Antidepressant effects of acupuncture in a murine model: regulation of neurotrophic factors.

BACKGROUND: GV20 and Yintang are important targets in acupuncture treatment for depression. In this study, we examined the antidepressant effects of simultaneous acupuncture stimulation at GV20 and Yintang. METHODS: We compared the antidepressant effects of manual acupuncture (MA) stimulation at GV20 and Yintang, compared to acupuncture stimulation at two control point locations on the back of the mice (overlying the spinal column) and imipramine administration in a forced swimming (FS)-induced mouse model of depression, and examined the mRNA and protein expression of neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 in the brains by real-time polymerase chain reaction in two different experimental schedules - preventive (MA given alongside FS modelling) and therapeutic (MA given after FS-induced depression was already established). RESULTS: MA at GV20 and Yintang significantly reduced the immobility time of mice with FS-induced depression in both preventive and therapeutic experimental designs, with effects that were comparable to those of imipramine administration. Immobility time following simultaneous acupuncture stimulation of the two control point locations overlying the spinal column was significantly suppressed only 2 weeks after the start of FS in the preventive effect experiment, and the suppressive effect was significantly lower than that of simultaneous acupuncture stimulation at GV20 and Yintang. In the therapeutic effect experiment, there was no change in the increase in immobility time after the end of FS. MA at GV20 and Yintang significantly increased the expression of BDNF and NT-3 in the preventive evaluation and NGF, BDNF, NT-3, and NT-4/5 in the therapeutic effect evaluation. CONCLUSION: Our findings suggest that simultaneous acupuncture stimulation at GV20 and Yintang is effective for the prevention and treatment of depression, and the effect likely involves modulation of the expression of multiple neurotrophic factors.

Observation of Acupuncture Effects on the Expression of Taurine Transporter and Taurine in the Senescence-Accelerated Mouse Brain: A Pilot Study.

In living organisms, taurine is important for homeostasis and is known to have preventive and inhibitory effects on various diseases. Taurine has been reported to play an important role in the development of the brain in newborns and in reducing the damage caused by cerebral ischemia. Previous studies indicated that acupuncture on a pair of acupoints of "DU16" and "DU20" can increase brain taurine transporter (TauT) expression in mice with penicillin-induced epilepsy and enhanced taurine anti-epilepsy effects. Our previous study reported that manual acupuncture stimulation of the head acupuncture points "Bai-Hui" (GV 20) and "Yintang" (Ex-HN3) could produce antidepressant effects. In this study, we investigated whether acupuncture stimulation of the head acupuncture points GV 20 and Ex-HN3 affects the expression of TauT and taurine in the cerebellum and hippocampus in senescence-accelerated mice. Acupuncture stimulation significantly increased the mRNA expression of TauT in the cerebellum and hippocampus. Immunohistochemical staining confirmed that the expression of TauT and taurine in the cerebellum and hippocampus increased. These results indicate that acupuncture stimulation might improve cognitive and behavioral abilities by increasing the expression of TauT and taurine.

Acupuncture Treatment for Social Defeat Stress.

Depression is a mood disorder characterized by disordered affect, thoughts, cognition, and behavior. Antidepressant therapy is often the primary treatment for depression. However, antidepressant therapy may cause unwanted side effects, and its effects are slow. Therefore, some patients are seeking alternative treatments for depression, such as acupuncture. However, there are many unclear points regarding the mechanism of the effect of acupuncture on depression. In recent years, we have reported that acupuncture improves the symptoms of mild depression induced by water-immersion stress in a rat model and depression induced by forced swimming in a mouse model. In this study, we examined the effect of acupuncture on the symptoms of social defeat stress (SDS)-induced depression in mice that most closely resemble human symptoms. In this study, we investigated the preventive and therapeutic effects of acupuncture as part of GV20 "Bai-Hui" and Ex-HN3 "Yintang" on model mice with depression induced by SDS. To examine the mechanism of the preventive and therapeutic effects of acupuncture on depression model mice, we examined the expression of neurotrophic factors in the brains of SDS mice. Two weeks of simultaneous acupuncture stimulation as part of GV20 and Ex-HN3 restored SDS-reduced brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 expression, which was not observed with antidepressants. In contrast, acupuncture stimulation suppressed nerve growth factor (NGF) expression induced by SDS. These results suggest that acupuncture treatment could be effective in correcting the imbalance in the expression of neurotrophic factors. Furthermore, the effects of acupuncture on the expression of neurotrophic factors appear earlier than those of antidepressants, suggesting that it may be a useful treatment for depression.

[A case of hepatocellular carcinoma with autoimmune hepatitis showing marked reduction of tumors by oral administration of UFT-E].

