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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.
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Carcinoma Hepatocelular , Hepatitis C Crónica , Cirrosis Hepática Biliar , Neoplasias Hepáticas , Biomarcadores , Humanos , Medición de Riesgo , Transducción de Señal , Proteína smad3 , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH. METHODS: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured. RESULTS: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 µmol/L, P = 0.001). CONCLUSIONS: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.
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Ácidos Grasos Volátiles/metabolismo , Frutas , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Obesidad Abdominal/dietoterapia , Oligosacáridos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Oligosacáridos/farmacologíaRESUMEN
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.
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Understanding of the pathogenesis of nonalcoholic steatohepatitis (NASH)-associated fibrosis has been hampered by the lack of a comprehensive and physiological small animal model of NASH with fibrosis. Feeding a high-fat and high-cholesterol (HFC) diet supplemented with cholic acid to rats is known to replicate human NASH pathology, and it induces fibrosis earlier than with an HFC diet alone. In the present study, physiological and histopathological observations from 65 Sprague-Dawley (SD) rats fed an HFC diet with or without cholic acid for 9 or 18 weeks in our laboratory between January 2013 and February 2018 were retrospectively reviewed. The liver weight/body weight ratio at the end of the rearing period was higher in rats fed an HFC diet than in rats fed a normal diet in a cholesterol dose-, cholic acid dose-, or rearing period dependent manner. Dietary fat, cholesterol and/or cholic acid and rearing period affected the histopathologic severity of NASH. Overall, 56 (86.2%) of 65 SD rats fed an HFC diet for 9 or 18 weeks developed histopathologically proven NASH. It is noted that the SD rats fed an HFC diet supplemented with 2% (w/w) cholic acid for 18 weeks frequently developed advanced fibrosis, including cirrhosis. Thus, this diet-induced NASH rat model is likely to be a highly reproducible.
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Colesterol en la Dieta/toxicidad , Ácido Cólico/toxicidad , Grasas de la Dieta/toxicidad , Modelos Animales de Enfermedad , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Cirrosis Hepática Experimental/etiología , Cirrosis Hepática Experimental/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Nonalcoholic steatohepatitis (NASH), a subtype of nonalcoholic fatty liver disease (NAFLD), has a potentially progressive course that can lead to liver cirrhosis. Age is strongly associated with the development and progression of NAFLD/NASH, but the natural history of pediatric NAFLD is still not fully understood. Here, we evaluated the age-related alterations of NASH in 5-, 9- and 13-wk-old male Sprague-Dawley rats that were fed a high-fat and high-cholesterol diet (30% fat, 1.25% cholesterol and 0.5% sodium cholate, w/w) for 9 wk (6 rats/group). Our results showed that the cumulative energy intake, body weight gain and food efficacy during the 9-wk rearing period were highest in the youngest group and lowest in the oldest group. Serologically, almost all parameters including the serum triglyceride and total cholesterol were similar regardless of age. Histopathological findings, such as hepatic steatosis, lobular inflammation and hepatocyte ballooning, were also similar regardless of age, but hepatic fibrosis was more evident in the oldest group. Also, the mRNA expression levels of some fibrogenic, inflammatory, oxidative stress and cholesterol or lipid metabolism-related genes in the liver were highest in the oldest group and lowest in the youngest group, although the difference was not statistically significant. These results indicated that aging is likely associated with the development of NASH. Because the cumulative energy intake and daily food intake/body weight were not similar among groups in the present study, further studies designed with an equivalent daily food intake/body weight among groups are needed in order to interpret the exact nutritional effect.
