Alterations in the Transcriptional Profile of the Liver Tissue and the Therapeutic Effects of Propolis Extracts in Alcohol-induced Steatosis in Rats.

The hepatoprotective effects of the ethanolic extracts of propolis (EEP) on alcohol-induced liver steatosis were investigated in Wistar rats. Chronic alcoholic fatty liver was induced by administration of 52% alcohol to male Wistar rats at the dose of 1% body weight for 7 weeks. Then animals were simultaneously treated with 50% ethanol solutions of EEP or normal saline at the dose of 0.1% body weight for 4 further weeks. Serological analyses and liver histopathology studies were performed to investigate the development of steatosis. Microarray analysis was conducted to investigate the alterations of hepatic gene expression profiling. Our results showed that 4-week treatment of EEP helped to restore the levels of various blood indices, liver function enzymes and the histopathology of liver tissue to normal levels. Results from the microarray analysis revealed that the hepatic expressions of genes involved in lipogenesis were significantly down-regulated by EEP treatment, while the transcriptional expressions of functional genes participating in fatty acids oxidation were markedly increased. The ability of EEP to reduce the negative effects of alcohol on liver makes propolis a potential natural product for the alternative treatment of alcoholic fatty liver.

Correlation Between Radiographic Area and Immunolocation of MMP-2 and MMP-9 in Unilocular Radiographic Lesions

Unilocular bone cysts are the most common entities affecting the maxillofacial region. The mechanism of proliferation and expansion remains unclear. Metalloproteinases (MMPs) are associated to diverse pathological conditions. The aim of the present study was to correlate the radiographic aspect (area) and the presence of MMP-2 and MMP-9 in dentigerous cysts, radicular cysts and keratocystic odontogenic tumors. The radiographic area of each lesion was calculated using the mathematical formula of the ellipse area. All specimens were subjected to immunohistochemical analysis for these enzymes. The average radiographic area was 284.17 mm2, 235.81 mm2 and 381.81 mm2, respectively. Statistical analyses revealed no association between the immunoreactivity of MMPs and radiographic area of the lesions in all pathologies studied, except for MMP-2 and radicular cysts, for which smaller lesions had increased immunostaining for this enzyme. The results demonstrate that quantities of MMP-2 and MMP-9 are especially involved with dentigerous and radicular cysts in expansion, whereas these enzymes seem to be related to the biological behavior of keratocystic odontogenic tumors, indicating invasion and cell proliferation. Moreover, there is an inverse association between MMP-2 and MMP-9 in keratocystic odontogenic tumors (p=0.03; rs=-0.660), indicating activity in different regions.

Cistos ósseos uniloculares são as entidades mais comuns que afetam a região maxilofacial. O mecanismo de proliferação e expansão permanece obscuro. As metaloproteinases (MMPs) estão associadas a diversas condições patológicas. O objetivo do presente estudo foi correlacionar o aspecto radiográfico (área) e a presença de MMP-2 e MMP-9 em cistos dentígeros, cistos radiculares e tumores odontogênicos queratocísticos. A área radiográfica de cada lesão foi calculada usando a fórmula matemática da área de elipse. Todas as amostras foram submetidas à análise imunoistoquímica para estas enzimas. A área radiográfica média foi de 284,17 mm2, 235,81 mm2 e 381,81 mm2, respectivamente. As análises estatísticas não mostraram associação entre a imunorreatividade de MMPs e área radiográfica das lesões em todas as patologias estudadas, exceto para MMP-2 e cistos radiculares, nas quais as lesões menores tinham maior imunomarcação para esta enzima. Os resultados demonstraram que a quantidade de imunomarcação da MMP-2 e MMP-9 estão envolvidos com cistos dentígeros e radiculares na expansão óssea, ao passo que estas enzimas parecem estar relacionados com o comportamento biológico dos tumores odontogénicos queratocísticos, indicando invasão e proliferação celular. Além disso, há uma relação inversa entre a MMP-2 e MMP-9 em tumores odontogénicos queratocísticos (p=0,03; rs= -0,660), indicando atividade em diferentes regiões.

The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice.

BACKGROUND AND AIM: Excessive ethanol consumption can lead to development of hepatic steatosis. Since the FXR receptor regulates adipose cell function and liver lipid metabolism, the aim of this work was to examine the effects of the FXR agonist 6ECDCA on alcoholic liver steatosis development and on oxidative stress induced by ethanol consumption. METHODS: Swiss mice (n=24) received a low-protein diet (6%) and a liquid diet containing 10% ethanol or water for 6weeks. In the last 15days mice received oral treatment with 6ECDCA (3mgkg(-1)) or 1% tween (vehicle). The experimental groups (n=6) were: water+tween, water+6ECDCA, ethanol+tween and ethanol+6ECDCA. Moreover, as a diet control, we used a basal group (n=6), fed by a normal-proteic diet (23%) and water. After the treatment period, the animals were anesthetized for sample collection to perform plasma biochemistry assays, hepatic oxidative stress assays, hepatic cholesterol and triglycerides measurements, liver histology and hepatic gene expression. RESULTS: Ethanol associated with low-protein diet induced hepatic oxidative stress, increased plasma transaminases and induced hepatic lipid accumulation. Many of these parameters were reversed by the administration of 6ECDCA, including amelioration of lipid accumulation and lipoperoxidation, and reduction of reactive oxygen species. These effects were possibly mediated by regulation of Srebpf1 and FAS gene expression, both reduced by the FXR agonist. CONCLUSIONS: Our data demonstrated that 6ECDCA reverses the accumulation of lipids in the liver and decreases the oxidative stress induced by ethanol and low-protein diet. This FXR agonist is promising as a potential therapy for alcoholic liver steatosis.

