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AIM: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection. METHODS: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function. RESULTS: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.
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Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.
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AIM: Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). METHODS: Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis. RESULTS: Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis. CONCLUSIONS: Hypozincemia is associated with hepatocarcinogenesis in C-LC patients.
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The fenestrations of liver sinusoidal endothelial cells (LSECs) play important roles in the exchange of macromolecules, solutes, and fluid between blood and surrounding liver tissues in response to hepatotoxic drugs, toxins, and oxidative stress. As excess iron is a hepatotoxin, LSECs may be affected by excess iron. In this study, we found a novel link between LSEC defenestration and hepatic nerve growth factor (NGF) in iron-overloaded mice. By Western blotting, NGF was highly expressed, whereas VEGF and HGF were not, and hepatic NGF mRNA levels were increased according to digital PCR. Immunohistochemically, NGF staining was localized in hepatocytes, while TrkA, an NGF receptor, was localized in LSECs. Scanning electron microscopy revealed LSEC defenestration in mice overloaded with iron as well as mice treated with recombinant NGF. Treatment with conditioned medium from iron-overloaded primary hepatocytes reduced primary LSEC fenestrations, while treatment with an anti-NGF neutralizing antibody or TrkA inhibitor, K252a, reversed this effect. However, iron-loaded medium itself did not reduce fenestration. In conclusion, iron accumulation induces NGF expression in hepatocytes, which in turn leads to LSEC defenestration via TrkA. This novel link between iron and NGF may aid our understanding of the development of chronic liver disease.
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Endotelio/metabolismo , Sobrecarga de Hierro/fisiopatología , Hígado/metabolismo , Factor de Crecimiento Nervioso/fisiología , Animales , Western Blotting , Células Cultivadas , Medios de Cultivo Condicionados , Endotelio/citología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Nervioso/biosíntesis , Reacción en Cadena de la PolimerasaRESUMEN
Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepcidinas/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular Tumoral , Exones , Células HEK293 , Humanos , Isoformas de Proteínas/genéticaRESUMEN
BACKGROUND & AIMS: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. METHODS: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. RESULTS: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models. CONCLUSIONS: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis.
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Aminoácidos de Cadena Ramificada/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
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Péptidos Catiónicos Antimicrobianos/metabolismo , Rosácea/metabolismo , Rosácea/patología , Serina Endopeptidasas/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/deficiencia , Péptidos Catiónicos Antimicrobianos/genética , Biopsia , Células Cultivadas , Citocinas/biosíntesis , Activación Enzimática , Humanos , Inflamación/metabolismo , Inflamación/patología , Queratinocitos/citología , Queratinocitos/metabolismo , Ratones , Ratones Noqueados , Inhibidor de Serinpeptidasas Tipo Kazal-5 , Serpinas/deficiencia , Serpinas/genética , Serpinas/metabolismo , CatelicidinasRESUMEN
AIM: There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD. METHODS: Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1ß, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated. RESULTS: The expression of inflammatory cytokines such as TNF, IL-1ß, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA. CONCLUSION: In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.
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BACKGROUND AND AIM: Interferon (IFN) activates various immune systems in vivo and is administered to patients with diseases such as viral hepatitis B, C, and malignant tumors. Iron dysregulation has been reported during treatment with IFN; however, it remains unclear whether IFN itself affects iron metabolism. We therefore determined the effect of IFN on iron metabolism. METHODS: Mouse IFNα was administered to mice, and serum, spleen, bone marrow, liver, and duodenum tissue samples were subsequently collected. The messenger RNA (mRNA) and protein expression of genes involved in iron metabolism were then analyzed by real-time reverse transcription-polymerase chain reaction, Western blotting, and liquid chromatography-tandem mass spectrometry. Immunofluorescence for ferroportin was also performed. RESULTS: Among the gene expressions analyzed, we found that the expression of hepcidin, an iron regulatory hormone produced in the liver, was highly upregulated after IFNα treatment. Serum hepcidin levels and hepcidin mRNA expression in the liver were both found to be increased in the IFNα-treated mice. The expression of ferroportin (the target molecule of hepcidin) in the duodenum of the IFNα-treated mice was observed to be decreased, indicating that hepcidin upregulation could be physiologically functional. In vitro analysis of primary hepatocytes treated with IFNα and human hepatoma-derived cells showed an upregulation of hepcidin mRNA, including an activation of signal transducer and activator of transcription3, which was shown to be involved in the hepcidin upregulation. CONCLUSIONS: Results indicate that iron absorption is decreased during IFN treatment; this favorable effect could inhibit iron overload during IFN treatment and may enhance the action of IFN.