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Envejecimiento/fisiología , Colesterol en la Dieta/efectos adversos , Dieta Alta en Grasa/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Animales , Colesterol en la Dieta/administración & dosificación , Ingestión de Alimentos , Ingestión de Energía , Expresión Génica , Inflamación/genética , Metabolismo de los Lípidos/genética , Lípidos/sangre , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico/etiología , Estrés Oxidativo/genética , Ratas , Ratas Sprague-DawleyRESUMEN
The changes in free amino acid (AA) levels in blood during the progression from non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) are unclear. We investigated serum AA levels, along with biochemical and histological events, in a mouse model of NASH. We induced NASH in male C57BL/6J mice with a streptozotocin injection and high-fat diet after 4 weeks of age (STAM group). We chronologically (6, 8, 10, 12, and 16 weeks, n=4-12 mice/group) evaluated the progression from steatohepatitis to HCC by biochemical and histological analyses. The serum AA levels were determined using an AA analyzer. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in the STAM group than in the normal group (non-NASH-induced mice). Histological analysis revealed that STAM mice had fatty liver, NASH, and fibrosis at 6, 8, and 10 weeks, respectively. Moreover, the mice exhibited fibrosis and HCC at 16 weeks. The serum branched-chain AA levels were higher in the STAM group than in the normal group, especially at 8 and 10 weeks. The Fischer ratio decreased at 16 weeks in the STAM group, with increasing aromatic AA levels. These results suggested that this model sequentially depicts the development of fatty liver, NASH, cirrhosis, HCC, and AA metabolism disorders within a short experimental period. Additionally, serum amyloid A was suggested to be a useful inflammation biomarker associated with NASH. We believe that the STAM model will be useful for studying AA metabolism and/or pharmacological effects in NASH.
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Aminoácidos/sangre , Carcinoma Hepatocelular/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Suero/química , Animales , Biomarcadores/metabolismo , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/etiología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Estreptozocina/farmacología , Factores de TiempoRESUMEN
We present a sensitive and selective method for the simultaneous determination of short-chain fatty acids (SCFAs), such as acetic acid (AA), propionic acid, butyric acid (BA), isobutyric acid, valeric acid, isovaleric acid, hydroangelic acid, caproic acid, 4-methylvaleric acid and succinic acid (SA) in feces samples using a ultra-high performance liquid-chromatography tandem mass spectrometry (UHPLC-MS/MS) with simple derivatization of 2-picolylamine. The main SFCAs were derivatized in the same condition, and showed the specific product ion (m/z 109) in the electrospray positive mode regarding to 2-picolylamine. The derivatized SA showed a different pattern of the product ion (m/z 191). The derivatized analytes showed LOD < 75 nM, LOQ < 100 nM and r2 in the calibration curve > 0.991. The QuEChERS was used for sample preparation of feces samples. In the recovery test, the recovery values appeared from 89.7 to 100.2% (RSD: 2.1 to 9.2%, n = 6). This developed method was applied to evaluate obese diabetes model mice. In the result, the branched-chain SCFAs levels in feces from model mice of spontaneous obese type II diabetes were on a declining trend compared with normal. The AA levels from model mice with high-calorie/fat diet are owed a declining trend for 3 to 9 months. The BA levels showed that normal mice were increasing, and model mice had decreased tendency for breeding months. High-calorie/fat diet showed that the SA levels increased.
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Cromatografía Líquida de Alta Presión/métodos , Ácidos Grasos Volátiles/análisis , Heces/química , Espectrometría de Masas en Tándem/métodos , Métodos Analíticos de la Preparación de la Muestra , Animales , Ácidos Grasos Volátiles/química , RatonesRESUMEN
BACKGROUND: Established treatments for non-alcoholic steatohepatitis (NASH) are few, thus it is imperative to develop novel dietary strategies that can prevent NASH. A fermented mixed tea (FMT) made with Camellia japonica (Japanese camellia) and third- crop green tea leaves by tea-rolling processing was reported to reduce body weight and adipose tissue weight in Sprague-Dawley (SD) rats. Because visceral fat is one of the most important factors for the development of hepatic steatosis, this FMT supplementation can be a candidate dietary strategy for the prevention of NASH. METHODS: Nine-week-old male SD rats were fed a high-fat and high-cholesterol (HFC) diets with or without FMT (camellia and third-crop green tea leaves at ratios of 1:5, 1:2 and 1:1) for 9 weeks (n=6-7/group). Histopathology, serology and expressions of fibrogenetic, proinflammatory, oxidative stress and lipid metabolism-related genes in the liver were evaluated. RESULTS: Histologically, HFC diet with FMT at a ratio of 1:5 dramatically reduced NASH progression (14%) compared to the HFC diet without FMT (100%). FMT at a ratio of 1:5 reduced hepatic steatosis due to the activation of microsomal triglyceride transfer protein, and FMT at a ratio of 1:2 reduced mRNA levels of some proinflammatory, lipid metabolism-related, fibrogenic and oxidative stress marker genes. CONCLUSIONS: Our data suggest that FMT at a ratio of 1:5 or 1:2 likely possesses a preventive effect on NASH progression.
