Teruaki Kishikawa

Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride

Abstract: We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)‐induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4‐induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se‐glutathione peroxidase (Se‐GSH‐Px), glutathione reductase (GSSG‐R), glucose‐6‐phosphate dehydrogenase (G‐6‐PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4‐treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G‐6‐PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G‐6‐PDH activity in addition to decreases in CAT and GSSG‐R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG‐R activities and the increase in hepatic XO activity in a dose‐dependent manner without affecting either hepatic Se‐GSH‐Px activity or the increased hepatic VE concentration and G‐6‐PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se‐GSH‐Px, G‐6‐PDH, and XO activities in CCl4‐untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG‐R, and XO, in addition to reduced glutathione, in CCl4‐treated rats.

Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation.

Abstract: We examined whether melatonin exerts a therapeutic effect on cholestatic liver injury in rats treated with bile duct ligation (BDL). Cholestatic liver injury was induced in male Wistar rats aged 4 wk by ligating the bile duct. Cholestatic liver injury developed 5 days after BDL and continued to 13 days, judging from the levels of serum hepatobiliary injury markers. The serum concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and the hepatic level of TBARS and the activity of hepatic myeloperoxidase, an index of tissue neutrophil infiltration, increased 5 days after BDL, and these increases were enhanced at 13 days. A similar increase in the serum total cholesterol concentration occurred 5 and 13 days after BDL, while the hepatic cholesterol concentration tended to increase at 13 days. When melatonin [10 or 100 mg/kg body weight (BW)] was orally administered to BDL‐treated rats everyday for 8 days, starting 5 days after BDL, the indoleamine attenuated cholestatic liver injury observed at 13 days after BDL was more effective at the higher dose than at the lower dose. The administered melatonin (10 or 100 mg/kg BW) reduced the increases in serum and hepatic TBARS concentrations and hepatic myeloperoxidase activity observed at 13 days after BDL and the higher dose of indoleamine was more effective than the lower dose. Neither dose of melatonin affected the increased serum total cholesterol concentration or the hepatic cholesterol concentration observed at 13 days after BDL. These results indicate that orally administered melatonin at pharmacological doses exerts a therapeutic effect on cholestatic liver injury in rats with BDL possibly through its antioxidant and anti‐inflammatory actions.

Preventive effect of melatonin on the progression of α-naphthylisothiocyanate-induced acute liver injury in rats

Abstract: The preventive effect of melatonin on the progression of α‐naphthylisothiocyanate (ANIT)‐induced acute liver injury with cholestasis was examined in rats treated once with the hepatotoxin [75 mg/kg body weight (BW), i.p.]. In rats treated with ANIT alone, liver injury with cholestasis occurred 24 hr after treatment and progressed at 48 hr, judging from the serum levels of hepatobiliary marker enzymes and components. Melatonin (10 or 100 mg/kg BW) was orally administered to the ANIT‐treated rats, 24 hr after the hepatotoxin treatment at which time hepatic injury had already developed. The administered indoleamine prevented the progression of liver cell damage rather than biliary cell damage more effectively at the higher dose than at the lower dose. In rats treated with ANIT alone, the serum and hepatic concentrations of thiobarbituric acid reactive substances, an index of lipid peroxidation, and the hepatic activity of myeloperoxidase, an index of tissue neutrophil infiltration, increased 24 hr after treatment and further increased at 48 hr. In the liver of rats treated with ANIT alone, Cu,Zn‐superoxide dismutase activity decreased 24 hr after treatment and was further reduced at 48 hr, although there was no change in Mn‐superoxide dismutase activity. Catalase and Se‐glutathione peroxidase activities also decreased at 48 hr, while reduced glutathione concentrations remained increased at 24 and 48 hr. The melatonin administered to the ANIT‐treated rats attenuated the increases in serum and hepatic concentrations of thiobarbituric acid reactive substances and the decreases in hepatic activities of Cu,Zn‐superoxide dismutase, catalase, and Se‐glutathione peroxidase found at 48 hr after the hepatotoxin treatment more effectively at the higher dose than at the lower dose; on the other hand, melatonin treatment had no effect on the increases in hepatic myeloperoxidase activity and reduced glutathione concentration found at 48 h. These results indicate that orally administered melatonin at pharmacological doses prevents the progression of ANIT‐induced acute liver injury, mainly liver cell damage, in rats, and suggest that the administered melatonin exerts these preventive effects through its direct and indirect antioxidant actions.

