8-Prenylnaringenin promotes recovery from immobilization-induced disuse muscle atrophy through activation of the Akt phosphorylation pathway in mice.

8-Prenylnaringenin (8-PN) is a prenylflavonoid that originates from hop extracts and is thought to help prevent disuse muscle atrophy. We hypothesized that 8-PN affects muscle plasticity by promoting muscle recovery under disuse muscle atrophy. To test the promoting effect of 8-PN on muscle recovery, we administered an 8-PN mixed diet to mice that had been immobilized with a cast to one leg for 14 days. Intake of the 8-PN mixed diet accelerated recovery from muscle atrophy, and prevented reductions in Akt phosphorylation. Studies on cell cultures of mouse myotubes in vitro demonstrated that 8-PN activated the PI3K/Akt/P70S6K1 pathway at physiological concentrations. A cell-culture study using an inhibitor of estrogen receptors and an in vivo experiment with ovariectomized mice suggested that the estrogenic activity of 8-PN contributed to recovery from disuse muscle atrophy through activation of an Akt phosphorylation pathway. These data strongly suggest that 8-PN is a naturally occurring compound that could be used as a nutritional supplement to aid recovery from disuse muscle atrophy.

Prevention of disuse muscle atrophy by dietary ingestion of 8-prenylnaringenin in denervated mice.

Flavonoids have attracted considerable attention in relation to their effects upon health. 8-Prenylnaringenin (8-PN) is found in the common hop (Humulus lupulus) and assumed to be responsible for the health impact of beer consumption. We wanted to clarify the effects of prenylation on the physiological functions of dietary flavonoids by comparing the effects of 8-PN with that of intact naringenin in the prevention of disuse muscle atrophy using a model of denervation in mice. Consumption of 8-PN (but not naringenin) prevented loss of weight in the gastrocnemius muscle further supported by the lack of induction of the protein content of a key ubiquitin ligase involved in muscle atrophy, atrogin-1, and by the activation of Akt phosphorylation. 8-PN content in the gastrocnemius muscle was tenfold higher than that of naringenin. These results suggested that, compared with naringenin, 8-PN was effectively concentrated into skeletal muscle to exert its preventive effects upon disuse muscle atrophy. It is likely that prenylation generates novel functions for 8-PN by enhancing its accumulation into muscle tissue through dietary intake.

Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis.

BACKGROUND AND AIM: The molecular mechanisms underlying the involvement of the renin-angiotensin system in hepatic fibrosis are unclear. Recently, it was reported that a Rho kinase inhibitor prevented fibrosis of various tissues and that the Rho/Rho kinase pathway was involved in the renin-angiotensin system of vascular smooth muscle cells. In this study, the involvement of the Rho/Rho kinase pathway on angiotensin II signaling in liver fibrogenesis and generation of steatosis was investigated. METHODS: Rats were fed a choline-deficient/L-amino acid-defined (CDAA) diet continuously and treated with a Rho kinase inhibitor, Y-27632, and an angiotensin II receptor blocker, TCV-116. Liver histology and hepatic stellate cell activation were analyzed. Free radical production was detected by 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine immunostaining and the expression of tumor necrosis factor-alpha was examined. Isolated hepatic stellate cells were pretreated with a Rho kinase inhibitor, Y-27632, or an angiotensin II receptor blocker, CV-11974, and stimulated with angiotensin II, and mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin was analyzed. RESULTS: Both the angiotensin II receptor blocker and the Rho kinase inhibitor improved fibrosis and steatosis of the liver in CDAA-fed rats. The increase in the number of hepatocytes positive for 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine in CDAA-fed rats was significantly prevented by the angiotensin II receptor blocker and the Rho kinase inhibitor. The levels of tumor necrosis factor-alpha mRNA in the liver of CDAA-fed rats were significantly increased and this increase was significantly inhibited by treatment with the angiotensin II receptor blocker and the Rho kinase inhibitor. mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin stimulated by angiotensin II was also significantly suppressed by these two drugs. CONCLUSION: These results suggest that the Rho/Rho kinase pathway is at least partly involved in the renin-angiotensin system and plays an important role in hepatic fibrosis and steatosis.

Efficacy of natural BALL-1 interferon-alpha treatment for patients with chronic hepatitis C and a possible enhancing effect of a twice-daily starting regimen with interferon-beta.

