Yasushi Matsuzaki

Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid

Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator‐activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell‐based enzymatic and gene expression assays. Nineteen patients with early‐stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7α‐hydroxy‐4‐cholesten‐3‐one (C4), a marker of bile acid synthesis, and increase of 4β‐hydroxycholesterol, a marker of CYP3A4/5 activity, were observed. In vitro experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPARα, as well as those of the pregnane X receptor (PXR); down‐regulating CYP7A1, CYP27A1, and sinusoidal Na+/taurocholate cotransporting polypeptide (NTCP), and up‐regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance‐associated protein 2 (MRP2). Conclusion: Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early‐stage PBC patients with an incomplete biochemical response to UDCA monotherapy. (HEPATOLOGY 2013)

Proton-Beam Therapy for Hepatocellular Carcinoma Associated with Portal Vein Tumor Thrombosis*

Background and Purpose:The prognosis of patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor, as effective treatment options are limited. The authors performed a retrospective review to evaluate the efficacy of proton-beam therapy (PBT) for patients presenting with PVTT in the setting of HCC.Patients and Methods:Between February 1991 and September 2005, 35 patients with HCC and tumor thrombi in the main trunk or major branches of the portal vein presented for consideration of PBT. Their tumor sizes ranged from 25 mm to 130 mm (median, 60 mm). A median total dose of 72.6 GyE in 22 fractions was delivered over 31 days to a target volume that encompassed both the primary hepatic lesion and the PVTT.Results:32 patients were progression-free during a median follow-up period of 21 months (range, 2–88 months) and three patients experienced disease progression. Local progression-free survival rates were 46% at 2 years and 20% at 5 years, and the median local progression-free survival was 21 months. Acute toxicity ≥ grade 3 was observed in three patients, and no patient experienced late toxicity ≥ grade 3. None of the patients had to discontinue treatment as a result of toxicity.Conclusion:PBT improved local control and significantly prolonged survival in HCC patients with PVTT.Hintergrund und Ziel:Die Prognose von Patienten mit fortgeschrittenem hepatozellulären Karzinom (HCC) mit Tumorthrombose der Pfortader ist in Ermangelung effektiver Behandlungsmöglichkeiten äußerst schlecht. In einer retrospektiven Studie untersuchten die Autoren die Wirksamkeit einer Protonenbestrahlung bei Patienten, die an einer durch das HCC verursachten Tumorthrombose der Pfortader litten.Patienten und Methodik:Zwischen Februar 1991 und September 2005 stellten sich 35 Patienten mit HCC und Tumorthromben in der Pfortader selbst oder in deren großen Ästen zur Erwägung einer Protonenbestrahlung vor. Die Tumorgröße betrug zwischen 25 mm und 130 mm (median 60 mm). Eine mediane Gesamtdosis von 72,6 GyE wurde in 22 Fraktionen über einen Zeitraum von 31 Tagen im Zielvolumen, das sowohl den Primärtumor als auch die Tumorthrombose in der Pfortader beinhaltete, appliziert.Ergebnisse:32 Patienten blieben über einen medianen Nachbeobachtungszeitraum von 21 Monaten progressionsfrei (Spanne 2–88 Monate), drei Patienten erlitten einen Krankheitsprogress. Das lokale progressionsfreie Überleben betrug 46% nach 2 Jahren und 20% nach 5 Jahren, das mediane lokale progressionsfreie Überleben lag bei 21 Monaten. Akuttoxizitäten ≥ Grad 3 wurden bei drei Patienten beobachtet, kein Patient erlitt Spättoxizitäten ≥ Grad 3. Bei keinem Patienten musste die Behandlung infolge von Toxizitäten abgebrochen werden.Schlussfolgerung:Die Protonenbestrahlung verbesserte die lokale Kontrolle und führte zu einer signifikanten Verlängerung des Überlebens von Patienten mit HCC und einer Tumorthrombose der Pfortader.

