulfilled the REFLECT inclusion criteria was significantly higher than that for those who did not. However, no significant differences in PFS were observed between the two groups. The incidence rate of adverse effects grade 3 or higher was 40.1%, which was similar for the two groups. CONCLUSION: Lenvatinib is safe and effective for patients, whether or not they satisfy REFLECT criteria. The result warrants replication in a larger study.
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Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Biomarcadores Farmacológicos/metabolismo , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Japão/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Resultado do TratamentoRESUMO
Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient l-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH. Treatment with both LOS and DSX suppressed choline-deficient L-amino acid-defined diet-induced liver fibrosis development and hepatocarcinogenesis. This combination treatment exerted a stronger inhibitory effect compared with treatment with a single agent. These inhibitory effects occurred almost concurrently with the suppression of oxidative stress, neovascularization, and HSC activation. Our in vitro study demonstrated that LOS and DSX inhibited angiotensin II-induced proliferation, transforming growth factor-ß(1) expression of activated HSC, and in vitro angiogenesis. These results indicated that dual inhibition by combined treatment of LOS and DSX attenuated the progression of NASH. Since both agents are widely used in clinical practice, this combination therapy may represent a potential new strategy against NASH in the near future.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Benzoatos/administração & dosagem , Carcinoma Hepatocelular/prevenção & controle , Quelantes de Ferro/administração & dosagem , Cirrose Hepática Experimental/prevenção & controle , Neoplasias Hepáticas Experimentais/prevenção & controle , Losartan/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Inibidores da Angiogênese/administração & dosagem , Angiotensina II/metabolismo , Animais , Antioxidantes/administração & dosagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Deficiência de Colina/complicações , Deferasirox , Progressão da Doença , Quimioterapia Combinada , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/metabolismo , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Neovascularização Patológica/etiologia , Neovascularização Patológica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The prognosis of congenital heart disease is dramatically improved by cardiac surgery. The Fontan procedure is the definitive palliative operation for patients with single-ventricle physiology. In parallel with the longer survival time achieved with the Fontan procedure, the incidence of Fontan-associated liver disease is increasing. A 40-year-old man who underwent Fontan procedures at the ages of 9 was referred to our hospital for further evaluation of multiple hepatic tumors. Enhanced computed tomography showed large hepatocellular carcinomas with portal thrombi (Vp3). Spontaneous hepatocellular carcinoma rupture occurred 2 weeks after the first visit to our hospital, and emergent transcatheter arterial embolization of the hepatic artery was performed. Three months later, the patient died of liver failure. Autopsy findings showed moderately differentiated hepatocellular carcinoma with a cirrhotic liver characterized by centrilobular fibrosis and sinusoidal dilation similar to that in Fontan-associated liver disease. We reported the first case of spontaneously ruptured hepatocellular carcinoma treated by emergent transcatheter arterial embolization in Fontan-associated liver disease. As the early diagnosis of liver cirrhosis and hepatocellular carcinoma results in better patients' outcome, cardiologists and hepatologists should be aware of Fontan-associated liver disease and advise patients to have regular follow-up of the liver.
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An orally bioavailable small molecule inhibitor of plasminogen activator inhibitor1 (PAI1) is currently being clinically assessed as a novel antithrombotic agent. Although PAI1 is known to serve a key role in the pathogenesis of metabolic syndrome (MetS) including nonalcoholic steatohepatitis (NASH), the pharmacological action of an oral PAI1 inhibitor against the development of MetSrelated liver fibrosis remains unclear. The current study was designed to explicate the effect of TM5275, an oral PAI1 inhibitor, on MetSrelated hepatic fibrogenesis. The in vivo antifibrotic effect of orally administered TM5275 was investigated in two different rat MetS models. Fischer 344 rats received a cholinedeficient Laminoaciddefined diet for 12 weeks to induce steatohepatitis with development of severe hepatic fibrosis. Otsuka LongEvans Tokushima Fatty rats, used to model congenital diabetes, underwent intraperitoneal injection of porcine serum for 6 weeks to induce hepatic fibrosis under diabetic conditions. In each experimental model, TM5275 markedly ameliorated the development of hepatic fibrosis and suppressed the proliferation of activated hepatic stellate cells (HSCs). Additionally, the hepatic production of tumor growth factor (TGF)ß1 and total collagen was suppressed. In vitro assays revealed that TGFß1 stimulated the upregulation of Serpine1 mRNA expression, which was inhibited by TM5275 treatment in cultured HSCT6 cells, a rat HSC cell line. Furthermore, TM5275 substantially attenuated the TGFß1stimulated proliferative and fibrogenic activity of HSCs by inhibiting AKT phosphorylation. Collectively, TM5275 demonstrated an antifibrotic effect on liver fibrosis in different rat MetS models, suppressing TGFß1induced HSC proliferation and collagen synthesis. Thus, PAI1 inhibitors may serve as effective future therapeutic agents against NASHbased hepatic fibrosis.