Treatment of alcoholic liver disease.

Alcoholic Liver Disease (ALD) is a major cause of morbidity and mortality both in the United States and worldwide. In the United States, it is projected that over 2,000,000 persons have ALD, and the mortality for cirrhosis with superimposed alcoholic hepatitis is much worse than that of many common types of cancer. Unfortunately, there is no FDA approved therapy for ALD. We have made major strides in the last decade in identifying mechanisms for the development of liver injury in ALD, and therapies are evolving directed at specific mechanisms. It is clear that life style modification with abstinence, cessation of smoking and weight loss (if overweight) are beneficial. It is also clear that most patients with advanced liver disease have some form of malnutrition, and nutritional supplementation is of benefit. Patients with alcoholic hepatitis that is relatively severe in nature, but not complicated by issues such as infection or GI bleeding, appear to benefit from steroids. A drop in bilirubin should be monitored in steroid treated patients. Pentoxifylline appears to be beneficial in patients with alcoholic hepatitis, especially those with early hepatorenal syndrome. A variety of other agents such as PTU, lecithin, colchicine, and anabolic steroids are probably not effective. Complementary and alternative medicine agents such as zinc, milk thistle, and SAM have great therapeutic rationale. Results of ongoing NIH studies evaluating agents such as specific anti-TNF's, SAM and Milk Thistle are eagerly awaited. Transplantation is clearly an option for end stage ALD in patients who are abstinent.

Colchicina na doença hepática crônica de etiologia alcoólica. Estudo duplo-cego, randomizado, de seus efeitos sobre os níveis séricos das proteínas plasmáticas e evoluçäo clínica dos pacientes / Colchicine in chronic liver disease of alcoholic etiology. Double-blind, randomized study of its effects on the serum levels of plasma proteins and clinical evolution of the patients

Pacientes portadores de hepatopatia crônica de etiologia alcoólica, quando tratados com colchicina durante período de 12 meses, apresentaram índices de recuperaçäo dos níveis plasmáticos de albumina e protrombina significantemente superiores aos de pacientes fazendo uso de placebo. Entretanto, nenhuma diferença estatística pôde ser observada entre os dois grupos quanto à taxa de mortalidade e de admissäo hospitalar dos pacientes, no período estudado. OBJETIVO. Analisar a evoluçäo clínica e os níveis plasmáticos de albumina, pré-albumina, transferrina e protrombina em portadores de hepatopatia crônica alcoólicaem uso de colchicina ou placebo, durante período de 12 meses. MÉTODOS. em um estudo duplo-cego, 41 pacientes portadores de hepatopatia crônica de etiologia alcoólica foram randomizados para receber placebo (20 pacientes) ou colchicina (21 pacientes), avaliando sua evoluçäo clínica e dos níveis das proteínas plasmáticasalbumina, pré-albumina e transferrina por imunodifusäo radial e do tempo e atividade de protrombina pelo método de Quick modificado. RESULTADOS. Apenas 7,3 por cento dos pacientes näo completaram os 12 meses de seguimento do estudo. Näo se observaram diferenças significantes entre os grupos, no que se refere à taxa de mortalidade ou ao número de internaçöes hospitalares. Quanto aos níveis séricos protéicos, observaram-se valores significantemente superiores no grupo da colchicina do que no grupo placebo, para as médias das variaçöes percentuais dos níveis de albumina (17,9 por cento colchicina x 3,6 por cento placebo, p<0,05) e da atividade de protrombina (19,2 por cento colchicina x 2,1 por cento placebo, p<0,05). As variaçöes dos valores da pré-albumina, apesar de apresentarem o mesmo comportamento observado para os níveis de albumina e protrombina, näo atingiram significância estatística. Já os níveis de transferrina sérica näo diferiram entreos dois grupos. CONCLUSÄO. Estes resultados sugerem que a administraçäo de colchicina tenha um efeito benéfico sobre os níveis de proteínas plasmáticas nos pacientes com hepatopatia crônica de etiologia alcoólica.

[Colchicine in chronic liver disease of alcoholic etiology. Double-blind, randomized study of its effects on blood levels of plasma proteins and clinical course in patients]. / Colchicina na doença hepática crônica de etiologia alcoólica. Estudo duplo-cego, randomizado, de seus efeitos sobre os níveis séricos das proteínas plasmáticas e evolução clínica dos pacientes.