Proton Beam Therapy for Large Hepatocellular Carcinoma

PURPOSEnTo investigate the safety and efficacy of proton beam therapy (PBT) in patients with large hepatocellular carcinoma (HCC).nnnMETHODS AND MATERIALSnTwenty-two patients with HCC larger than 10 cm were treated with proton beam therapy at our institution between 1985 and 2006. Twenty-one of the 22 patients were not surgical candidates because of advanced HCC, intercurrent disease, or old age. Median tumor size was 11 cm (range, 10-14 cm), and median clinical target volume was 567 cm(3) (range, 335-1,398 cm(3)). Hepatocellular carcinoma was solitary in 18 patients and multifocal in 4 patients. Tumor types were nodular and diffuse in 18 and 4 patients, respectively. Portal vein tumor thrombosis was present in 11 patients. Median total dose delivered was 72.6 GyE in 22 fractions (range, 47.3-89.1 GyE in 10-35 fractions).nnnRESULTSnThe median follow-up period was 13.4 months (range, 1.5-85 months). Tumor control rate at 2 years was 87%. One-year overall and progression-free survival rates were 64% and 62%, respectively. Two-year overall and progression-free survival rates were 36% and 24%, respectively. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No late treatment-related toxicity of Grade 3 or higher was observed.nnnCONCLUSIONSnThe Bragg peak properties of PBT allow for improved conformality of the treatment field. As such, large tumor volumes can be irradiated to high doses without significant dose exposure to surrounding normal tissue. Proton beam therapy therefore represents a promising modality for the treatment of large-volume HCC. Our study shows that PBT is an effective and safe method for the treatment of patients with large HCC.

Ursodeoxycholic acid: Mechanism of action and novel clinical applications

Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, gallstone dissolution, and for patients with hepatitis C virus infection to ameliorate elevated alanine aminotransferase levels. The efficacy of UDCA treatment has been debated and the mechanisms of action in humans have still not defined. Suggested mechanisms include the improvement of bile acid transport and/or detoxification, cytoprotection, and anti‐apoptotic effects. In this review, we summarize the proposed molecular mechanisms for the action of UDCA, especially in hepatocytes, and also discuss the putative future clinical usage of this unique drug.

Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study.

Oxidative stress plays a pivotal role in the transition from simple steatosis to non‐alcoholic steatohepatitis (NASH). Probucol is a lipid‐lowering agent with strong antioxidant properties, and is reported to be effective for the treatment of NASH in several studies. The aim of the present study was to evaluate the efficacy of probucol for the treatment of NASH with dyslipidemia.

Liver Fibrosis: Possible Involvement of EMT

Hepatic fibrosis is a wound-healing process in the liver with acute and chronic injury and is characterized by an excess production and deposition of extracellular matrix components. Hepatic stellate cells as well as portal fibroblasts play a pivotal role in the liver fibrogenesis. Regarding the origin of these mesenchymal cells, two hypotheses emerge. One hypothesis argues in favor of BM-derived progenitor cells and a second hypothesis favors epithelial-mesenchymal transition (EMT) in the local formation of these mesenchymal cells from hepatic epithelium. In this short review, we describe (1) the principle mechanisms of hepatic fibrosis, (2) the cells which play a crucial role in hepatic fibrosis, and (3) the possible involvement of EMT in the process of hepatic fibrosis and carcinogenesis.

