Tumor necrosis factor-inducible gene 6 protein ameliorates chronic liver damage by promoting autophagy formation in mice

Tumor necrosis factor-inducible gene 6 protein (TSG-6) has recently been shown to protect the liver from acute damage. However, the mechanism underlying the effect of TSG-6 on the liver remains unclear. Autophagy is a catabolic process that targets cell components to lysosomes for degradation, and its functions are reported to be dysregulated in liver diseases. Here we investigate whether TSG-6 promotes liver regeneration by inducing autophagic clearance in damaged livers. Mice fed a methionine choline-deficient diet supplemented with 0.1% ethionine (MCDE) for 2 weeks were injected with TSG-6 (the M+TSG-6 group) or saline (the M+V group) and fed with MCDE for 2 additional weeks. Histomorphological evidence of injury and increased levels of liver enzymes were evident in MCDE-treated mice, whereas these symptoms were ameliorated in the M+TSG-6 group. Livers from this group contained less active caspase-3 and more Ki67-positive hepatocytic cells than the M+V group. The autophagy markers ATG3, ATG7, LC3-II, LAMP2A and RAB7 were elevated in the M+TSG-6 group compared with those in the M+V group. Immunostaining for LC3 and RAB7 and electron microscopy analysis showed the accumulation of autophagy structures in the M+TSG-6 group. TSG-6 also blocked both tunicamycin- and palmitate-induced apoptosis of hepatocytes and increased their viability by inducing autophagy formation in these cells. An autophagy inhibitor suppressed TSG-6-mediated autophagy in the injured hepatocytes and livers of MCDE-treated mice. These results therefore demonstrate that TSG-6 protects hepatocytes from damage by enhancing autophagy influx and contributes to liver regeneration, suggesting that TSG-6 has therapeutic potential for the treatment of liver diseases.

Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats

OBJECTIVE: To evaluate the effect of ginger extract on the expression of NFêB and TNF-á in liver cancer-induced rats. METHODS: Male Wistar rats were randomly divided into 5 groups based on diet: i) control (given normal rat chow), ii) olive oil, iii) ginger extract (100mg/kg body weight), iv) choline-deficient diet + 0.1 percent ethionine to induce liver cancer and v) choline-deficient diet + ginger extract (100mg/kg body weight). Tissue samples obtained at eight weeks were fixed with formalin and embedded in paraffin wax, followed by immunohistochemistry staining for NFêB and TNF-á. RESULTS: The expression of NFêB was detected in the choline-deficient diet group, with 88.3 ± 1.83 percent of samples showing positive staining, while in the choline-deficient diet supplemented with ginger group, the expression of NFêB was significantly reduced, to 32.35 ± 1.34 percent (p<0.05). In the choline-deficient diet group, 83.3 ± 4.52 percent of samples showed positive staining of TNF-á, which was significantly reduced to 7.94 ± 1.32 percent (p<0.05) when treated with ginger. There was a significant correlation demonstrated between NFêB and TNF-á in the choline-deficient diet group but not in the choline-deficient diet treated with ginger extract group. CONCLUSION: In conclusion, ginger extract significantly reduced the elevated expression of NFêB and TNF-á in rats with liver cancer. Ginger may act as an anti-cancer and anti-inflammatory agent by inactivating NFêB through the suppression of the pro-inflammatory TNF-á.

The Preliminary Report of Rapid Production of Pancreas Cancer and Cholangiocarcinoma by Cyclic Injection of Carcinogens in Syrian Hamster initiated with N-nitrosobis(2-oxopropyl)amine / 한국간담췌외과학회지

BACKGROUND/AIMS: It is well known that N-nitrosobis(2-oxopropyl)amine(BOP)-induced pancreas cancer and cholangiocarcinoma in Syrian hamster is similar to that of humans in morphological, biological and immunological aspects. The cyclic administration of BOP and ethionine, choline-deficient diet and methionine is known to rapidly induce the ductal type of carcinoma in pancreas and bile duct. Authors studied whether the rapid production of this cancer can occur in Syrian hamster and what its features are. METHODS: Sixteen Syrian hamsters aged 6-7 weeks and weighing 100 gm were used. All hamsters received 70 mg/kg body weight of BOP followed by three cycles of dl-ethionine, choline-deficient diet, l-methionine and 20mg/kg BOP. Hamsters were killed 9, 10 and 11 weeks after the beginning of the experiment and their gross and histologic features were observed. RESULTS: Nine cases, killed withan 10weeks after the begining of experiment, showed no development of cancer. Of seven Syrian hamsters, killed more than 10weeks after the begining of experiment, the incidences of BOP-induced cancer included one case(14.3%) of pancreas cancer and five cholangiocarcinomas( 71.4%). The morphological change of pancreas carcinogenesis was shown at first in cell mitosis and atypia(6 weeks) and then in atypical ductal hyperplasia(9 weeks) and carcinoma in situ(10 weeks). The change in cholangiocarcinoma, first progressed with ductular proliferation and surrounding fibrosis(6 weeks) followed by focal cholangiocarcinoma(10 weeks) and multiple invasive cholangiocarcinomas( 11 weeks). CONCLUSION: Pancreas cancer and intrahepatic cholangiocarcinomas can be induced rapidly within 10 weeks by cyclic injections of carcinogens in Syrian hamsters initiated with Nnitrosobis( 2-oxopropyl)amine and the morphologic changes can be observed.

