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1.
Int J Mol Sci ; 23(11)2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35682957

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-ß signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-ß type I receptor (TßRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TßRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-ß/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.


Assuntos
Carcinoma Hepatocelular , Resistência à Insulina , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Carcinogênese , Carcinoma Hepatocelular/metabolismo , Humanos , Cirrose Hepática , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
2.
Molecules ; 25(8)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331471

RESUMO

Thermal stabilities of four major components (l-menthol, l-menthone, piperitone, and l-menthyl acetate) of Japanese mint essential oil were evaluated via subcritical water treatment. To improve experimental throughput for measuring compound stabilities, a small-scale subcritical water treatment method using ampoule bottles was developed and employed. A mixture of the four major components was treated in subcritical water at 180-240 °C for 5-60 min, and then analyzed by gas chromatography. The results indicated that the order of thermal resistance, from strongest to weakest, was: l-menthyl acetate, l-menthol, piperitone, and l-menthone. In individual treatments of mint flavor components, subsequent conversions of l-menthyl acetate to l-menthol, l-menthol to l-menthone, l-menthone to piperitone, and piperitone to thymol were observed in individual treatments at 240 °C for 60 min. As the mass balance between piperitone and thymol was low, the hydrothermal decomposition of the components was considered to have occurred intensely during, or after the conversion. These results explained the degradation of mint essential oil components under subcritical water conditions and provided the basis for optimizing the extraction conditions of mint essential oils using subcritical water.


Assuntos
Mentha/química , Óleos Voláteis/química , Monoterpenos Cicloexânicos/química , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Óleos de Plantas/química , Timol/química
3.
Hepatol Res ; 43(12): 1327-42, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23458062

RESUMO

AIM: Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-ß signaling. TGF-ß type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling. METHODS: We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group). RESULTS: Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. CONCLUSION: HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.

4.
JMIR Form Res ; 7: e44762, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38113066

RESUMO

BACKGROUND: Screening and intervention for alcohol use disorders (AUDs) are recommended to improve the prognosis of patients with alcohol-related liver disease (ALD). Most patients' smartphone app diaries record drinking behavior for self-monitoring. A smartphone app can be expected to also be helpful for physicians because it can provide rich patient information to hepatologists, leading to suitable feedback. We conducted this prospective pilot study to assess the use of a smartphone app as a journaling tool and as a self-report-based feedback source for patients with ALD. OBJECTIVE: The aims of this study were assessment of whether journaling (self-report) and self-report-based feedback can help patients maintain abstinence and improve liver function data. METHODS: This pilot study used a newly developed smartphone journaling app for patients, with input data that physicians can review. After patients with ALD were screened for harmful alcohol use, some were invited to use the smartphone journaling app for 8 weeks. Their self-reported alcohol intake, symptoms, and laboratory data were recorded at entry, week 4, and week 8. Biomarkers for alcohol use included gamma glutamyl transferase (GGT), percentage of carbohydrate-deficient transferrin to transferrin (%CDT), and GGT-CDT (GGT-CDT= 0.8 × ln[GGT] + 1.3 × ln[%CDT]). At each visit, their recorded data were reviewed by a hepatologist to evaluate changes in alcohol consumption and laboratory data. The relation between those outcomes and app usage was also investigated. RESULTS: Of 14 patients agreeing to participate, 10 completed an 8-week follow-up, with diary input rates between 44% and 100% of the expected days. Of the 14 patients, 2 withdrew from clinical follow-up, and 2 additional patients never used the smartphone journaling app. Using the physician's view, a treating hepatologist gave feedback via comments to patients at each visit. Mean self-reported alcohol consumption dropped from baseline (100, SD 70 g) to week 4 (13, SD 25 g; P=.002) and remained lower at week 8 (13, SD 23 g; P=.007). During the study, 5 patients reported complete abstinence. No significant changes were found in mean GGT and mean %CDT alone, but the mean GGT-CDT combination dropped significantly from entry (5.2, SD 1.2) to the week 4 visit (4.8, SD 1.1; P=.02) and at week 8 (4.8, SD 1.0; P=.01). During the study period, decreases in mean total bilirubin (3.0, SD 2.4 mg/dL to 2.4, SD 1.9 mg/dL; P=.01) and increases in mean serum albumin (3.0, SD 0.9 g/dL to 3.3, SD 0.8 g/dL; P=.009) were recorded. CONCLUSIONS: These pilot study findings revealed that a short-term intervention with a smartphone journaling app used by both patients and treatment-administering hepatologists was associated with reduced drinking and improved liver function. TRIAL REGISTRATION: UMIN CTR UMIN000045285; http://tinyurl.com/yvvk38tj.