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Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo-oligosaccharides on intestinal barrier function and steatohepatitis in methionine-choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine-choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short-chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides.
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Deficiencia de Colina , Modelos Animales de Enfermedad , Intestinos/fisiología , Metionina/deficiencia , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Oligosacáridos/administración & dosificación , Animales , Suplementos Dietéticos , Intestinos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/patología , Prebióticos/administración & dosificaciónRESUMEN
Osteoporosis is a bone disease that poses a tremendous burden to health care. The receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) have been a major focus of this research field. RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also adjusts bone homeostasis both in normal physiology and in bone disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various bone diseases such as osteoporosis. Osteoclasts are the exclusive cells involved in bone resorption. Abnormal activation of osteoclasts can lead to reduced bone density, resulting in osteopenia, osteoporosis and other bone disorders. To date, the mechanism of how osteoclast precursors differentiate into mature osteoclasts remains elusive. Cell proliferation and cell death may be key processes in the progression as well as other cell types. Oncogene products and tumor-suppressor molecules play a pivotal role in regulating the processes, which are important in regulating the configuration of bone disorders. Based on the understanding of these processes, promising alternatives to the use of medications against osteoporosis include specific diets with plant-derived supplements to modulate the expression and/or activity of these molecules. In this review, we summarize the progress of research with a focus on the modulatory roles of oncogene products and tumor-suppressor molecules and suggest the scope of further research concerning the prevention of osteoporosis in this field.
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Resorción Ósea/genética , Regulación de la Expresión Génica , Genes Supresores de Tumor , Oncogenes , Osteoclastos/metabolismo , Animales , Humanos , Osteoporosis/dietoterapia , Osteoporosis/genética , Osteoporosis/metabolismo , Transducción de SeñalRESUMEN
Mitochondrial dysfunction is involved in the pathology of Parkinson's disease, an age-associated neurodegenerative disorder. Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1) is responsible for the most common form of recessive Parkinson's disease. PINK1 is a mitochondrial kinase that is involved in mitrochondrial quality control and promotes cell survival. PINK1 has been shown to protect against neuronal cell death induced by oxidative stress. Accordingly, PINK1 deficiency is associated with mitochondrial dysfunction as well as increased oxidative cellular stress and subsequent neuronal cell death. In addition, several mitochondrial chaperone proteins have been shown to be substrates of the PINK1 kinase. In this review, we discuss recent studies concerning the signaling cascades and molecular mechanisms involved in the process of mitophagy, which is implicated in neurodegeneration and in related aging associated with oxidative stress. Particular attention will be given to the molecular mechanisms proposed to explain the effects of natural compounds and/or food ingredients against oxidative stress. Knowledge of the molecular mechanisms involved in this cellular protection could be critical for developing treatments to prevent and control excessive progression of neurodegenerative disorders.