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Hepcidinas/metabolismo , Interferón-alfa/farmacología , Hierro/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , Western Blotting , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte de Catión/metabolismo , Células Cultivadas , Cromatografía Liquida , Duodeno/metabolismo , Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Hepcidinas/sangre , Hepcidinas/genética , Sobrecarga de Hierro/prevención & control , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Espectrometría de Masas en Tándem , Células Tumorales CultivadasRESUMEN
AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
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Hígado Graso , Células Estrelladas Hepáticas , Cirrosis Hepática , Lisofosfolípidos , Fosfotransferasas (Aceptor de Grupo Alcohol) , Receptores de Esfingosina-1-Fosfato , Esfingosina , Animales , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Lisofosfolípidos/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Cirrosis Hepática/etiología , Ratones , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Humanos , Receptores de Esfingosina-1-Fosfato/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Masculino , Ratones Noqueados , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/patología , Deficiencia de Colina/complicaciones , Deficiencia de Colina/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Lisoesfingolípidos/genética , Pirazoles , PiridinasRESUMEN
BACKGROUND: The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation. METHODS: The microRNA profile in interleukin-10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study. RESULTS: The overexpression of miR-146b activated the NF-κB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-κB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-κB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-κB. CONCLUSIONS: miR-146b improves intestinal inflammation by up-regulating NF-κB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-κB pathway.
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Colitis/terapia , Mucosa Intestinal/efectos de los fármacos , MicroARNs/farmacología , Animales , Antiinflamatorios/farmacología , Western Blotting , Colitis/mortalidad , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , FN-kappa B/metabolismo , Unión Proteica , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
AIM: The aim of this survey was to reveal clinical features for each etiology of non-B, non-C liver cirrhosis (NBNC LC) in Japan. METHODS: In a nationwide survey of NBNC LC in Japan at the 15th General Meeting of the Japan Society of Hepatology, 6999 NBNC LC patients were registered at 48 medical institutions. Epidemiological and clinical factors were investigated. RESULTS: The percentage of NBNC LC among LC patients was 26%. NBNC LC patients were categorized into 11 types according to etiological agents: non-alcoholic steatohepatitis (NASH), 14.5%; alcoholic liver disease (ALD), 55.1%; fatty liver disease (FLD), except NASH, ALD, and other known etiology, 2.5%; primary biliary cirrhosis, 8.0%; other biliary cirrhosis, 0.8%; autoimmune hepatitis, 6.8%; metabolic disease, 0.6%; congestive disease, 0.8%; parasitic disease, 0.2%; other known etiology, 0.2%; and unknown etiology, 10.5%. Compared with previous surveys, the percentage of ALD remained unchanged, whereas that of NASH increased. The mean age and percentage of females were significantly higher in NASH patients than in ALD and FLD patients. Prevalence of diabetes mellitus was significantly higher in NASH and FLD patients than in ALD ones. Prevalence of hepatocellular carcinoma (HCC) in NBNC LC patients was 35.9%. Among NASH, ALD and FLD patients, 50.9%, 34.3% and 54.5% had HCC, respectively. Positivity of hepatitis B core antibody was significantly higher in HCC patients than in those without HCC (41.1% vs 24.8%). CONCLUSION: This survey determined the etiology of NBNC LC in Japan. These results should contribute new ideas toward understanding NBNC LC and NBNC HCC.
