Silymarin enhanced cytotoxic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells

Silymarin is a polyphenolic flavonoid from milk thistle (Silybum marianum), which has anti-inflammatory, cytoprotective as well as antioxidant effects. Our previous study demonstrated that silymarin has anti-apoptotic effect against UV irradiation. In this study, we assessed the effect of silymarin on anti-Fas agonistic antibody CH11-treated human malignant melanoma, A375-S2 cells. Pretreatment with silymarin (3 × 10^- 4 mol/L) significantly induced cell apoptosis in CH11-treated A375-S2 cells. Mitochondrial transmembrane potential (ΔΨ_m) was also down-regulated by silymarin pretreatment. Caspase-8, -9, -3 and pan-caspase inhibitors partially reversed silymarin-induced apoptosis of CH11-treated cells. The expression of Fas-associated proteins with death domain (FADD), a downstream molecule of the death receptor pathway, was increased by silymarin pretreatment, followed by cleavage of procaspase-8, whose activation induced cell apoptosis. Moreover, cleavage of procaspase-3 and digestion of its substrate, the inhibitor of caspase-activated DNase (ICAD), were also increased by silymarin pretreatment. These results suggested that silymarin could also exaggerate the apoptotic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells.     

Pancreatic Hormone Changes in Infantile Obstructive jaundice

Metabolic disturbances of pancreatic hormones in obstructive jaundice in infancy were evaluated experimentally and clinically. In our experimental study, using young rats, the level of plasma insulin (IRI) gradually increased after ligation of the common bile duct. These levels were a little lower than those in the non-treated controls. The level of plasma glucagon (IRG) incerased remarkably 4 weeks after ligation of the common bile duct. Clinically, there were no significant differnces in the levels of IRI and IRG among normal controls and cases of neonatal hepatitis and congenital biliary atresia (CBA). In CBA patients, these levels can be correlated with the progression of hepatic fibrosis; an increase in IRG and a decrease in teh IRI/IRG mol ratio was noticed in patients with grade III of hepatic fibrosis. These indicate that, in obstructive jaundice in infancy, the more severe the hepatic damage due to obstructive jaundice, the higher the level of plasma glucagon concentration will rise.     

Prevalence of abnormal findings in magnetic resonance images of asymptomatic knees

 One hundred fifteen asymptomatic Japanese volunteers aged from 13 to 76 years were examined by magnetic resonance imaging (MRI) to evaluate age-related meniscal degeneration and to determine the prevalence of discoid menisci. Each meniscus was graded in the anterior and posterior portions according to intrameniscal MRI signals. Discoid meniscus was diagnosed if a bow-tie configuration was noted on three or more contiguous sagittal sections. Meniscal abnormalities on MRI became more prevalent with age in both men and women. The posterior horn of the medial meniscus showed a significantly higher prevalence of degeneration than other parts of the meniscus. Discoid menisci were noted in 15 subjects (13% prevalence), always representing the lateral meniscus. Subchondral changes were observed in 13 subjects more than 40 years old, mostly women, and were located in the medial compartment. These abnormalities were not correlated with severity of degeneration in the posterior portion of the medial meniscus. This study demonstrates considerable prevalence of meniscal abnormalities in asymptomatic Japanese subjects. Received: January 15, 2001 / Accepted: December 13, 2001     

Effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients

BACKGROUND: Orthostatic hypotension (OH) is a serious complication observed in hemodialysis (HD) patients after HD as well as during the interdialytic period. L-Threo-3,4-dihydroxyphenylserine (L-DOPS) is a nonphysiological neutral amino acid that is directly converted to the neurotransmitter norepinephrine by aromatic L-amino acid decarboxylase. METHODS: A placebo-controlled double-blind study for 4 consecutive weeks and a long-term study (24-52 weeks) were conducted to evaluate the efficacy of L-DOPS for OH after HD. The drug was administered orally 30 min before the start of each HD period in both studies. Doses of 400 mg of L-DOPS or placebo were given to HD patients with OH (45 and 41 patients, respectively) in the double-blind study, and doses of 200 or 400 mg of L-DOPS were given to 74 HD patients in the long-term study. RESULTS: In the double-blind study, L-DOPS significantly ameliorated subjective symptoms related to OH, including dizziness/light-headed feeling, and malaise, throughout the interdialytic period. For 19 patients with delayed-type OH, hypotension with the lowest blood pressure recorded 10 min after standing, the decrease in blood pressure was suppressed significantly after L-DOPS treatment (10 patients) as compared with the placebo-treated group (9 patients). In the long-term study, the efficacy of L-DOPS was not attenuated, and the marked fluctuations in the plasma L-DOPS and norepinephrine levels were not noted after long-term use, without increases in incidence or severity of adverse reactions. CONCLUSIONS: These results indicate that L-DOPS is effective for improving OH-related interdialytic subjective symptoms in HD patients after short-term as well as after long-term administration.     