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Envejecimiento/metabolismo , Homeostasis , Mitocondrias/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal , Dieta , HumanosRESUMEN
Certain modified diets containing saturated fatty acids, cholesterol or fructose lead to the development of nonalcoholic steatohepatitis (NASH)-related fibrosis in rodents; however, progression to cirrhosis is rare. Experimental liver cirrhosis models have relied on genetic manipulation or administration of hepatotoxins. This study aimed to establish a reliable dietary model of NASH-related cirrhosis in a relatively short period. Male Sprague-Dawley rats (9 weeks of age) were randomly assigned to normal, high-fat (HF), or two types (1.25% or 2.5% cholesterol) of high-fat and high-cholesterol (HFC) diets for 18 weeks. All HFC diets contained 2% cholic acid by weight. Histopathological analysis revealed that the HFC diets induced obvious hepatic steatosis, inflammation with hepatocyte ballooning and advanced fibrosis (stage 3-4) in all 12 rats at 27 weeks of age. In contrast, all five rats given the HF diet developed mild steatosis and inflammation without fibrosis. The amount of cholesterol in the liver and hepatocellular mitochondrial and microsomal fractions was significantly higher in rats fed the HFC diets than the normal or HF diets. The HFC diets significantly suppressed mRNA levels of microsomal triglyceride transfer protein, adenosine triphosphate binding cassette transporter G5, bile acid CoA: amino acid N-acyltransferase and bile salt export pump, as well as the enzymatic activity of carnitine palmitoyltransferase in the liver. In conclusion, the HFC diets induced liver cirrhosis in conjunction with hepatic features of NASH in Sprague-Dawley rats within 18 weeks, and altered gene expression and enzyme activity to accumulate lipid and bile acid in the liver.
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Colesterol en la Dieta/efectos adversos , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Peso Corporal , Colesterol/sangre , Modelos Animales de Enfermedad , Enzimas/metabolismo , Regulación de la Expresión Génica , Hígado/metabolismo , Masculino , Tamaño de los Órganos , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
Parkinson's disease (PD) is a common progressive and multifactorial neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons. Numerous pathological processes including, inflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalance, and apoptosis as well as genetic factors may lead to neuronal degeneration. Motor deficits in PD are due mostly to the progressive loss of nigrostriatal dopaminergic neurons. Neuroprotection of functional neurons is of significance in the treatment of PD. G proteincoupled receptors (GPCRs) have been implicated in the neuroprotection against PD through the survival of dopaminergic neurons. In addition, phosphatidylinositol3kinase (PI3K)/AKT signaling has also been demonstrated to be neuroprotective. Knowledge of the mechanisms involved in this cellular protection could be critical for developing treatments to prevent this neurodegenerative disorder. In this review, we highlight the protective roles of the PI3K/AKT signaling pathway in the function of representative serotonin GPCRs. Particular attention is given to the molecular mechanisms of this pathway proposed to explain the favorable effects of food ingredients against neurodegenerative disease.
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Enfermedad de Parkinson/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Neuronas Dopaminérgicas/metabolismo , Humanos , Proteínas de Unión al GTP Monoméricas/metabolismo , Degeneración Nerviosa/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores , Serotonina/metabolismo , Transducción de SeñalRESUMEN
Due to the key role in various cellular processes including cell proliferation and cell survival on many cell types, dysregulation of the PI3K/AKT pathway represents a crucial step of the pathogenesis in many diseases. Furthermore, the tumor suppressor PTEN negatively regulates the PI3K/AKT pathway through its lipid phosphatase activity, which is recognized as one of the most frequently deleted and/or mutated genes in human cancer. Given the pervasive involvement of this pathway, the development of the molecules that modulate this PI3K/AKT signaling has been initiated in studies which focus on the extensive effective drug discovery. Consequently, the PI3K/AKT pathway appears to be an attractive pharmacological target both for cancer therapy and for neurological protection necessary after the therapy. A better understanding of the molecular relations could reveal new targets for treatment development. We review recent studies on the features of PI3K/AKT and PTEN, and their pleiotropic functions relevant to the signaling pathways involved in cancer progress and in neuronal damage by the therapy.
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Encefalopatías/tratamiento farmacológico , Terapia Combinada/efectos adversos , Neoplasias/terapia , Neuroprotección/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Encefalopatías/enzimología , Encefalopatías/etiología , Humanos , Terapia Molecular Dirigida , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson's disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of neuronal tissues. Recent evidence suggests that PTEN (phosphatase and tensin homolog on chromosome 10) may be involved in the pathophysiology of the neurodegenerative disorders. Since PTEN expression appears to be one dominant determinant of the neuronal cell death, PTEN should be a potential molecular target of novel therapeutic strategies against Parkinson's disease. In addition, defects in DNA damage response and DNA repair are often associated with modulation of hormone signaling pathways. Especially, many observations imply a role for estrogen in a regulation of the DNA repair action. In the present review, we have attempted to summarize the function of DNA repair molecules at a viewpoint of the PTEN signaling pathway and the hormone related functional modulation of cells, providing a broad interpretation on the molecular mechanisms for treatment of Parkinson's disease. Particular attention will be paid to the mechanisms proposed to explain the health effects of food ingredients against Parkinson's disease related to reduce oxidative stress for an efficient therapeutic intervention.