5.
Chem Pharm Bull (Tokyo) ; 60(7): 892-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22790824

RESUMO

In the course of screening for leishmanicidal constituents from Asian and South American medicinal plants, a Pakistani medicinal plant, Withania coagulans, showed activity. We therefore studied the active components of the methanol extract of aerial parts of W. coagulans. From the ethyl acetate soluble fraction of the extract, four new withanolides (1-4) were isolated along with seven known withanolides (5-11). The new compounds were elucidated to be (14R,15R,17S,20S,22R)-14,15,17,20-tetrahydroxy-1-oxowitha-2,5,24-trienolide (1), (14R,15R,17S,20S,22R)-14,15,17,20-tetrahydroxy-1-oxowitha-3,5,24-trienolide (2), (14S,17R,20S,22R)-14,17,20-trihydroxy-1-oxowitha-2,5,24-trienolide (3), and (14S,17R,20S,22R)-14,17,20-trihydroxy-1-oxowitha-3,5,24-trienolide (4), from 1H-NMR, 13C-NMR, 2D-NMR and high resolution (HR)-MS data. Some of these compounds having the partial structure 1-oxo-2,5-diene showed strong leishmanicidal activity against Leishmania major.


Assuntos
Antiprotozoários/química , Withania/química , Vitanolídeos/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Paquistão , Plantas Medicinais/química , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia
6.
Hepatology ; 51(3): 777-87, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20198633

RESUMO

Chronic infection with hepatitis B virus (HBV) is strongly associated with hepatocellular carcinoma (HCC), and the viral HBx protein plays a crucial role in the pathogenesis of liver tumors. Because the protooncogene pituitary tumor-transforming gene 1 (PTTG1) is overexpressed in HCC, we investigated the regulation of this protein by HBx. We analyzed PTTG1 expression levels in liver biopsies from patients chronically infected with HBV, presenting different disease stages, and from HBx transgenic mice. PTTG1 was undetectable in biopsies from chronic hepatitis B patients or from normal mouse livers. In contrast, hyperplastic livers from transgenic mice and biopsies from patients with cirrhosis, presented PTTG1 expression which was found mainly in HBx-expressing hepatocytes. PTTG1 staining was further increased in HCC specimens. Experiments in vitro revealed that HBx induced a marked accumulation of PTTG1 protein without affecting its messenger RNA levels. HBx expression promoted the inhibition of PTTG1 ubiquitination, which in turn impaired its degradation by the proteasome. Glutathione S-transferase pull-down and co-immunoprecipitation experiments demonstrated that the interaction between PTTG1 and the Skp1-Cul1-F-box ubiquitin ligase complex (SCF) was partially disrupted, possibly through a mechanism involving protein-protein interactions of HBx with PTTG1 and/or SCF. Furthermore, confocal analysis revealed that HBx colocalized with PTTG1 and Cul1. We propose that HBx promotes an abnormal accumulation of PTTG1, which may provide new insights into the molecular mechanisms of HBV-related pathogenesis of progressive liver disease leading to HCC development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Hepatite B Crônica/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/metabolismo , Ubiquitinação , Animais , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Transgênicos
7.
Rheumatology (Oxford) ; 50(5): 852-61, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21177334

RESUMO

OBJECTIVE: To clarify the contribution of heat shock protein 90 (HSP90) to the pathogenesis of RA, we studied the effects of geldanamycin (GA), an inhibitor of HSP90, on excessive cellular extension and resistance to apoptosis induction of rheumatoid synovial cells. METHODS: Expression of integrin-α5ß1 and integrin-linked kinase (ILK) in synovial cells was determined by western blot. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with particularly interesting new cysteine-histidine protein (PINCH) and α-parvin, and activation of Rac/cdc42 in synovial cells were examined by using immunohistochemistry and immunoprecipitation. Apoptosis induction by GA treatment was analysed by nuclear staining, cell proliferation assay and western blot of caspase. Effects of GA on mitogen-activated protein kinase (MAPK), PI-3K/protein kinase B (Akt) pathway, mitochondrial Bcl-2 pathway and activation of nuclear factor-κB (NF-κB) were examined by western blot and ELISA. RESULTS: HSP90 was overexpressed in synovial cells while GA decreased the expression of integrin-α5ß1 and ILK. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with PINCH and α-parvin, and activation of Rac/cdc42 in synovial cells were all inhibited by GA treatment. We found that HSP90 stabilized and regulated the MAPK and PI-3K/Akt pathway, thereby inhibiting HSP90-potentiated synovial apoptosis by stimulating caspases and the mitochondrial Bcl-2 pathway on the one hand and inhibiting the activation of NF-κB on the other. CONCLUSION: The contribution of HSP90 is important in the pathogenesis of RA that potentiates a tumour-like synovial overgrowth by stabilizing ILK, extracellular signal-regulated kinase and Akt.


Assuntos
Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Proteínas de Choque Térmico HSP90/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Membrana Sinovial/patologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Humanos , Lactamas Macrocíclicas/farmacologia , NF-kappa B/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/fisiopatologia
8.
Plants (Basel) ; 10(7)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34371623

RESUMO

Environmental light conditions influence the biosynthesis of monoterpenes in the mint plant. Cyclic terpenes, such as menthol, menthone, pulegone, and menthofuran, are major odor components synthesized in mint leaves. However, it is unclear how light for cultivation affects the contents of these compounds. Artificial lighting using light-emitting diodes (LEDs) for plant cultivation has the advantage of preferential wavelength control. Here, we monitored monoterpene contents in hydroponically cultivated Japanese mint leaves under blue, red, or far-red wavelengths of LED light supplements. Volatile cyclic monoterpenes, pulegone, menthone, menthol, and menthofuran were quantified using the head-space solid phase microextraction method. As a result, all light wavelengths promoted the biosynthesis of the compounds. Remarkably, two weeks of blue-light supplement increased all compounds: pulegone (362% increase compared to the control), menthofuran (285%), menthone (223%), and menthol (389%). Red light slightly promoted pulegone (256%), menthofuran (178%), and menthol (197%). Interestingly, the accumulation of menthone (229%) or menthofuran (339%) was observed with far-red light treatment. The quantification of glandular trichomes density revealed that no increase under light supplement was confirmed. Blue light treatment even suppressed the glandular trichome formation. No promotion of photosynthesis was observed by pulse-amplitude-modulation (PAM) fluorometry. The present result indicates that light supplements directly promoted the biosynthetic pathways of cyclic monoterpenes.

9.
Abdom Radiol (NY) ; 46(8): 3790-3797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33675382

RESUMO

PURPOSE: To evaluate the efficacy and safety of radiofrequency ablation (RFA) and new-generation microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC). METHODS: The propensity score matching method was applied to patients with HCC treated with MWA (93 patients) or RFA (156 patients) at a single institution from January 2014 to April 2020. The local tumor progression (LTP), intrahepatic distant recurrence (IDR), and recurrence-free survival (RFS) of the two matched therapies were analyzed using the Kaplan-Meier method. Cox proportional hazard models were used to identify risk factors for LTP and RFS. The therapeutic effects and complications of the two treatments were also compared. RESULTS: The LTP, IDR, and RFS of MWA and RFA were equivalent (LTP: hazard ratio [HR] = 0.87; 95% confidence interval [95% CI] 0.36- 2.07; P = 0.746, IDR: HR = 1.03; 95% CI 0.61-1.73; P = 0.890, RFS: HR = 1.15; 95% CI 0.69-1.91; P = 0.566). Para-vessel lesions was the only risk factor for LTP, whereas age, previous treatment, Albumin-Bilirubin score, and tumor diameter were risk factors for RFS. On the other hand, the ablation time per nodule (6.79 ± 2.73 and 9.21 ± 4.90 min; P = 0.008) and number of sessions per nodule required to achieve technical success (1.16 ± 0.39 and 1.34 ± 0.57; P = 0.009) were significantly lower in MWA than in RFA. The major complication rate of MWA and RFA was also equivalent. CONCLUSION: MWA and RFA have similar therapeutic effects and safety, although MWA has advantages over RFA regarding efficacy, including shorter ablation time and fewer sessions required.


Assuntos
Carcinoma Hepatocelular , Ablação por Cateter , Neoplasias Hepáticas , Ablação por Radiofrequência , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Micro-Ondas/uso terapêutico , Recidiva Local de Neoplasia , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
10.
Front Biosci (Landmark Ed) ; 26(12): 1480-1492, 2021 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-34994163

RESUMO

INTRODUCTION: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-ß/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. METHODS AND RESULTS: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. CONCLUSION: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Cirrose Hepática Biliar , Neoplasias Hepáticas , Biomarcadores , Humanos , Medição de Risco , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta/metabolismo
11.
Medicine (Baltimore) ; 100(14): e25048, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832073

RESUMO

RATIONALE: Brunner gland hamartoma (BGH) is a rare tumor of the duodenum. Although BGH is a benign tumor, larger lesion with gastrointestinal symptoms requires tumor removal. We report a giant BGH, successfully treated by endoscopic excision followed by transanal retrieval. PATIENT CONCERNS: A 38-year-old woman complained of severe anemia, tarry stool, and vomiting. DIAGNOSES: Esophagogastroduodenoscopy (EGD) showed a pedunculated giant submucosal mass at the duodenal bulb. INTERVENTIONS: We attempted to remove it because the lesion seemed to be responsible for patient's anemia and vomiting. The lesion had clear but bulky stalk. We carefully cut the stalk using needle-knife and IT knife2. We tried to retrieve specimen, but the mass could not pass through the pyloric ring because of its size. Then we tried to obtain the specimen from anus. Polyethylene glycol solution was administered to accelerate rapid excretion. OUTCOMES: The mass was successfully removed and was histologically confirmed as a giant BGH, measuring 55 mm in size. LESSONS: Reports about endoscopic resection of giant BGH are rare. Moreover, our case is the first report of transanal retrieval of resected specimen using polyethylene glycol solution. Endoscopic resection of BGH is less-invasive but can be more challenging if the mass is large. Our case provides useful option for endoscopic treatment of giant BGH.


Assuntos
Glândulas Duodenais/cirurgia , Duodenopatias/cirurgia , Hamartoma/cirurgia , Adulto , Canal Anal/cirurgia , Glândulas Duodenais/diagnóstico por imagem , Glândulas Duodenais/patologia , Duodenopatias/diagnóstico por imagem , Duodenopatias/patologia , Endoscopia do Sistema Digestório , Feminino , Hamartoma/diagnóstico por imagem , Hamartoma/patologia , Humanos
12.
Hepatology ; 49(4): 1203-17, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19263472

RESUMO

UNLABELLED: Hepatitis B virus X (HBx) protein is suspected to participate in oncogenesis during chronic hepatitis B progression. Transforming growth factor beta (TGF-beta) signaling involves both tumor suppression and oncogenesis. TGF-beta activates TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Reversible shifting of Smad3-mediated signaling between tumor suppression and oncogenesis in HBx-expressing hepatocytes indicated that TbetaRI-dependent pSmad3C transmitted a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promoted cell growth. We used immunostaining, immunoblotting, and in vitro kinase assay to compare pSmad3L- and pSmad3C-mediated signaling in biopsy specimens representing chronic hepatitis, cirrhosis, or hepatocellular carcinoma (HCC) from 90 patients chronically infected with hepatitis B virus (HBV) with signaling in liver specimens from HBx transgenic mice. In proportion to plasma HBV DNA levels, early chronic hepatitis B specimens showed prominence of pSmad3L in hepatocytic nuclei. HBx-activated JNK/pSmad3L/c-Myc oncogenic pathway was enhanced, while the TbetaRI/pSmad3C/p21(WAF1) tumor-suppressive pathway was impaired as human and mouse HBx-associated hepatocarcinogenesis progressed. Of 28 patients with chronic hepatitis B who showed strong oncogenic pSmad3L signaling, six developed HCC within 12 years; only one of 32 patients showing little pSmad3L developed HCC. In contrast, seven of 30 patients with little Smad3C phosphorylation developed HCC, while no patient who retained hepatocytic tumor-suppressive pSmad3C developed HCC within 12 years. CONCLUSION: HBx shifts hepatocytic TGF-beta signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway in early carcinogenic process. Hepatocytic pSmad3L and pSmad3C assessment in HBV-infected liver specimens should prove clinically useful for predicting risk of HCC.


Assuntos
Transformação Celular Neoplásica , Hepatite B Crônica/metabolismo , Proteína Smad3/metabolismo , Transativadores/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Adulto , Animais , Carcinoma Hepatocelular/virologia , Núcleo Celular/metabolismo , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA Viral/sangue , Proteínas de Ligação a DNA/metabolismo , Feminino , Hepatite B Crônica/complicações , Hepatócitos/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cirrose Hepática/complicações , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Transdução de Sinais , Fatores de Transcrição/metabolismo , Adulto Jovem
13.
Hepatology ; 49(6): 1944-53, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19418558

RESUMO

UNLABELLED: Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.


Assuntos
Antracenos/farmacologia , Carcinoma Hepatocelular/enzimologia , Genes Supressores de Tumor/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Hepáticas/enzimologia , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/fisiologia , Animais , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
14.
Mol Clin Oncol ; 12(3): 230-236, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32064099

RESUMO

The aim of the present study was to evaluate the efficacy and safety of the new-generation percutaneous microwave ablation (MWA) compared with the radiofrequency ablation (RFA) system for the treatment of hepatocellular carcinoma (HCC). A retrospective study was conducted from January 2014 to February 2019. A total of 44 patients and 52 nodules (mean tumor size, 17.2±4.9 mm) were treated with MWA, and 55 patients and 70 nodules (mean tumor size, 17.7±6.4 mm) were treated with RFA. After 4 days of treatment, the direct effects of ablation were assessed using dynamic CT, and after discharge, a follow-up dynamic CT scan was performed every 3-4 months. Treatment efficacy, complications and local recurrence were recorded. For MWA and RFA, the average number of CT sessions were 1.05±0.23 and 1.28±0.54, respectively, and the mean ablation times were 5.0±2.0 and 8.1±4.8 min. Following MWA and RFA, the ablation ranges that were evaluated with the axial images were 31.9±5.5 and 33.3±9.0 mm, respectively, in the long-axis diameter and 27.6±5.3 and 23.4±6.8 mm, respectively, in the short-axis diameter. The flatness ratios of the ablation regions were 0.13±0.09 and 0.29±0.14 (axial image) and 0.11±0.07 and 0.28±0.14 (coronal image), respectively. The rates of complete tumor necrosis were comparable. The complication rates were 13.6% (MWA) and 14.5% (RFA), which were not significantly different. The cumulative local recurrence rates were not significantly different between the two methods (one-year recurrence rate, MWA: 6.91%, RFA: 5.17%). MWA was therefore indicated to be an effective treatment for HCC in respect to session number, treatment time and spherical ablation.

15.
J Oleo Sci ; 69(6): 635-642, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32404544

RESUMO

In this study, we provide a method for obtaining essential oil from Mentha arvensis L. in large quantities. Three types of polysaccharide-degrading enzymes were investigated, namely cellulase A "Amano" 3, cellulase T "Amano" 4, and hemicellulase "Amano" 90. The optimum extraction conditions were the combined use of 2 wt% cellulase T and 2 wt% hemicellulase 90, and 3 h of incubation. Enzymeassisted extraction increased the amount of the essential oil from 2.2 mL to 3.0 mL, compared with the amount extracted without an enzyme.


Assuntos
Celulase , Glicosídeo Hidrolases , Extração Líquido-Líquido/métodos , Mentha/química , Mentol/isolamento & purificação , Óleos Voláteis/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Fatores de Tempo
16.
Cancers (Basel) ; 12(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991602

RESUMO

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-ß signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-ßtype I receptor (TßRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TßRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.

17.
Dement Geriatr Cogn Dis Extra ; 10(1): 27-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308665

RESUMO

BACKGROUND/AIMS: Age-related changes in impairments in activities of daily living (ADL) in older adults with very mild Alzheimer's disease (vmAD) have been scarcely explored. We clarified the characteristics of ADL impairment and examined how ADL impairments differed by age in such patients compared with community-dwelling cognitively normal older adults. METHODS: The participants were 107 older adults with vmAD (Mini-Mental State Examination [MMSE] score ≥24), all of whom were first-visit outpatients at the Dementia Clinic of the Department of Neuropsychiatry, Kumamoto University Hospital. The controls were 682 community-dwelling older adults who participated in the 3rd Nakayama Study with MMSE score ≥24. We examined the association of instrumental and basic ADL (IADL and BADL, respectively) independence with the odds of vmAD using multiple logistic regression analysis and determined differences in ADL impairment by age using age- and sex-matched analysis. RESULTS: Impairments in handling finances (OR 57.08), managing medication (OR 5.13), and dressing (OR 3.35; BADL) were associated with greater odds of vmAD. Among those aged 65 years and above, there were fewer patients with vmAD than healthy controls who could independently handle finances and medication. Among patients with vmAD, the percentages of those who could independently manage shopping, food preparation, and housekeeping only decreased after age 74. Age-related decreases in independence were observed in few BADL items; these, however, were temporary. CONCLUSIONS: Patients with vmAD show significantly decreased IADL independence from early old age.

18.
Mod Rheumatol ; 19(6): 637-42, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19626390

RESUMO

Clinical squeal of the treatment of rheumatoid arthritis patients with methotrexate (MTX) according to the Japanese government recommended dose of 8 mg/week was evaluated prospectively. A total of 176 patients with active RA attending Konan Kakogawa Hospital and Kobe University Hospital were enrolled. Patients' profile at the start of study was Class 2.0 +/- 1.1 and X-ray stage 2.6 +/- 1.0. The effects of MTX treatment were evaluated by the American College of Rheumatology (ACR) core set, disease activity score of 28 joints (DAS28), and European League Against Rheumatism (EULAR) response criteria. A modified Sharp method was used to evaluate the radiographs. The improvement in the clinical signs and symptoms of the ACR core set was maintained for a 24-month period (p < 0.05). The ACR20/50/70 and DAS28 were also improved at the 12- and 24-month assessments. However, 82 of 130 patients (63.5%) were found to be nonresponders at 24 months of MTX therapy, as evaluated by EULAR response criteria. The X-ray study showed that joint destruction progressed despite the treatment. Thus, long-term MTX treatment performed in accordance with the Japanese 8 mg/week regimen appears to be favorable in terms of the signs and symptoms of RA; however, it is clearly insufficient for and cannot halt the progression of rheumatic joint destruction.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Cancer Res ; 67(11): 5090-6, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17545585

RESUMO

Cancer cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor-beta (TGF-beta) together with stimulation of its oncogenic activity as in Ras-transformed cells; however, molecular mechanisms remain largely unknown. TGF-beta activates both its type I receptor (TbetaRI) and c-Jun NH2-terminal kinase (JNK), which phosphorylate Smad2 and Smad3 at the COOH-terminal (pSmad2/3C) and linker regions (pSmad2/3L). Here, we report that Ras transformation suppresses TbetaRI-mediated pSmad3C signaling, which involves growth inhibition by down-regulating c-Myc. Instead, hyperactive Ras constitutively stimulates JNK-mediated pSmad2/3L signaling, which fosters tumor invasion by up-regulating plasminogen activator inhibitor-1 and matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9. Conversely, selective blockade of linker phosphorylation by a mutant Smad3 lacking JNK-dependent phosphorylation sites results in preserved tumor-suppressive function via pSmad3C in Ras-transformed cells while eliminating pSmad2/3L-mediated invasive capacity. Thus, specific inhibition of the JNK/pSmad2/3L pathway should suppress cancer progression by shifting Smad-dependent signaling from oncogenesis to tumor suppression.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Genes Supressores de Tumor/fisiologia , Genes ras/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular , Transformação Celular Neoplásica/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , MAP Quinase Quinase 4/metabolismo , Metaloproteinases da Matriz/metabolismo , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Transdução de Sinais/fisiologia , Proteínas ras/metabolismo
20.
Int J Oncol ; 32(6): 1221-6, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18497983

RESUMO

Chronic inflammation predisposes to cancer. Transforming growth factor (TGF)-beta, a multifunctional protein, suppresses the growth of normal colonic epithelial cells, whereas it stimulates the proliferation of cancer cells. Interleukin (IL)-10-deficient mice, which develop colitis and colorectal cancer, show an increased level of plasma TGF-beta. Although TGF-beta may be a key molecule in the development of colon cancer arising from chronic colitis in IL-10-deficient mice, the role of TGF-beta still remains unclear. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which converts the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). We studied C57BL/6-IL-10-deficient mice (n=18) at 4 to 32 weeks of age. We investigated histology, and pSmad2/3L, pSmad2/3C, and p53 by immunohistochemistry. pSmad3L staining was detected in the cancer cells in all 10 mice with colonic cancer and in the epithelial cells in 7 of 12 mice with colonic dysplasia, but not in the normal or colitic mice. pSmad3c was detected without any significant difference between stages. p53 was weakly stained in a few cancer cells in 5 out of 10 mice. Smad3L signaling plays an important role in the carcinogenesis of chronic colitis in IL-10-deficient mice.


Assuntos
Colite/metabolismo , Neoplasias Colorretais/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad3/fisiologia , Animais , Doença Crônica , Neoplasias Colorretais/patologia , Técnicas Imunoenzimáticas , Interleucina-10/genética , Intestino Grosso/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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