Falling asleep while driving and automobile accidents among patients with obstructive sleep apnea-hypopnea syndrome

Among 448 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), 40 patients (8.9%) had been involved in one or more automobile accidents during the preceding 5 years. The main cause of these accidents was falling asleep while driving. Excessive sleepiness during driving was associated with an Epworth sleepiness scale (ESS) score of > 11 and/or an apnea-hypopnea index (AHI) of > 15. The automobile accident rate among 182 patients with severe OSAHS (AHI > 30) was significantly higher than the rate among 106 simple snorers (AHI < 5). Although four of the simple snorers were involved in automobile accidents, their ESS scores were all very high (15 or more).     

Compartments in the lamprey embryonic brain as revealed by regulatory gene expression and the distribution of reticulospinal neurons

The vertebrate neural tube consists of a series of neuromeres along its anteroposterior axis. Between amphioxus that possesses no neuromeres and gnathostomes, the lamprey occupies a critical position in the phylogeny for the origin of the segmented brain. To clarify the rhombomeric configuration of the Japanese lamprey, Lampetra japonica, we injected rhodamine- and fluorescein-labeled dextrans into the larval spinal cord, and retrogradely labeled the reticulospinal neurons. We also isolated prosomere marker genes from the embryonic cDNA library of L. japonica, and performed in situ hybridization on the embryonic brain. Of the genes examined, LjOtxA, LjPax6, LjPax2/5/8, LjDlx1/6, and LjTTF-1 were expressed in clearly demarcated polygonal domains. In the telencephalon, LjDlx1/6, LjPax6, and a putative paralogue of LjEmx were expressed in different domains; the LjEmx paralogue was expressed in the dorsal region, and LjDlx1/6 and LjPax6 in a complimentary fashion of the middle part. These expression patterns implied existence of a tripartite configuration of the lamprey telencephalon similar to that in gnathostomes. All these evidences strongly suggest that the segmental and compartmental architecture of the vertebrate brain was already established before the divergence of agnathans and gnathostomes.     

Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats

Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. Food-deprived (18 h) normal and diabetic rats were orally administered 135 mg/ 100 g body weight L-leucine and sacrificed at 1 h after administration. Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes     

Lymphatic absorption of docosahexaenoic acid given as monoglyceride,diglyceride, triglyceride,and ethyl ester in rats

Lymphatic absorption of docosahexaenoic acids (DHA) given as monoglyceride (MG), consisting of 1(or 3)-species (9 1.4%), 2-species (4.2%) and diglyceride (DG) consisting of 1,3-species (70.8%), 1(or 3),2-species (28.6%), were investigated in comparison with that of triglyceride (TG) and ethyl ester (EE). Rats were infused with a lipid emulsion containing 200 mg of DHA-MG, DG, TG, or EE via a gastric cannula. Lymph was collected through the thoracic lymph duct at 2 h intervals for 10 h and at a single collection from 10 to 30 h. Physiological saline containing glucose was infused (2 mL/h) throughout the lymph collection. The overall recovery of DHA at 30 h after its infusion was significantly higher in the rank order DHA-MG>DG>TG=EE. Moreover, time-dependent changes in recovery rates from 2 to 10 h of DHA given as MG were significantly higher than those of the corresponding DG, TG, and EE. These results indicate that DHA-MG and DG are absorbed and transported more effectively than TG and EE forms under restricted water supply, even if they mainly consist of 1(or 3)-species. Lymph lipids were mainly transported as TG, and a large amount of DHA was incorporated into a TG fraction in all fat types examined. Furthermore, the intramolecular distribution of DHA in lymph TG was similar in all groups. docosahexaenoic acid, monoglyceride, diglyceride triglyceride, ethyl ester