Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice.

Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.

Acanthopanax senticosus Harms extract causes G0/G1 cell cycle arrest and autophagy via inhibition of Rubicon in human liver cancer cells.

Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH­7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7­AAD­positive cells. Furthermore, the expression of LC3­II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3­II induction was further enhanced by co­treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE­treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin­1­interacting and cysteine­rich domain­containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome­lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy­related diseases.

Alteration of masticatory function by diet change induces stress responses in Wistar rats.

The occlusion-mastication system has extradigestive functions; however, whether liquid feeding evokes stress responses remains unclear. In this study, reactions to low masticatory performance were analyzed using a diet-alteration model in Wistar rats. Seven days after the diet of the rats was changed from solid to liquid, serum epinephrine and norepinephrine concentrations were found to be elevated by 205% and 158% compared to baseline values, respectively. Superoxide production by peritoneal neutrophils was higher in rats fed with a liquid diet than in those fed with a solid diet. Serum superoxide dismutase activity (i.e. the potential to eradicate serum superoxide) was lower in rats fed with liquid than in those fed with a solid diet, indicating that the former experienced oxidative stress. Conversely, the oxidative stress was removed following reversion of the liquid diet to solid diet. These results suggest that liquid diet mastication can cause mental stress, including an oxidative stress response.

Association between lifestyle habits and bone mineral density in Japanese juveniles.

OBJECTIVES: We explored the relationship between bone mineral density (BMD) and lifestyle in juveniles to identify factors leading to higher peak bone mass and prevention of osteoporosis in later life. METHODS: Juveniles (1,364 students: 770 boys and 594 girls, aged 6-18 years) attending school in Hokkaido prefecture, Japan, were asked to complete a brief self-administered diet history questionnaire for 10-year-olds (BDHQ10y) providing information about personal history, lifestyle, and intake of nutritional elements. In addition, BMD and grip strength were measured. We analyzed the relationship between BMD and lifestyle factors. RESULTS: The difference in BMD for boys was larger among the junior and senior high school groups. The difference in BMD for girls was larger among older elementary and later school children. Anthropometric variables and grip strength were strongly correlated with BMD. Having a nap-time routine was significantly correlated with BMD, but sleep time and sports club activities were not. BMD among juveniles who attained secondary sexual characteristics was significantly higher than that of juveniles of the same age who had not attained these characteristics. Calcium intake was significantly lower in senior high school students compared with other grades. Consumption of milk by senior high school boys and junior high school girls was weakly correlated with BMD. CONCLUSIONS: Our findings encourage educational interventions to counsel students to avoid weight loss and calcium deficiency. This effective intervention should begin before the higher elementary school, when juveniles have the greatest likelihood for preventing lower peak bone mass and osteoporosis.

A pilot study on effectiveness of music therapy in hospice in Japan.

This study aims at determining the effectiveness of music therapy in a hospice setting. We employed the salivary cortisol level, which is widely used to measure stress level, as an objective and physical indicator and the Mood Inventory, which measures mood change, as the subjective and psychological indicators. Though many preceding studies have demonstrated that listening to music lowers cortisol levels and reduces stress, no study seems to have included hospice patients. This study measured, with the consent of 10 hospice inpatients, their salivary cortisol levels. Individual interviews, according to the Mood Inventory, were conducted before and after a small-group session. Since all the participants had terminal cancer, the 40-minute live session of songs of seasons and the participants' requests was given in a mostly passive manner considering their physical strength. Results showed significant lowering of salivary cortisol levels after the therapy session. As for the parameters of mood, refreshment was significantly increased. Though fatigue remained unchanged, anxiety and depression decreased while the score for excitement tended to increase. Thus, it was indicated that music therapy in a hospice setting reduces the stress level of patients and thereby plays a positive role in improving patients' quality of life.

The Change of Grip Strength in a Patient with Congenital Myotonic Dystrophy Over a 4-year Period.