Assuntos
Fibrinolíticos/administração & dosagem , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Cirrose Hepática Experimental/etiologia , Síndrome Metabólica/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Piperazinas/administração & dosagem , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , para-Aminobenzoatos/administração & dosagem , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Estreladas do Fígado/metabolismo , Masculino , Síndrome Metabólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Periostin is a 90kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (ATII) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. ATII induces periostin expression by regulating transforming growth factorß1 (TGFß1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between ATII and periostin during liver fibrosis development. Fischer 344 rats were fed a cholinedeficient Laminoacid (CDAA)defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an ATII type I receptor blocker, was administered to inhibit the effect of ATII. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between ATII and periostin in activated hepatic stellate cells (AcHSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic AcHSC expansion and hepatic TGFß1 expression. In vitro analysis using LX2 HSC cells indicated that ATII can augment TGFß1 and collagen type I α1 mRNA expression via periostin expression, suggesting that the interaction between ATII and periostin may serve a role in liver fibrosis development. In conclusion, blockade of ATIIinduced periostin may suppress the progression of liver fibrosis development.
Assuntos
Moléculas de Adesão Celular/genética , Colágeno Tipo I/genética , Cirrose Hepática/genética , Fator de Crescimento Transformador beta1/genética , Angiotensina II/genética , Animais , Cadeia alfa 1 do Colágeno Tipo I , Regulação da Expressão Gênica/genética , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Losartan/administração & dosagem , Ratos , Sistema Renina-Angiotensina/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
AIM: To evaluate the diagnostic performance of angiotensin-converting enzyme (ACE) on significant liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: In total, 100 patients with CHB who underwent liver biopsy in our hospital were enrolled, and 70 patients except for 30 patients with hypertension, fatty liver or habitual alcoholic consumption were analyzed. We compared histological liver fibrosis and serum ACE levels and evaluated the predictive potential to diagnose significant liver fibrosis by comparison with several biochemical marker-based indexes such as the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), the Mac-2 binding protein glycosylation isomer (M2BPGi) level and the number of platelets (Plt). RESULTS: Serum ACE levels showed moderately positive correlation with liver fibrotic stages (R2 = 0.181). Patients with significant, advanced fibrosis and cirrhosis (F2-4) had significantly higher serum ACE levels than those with early-stage fibrosis and cirrhosis (F0-1). For significant fibrosis (≥ F2), the 12.8 U/L cut-off value of ACE showed 91.7% sensitivity and 75.0% specificity. The receiver-operating characteristic (ROC) curves analysis revealed that the area under the curve (AUC) value of ACE was 0.871, which was higher than that of APRI, FIB-4, M2BPGi and Plt. CONCLUSION: The serum ACE level could be a novel noninvasive, easy, accurate, and inexpensive marker of significant fibrosis stage in patients with CHB.
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Hepatite B Crônica/sangue , Cirrose Hepática/sangue , Fígado/patologia , Peptidil Dipeptidase A/sangue , Adulto , Antígenos de Neoplasias/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Biópsia , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/patologia , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Contagem de Plaquetas , Curva ROCRESUMO
BACKGROUND: It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. METHODS: Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro. RESULTS: OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-ß), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs. CONCLUSION: In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.