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Reparación del ADN , Fosfohidrolasa PTEN/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Supervivencia Celular/genética , Daño del ADN , Dieta , Estrógenos/metabolismo , Humanos , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Estrés Oxidativo , Enfermedad de Parkinson/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/metabolismo , Transducción de SeñalRESUMEN
AIM: The development of fibrosis is considered an important phase in the progress of non-alcoholic steatohepatitis (NASH) towards the end stage of liver disease, including cirrhosis. However, few small animal models can display NASH-associated fibrosis. We aimed to establish a dietary model of NASH with rapid progression to fibrosis using genetically normal rats. METHODS: Nine-week-old male Sprague-Dawley rats were fed with normal, high-fat (HF), or two types of high-fat and high-cholesterol (HFC) diets for 9 weeks (n = 5 each). All HFC diets contained 1.25% or 2.5% cholesterol. RESULTS: The rats fed with the HF diet developed mild steatosis and inflammation without fibrosis at 18 weeks of age, whereas all rats given the HFC diet developed obvious steatosis and inflammation with hepatocyte ballooning and fibrosis. Two of five (40%) rats given the HFC diet containing 2.5% cholesterol progressed to liver cirrhosis. Hepatic total cholesterol levels were significantly higher in rats given the HFC, than the normal or HF diets. The HFC diet significantly and dose-dependently decreased microsomal triglyceride transfer protein expression. Cholesterol tended to suppress carnitine palmitoyltransferase activity and adenosine triphosphate-binding cassette transporter G5 expression. Adding cholesterol to the HF diet modified hepatic lipid metabolism at the molecular level. CONCLUSION: The HFC diet induced hepatic features of NASH and eventually progressed cirrhosis in Sprague-Dawley rats within 9 weeks.
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Depression has been reported to be more prevalent among diabetic patients than non-diabetic individuals. Although depression and diabetes are causally and bi-directionally related, the influence of food intake frequency on depressive symptoms in diabetic patients has not been fully evaluated. This cross-sectional study analyzed data obtained from 89 patients with type 2 diabetes who completed self-administered questionnaires regarding food intake frequency, diabetic variables, physical activity and depressive states. The prevalence of a "definite" depressive state was 16.9%. The duration of diabetes, hemoglobin A1c levels, diabetic microvascular complications and physical activity levels were similar between depressed and non-depressed patients. Daily intakes of total lipids, n-6 polyunsaturated fatty acids and lipid energy ratios were significantly lower, and the carbohydrate energy ratio was significantly higher in depressed than in non-depressed patients. Coffee consumption was inversely associated with depressive symptoms, but no significant association was found between tea or green tea consumption and depressive symptoms. The logistic regression analysis showed that coffee consumption was an independent predictor of non-depressed status in diabetic patients. This might be due to biologically active compounds containing in coffee other than caffeine.
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OBJECTIVE: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. The pathogenesis of IBS is multifactorial. The aim of this study was to investigate the prevalence of IBS using the Rome III criteria in young Japanese women and to assess the effects of mental, physical, dietary and nutritional factors on IBS. METHODS: In this cross-sectional study, data obtained from self-administered questionnaires, including age, height, weight, lifestyle, food habits, anxiety and depressive states and IBS-related symptoms, were analyzed in 245 participants. An established semiquantitative questionnaire available for clinical investigation (FFQg) was used to obtain a detailed assessment of food intake and the physical activity levels. RESULTS: The prevalence of IBS was 12.0%. Of the IBS participants, constipation-predominant IBS (25.0%) was more prevalent than the diarrhea-predominant subtype (17.9%). The IBS participants had lower body mass indices, consumed less eggs and milk and were more physically active than the non-IBS participants. In addition, an anxiety state was more common in the IBS participants. Those who hesitated with evacuation of stool and who thought that there is an association between abdominal symptoms, such as constipation and diarrhea, and menstruation were more predominant among the IBS participants. The percentage of individuals who reported often rushing to the toilet within the past year and experiencing borborygmus (rumbling stomach) was greater among the IBS participants. A logistic regression analysis revealed that milk intake was an independent predictor of IBS. CONCLUSION: The prevalence of IBS observed in this study was similar to that reported in previous studies conducted in Japan and other countries. Mental, physical, dietary and nutritional factors have an impact on IBS.