Myotonic dystrophy (MyD) is a neuromuscular disease that is autosomal dominant and the most common form of muscular dystrophy affecting adults. The clinical features of MyD include a multisystemic disorder characterized by myotonia, progressive muscle weakness and wasting, cataracts, premature balding and mental retardation. The most severe type of MyD is classified as congenital MyD (CMyD). The muscle weakness in CMyD is very severe, but muscle development can be observed in the period of growth. However, no clinical case of this type has been reported yet. Therefore, we report on a girl with CMyD who had an increase in muscle strength over a four-year period. The girl with CMyD participated in this study from the age of 9 to the age of 12. The measurement of muscle strength was recorded as the maximum score of grip strength with the use of dynamometers. Grip strength was assessed once a year by the same two physical therapists. Grip strength of CMyD for each year was markedly weak when compared with the normal controls, but muscle strength changed within some specific growth areas. The muscle weakness in CMyD was remarkable, but the result showed that specific muscle strength of CMyD in childhood was actually increased.

Garlic as an anti-fatigue agent.

More than three thousand publications in the past have confirmed the efficacy of garlic for the prevention and treatment of a variety of diseases, acknowledging and validating its traditional uses. Garlic is also used for the treatment of fatigue, although the mechanism involved remain unclear. The anti-fatigue function of garlic may be closely related to its many favorable biological and pharmacological effects. In animal studies, garlic has been shown to promote exercise endurance. Differences in the methods of processing garlic result in differences in the intensity of its anti-fatigue effect, and the most favorable form of processing has been shown to be extraction of raw garlic followed by its natural aging for a long period in a water-ethanol mixture. In human studies, it has been confirmed that garlic produces symptomatic improvement in persons with physical fatigue, systemic fatigue due to cold, or lassitude of indefinite cause, suggesting that garlic can resolve fatigue through a variety of actions. Recently, primarily in Japan, attempts have been made to measure the intensity of fatigue objectively and quantitatively using biomarkers. Currently available data strongly suggest that garlic may be a promising anti-fatigue agent, and that further studies to elucidate its application are warranted.

Muscle IGF-I Ea, MGF, and myostatin mRNA expressions after compensatory overload in hypophysectomized rats.

To determine whether IGF-I Ea, MGF, and myostatin mRNAs are related to GH-independent overload-induced muscle growth, we examined the expressions of IGF-I Ea and MGF mRNAs in the plantaris muscle after compensatory overload in hypophysectomized rats. The muscles were divided into four groups: normal-control, normal-overloaded, hypophysectomized-control, and hypophysectomized-overloaded. The weights of the plantaris muscle in the normal-overloaded were significantly higher than those of the normal-control. The weights of the hypophysectomized-overloaded were also significantly higher than those of the hypophysectomized-control. IGF-I Ea and MGF mRNAs in normal-overloaded and hypophysectomized-overloaded 3 days after overload were significantly higher than those of normal-control and hypophysectomized-control, respectively. Myostatin mRNAs in normal-overloaded and hypophysectomized-overloaded 3 days after the overload were significantly lower than those of normal-control and hypophysectomized-control, respectively. Thus, it was shown that IGF-I Ea, MGF, and myostatin mRNAs were expressed in association with muscle enlargement after compensatory overload independently of pituitary state. These observations suggest that the expression of IGF-I Ea, MGF, and myostatin mRNAs due to compensatory overload would be associated in a growth-hormone-independent manner.

Aged garlic extract ameliorates physical fatigue.