Hepatic mensenchymal hamartoma of an infant

An 8-month-old boy was found to have a solitary hepatic mesenchymal hamartoma. Histologically, the lesion appeared as a large island of loose mesenchymal tissue with few cystic bile ducts and liver cells. Electronmicroscopy showed microvilli on the surface of tumor cells and desmosomes between the cells. Immunohistochemical studies showed that alpha-fetoprotein was localized in the proliferating liver cells and bile ductal epithelium of this neoplasm. This case is the 17th case of hepatic mesenchymal hamartoma reported in Japan.

Effect of melatonin on changes in hepatic antioxidant enzyme activities in rats treated with alpha-naphthylisothiocyanate

We have reported that melatonin protects against α‐naphthylisothiocyanate (ANIT)‐induced acute liver injury in rats by preventing enhanced lipid peroxidation. Herein, we examine the effect of melatonin on hepatic antioxidant enzyme activities in rats with a single i.p. injection of ANIT (75 mg/kg body weight) in order to clarify the protective mechanism of the indoleamine against ANIT‐induced acute liver injury. Rats received a single oral administration of melatonin (10 or 100 mg/kg body weight) at 12 hr after ANIT treatment. Hepatic Cu,Zn‐superoxide dismutase (Cu,Zn‐SOD), Mn‐superoxide dismutase (Mn‐SOD), catalase (CAT), Se‐glutathione peroxidase (Se‐GSH‐Px), glutathione reductase (GSSG‐R), and glucose‐6‐phosphate dehydrogenase (G‐6‐PDH) activities and reduced glutathione (GSH) concentration were determined 12 and 24 hr after ANIT treatment. ANIT‐treated rats showed decreases in hepatic Cu,Zn‐SOD and GSSG‐R activities at 24 hr after treatment, transient increases in hepatic CAT and Se‐GSH‐Px activities at 12 hr, and no changes in hepatic Mn‐SOD and G‐6‐PDH activities at 12 or 24 hr. Only the high dose of melatonin attenuated the decrease in hepatic Cu,Zn‐SOD activity, while both doses of the indoleamine almost completely attenuated the decrease in hepatic GSSG‐R activity. Neither dose of melatonin affected hepatic CAT, Se‐GSH‐Px, and G‐6‐PDH activities. ANIT‐treated rats showed an increase in hepatic GSH concentration at 24 hr after treatment. Neither dose of melatonin affected the increase in hepatic GSH concentration. These results indicate that orally administered melatonin prevents decreases in Cu,Zn‐SOD and GSSG‐R activities in the liver of ANIT‐treated rats, and suggest that the indoleamine may protect against ANIT‐induced acute liver injury by attenuating the disruption of hepatic antioxidant defense systems.

Therapeutic Effect of Melatonin on Cholestatic Liver Injury in Rats with Bile Duct Ligation

We examined the therapeutic effect of melatonin (MT) on cholestatic liver injury in rats with bile duct ligation (BDL). Cholestatic liver injury occurred 5 days after BDL and proceeded at 13 days, judging from the levels of serum hepatobiliary injury markers. Increases in the hepatic levels of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and reduced glutathione (GSH) and the hepatic activity of myeloperoxidase (MPO), an index of tissue neutrophil infiltration, were observed 5 and 13 days after BDL. When MT at a dose of 10 or 100 mg/kg body weight was orally administered to rats with BDL everyday for one week, starting 6 days after BDL, a high dose of the indoleamine significantly attenuated cholestatic liver injury at 13 days after BDL. The daily administration of a high dose of MT significantly attenuated the increases in hepatic TBARS and GSH levels and MPO activity observed 13 days after BDL. These results indicate that MT administered orally at pharmacological doses exerts a therapeutic effect on cholestatic liver injury in rats with BDL possibly through its antioxidant and anti-inflammatory actions.