UNLABELLED: Patients with alcoholic chronic liver disease when treated with colchicine during a 12 month-period improved significantly the plasmatic levels of albumin and prothrombin when compared with a similar group of patients who took placebo. No differences in the mortality rate and in number of patients admitted at the hospital could be detected among those groups during this period. PURPOSE: To evaluate the clinical outcome and the plasmatic levels of albumin, pre-albumin, prothrombin and transferrin in patients presenting alcoholic chronic liver disease taking colchicine or placebo, during a 12-month period. METHODS: In a double-blind, randomized, controlled trial, 41 patients with alcoholic chronic liver disease were assigned to either placebo (20 patients) or a colchicine (21 patients) treatment group, assessing their clinical course (mortality rate and hospital admission) and plasmatic protein levels during a 12-month period. Albumin, pre-albumin and transferrin plasmatic levels were assessed through a immunodiffusion radial method and prothrombin time and activity was assessed by a one stage Quick modified method. RESULTS: At the end of the trial, only 7.3% of the patients were lost during follow-up. No statistical differences could be found in mortality and number of patients admitted at the hospital among placebo and colchicine groups. Comparatively to the placebo group, a significant increase in the mean of percentage variation was found in patients of the colchicine group for serum albumin levels (17.9% colchicine x 3.6% placebo, p < 0.05) and for prothrombin activity (19.2% colchicine x 2.1% placebo, p < 0.05). A similar pattern of response was found in pre-albumin serum levels, but such differences were not statistically different. No differences were found in serum transferrin levels among both groups. CONCLUSION: These results suggest that colchicine intake has a positive effect on plasmatic protein levels in patients with alcoholic chronic liver disease.

[Controlled study of the effect of silymarin on alcoholic liver disease]. / Estudio controlado sobre el efecto de la silimarina en la enfermedad hepática alcohólica.

A controlled trial on the use of Silymarin in patients with alcoholic liver disease was performed. Seventy two patients were admitted to the trial and randomly assigned to an experimental or controls group. Experimentals received 280 mg/day of Silymarin and controls an equal number of placebo tablets. Three patients on placebo and nine on Silymarin were lost from control (p = 0.035), remaining in control 34 patients receiving placebo and 25 patients receiving the drug. Both groups did not differ in their initial laboratory assessment and were followed up for an average of 15 months. Ten patients died during the follow up (5 in placebo and 5 in Silymarin); life table analysis did not show significant differences in mortality. Patients who died had lower serum albumin and prothrombin time and higher total bilirubin, alkaline phosphatases and CCLI on the initial clinical and laboratory assessment. Final laboratory values and their changes in those who survived did not differ between Silymarin and placebo. Twenty two patients on placebo (65%) and 14 on Silymarin (58%) recognized alcohol ingestion or had a positive urine sample analysis for alcohol during follow up. Those who abstained from alcohol had a significant fall in gamma glutamyl transferase during follow up. No other significant differences were observed between these two groups. It is concluded that in this trial, Silymarin did not change the evolution or mortality of alcoholic liver disease.

Acción de la SAMe en hepatopatía alcohólica / Effect of SAMe in alcoholic liver disease

Se presenta una experiencia en el tratamiento de la hepatopatia alcohólica con sulfo-adenosil-L-metionina (SAMe). La misma, se efectuó en un grupo de 20 pacientes durante 60 días y en una dosis de 200 mg/día de SAMe (i.m.) durante 30 días y 100 mg/día los 30 restantes. La respuesta clínica, valorada en forma subjetiva, evidenció una mejoría en el apetito, la astenia y la respuesta intelectual. Desde el punto de vista analítico se observaron mejorías significativas (p < .05 en adelante) en la gamaGT, TGP, TGO, bilirrubinemia, tiempo de Quick y colesterolemia. Los autores concluyen que la SAMe constituye un elemento terapéutico en la hepatopatía alcohólica, permitiendo una mejoría de la función hepática expresada mediante la clínica y las pruebas de síntesis proteica, de necrosis y de colestasis

Acción de la SAMe en hepatopatía alcohólica / Effect of SAMe in alcoholic liver disease

Se presenta una experiencia en el tratamiento de la hepatopatia alcohólica con sulfo-adenosil-L-metionina (SAMe). La misma, se efectuó en un grupo de 20 pacientes durante 60 días y en una dosis de 200 mg/día de SAMe (i.m.) durante 30 días y 100 mg/día los 30 restantes. La respuesta clínica, valorada en forma subjetiva, evidenció una mejoría en el apetito, la astenia y la respuesta intelectual. Desde el punto de vista analítico se observaron mejorías significativas (p < .05 en adelante) en la gamaGT, TGP, TGO, bilirrubinemia, tiempo de Quick y colesterolemia. Los autores concluyen que la SAMe constituye un elemento terapéutico en la hepatopatía alcohólica, permitiendo una mejoría de la función hepática expresada mediante la clínica y las pruebas de síntesis proteica, de necrosis y de colestasis (AU)