Aged garlic extract (AGE) has recently received attention as a potent anti-fatigue agent. The principal aim of this study was to elucidate the mechanism responsible for the ameliorating effect of AGE on physical fatigue in rats caused by repeated endurance exercise on a mechanical treadmill apparatus. Rats were subjected to endurance exercise 5 times per week for 4 weeks. AGE at a dosage of 2.86 g/kg was administrated to rats 30 min before every exercise. Succinate dehydrogenase (SDH) activity in the gastrocnemius and soleus muscles and superoxide dismutase (SOD) activity, nitric oxide (NO) metabolites, and lactic acid concentration in plasma were evaluated as biomarkers of physical fatigue. SDH activity was increased 2-4-fold by repeated endurance exercise in comparison with unexercised (intact) rats, and AGE further up-regulated this activity by 40%. SOD activity was increased 5-fold, whereas AGE maintained it at a level equivalent to that in intact rats. Levels of NO metabolites were slightly decreased, whereas AGE enhanced them 2-fold. Lactic acid concentration was not changed in any of the groups. These results indicate that AGE may facilitate the turnover of aerobic glucose metabolism, attenuate oxidative stress, and promote oxygen supply based on vasodilation, suggesting that AGE ameliorates the various impairments associated with physical fatigue.

mRNA expression of fibroblast growth factors and hepatocyte growth factor in rat plantaris muscle following denervation and compensatory overload.

We addressed the question of whether hypertrophy induced by compensatory overload differs according to innervation status, and how fibroblast growth factors (FGF) and hepatocyte growth factor (HGF) mRNAs are expressed in the rat plantaris muscle during overload (OL) and/or denervation. Male Wistar rats were divided into four groups (Normal-Cont, Normal-OL, Denervated-Cont, and Denervated-OL). according to the plantaris denervation and/or overload. Three weeks later, plantaris weight in Denervated-Cont and Denervated-OL was significantly lower than in the Normal-Cont. The muscle weights in the Normal-OL were higher than in the Normal-Cont. The muscle weights in the Denervated-OL were higher than in the Denervated-Cont. Three days after the treatment, FGF-2, FGF-6, FGF-7 and HGF mRNAs in the Normal-OL were significantly higher than those in the Normal-Cont. FGF-2, FGF-6, FGF-7 and HGF mRNAs in the Denervated-OL were also significantly higher after 3 days than those in the Denervated-Cont. After 7 days, FGF-2, FGF-5, FGF-6, FGF-7 and HGF mRNAs were significantly higher in the Normal-OL than those in the Normal-Cont. At 21 days, FGF-1, FGF-6 and HGF mRNA levels were significantly increased. In the Denervated-OL, FGF-2, FGF-7 and HGF mRNAs at 7 days, and FGF-2 mRNA at 21 days were significantly higher than those in the Denervated-Cont. FGF-2 and FGF-6 mRNA levels decreased significantly following denervation; however, FGF-1, FGF-5, FGF-7 and HGF mRNA levels increased and maintained this increase for the 21-days treatment period. Muscle hypertrophy was thus induced by compensatory overload irrespective of innervation status, possibly in association with certain FGFs and HGF. The differential mRNA expression patterns of FGFs and HGF observed following compensatory overload and/or denervation suggest distinct roles for individual FGFs and HGF in muscle hypertrophy and/or atrophy.

Effect of Acanthopanax senticosus Harms on biogenic monoamine levels in the rat brain.

The extract of the stem bark of Acanthopanax senticosus Harms (ASH) is known to have healing and protective effects on stress-induced disturbance of mental status. We have analysed whether a single or chronic (2 week) administration of ASH can affect concentrations of noradrenaline (NA), dopamine (DA) and their metabolites in the normal rat brain. A single p.o. administration of ASH elevated the NA and DA levels in the whole brain of rats in a dose-dependent manner. A single or 2 week administration of ASH (500 mg/kg) showed a marked increase in the DA level only in the striatum. However, NA levels were increased by a single dose of ASH in a wide range of brain regions such as the cortex, hypothalamus, striatum, hippocampus, substantia nigra and pons. When administered for 2 weeks no increase in NA levels was seen in these brain regions, except for an increase in the frontal cortex and anterior hypothalamus. The present results suggest that ASH may act by regulating NA and DA levels in specific brain regions related to stress response and Parkinson's disease.