A child with adrenocortical adenoma accompanied by congenital hemihypertrophy: report of a case.

Abstract We report herein the findings of a 7-year-old male child with a ruptured adrenocortical adenoma and congenital hemihypertrophy which was incidentally detected after suffering a trauma. A review of 21 pediatric cases of adrenocortical neoplasms in the literature was made. The patient showed precocious puberty such as pubis and advanced bone age, but an endocrinological examination revealed no definite abnormalities. The right adrenal tumor with hematoma was resected after these evaluations. Adrenocortical adenoma is considered to occur more frequently in female children. However, the incidence of adrenocortical tumors accompanied by congenital hemihypertrophy does not differ between males and females. The outcomes were relatively good, although the observation periods were short in some patients. A large number of patients presented with a tumor and hemihypertrophy on the same side. This finding is of interest when considering the possible association between hemihypertrophy of the organs and tumor proliferation. However, their association in terms of development was unclear. It is necessary for patients with hemihypertrophy to have regular examinations for the possible development of malignant tumors, especially in the kidney, adrenal gland, and liver.

A cellular uptake of cis-platinum-encapsulating liposome through endocytosis by human neuroblastoma cell

To explore the mechanisms involved in the efficient intracellular delivery of an antitumor agent, the uptake mechanism of cis-diamminedichloroplatinum (CDDP)-encapsulating liposome (phosphatidylcholine:phosphatidylserine:cholesterol = 6:2:3 in molar ratio) (CDDP-liposome) by the human neuroblastoma cell, IMR-32, was investigated. Dansylcadaverine, chloroquine and antimycin A suppressed the growth-inhibitory activity of CDDP-liposome mostly due to the interference of the energy-dependent internalization process. Colchicine and vinblastine also neutralized the DNA synthesis-inhibitory activity of CDDP-liposomes. Stimulation with CDDP-liposomes at low temperature (4 degrees C), which induces the disruption of microtubules under immunofluorescent visualization, markedly lowered the growth-inhibitory activity of CDDP-liposomes. These findings suggested that the action of CDDP-liposome was temperature-dependent and microtubules participated in the intracellular drug delivery. A23187 (0.4 ?M), further, promoted the action of CDDP-liposome, suggesting that an increase of intracellular Ca(2+) levels promotes the growth inhibitory activities of CDDP-liposomes. Taking the uptake-mechanisms and intracellular delivery processes of CDDP-liposomes into consideration, the use of CDDP-liposomes may present a promising tool for neuroblastoma chemotherapy.

A child with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy for liver metastasis

The authors encountered a 2-year-old-girl with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy (PEIT) for liver metastasis. The patient had functional adrenocortical carcinoma diagnosed and underwent excision of the tumor in the right adrenal gland. Because liver metastasis was detected 11 months after surgery, the patient underwent PEIT under general anesthesia. After the treatment, the size of the metastatic tumor was reduced with calcification and then disappeared. The patient was in a good condition 3 years, 3 months after the occurrence of liver metastasis.

Serum acute phase reactants in pediatric patients; especially in neonates.

We studied serum acute phase reactant (APR) levels in 45 pediatric surgical patients. Alpha 1-acid glycoprotein (α1-AG) showed a peak value on day 3 postoperatively (P.O.) and alpha 1-antitrypsin (α1-AT) showed a high value on days 3–5 P.O. These glycoproteins returned to normal levels by day 21 P.O., but the level of haptoglobin (Hp) remained high until day 21 P.O. The postoperative changes of α1-AG and α1-AT correlated with the process of recovery from inflammatory conditions, but C-reactive protein (CRP) reached a peak on days 1–2 P.O. and returned to normal limits by day 14 P.O. In patients with infection, CRP returned to the normal level rapidly before recovery from infection. Of the 3 glycoproteins, α1-AG seemed to be a valuable indicator of the pathological conditions. Postoperative changes in APR levels should be useful for early detection of postoperative complications. Persistent ileus led to an increase in APR levels, as a consequence of an inflammatory reaction due to breakdown of the intestinal mucosal barrier.