Morphometric evaluation of acinar cell number and volume in rat pancreas treated with dl-ethionine

1. The morphological changes of the pancreas induced by administration of dl-eyhionine were determined for treated rats and for a group of pair-fed untreated controls in order to separate the direct effect of dl-ethionine from the effect of accompanying reduction of food intake. 2. Adult male Wistar rats were studied in 3 groups of 10 animals each: 1) fed ad libitum and treated daily with dl-ethionine (35 mg/100 g body weight, ip) for 10 days; 2) treated daily with vehicle (saline) as group 1 and pair-fed to group 1; 3) treated daily with vehicle (saline) and fed ad libitum. Two rats from each group were killed on days 2, 4, 6, 8 and 10 to characterize the ancreas in terms of morphological properties using morphometric analysis. 3. Exposure to del-ethionine induced a progressive and significant decrease in both pancreas weight and acinar cell number and volume. Pair feeding induced less pronounced decreases in pancreas weight and acinar cell volume. Pancreas weight was 125 mg/100g body weight for dl-ethionine-treated vs 205mg/100g body weight for pair-fed controls and 320 mg/100 g body weight for ad libitum-fed controls after 10 days. Acinar cell number (x ñ o-/Vn): 175 x 10**6 ñ 28.4 per µm3 for dl-ethionine-treated vs 221 x 10**6 ñ 17.3 per µm3 for pair-fed controls and 271 x 10**6 ñ 23.9 per µm3 for ad libitum-fed controls. Acinar cell volume (x ñ o-/Vn) was 1292 ñ 65.4 µm3 for dl-ethionine-treated vs 1436 ñ 74.9 µm3 for pair-fed controls and 1758 ñ 117.1 µm3 for ad libitum-fed controls. 4. Continuous treatment with dl-ethionine for 10 days induced pancreatic weight loss for two main reasons: 1) reduction of the number of acinar cells, an effect apparently induced by dl-ethionine administration, and 2) acinar cell atrophy consequent to food restriction

Mecanismo teórico de la hepatocarcinogénesis / Theoretical mechanism of ethionine hepatocarcinogenesis

En resumen, parece ser que el proceso necesario, al menos conceptualmente que le permita a uno construir una noción adecuada del mecanismo involucrado durante la carcinogénesis inducida por etionina, puede ser relevante a un proceso más general y fundamental aplicable a todos los carcinógenos. Se ha descrito un intento que trata de aportar un mecanismo considerado en este artículo, también enfatiza la importancia de la activación de proteínas embriónicas como un ejemplo de un proceso más general que se requiere para la carcinogénesis

Efecto de la etionina sobre el hígado de rata en condiciones de diferente aporte de proteina en la dieta / Ethionine effects on rat liver under different protein dietary contents

Durante el desarrollo de la vida de un ser vivo reviste sinbgular importancia la capacidad de adaptación de su organismo a los cambios cambientales. Esta adaptabilidad parece depender en grado sumo del aporte de proteínas en la alimentación. Por ejemplo, la deficiencia proteínica en la dieta provoca un marcado descenso de las defensas del organismo, elevando a la vez su susceptibilidad a los agentes tóxicos ambientales cuyo número y variedad actualmente cada vez es mayor. En estas condiciones es clara la necesidad de la fórmula óptima alimentaria como media de protección fisiológico frente a un agresivo entorno. Este trabajo es un grano de arenas, camino de esta búsqueda, el cual se realizó en animales de experimentación (ratas) a nivel subcelular (lisosoma), abarcando dos aspectos: morfológico y enzimático (enzimas marcadoras-fosfatasa ácida, ribonucleasa ácida y catepsina). Se encontró: la etionina en condiciones de alimentación con aporte normal proteínico (18.5%) provoca alteraciones leves en los hepatocitos (infiltración grasa periportal, mínimas alteraciones del patrón enzimático y de la permeabilidad celular). En condiciones de alimentación deficiente en proteínas la manifestación histológica es más severas (disminución de ARN celular, infiltración grasa difusa), siendo mínimo el cambio en el patrón enzimático y en la permeabilidad celular. En condiciones de alimentación con exceso de proteína (44.5%) los cambios histológicos y de permeabilidad son discretos y se registró una tendencia a la transformación favorable anabólica patrón enzimático. Se concluye: el aporte elevado de proteína en la dieta surte en ratas el efecto de antídoto de la acción hepatotóxica de la etionina

Açäo de sais de cobre sobre a xantina desidrogenase na carcinogênese hepática de ratas / Action of copper salts on xanthine dehydrogenase in hepatic carcinogenesis of rats

Estudou-se a inibiçäo da atividade de xantina desidrogenase (XD) do soro de ratas pelo acetado de cobre (AcCu). Verificou-se também a relaçäo entre a atividade XD e a degeneraçäo hepática e carcinogênese pela D-L-etionina. Experiências mostraram que a AcCu é um potente inibidor da XD e que esta inibiçäo é näo-competitiva quando se mantém constante a concentraçäo do receptor de eletrons, e do tipo competitivo quando esta concentraçäo varia permanecendo constante a concentraçäo de substrato. Comparando-se estes estudos com os resultados da dosagem da atividade de xantina oxidase (oxigênio como receptor de eletrons) sugere-se que radicais estariam, envolvidos na açäo citotóxica do complexo AcCu-etionina com provável necessidade de ocorrência de uma reaçäo de reduçäo