We report a case of hepatocellular carcinoma (HCC) in association with autoimmune hepatitis (AIH). In May 2003, a 66- year-old man was admitted to our hospital because of acute liver dysfunction. He was diagnosed with AIH, and his liver function was normalized by oral administration of the corticosteroid. In July 2007, when he was admitted for the treatment of bacterial pneumonia, two liver tumors (S4: ø4 cm and S2: ø1 cm) were revealed by abdominal CT scan, and the serum level of AFP was high. According to the findings of imaging diagnosis and laboratory data, the patient was diagnosed as having HCC. Since the standard invasive therapies of HCC were not accepted by the patient and his family, he was treated by oral administration of UFT-E (tegafur/uracil: 200 mg/day). Three months after the initiation of administration, CT scan showed a remarkable reduction of the tumors, and his serum AFP level was decreased to the normal range. This case shows that HCC develops in an AIH patient even if liver function is maintained in the normal range. It also suggests the clinical usefulness of UFT-E in the management of HCC given the difficulty of treatment by the standard therapies.

Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma.

PURPOSE: This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC). METHODS: This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks. RESULTS: There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045-0.561, P = 0.004), and the serum albumin level was retained. CONCLUSION: These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.

Vitamin K2 downregulates the expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma cells.

AIM: Vitamin K2 exerts an antitumor activity on human hepatocellular carcinoma (HCC), however, its inhibitory mechanism has not yet been clarified. This study was designed to identify the attractive target molecule of vitamin K2 and shed some light on its effects on fibroblast growth factor receptor (FGFR)3 in HCC cells. METHODS: The changes in the gene expression of HuH-7 after vitamin K2 treatment were evaluated by a DNA chip analysis. The mRNA and protein levels of FGFR were evaluated by semiquantitative reverse transcription polymerase chain reaction (RT-PCR), real-time PCR and western blot analysis. The promoter activity of the FGFR3 gene was measured by a dual-luciferase assay. RESULTS: The DNA chip analysis revealed different inhibitory rates of gene expression of FGFR3 (60.6%) and FGFR1 (19.4%) after vitamin K2 treatment. Vitamin K2 suppresses the proliferation of HuH-7 in a dose-dependent manner and its inhibitory rate reached approximately 61.8% at the dose of 30 microM. FGFR3 mRNA was significantly reduced based on semiquantitative RT-PCR and decreased 61.5% by a real-time PCR method after vitamin K2 treatment, but FGFR1 mRNA was not. The level of FGFR3 protein was also reduced by vitamin K2 treatment. The luciferase assay demonstrated that vitamin K2 significantly suppressed the promoter activity of FGFR3. Furthermore, the FGFR3-ERK1/2 signaling pathway was suppressed by vitamin K2 treatment. CONCLUSION: These findings suggest that vitamin K2 may suppress the proliferation of HCC cells through the downregulation of the FGFR3 expression. The transcriptional suppression of FGFR3 may be a novel mechanism of the vitamin K2 action for HCC cells.

Alpha-sulfanyl and alpha-selanyl propadienyl cations: regioselective generations and cycloadditions with thioamides and selemides controlled by MeNO2-H2O system.

Alpha-sulfanyl and alpha-selanyl propadienyl cations were easily generated by the catalytic system, scandium triflate-nitromethane-H(2)O in the presence of Bu(4)NHSO(4), to regioselectively afford the multifunctionalized thiazoles and selenazoles in high yields.

Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2).

BACKGROUND: Vitamin K(2) has been reported to suppress the growth of human hepatocellular carcinoma (HCC) in vitro and hepatocarcinogenesis in hepatitis C virus (HCV)-related cirrhosis in vivo. Hepatoma-derived growth factor (HDGF) is a unique nuclear targeting growth factor that is highly expressed in HCC cells and is a possible prognostic factor for patients with HCC. We investigated the regulation of HDGF expression by vitamin K(2). METHODS: Three HCC-derived cell lines, HepG2, HuH-7, and SK-Hep-1, were used. Cell number was determined with the MTT assay. The expression levels of HDGF mRNA and protein were measured by the real-time reverse transcriptase-polymerase chain reaction (PCR) method and ELISA and Western blot analysis, respectively. The HDGF promoter activity was measured by a dual luciferase-reporter assay. RESULTS: Vitamin K(2) suppressed the growth of the three HCC cell lines in a dose-dependent manner. Vitamin K(2) significantly suppressed the expression of the HDGF protein and mRNA in three cell lines. By a luciferase assay, vitamin K(2) significantly suppressed the promoter activity of the HDGF protein. Based on some luciferase-reporter plasmids containing truncated promoter regions, the possible responsive site of vitamin K(2) seems to reside in the region -1 to -150 bp of the HDGF gene. CONCLUSIONS: These findings suggested that regulation of the HDGF gene expression is one of the crucial mechanisms of vitamin K(2)-induced cell growth suppression for HCC.

Partial blockage of hepatocyte maturation in hepatoma-derived growth factor transgenic mice.