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Síndrome del Colon Irritable/etiología , Adolescente , Adulto , Animales , Ansiedad/complicaciones , Pueblo Asiatico , Estudios Transversales , Depresión/complicaciones , Dieta/efectos adversos , Femenino , Humanos , Síndrome del Colon Irritable/epidemiología , Japón/epidemiología , Estilo de Vida , Modelos Logísticos , Leche/efectos adversos , Actividad Motora , Prevalencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Endothelial dysfunction is associated with hypertension, atherosclerosis, and metabolic syndrome. Phycocyanin is a pigment found in the blue-green algae, Spirulina, which possesses antihypertensive effect. In this study, we hypothesized that phycocyanin derived from Spirulina exerts antihypertensive actions by improving endothelial dysfunction in metabolic syndrome. Spontaneously hypertensive/NIH-corpulent (SHR/NDmcr-cp) rats were divided into 4 groups then fed a normal diet with or without phycocyanin (2500-, 5000-, or 10,000-mg/kg diet) for 25 weeks. At 34 weeks of age, although systolic blood pressure was not significantly different among groups, phycocyanin-fed groups exhibited a dose-dependent decrease in blood pressure. Serum levels of adiponectin and messenger RNA levels of adiponectin and CCAAT/enhancer-binding protein α in the adipose tissue of rats fed diets containing phycocyanin tended to be higher than those of rats fed a normal diet, but the differences were not statistically significant. Immunohistochemistry analysis showed a significant and positive correlation between aortic endothelial nitric oxide synthase (eNOS) expression levels, a downstream target of the adiponectin receptor, and serum adiponectin levels, although there were no significant differences in eNOS expression among groups. There was also no significant correlation between eNOS expression levels and systolic blood pressure. These results suggest that long-term administration of phycocyanin may ameliorate systemic blood pressure by enhancing eNOS expression in aorta that is stimulated by adiponectin. Phycocyanin may be beneficial for preventing endothelial dysfunction-related diseases in metabolic syndrome.
Asunto(s)
Adiponectina/sangre , Antihipertensivos/farmacología , Hipertensión/prevención & control , Síndrome Metabólico/sangre , Ficocianina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Cianobacterias/química , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Ingestión de Energía , Hipertensión/fisiopatología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Receptores de Adiponectina/efectos de los fármacosRESUMEN
Serum alanine aminotransferase (ALT) concentration is the most commonly used marker for hepatocellular injury. We investigated the suitable cutoff value of serum ALT for the diagnosis or prediction of fatty liver. In 1578 Japanese adults (1208 men, 370 women; 35-69 years of age) who visited our center both in 2000 and between April 2007 and March 2008 (2007-2008), serum ALT concentration was an independent predictor of fatty liver in men in 2000 and in both sexes in 2007-2008. A significant increase in the frequency of fatty liver was detected in participants with elevated serum ALT concentrations, and serum levels of ALT in 2000 were associated with fatty liver in 2007-2008 when the cutoff value was set at 30 IU/L in men and 19 IU/L in women. The frequency of fatty liver in 2007-2008 was significantly lower in participants without fatty liver in 2000 whose serum ALT decreased between 2000 and 2007-2008. Our results suggest that serum ALT might be not only an indicator of fatty liver but also a predictor of the regression of fatty liver, and cutoff values of serum ALT of 30 IU/L in men and 19 IU/L in women are suitable for the screening of fatty liver.