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Objective One of the therapeutic goals for chronic infection with hepatitis B virus is the clearance of hepatitis B surface antigen (HBsAg) from the blood, as a high load of HBsAg has been proposed to induce antigen-specific immunotolerance. To achieve HBsAg reduction, Pegylated interferon and nucleos (t) ide analogs are used to treat chronic hepatitis B. Following the coronavirus disease 2019 (COVID-19) outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide, and vaccination with mRNA COVID-19 vaccines has been conducted since 2021 in Japan. We experienced three clinical cases in which HBsAg levels rapidly decreased after injection of the COVID-19 vaccine without any incentive. Method To examine whether the vaccine administration was involved in the HBsAg reduction, the number of patients with chronic hepatitis B showing a change in the HBsAg levels during the period before the commencement of the COVID-19 vaccination program in Japan (i.e. until the end of 2020; pre-vaccination-program period) was compared to the number of those who showed a change in HBsAg levels after the initiation of the program (i.e. 2021 onwards; post-vaccination-program period). Results The number of patients whose HBsAg levels was reduced by >50% per year was prominent after the initiation of the vaccination program. Although the involvement of vaccination in HBsAg reduction was not statistically proven (p=0.0532), the result suggests that the administration of COVID-19 vaccines may have been involved in HBsAg reduction in patients with chronic hepatitis B. Conclusion COVID-19 vaccines may be involved in HBsAg reduction.
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Vacunas contra la COVID-19 , COVID-19 , Hepatitis B Crónica , Hepatitis B , Humanos , Antivirales/uso terapéutico , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Hepatitis B/tratamiento farmacológico , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológico , SARS-CoV-2 , VacunaciónRESUMEN
False cysts have no cellular lining and usually originate from past abdominal trauma. We herein report a 23-year-old woman with an asymptomatic splenic false cyst. She had no history of abdominal trauma. Abdominal computed tomography showed a cystic lesion without internal structure. In contrast, magnetic resonance imaging and ultrasonography revealed an inhomogeneous internal structure without fluid/debris level. Although the images were not typical of a splenic false cyst, the surgically excised mass histologically showed a splenic false cyst (no epithelial element). Non-traumatic splenic false cysts are rare and show nonspecific clinical findings and symptoms. The recommended treatment is splenectomy.
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Quistes , Enfermedades del Bazo , Femenino , Humanos , Adulto Joven , Adulto , Quistes/diagnóstico por imagen , Quistes/cirugía , Esplenectomía/métodos , Enfermedades del Bazo/diagnóstico por imagen , Enfermedades del Bazo/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Hypoxia inducible factor-1α (HIF-1α) has a central role in cellular oxygen-sensing, and its overexpression in many types of cancer is considered important in tumor progression. Thus, targeting HIF-1α production and activity has been of great therapeutic interest. In normoxic conditions, HIF-1α is hydroxylated by oxygen-dependent prolyl-hydroxylases, which require ferrous iron for its activity. The tumor suppressor protein von Hippel Lindau binds to the hydroxylated HIF-1α, which is then ubiquitinated and degraded by proteasomes. We focused on the physiological degradation machinery of HIF-1α mediated by prolyl hydroxylases. Previously, we identified a small molecule, LS081, that is capable of stimulating iron uptake into cells. In the present study, we aimed to inhibit the expression of HIF-1α protein and growth of hepatocellular carcinoma by using the iron-facilitating activity of LS081. In the human hepatocellular carcinoma cell lines Hep3B and HepG2, a combination of LS081 and ferric ammonium citrate (LS081/FeAC) inhibited HIF-1α protein expression but did not inhibit HIF-1α mRNA expression. A mutated HIF-1α protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS081 and FeAC. Furthermore, the iron-facilitating activity of LS081 resulted in Hep3B and HepG2 growth inhibition in vitro and in vivo. These results indicate that the iron-facilitating activity of LS081 inhibits HIF-1α expression through prolyl-hydroxylation of HIF-1α and might have a therapeutic effect in the treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular/metabolismo , Hidrazonas/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Niacinamida/análogos & derivados , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Células HEK293 , Células Hep G2 , Humanos , Hidroxilación , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Hierro/metabolismo , Ratones , Niacinamida/farmacología , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: The improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the mechanism of the combining effect of tyrosine kinase inhibitor sorafenib (SOR) and iron chelator deferasirox (DFX) in human hepatoma cell lines, HepG2 and Huh-7. METHODS: The types of programmed cell deaths (PCDs); necrosis/necroptosis and apoptosis, were evaluated by flow cytometry and fluorescent microscopy. Human cleaved caspase-3 was analyzed by ELISA for apoptosis. GSH assay was used for ferroptosis. PCDs inhibition was analyzed by adding apoptosis inhibitor Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1, necroptosis inhibitor necrosulfonamide, respectively. The expression of NF-κB was quantified by Western blotting. RESULTS: In SOR monotherapy, cleaved caspase-3 expression was increased in all concentrations, confirming the result that SOR induces apoptosis. In SOR monotherapy, GSH/GSSG ratio was decreased on concentration-dependent, showing that SOR also induced ferroptosis. Lipid Peroxidation caused by SOR, corresponding to ferroptosis, was suppressed by DFX. In fluorescence microscopy of SOR monotherapy, apoptosis was observed at a constant rate on all concentrations, while necroptosis and ferroptosis were increased on high concentration. In sorafenib and deferasirox combinations, sub G1 phase increased additively. In SOR and DFX combinations, the cytotoxic effects were not suppressed by ferrostatin-1, but suppressed by Z-VAD-FMK and necrosulfonamide. In each monotherapy, and SOR + DFX combinations, the expression of NF-κB in nucleus was suppressed. Regarding PCD by SOR and DFX combination, ferroptosis was suppressed and both apoptosis and necroptosis became dominant. CONCLUSION: Suppression of NF-κB is possibly involved in the effect of DFX. As a result, SOR and DFX combination showed additive antitumor effects for HCC through the mechanism of programed cell deaths and NF-kB signal modification.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptosis , Carcinoma Hepatocelular/patología , Caspasa 3 , Línea Celular , Línea Celular Tumoral , Deferasirox/farmacología , Deferasirox/uso terapéutico , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Neoplasias Hepáticas/patología , FN-kappa B/farmacología , Sorafenib/farmacología , Sorafenib/uso terapéuticoRESUMEN
Two cases of alveolar echinococcosis (AE) with multiple-organ involvement (the liver, lungs, and bone) were monitored by imaging and serology for 20 years. Resection of the bone lesion was complete in one case but incomplete in the other case. Albendazole treatment was markedly to moderately effective against hepatic and pulmonary AE lesions in both cases, whereas it had almost no effect against the bone lesion in one case. The results of the serological tests with recombinant Em18 antigen coincided with the clinical findings in each case. An enzyme-linked immunosorbent assay for the detection of immunoglobulin G (IgG) responses, especially IgG4 responses, is expected to be a real-time indicator of the dynamics of active AE.
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Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos , Equinococosis/inmunología , Equinococosis/patología , Echinococcus/inmunología , Adulto , Albendazol/uso terapéutico , Animales , Antihelmínticos/uso terapéutico , Huesos/parasitología , Huesos/patología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Inmunoglobulina G/sangre , Hígado/parasitología , Hígado/patología , Pulmón/parasitología , Pulmón/patología , Resultado del TratamientoAsunto(s)
Adenina/análogos & derivados , Antivirales/administración & dosificación , Síndrome de Fanconi/inducido químicamente , Fracturas Espontáneas/etiología , Organofosfonatos/efectos adversos , Fosfatos/administración & dosificación , Cúbito/lesiones , Adenina/administración & dosificación , Adenina/efectos adversos , Administración Oral , Anciano , Antivirales/efectos adversos , Femenino , Hepatitis B/tratamiento farmacológico , Humanos , Organofosfonatos/administración & dosificaciónRESUMEN
Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. In this study, we firstly revealed that a new alternative HAMP transcript was found in hepatoma-derived cell line HLF, which was identical to the wild-type preprohepcidin sequence except lacking of an internal 60 bases. In addition to HLF, most of hepatoma-derived cell lines have significant copy numbers of variant-type hepcidin mRNA by a copy-based-digital PCR. Furthermore, the copy number of hepcidin mRNA variant was significantly higher in serum exosomes of hepatocellular carcinoma patients. The quantification of exosomal hepcidin mRNA variant may serve as a potential new biomarker for HCC diagnosis.
Asunto(s)
Empalme Alternativo , Exosomas/metabolismo , Hepcidinas/metabolismo , Hierro/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/metabolismo , Estudios de Casos y Controles , Femenino , Variación Genética , Hepcidinas/genética , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.