AIM: To investigate the role of hepatoma-derived growth factor (HDGF) in liver development, especially in the hepatocyte differentiation. METHODS: We generated transgenic mice which overexpressed HDGF in hepatocytes under the transcriptional control of mouse albumin promoter/enhancer. To examine the effects of HDGF overexpression on hepatocyte differentiation, we investigated the expression patterns of the differentiation marker genes. RESULTS: The HDGF transgenic mice developed normally and showed no apparent abnormality in the liver. However, the gene expression patterns of the liver in adult transgenic mice were similar to those of the neonatal liver in control mice. CONCLUSION: These findings suggest that HDGF-overexpression partially suppresses hepatocyte maturation.

Scandium-catalyzed carbon-carbon bond-forming reactions of 3-sulfanyl- and 3-selanylpropargyl alcohols.

The scandium-catalyzed substitution reactions of the phenylsulfanyl and phenylselanyl propargyl alcohols 3a- i and 7a- h regioselectively proceeded to give the propargylated compounds 4 and 8 in high yields.

Vitamin K2 inhibits the proliferation of HepG2 cells by up-regulating the transcription of p21 gene.

AIM: Vitamin K2 has been reported to inhibit the growth of human hepatocellular carcinoma (HCC) in vitro and suppress hepatocarcinogenesis in vivo. However, its inhibitory mechanism has not yet been clarified. METHODS: Different concentrations of vitamin K2 (30, 10, 1, 0.1 and 0.01 muM) were added to the HCC cell line HepG2 to assess effects on cell growth. The effect of vitamin K2 on cell cycle progression was determined by flow-cytometric analysis. The expression of cell cycle regulatory proteins p21 and p27 was then examined by Western blot. Whether vitamin K2 regulates the gene expression through action on the p21 promoter region was investigated by luciferase assay. RESULTS: Vitamin K2 inhibited the growth of HepG2 cells dose-dependently, and its inhibitory rate reached approximately 50% at the dose of 30 muM after 96 h treatment. After treatment with vitamin K2, the proportion of cells in G0-G1 phase increased, and in S phase decreased. Apoptotic cells were not detected. The expression of cell cycle regulatory protein p21 was induced by vitamin K2 treatment, but p27 was not. By the luciferase assay, vitamin K2 significantly activated the promoter of p21. Knock-down of p21 by siRNA reversed the growth inhibition of HepG2 cells by vitamin K2. CONCLUSIONS: The findings suggest that vitamin K2 suppresses the proliferation of HCC cells by blocking the cell cycle G1/S progression through the transcriptional induction of p21.

Scandium-catalyzed carbon-carbon bond formations using alpha-organosulfanyl and organoselanyl-alpha-fluoroacetic acid derivatives.

The scandium-catalyzed reactions of alpha-organosulfanyl and organoselanyl-alpha-fluoroacetates 1-2, acetamides 3-4 and acetonitrile 5 with soft nucleophiles proceeded to give the products 6a-b, 7a-c, 8a-c, 9a-e in good to high yields. We also successfully performed the scandium-catalyzed intramolecular cyclization reactions and obtained the unique 5-methylene-2-oxotetrahydropyrans 16-17.

Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase-2 inhibitor.

Cyclooxygenase 2 (COX-2) and retinoid X receptor alpha (RXRalpha) are suggested to have roles in carcinogenesis. COX-2 inhibitors have been reported to suppress growth of hepatocellular carcinoma (HCC) cell lines in vitro. However, little is known about the preventive effect of these drugs on spontaneous hepatocarcinogenesis in vivo. Etodolac exists in a racemic mixture containing S- and R-etodolac. S-etodolac is responsible for COX-2 inhibitory activity and R-etodolac is related to the downregulation of RXRalpha. Here, the effect of etodolac on spontaneous development of HCC in fatty liver Shionogi mice is evaluated. Etodolac was administered at a low (2 mg/kg) or high (10 mg/kg) dose three times a week for 16 months starting at the age of 3 months. The development of HCC was suppressed slightly in the high-dose group, and suppressed markedly in the low-dose group, although the development of fatty liver was not inhibited in either group. Plasma prostaglandin E2 levels were also decreased significantly in the low-dose group, consistent with the suppression of HCC. The expression of RXRalpha and proliferating cell nuclear antigen in non-tumorous liver tissues was decreased significantly in both the low-dose and high-dose groups. These findings show that etodolac treatment at an optimum dose suppresses hepatocarcinogenesis in vivo, and may be useful for preventing the development of HCC in humans.

[Mechanism and clinical application of carcinogenesis control by IFN].

In Japan, most of hepatocellular carcinoma (HCC) developed in the patients with hepatitis C virus (HCV) related chronic liver disease. In these patients, hepatic cells repeat necrosis and rebirth. As a result, it is considered that persistent inflammation accumulate DNA mutation and finaly develop HCC. In patients infected with HCV, IFN therapy prevents the development of HCC by eradication of HCV. Our findings demonstrated that cell prolificaion was suppressed in proportion to the dose of IFN in human liver cancer cell lines. It is important to establish the clinical marker to assess the carcinogenic potential in each patient. Because it is related to the analysis of carcinogenic control and/or the accurate evaluations of clinical effect by IFN in HCC.