BACKGROUND/AIMS: Two distinct natural interferon-alpha (BALL-1 and Namalwa) are available for patients with chronic hepatitis C in Japan, but the efficacy has not been well documented. We investigated two studies using a natural BALL-1 interferon-alpha treatment for chronic hepatitis C and assessed its efficacy. METHODOLOGY: In interferon-alpha monotherapy (Study I), 42 patients with chronic hepatitis C received 10 mega units of BALL-1 interferon-alpha intramuscularly consecutively for an initial 2 weeks followed by three times a week for 6 months totally. In a combination therapy of natural interferon-alpha and interferon-beta (Study II), 24 patients received intravenous 3 mega units of interferon-beta twice daily for the initial 2 weeks followed by 10 mega units of natural BALL-1 interferon-alpha consecutively for 2 weeks and three times a week for 6 months totally. Efficacy and predictive factors for sustained viral response was investigated. RESULTS: Study II included significant younger patients than study I. Sustained virological response was obtained in 31.0% in Study I and 56.5% in Study II by intention-to-treat analysis. Sustained viral response in the group of genotype 1b and viral load more than 100 KIU/mL was 3/23 (13.0%) and 8/18 (44.4%) in Study I and II, respectively. The response rate in Study II was higher than that of Study I especially among the patients with high pretreatment viral load or genotype 1b (p<0.05). Multivariate analysis showed that pre-treatment HCV-RNA levels, HCV-genotype, and histological staging before the interferon treatment were significant predictive factors of sustained viral response. CONCLUSIONS: These studies suggest that natural BALL-1 interferon-alpha is useful for inducing sustained viral response in patients with chronic hepatitis C, even in those possessing genotype 1b and high viral load. In addition, the combination therapy with a starting regimen with twice-daily interferon-beta administration for 2 weeks may be more effective than monotherapy.

Effect of long-term interferon therapy for refractory chronic hepatitis c: preventive effect on hepatocarcinogenesis.

BACKGROUND/AIMS: Effect of interferon (IFN) therapy for refractory chronic hepatitis C is not sufficient. For patients with persistent hepatitis C virus (HCV) infection, one of the clinical goals is prevention of progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In this study, we evaluated effect of long-term IFN administration for refractory chronic hepatitis C. METHODOLOGY: The patients who were positive for HCV of genotype lb in high viral load and failed in HCV elimination by standard IFN therapy were retrospectively analyzed. The patients were divided into three groups according to administration duration of IFN therapy. The patients in group 1, 2 and 3 received IFN therapy for 6 months, 6-24 months and more than 24 months, respectively. RESULTS: The normalization rate of alanine aminotransferase (ALT) levels less than twice that of the normal limit 6 months after the treatment was highest in group 3 (85%). The platelet counts in group 1 gradually decreased more than 3 x 10(4)/microL from the pretreatment levels at 100 months after the start of treatment. Cumulative hepatocarcinogenesis rate in groups 1, 2 and 3 were 34.7%, 5.9% and 0%, respectively. We found distinct improvement in both ALT levels and histopathological findings in the case that received the longest term of IFN therapy (91 months). CONCLUSIONS: Long-term IFN therapy is effective in preventing hepatocarcinogenesis through reduction of chronic necroinflammation and accumulation of fibrosis in the liver and may be a good indication even for refractory chronic hepatitis C.

Efficacy of non-invasive elastometry on staging of hepatic fibrosis.

To assess the efficacy of elastmetry in the determination of fibrotic stage in the liver, we investigated correlation between liver histology and the elastometry using a device equipped with a vibrator and an ultrasound system (Echosens, Paris, France) in patients with chronic hepatitis C. Totally 75 patients, 24 in F1 stage, 17 in F2 stage, 18 in F3 stage, and 16 in F4 stage according to the new Inuyama classification without fatty change were investigated. Correlations between the staging of liver fibrosis and elastometry, serum fibrosis makers and platelet counts were investigated. The elastometry was absolutely non-invasive. Serum fibrosis markers did not well correlate with the stage of liver fibrosis. Platelet counts significantly ( [Formula: see text] ) correlated with the fibrotic stage. Median platelet counts in each stage was; F1, 191.5; F2, 172.0; F3, 132.0; F4, 77.5 (x10(3)microl(-1)). However, the deviation was comparatively broad. On the contrary, the elastometry correlated well to the stage of fibrosis and the deviation was small. Median elastometric levels in each stage were; F1, 6.25; F2, 7.80; F3, 13.85; F4, 34.00 (kPa). These results suggest that elastometry is significantly useful for evaluating fibrotic staging of the liver without any invasiveness.