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Diabetes Mellitus Experimental/complicações , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Glucosídeos/administração & dosagem , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Resistência à Insulina/fisiologia , Fígado/patologia , Cirrose Hepática Experimental/patologia , Masculino , Obesidade/complicações , Tamanho do Órgão/efeitos dos fármacos , Ratos Endogâmicos OLETF , Transportador 2 de Glucose-Sódio , Tiofenos/administração & dosagemRESUMO
BACKGROUND AND AIMS: Ursodeoxycholic acid (UDCA) is considered to be effective in the treatment of nonalcoholic steatohepatitis (NASH), particularly in combination with other pharmacological agents. UDCA reportedly counteracts the effects of endotoxemia. Previously, we demonstrated attenuated hepatic fibrogenesis and suppression of activated hepatic stellate cells (Ac-HSC) with an angiotensin-II (AT-II) type 1 receptor blocker (ARB). Here we evaluated the simultaneous effect of both agents on hepatic fibrogenesis in a rat model of NASH. METHODS: Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 8 weeks. The therapeutic effect of UDCA and ARB was evaluated along with hepatic fibrogenesis, lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. The direct inhibitory effect of both UDCA and ARB on Ac-HSC was assessed in vitro. RESULTS: Both UDCA and ARB had a potent inhibitory effect on hepatic fibrogenesis with suppression of the HSC activation and hepatic expression of transforming growth factor (TGF)-ß1 and TLR4. UDCA decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption induced by the CDAA diet. ARB was found to directly suppress regulation of Ac-HSC. CONCLUSIONS: UDCA and ARB have a synergistic repressive effect on hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing the activation of Ac-HSC. Because both agents are currently used in clinical practice, combined UDCA and ARB may represent a promising novel therapeutic approach for NASH.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Actinas/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Endotoxinas/metabolismo , Mediadores da Inflamação/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/genética , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genéticaRESUMO
Ancylostoma (A.) ceylanicum, one of the most common species of hookworms infecting dogs and cats, also causes patent infections in humans and is now considered to be the second most common hookworm species infecting populations in southeast Asia. A Japanese patient who returned from a visit to Thailand and Lao People's Democratic Republic (PDR) was presented with intermittent watery diarrhea with eosinophilia. Hookworm eggs were found in feces samples, and adult worms were confirmed to be present in the jejunum with capsule endoscopy and double balloon enteroscopy. A diagnosis of A. ceylanicum infection was made based on the morphology of the adult worms along with findings of a PCR-based molecular study using larvae obtained from a fecal sample culture. The infection was considered likely to have been obtained during a 1-month stay in a Laotian village, where the patient had eaten local food, worn sandals on bare feet, and lived as a local native villager, though he had stayed in modern hotels during the visit to Thailand.
Assuntos
Ancylostoma/isolamento & purificação , Ancilostomíase/diagnóstico , Ancilostomíase/tratamento farmacológico , Antinematódeos/uso terapêutico , Pamoato de Pirantel/uso terapêutico , Ancylostoma/genética , Ancilostomíase/parasitologia , Animais , Endoscopia por Cápsula , Gatos , Cães , Enteroscopia de Duplo Balão , Eosinofilia/parasitologia , Fezes/parasitologia , Humanos , Japão , Laos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , ViagemRESUMO
AIM: To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats. METHODS: A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs. RESULTS: The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher (P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P < 0.01). Interestingly, although Agtr1a was hypermethylated, the Agtr1a mRNA level increased up to 2.2-fold (P < 0.05) in activated HSCs compared with that in quiescent HSCs, suggesting that Agtr1a methylation did not silence its expression but instead had the potential to upregulate its expression. These findings indicate that Agtr1a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis. CONCLUSION: This is the first study to show that DNA methylation is potentially involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.
RESUMO
Nonlinear optics deals with phenomena where "light controls light"; e.g., there is mediation by an intensity-dependent medium through which light propagates. This field has attracted much attention for its immense potential in applications dependent on nonlinear processes, such as frequency conversion, multiple-photon absorption, self-phase modulation, and so on. However, such nonlinearities are typically only observed at very high light intensities and thus they require costly lasers. Here, we report on a self-focusing effect induced with a 1 mW handheld laser pointer. We prepared polymer-stabilized dye-doped liquid crystals, in which the molecular director orientation gradually changes from homeotropic at one surface to homogeneous at the other. This is referred to as hybrid alignment. In such films, the threshold intensity needed to form diffraction rings was reduced by a factor of 8.5 compared to that in conventional homeotropic cells, which enabled the induction of the self-focusing effect with a laser pointer.
RESUMO
Previous clinical studies have demonstrated that endotoxin/tolllike receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with nonalcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGFß and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPSTLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAAinduced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAAinduced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the cholinesupplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPSTLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH.