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1.
Hepatol Res ; 54(3): 252-260, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37897705

RESUMEN

AIM: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are considered safe nucleoside/nucleotide analogs (NA) for the kidney. This study aimed to investigate the long-term effects of ETV or TAF on renal function in elderly patients with chronic hepatitis B (CHB) in Japan. METHODS: The study included 246 CHB patients treated with ETV (184 patients) or TAF (62 patients) for at least 2 years. These patients were divided into two groups: those <65 years of age (130 patients) and those ≥65 years of age (116 patients). The effects of the NAs on renal functions were examined by comparing the estimated glomerular filtration rates (eGFR) from baseline to 2 years between the two groups. RESULTS: The change in eGFR from baseline to 1 or 2 years after treatment was significantly decreased in both groups. However, the amount of change at 1 and 2 years was significantly greater in the group aged ≥65 years than in the group aged <65 years. The amount of change in eGFR from baseline to 1 and 2 years after treatment was significantly greater in the group aged ≥65 years than in the group aged <65 years, regardless of the type of NA, the prior treatment history, cirrhosis/chronic hepatitis, hypertension, dyslipidemia, and diabetes. Additionally, logistic regression analysis showed that age ≥65 years was independently associated with a decreased eGFR after 2 years of NA treatment. CONCLUSIONS: Long-term administration of NA to CHB patients over 65 years of age should be carefully monitored for renal impairment.

2.
Hepatol Res ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838066

RESUMEN

AIM: Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct-acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin-like metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13) can predict EGV progression with HCV-LC after SVR achievement. METHODS: This retrospective study enrolled 47 patients with HCV-LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty-nine patients did not experience EGV progression after the SVR was achieved (non-EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment. RESULTS: The EGV progression group had significantly higher plasma VWF antigen levels (p = 0.00331) and VWF-to-ADAMTS13 ratios (p = 0.000249) than the non-EGV progression group. Multivariate logistic regression models found that a VWF-to-ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08-109; p = 0.00138). During the observation period, patients with a VWF-to-ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF-to-ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78-22.96; p = 0.0044). CONCLUSIONS: The VWF-to-ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.

3.
Dig Dis Sci ; 69(3): 851-869, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38244124

RESUMEN

AIM: We investigated the von Willebrand factor to ADAMTS13 ratio (von Willebrand factor [VWF]:Ag/ADAMTS13:AC) as a potential biomarker for the outcomes of acute kidney injury (AKI) in liver cirrhosis (LC). METHODS: This retrospective cross-sectional study included patients with LC who developed AKI (AKI group: n = 91) and patients with LC who did not develop AKI [non-AKI (NAKI) group, n = 91] as a control group. Plasma levels of the von Willebrand factor antigen (Ag) and ADAMTS13 activity (AC) were measured in patients with AKI or NAKI. Moreover, risk factors for onset of AKI, AKI-associated 90-day mortality, and poor AKI treatment response were identified. RESULTS: The AKI group had a significantly higher VWF:Ag/ADAMTS13:AC than the NAKI group. Values of VWF:Ag/ADAMTS13:AC ≥ 5.7 were identified as risk factors for AKI onset in patients with LC (odds ratio [OR] 2.56; 95% CI 1.26-4.99; p < 0.001). Among patients with AKI, values of VWF:Ag/ADAMTS13:AC ≥ 9.0 were identified as risk factors for 90-day mortality (OR 6.83; 95% CI 2.32-20.10; p < 0.001). Cumulative survival was significantly lower in those with high (≥ 9.0) than in those with low (< 9.0) VWF:Ag/ADAMTS13:AC. Furthermore, values of VWF:Ag/ADAMTS13:AC ≥ 7.4 were identified as risk factors for poor treatment response (OR 4.2; 95% CI 1.39-12.70; p < 0.001). The treatment response rates were significantly higher in those with low (< 7.4) VWF:Ag/ADAMTS13:AC than in those with high (≥ 7.4) VWF:Ag/ADAMTS13:AC. CONCLUSION: VWF:Ag/ADAMTS13:AC potentially predicts the onset, prognosis, and treatment response of AKI in patients with LC.


Asunto(s)
Lesión Renal Aguda , Factor de von Willebrand , Humanos , Estudios Retrospectivos , Estudios Transversales , Cirrosis Hepática/diagnóstico , Biomarcadores , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Proteína ADAMTS13
4.
Int J Mol Sci ; 25(8)2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38673992

RESUMEN

Lipopolysaccharides (LPSs) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression with epidermal growth factor receptor (EGFR) expression in the tumor microenvironment. We used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by a reverse transcription polymerase chain reaction revealed higher vascularization, with increased interleukin-8 (IL-8) expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only the tumor cell growth and migration/invasion of EGFR-positive HCC cells but also tumor neovascularization via IL-8 signaling.


Asunto(s)
Carcinoma Hepatocelular , Epirregulina , Receptores ErbB , Lipopolisacáridos , Neoplasias Hepáticas , Transducción de Señal , Microambiente Tumoral , Epirregulina/metabolismo , Epirregulina/genética , Animales , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Ratones , Línea Celular Tumoral , Neovascularización Patológica/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Interleucina-8/metabolismo , Interleucina-8/genética , Proliferación Celular , Masculino , Células Estrelladas Hepáticas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
5.
Int J Mol Sci ; 25(5)2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38473925

RESUMEN

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21-3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC.


Asunto(s)
Trombosis de la Vena , Factor de von Willebrand , Humanos , Factor de von Willebrand/metabolismo , Vena Porta/metabolismo , Proteína ADAMTS13 , Pronóstico , Japón , Cirrosis Hepática/patología , Trombosis de la Vena/complicaciones , Biomarcadores
6.
Hepatol Res ; 53(8): 713-722, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37050844

RESUMEN

AIM: This study aimed to elucidate a surrogate marker of sarcopenia in patients with liver cirrhosis (LC). METHODS: A total of 424 patients were assessed for handgrip strength (HGS) and skeletal muscle index (SMI). They were divided into two groups: sarcopenia (Group S; n = 80) and nonsarcopenia (Group NS; n = 344). RESULTS: Group S showed significantly lower HGS, SMI, and hemoglobin (Hb) levels in males and female patients, and lower serum levels of albumin, cholinesterase, and zinc (all p < 0.001), along with significantly higher serum levels of procollagen type III-N-peptide and type IV collagen 7S-domain (p < 0.001 and p < 0.0017) than Group NS. The risk factors for sarcopenia were age 65 years or older, female gender, Child-Pugh class C, and Hb levels <10.9 g/dL in women and <12.4 g/dL in men (p = 0.012, p < 0.001, p = 0.031, and p < 0.001, respectively). Significant positive correlations were found between the Hb level and the SMI and HGS (r = 0.4, p < 0.001 and r = 0.4, p < 0.001, respectively). Sarcopenia, low HGS, and low SMI were significantly associated with overall survival in patients with LC (all p < 0.001). The predictive accuracy of Hb levels for predicting sarcopenia was significantly higher than for predicting SMI and tended to be higher than for predicting HGS (p = 0.014 and p = 0.059, respectively). CONCLUSION: Hemoglobin levels are predictive of sarcopenia in patients with LC and warrants further investigation as a biomarker for sarcopenia in LC.

7.
J Infect Chemother ; 29(1): 115-117, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36183991

RESUMEN

TRCReady® SARS-CoV-2 i is a reagent for transcription-reverse transcription concerted reaction (TRC) to detect SARS-CoV-2 N2 gene, used with the automated rapid isothermal nucleic acid amplification test (NAAT) analyzer TRCReady®-80. Sensitivity and specificity of TRCReady® SARS-CoV-2 i was assessed by comparison with the results of real-time reverse transcription-polymerase chain reaction (RT-PCR) using nasopharyngeal swab samples. From November 2020 to March 2021, a total of 441 nasopharyngeal swabs were obtained and analyzed both with TRCReady® SARS-CoV-2 i and RT-PCR. Sensitivity and specificity of TRCReady® SARS-CoV-2 i were 94.6% (53/56) and 99.2% (382/385), respectively. Reaction time to positivity of TRCReady® SARS-CoV-2 i ranged from 1.166 to 9.805 (median: 2.887) min, and minimum detection sensitivity of TRCReady® SARS-CoV-2 i was 9 copies per test, with reaction time as 5.014 min. Detection of SARS-CoV-2 gene from nasopharyngeal swab sample using TRCReady® SARS-CoV-2 i shows comparative diagnostic test accuracy with RT-PCR, and can be used as a useful test to diagnose SARS-CoV-2 infection.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Transcripción Reversa , Indicadores y Reactivos , Pruebas Diagnósticas de Rutina , Sensibilidad y Especificidad , Nasofaringe
8.
Nihon Shokakibyo Gakkai Zasshi ; 118(6): 562-570, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34108356

RESUMEN

Contrast medium-enhanced computed tomography revealed a mass in the liver of a 65-year-old man. The edge but not the center of the mass was enhanced. Ultrasonography-guided percutaneous needle biopsy revealed the diagnosis of angiosarcoma of the liver, and it was treated with chemotherapy. Angiosarcoma of the liver has various appearances on imaging and is not often diagnosed while patients are alive. If the tumor is difficult to diagnose by imaging and thought to be unresectable, a biopsy can help in guiding treatment, but treatment should be adapted with caution.


Asunto(s)
Hemangiosarcoma , Neoplasias Hepáticas , Anciano , Autopsia , Biopsia con Aguja , Hemangiosarcoma/diagnóstico por imagen , Humanos , Hígado , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Ultrasonografía
9.
J Radiol Prot ; 39(4): 1092-1104, 2019 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-31163409

RESUMEN

This paper describes an overview of the radiation protection response to the Plutonium intake accident that occurred at the Plutonium Fuel Facility of the Oarai Research and Development Center of the Japan Atomic Energy Agency on 6 June 2017. In the hood of the analyzing room at the Plutonium Fuel Facility five workers were checking a storage container of fast reactor nuclear fuel material. Around 11:15 a.m., vinyl bags inside the fuel material container containing Plutonium and enriched uranium burst during the inspection work. All the workers heard the bang, which caused misty dust leakage from the container. This event caused significant both skin and nasal α-contamination for three workers and just skin α-contamination for one worker. Decontamination was conducted in the shower room. Then the five workers were transferred to the Nuclear Fuel Cycle Engineering Laboratory to evaluate inhalation intake of Plutonium etc in the lungs. The maximum values of 2.2 × 104 Bq for 239Pu and 2.2 × 102 Bq for 241Am were estimated by the lung monitor. Based on these results, injection of a chelate agent was conducted for prompt excretion of Plutonium etc. The next morning, the five workers were transferred to the National Institute of Radiological Sciences for treatment including decontamination of their skin and measurement by a lung monitor. At that time no obvious energy peak was confirmed for Plutonium. The Japan Health Physics Society launched an ad-hoc working group for Plutonium intake accident around the middle of June to survey issues and to extract lessons for radiological protection. The authors, who are the members of the ad-hoc working group, here report the activity of the working group.

10.
J Radiol Prot ; 37(3): 659-683, 2017 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-28516892

RESUMEN

Since the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens of the eye in 2011, there have been extensive discussions in various countries. This paper reviews the current situation in radiation protection of the ocular lens and the discussions on the potential impact of the new lens dose limit in Japan. Topics include historical changes to the lens dose limit, the current situation with occupational lens exposures (e.g., in medical workers, nuclear workers, and Fukushima nuclear power plant workers) and measurements, and the current status of biological studies and epidemiological studies on radiation cataracts. Our focus is on the situation in Japan, but we believe such information sharing will be useful in many other countries.


Asunto(s)
Cristalino/efectos de la radiación , Exposición Profesional/normas , Dosis de Radiación , Traumatismos por Radiación/prevención & control , Relación Dosis-Respuesta en la Radiación , Humanos , Japón , Medición de Riesgo
11.
Am J Emerg Med ; 34(5): 825-9, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26883982

RESUMEN

INTRODUCTION: Plasma lactate concentration is known to increase after alcohol intake. However, this increase has rarely been analyzed quantitatively in emergency department (ED) settings. Evaluating plasma lactate elevation in ED patients after alcohol intake is important because it can affect patients' evaluation based on the plasma lactate level. METHODS: This study analyzed venous lactate concentrations of 196 continuous patients presented to our ED after alcohol intake. The control group comprised 219 successive ED patients without alcohol intake. Patients who had conditions that might induce lactate elevation were excluded from both groups. RESULTS: Venous lactate concentration was significantly higher in the alcohol intake group (2.83 mmol/L; 95% confidence interval, 2.69-2.96 mmol/L) than in the control group (1.65 mmol/L; 95% confidence interval, 1.53-1.77 mmol/L; P<.05). Lactate concentrations exceeding 3 mmol/L and exceeding 4 mmol/L were found, respectively, in 41.8% and 12.2% of the alcohol intake group compared with in 8.7% and 2.3% of the control group (P<.05). Lactate concentrations do not correlate with patients' level of consciousness. Therefore, a higher plasma ethanol level is apparently unrelated to elevated lactate. DISCUSSION AND CONCLUSION: Analyses show that plasma lactate concentration is significantly higher in ED patients after alcohol intake and to a greater degree than previously reported, even in patients without previously known alcohol-related diseases. Emergency department physicians must be careful when interpreting the lactate level of the patients with alcohol intake.


Asunto(s)
Consumo de Bebidas Alcohólicas/sangre , Servicio de Urgencia en Hospital , Ácido Láctico/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
12.
Cells ; 12(5)2023 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-36899823

RESUMEN

Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial-mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Animales , Ratones , Gemcitabina , Apoptosis , Línea Celular Tumoral , Puntos de Control de la Fase G2 del Ciclo Celular , Colangiocarcinoma/patología , Conductos Biliares Intrahepáticos/patología
13.
J Nutr Biochem ; 122: 109450, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37777163

RESUMEN

Endogenous lipopolysaccharide (LPS) that translocates via the disrupted intestinal barrier plays an essential role in the progression of alcohol-related liver disease (ALD). Vitamin D deficiency is observed in ALD, and it participates in regulating gut barrier function. The current study aimed to examine the association between vitamin D deficiency and endotoxemia in patients with ALD-related cirrhosis. Moreover, the effect of vitamin D deficiency on ethanol (EtOH)- and carbon tetrachloride (CCl4)-induced liver injury relevant to gut barrier disruption in mice was investigated. Patients with ALD-related cirrhosis (Child-Pugh Class A/B/C; n=56/15/7) had lower 25(OH)D levels and higher endotoxin activities than non-drinking healthy controls (n=19). The serum 25(OH)D levels were found to be negatively correlated with endotoxin activity (R=-0.481, P<.0001). The EtOH/CCl4-treated mice developed hepatic inflammation and fibrosis, which were significantly enhanced by vitamin D-deficient diet. Vitamin D deficiency enhanced gut hyperpermeability by inhibiting the intestinal expressions of tight junction proteins including ZO-1, occludin, and claudin-2/5/12/15 in the EtOH/CCl4-treated mice. Consequently, it promoted the accumulation of lipid peroxidases, increased the expression of NADPH oxidases, and induced Kupffer cell infiltration and LPS/toll-like receptor 4 signaling-mediated proinflammatory response. Based on the in vitro assay, vitamin D-mediated vitamin D receptor activation inhibited EtOH-stimulated paracellular permeability and the downregulation of tight junction proteins via the upregulation of caudal-type homeobox 1 in Caco-2 cells. Hence, vitamin D deficiency exacerbates the pathogenesis of ALD via gut barrier disruption and hepatic overload of LPS.


Asunto(s)
Hepatopatías , Deficiencia de Vitamina D , Humanos , Ratones , Animales , Endotoxinas/toxicidad , Lipopolisacáridos , Células CACO-2 , Etanol/toxicidad , Deficiencia de Vitamina D/complicaciones , Vitamina D , Proteínas de Uniones Estrechas
14.
Biochim Biophys Acta Mol Basis Dis ; 1869(7): 166770, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37276988

RESUMEN

A glucagon-like peptide-1 receptor agonist (GLP-1RA) has recently been established as a pharmacological option for the treatment of type 2 diabetes. Recent studies have demonstrated the molecular role of GLP-1R in skeletal muscle homeostasis; however, the therapeutic efficacy of semaglutide, a GLP-1RA, on skeletal muscle atrophy in chronic liver disease (CLD) under diabetic conditions remains unclear. In the present study, semaglutide effectively inhibited psoas muscle atrophy and suppressed declines in grip strength in a diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-fed diabetic KK-Ay mouse model. Moreover, semaglutide inhibited ubiquitin-proteosome-mediated skeletal muscle proteolysis and promoted myogenesis in palmitic acid (PA)-stimulated C2C12 murine myocytes. Mechanistically, this effect of semaglutide on skeletal muscle atrophy was mediated by multiple functional pathways. First, semaglutide protected against hepatic injury in mice accompanied by increased production of insulin-like growth factor 1 and reduced accumulation of reactive oxygen species (ROS). These effects were associated with decreased proinflammatory cytokines and ROS accumulation, leading to the suppression of ubiquitin-proteosome muscle degradation. Moreover, semaglutide inhibited the amino acid starvation-related stress signaling that was activated under chronic liver injury, resulting in the recovery of the mammalian target of rapamycin activity in the skeletal muscle of DDC-diet fed KK-Ay mice. Second, semaglutide improved skeletal muscle atrophy by directly stimulating GLP-1R in myocytes. Semaglutide induced cAMP-mediated activation of PKA and AKT, enhanced mitochondrial biogenesis, and reduced ROS accumulation, thereby resulting in inhibition of NF-κB/myostatin-mediated ubiquitin-proteosome degradation and the augmentation of heat-shock factor-1-mediated myogenesis. Collectively, semaglutide may have potential as a new therapeutic strategy for CLD-related skeletal muscle wasting.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hepatopatías , Ratones , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Hepatopatías/patología , Ubiquitinas/metabolismo , Mamíferos
15.
Biomedicines ; 11(5)2023 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-37238965

RESUMEN

The renin-angiotensin-aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-ß-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.

16.
In Vivo ; 37(3): 1226-1235, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37103093

RESUMEN

BACKGROUND/AIM: The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and refractory ascites, with a focus on changes in coagulation and fibrinolytic factors in ascitic fluid following CART. PATIENTS AND METHODS: This was a retrospective cohort study including 23 patients with refractory ascites undergoing CART. Serum endotoxin activity (EA) before and after CART and the levels of coagulation and fibrinolytic factors and proinflammatory cytokines in original and processed ascitic fluid were measured. The Ascites Symptom Inventory-7 (ASI-7) scale was used for subjective symptom assessment before and after CART. RESULTS: Body weight and waist circumference significantly decreased after CART, whereas serum EA did not significantly change after CART. Similar to the previous reports, ascitic fluid concentrations of total protein, albumin, high-density lipoprotein cholesterol, γ-globulin, and immunoglobulin G levels were significantly increased after CART; mild elevations in body temperature and interleukin 6 and tumor necrosis factor-alpha levels in ascitic fluid were also observed. Importantly, the levels of antithrombin-III, factor VII, and X, which are useful for patients with decompensated cirrhosis, were markedly increased in the reinfused fluid during CART. Finally, the total ASI-7 score was significantly lower following CART, compared with the pre-CART score. CONCLUSION: CART is an effective and safe approach for the treatment of refractory ascites that allows the intravenous reinfusion of coagulation and fibrinolytic factors in the filtered and concentrated ascites.


Asunto(s)
Ascitis , Líquido Ascítico , Humanos , Ascitis/terapia , Ascitis/metabolismo , Ascitis/patología , Estudios Retrospectivos , Japón , Líquido Ascítico/metabolismo , Cirrosis Hepática/complicaciones , Cirrosis Hepática/terapia , Cirrosis Hepática/metabolismo
17.
Diagnostics (Basel) ; 13(13)2023 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-37443613

RESUMEN

Alcohol is a major risk factor of liver cirrhosis (LC). This study aimed to elucidate a surrogate marker of sarcopenia in patients with LC of different etiology. Out of 775 patients with LC, 451 were assessed for handgrip strength and skeletal muscle mass (by computed tomography). They were then divided into two groups: alcoholic cirrhosis (AC; n = 149) and nonalcoholic cirrhosis (NAC; n = 302). Endotoxin activity (EA) levels were measured with an EA assay. Group AC showed significantly higher platelet counts (p = 0.027) and lower blood urea nitrogen levels and fibrosis-4 index than group NAC (p = 0.0020 and p = 0.038, respectively). The risk factors of sarcopenia were age ≥ 65 years, female sex, CP-C LC, Hb levels < 12 g/dL, and EA level > 0.4 in all patients with LC; hemoglobin (Hb) levels < 12 g/dL and EA level > 0.4 in group AC; and age ≥ 65 years, CP-C LC, and Hb levels < 12 g/dL in group NAC. The prediction accuracy of Hb for sarcopenia in group AC, group NAC, and all patients was 83.6%, 75.9%, and 78.1% (sensitivity: 92.0%, 69.0%, and 80.2%; specificity: 66.4%, 71.0%, and 64.0%), respectively. Although not significant, the predictive performance was better when using the combination of Hb and EA measurements than when using Hb alone in group AC but was comparable in all patients. Hb levels can predict sarcopenia in patients with LC, but in those with AC, the combination of Hb and EA improves the prediction performance.

18.
DEN Open ; 3(1): e177, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36304177

RESUMEN

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer. Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021. Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography. Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration.

19.
J Clin Med ; 11(7)2022 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-35407443

RESUMEN

ADAMTS13 specifically cleaves the multimeric von Willebrand factor (VWF), and an imbalance between ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) levels is associated with the severity of liver cirrhosis (LC). However, the reason for this imbalance in patients with LC is unknown. This study investigated the relationship among ADAMTS13:AC, VWF:Ag, and endotoxin (Et) levels in patients with LC. ADAMTS13:AC and VWF:Ag levels were determined using ELISA, whereas Et levels were estimated using a chromogenic substrate assay. The levels of ADAMTS13 inhibitor (ADAMTS13:INH) were evaluated by measuring the extent that heat-inactivated patient's plasma reduces the ADAMTS13:AC of the control. The status (degraded, normal, or unusually large [UL]) of the VWF multimer (VWFM) was determined through vertical agarose gel electrophoresis. ADAMTS13:AC, VWF:Ag, and Et levels decreased, increased, and increased, respectively, with the severity of LC. Patients with cirrhosis with high Et levels had lower and higher ADAMTS13:AC and VWF:Ag levels, respectively, than those with low Et levels. Patients with cirrhosis with detectable ADAMTS13:INH had higher Et levels than those with undetectable ADAMTS13:INH. Patients whose VWFM was either normal or UL had higher Et levels than those with degraded VWFM. In conclusion, ADAMTS13, VWF, and Et may be interrelated and associated with the severity of LC via hypercoagulability.

20.
Cancer Diagn Progn ; 2(2): 184-193, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35399181

RESUMEN

Background/Aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis. Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 µg/dl; n=38) and group with subclinical zinc deficiency (Group D: <80 µg/dl; n=113). The risk factors for sarcopenia were then investigated. Results: Group D had more sarcopenia cases than Group N (31.0% vs. 13.2%). In group D, HGS exhibited a weakly positive but significant correlation with serum zinc levels (R=0.287, p=0.00212), serum zinc levels negatively correlated with both ammonia and myostatin levels (R=-0.254, p=0.0078; R=-0.33, p<0.01), and low zinc levels were independently associated with sarcopenia development. Conclusion: Patients with cirrhosis showing subclinical zinc deficiency have a significantly higher risk of developing sarcopenia.

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