Cholesterol 25-hydroxylation activity of CYP3A

To date, many studies have been conducted using 25-hydroxycholesterol, which is a potent regulator of lipid metabolism. However, the origins of this oxysterol have not been entirely elucidated. Cholesterol 25-hydroxylase is one of the enzymes responsible for the metabolism of 25-hydroxycholesterol, but the expression of this enzyme is very low in humans. This oxysterol is also synthesized by sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase(CYP46A1), but it is only a minor product of these enzymes. We now report that CYP3A synthesizes a significant amount of 25-hydroxycholesterol and may participate in the regulation of lipid metabolism. Induction of CYP3A by pregnenolone-16α-carbonitrile caused the accumulation of 25-hydroxycholesterol in a cell line derived from mouse liver. Furthermore, treatment of the cells with troleandomycin, a specific inhibitor of CYP3A, significantly reduced cellular 25-hydroxycholesterol concentrations. In cells that overexpressed human recombinant CYP3A4, the activity of cholesterol 25-hydroxylation was found to be higher than that of cholesterol 4β-hydroxylation, a known marker activity of CYP3A4. In addition, 25-hydroxycholesterol concentrations in normal human sera correlated positively with the levels of 4β-hydroxycholesterol (r = 0.650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol.

Highly sensitive and specific analysis of sterol profiles in biological samples by HPLC-ESI-MS/MS.

High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) is a powerful method for the microanalysis of compounds in biological samples. Compared with gas chromatography-mass spectrometry (GC-MS), this method is more broadly applicable to various compounds and usually does not require a derivatization step before analysis. However, when neutral sterols are analyzed, the sensitivities of usual HPLC-MS/MS method are not superior to those of GC-MS because the sterols are relatively resistant to ionization. In this review, we introduce the recent development of HPLC-MS/MS analysis for the quantification of non-cholesterol sterols. By adding an effective derivatization step to the conventional procedure, sterol analysis by HPLC-MS/MS surpassed that obtained by GC-MS in sensitivity. In addition, sufficient specificity of this method was achieved by selected reaction monitoring (SRM) and thorough chromatographic separation of each sterol.

Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine

Taurine (2-aminoethylsulfonic acid) has many physiological and pharmacological functions in most tissues. It is abundantly maintained in the liver by both endogenous biosynthesis and exogenous transport, but is decreased in liver diseases. In the hepatic lobule, there are heterogeneous differences in metabolism between the pericentral (PC) and periportal regions, and the distributions of the biosynthesis capacity and specific taurine transporter expression are predominantly in the PC region. In cases of depletion of hepatic taurine level, serious liver damages were observed in the PC region. Taurine has protective effects against xenobiotics-induced liver damages in the PC region, but not xenobiotics-induced PP region damages. The xenobiotics that injure the PC region are mainly catabolized by NADPH-dependent cytochrome P450 2E1 that is also predominantly expressed in the PC region. Taurine treatment seems to be a useful agent for CYP2E1-related liver diseases with predominant damages in the PC region.

Combined effect of branched-chain amino acids and taurine supplementation on delayed onset muscle soreness and muscle damage in high-intensity eccentric exercise

BackgroundPrevious studies have evaluated the effectiveness of branched-chain amino acid (BCAA) supplementation for preventing delayed onset muscle soreness (DOMS) and muscle damage induced by eccentric exercise, their findings have been inconclusive. Since taurine has anti-inflammatory and anti-oxidative effects, the present study investigated the combined effect of BCAA and taurine on DOMS and muscle damage.MethodsThirty-six untrained male subjects (22.5u2009±u20093.8 years) were assigned to four groups (placebo + placebo [placebo], BCAA + placebo, placebo + taurine, and BCAA + taurine [combined]) and given a combination of 3.2 g BCAA (or placebo) and 2.0 g taurine (or placebo), three times a day, for two weeks prior to and three days after eccentric elbow flexor exercises. DOMS and muscle damage in the biceps brachii were subjectively and objectively evaluated using the visual analogue scale (VAS), upper arm circumference (CIR), and blood parameters (creatine kinase, lactate dehydrogenase [LDH], aldolase, and 8-hydroxydeoxyguanosine [8-OHdG]).ResultsIn the combined group, VAS and 8-OHdG two days after exercise, CIR two and three days after exercise and LDH from one to three days after exercise were significantly lower than the placebo group. The area under the curve from before exercise to four days later for CIR, LDH, and aldolase was also significantly lower in the combined group than in the placebo group.ConclusionA combination of 3.2 g BCAA and 2.0 g taurine, three times a day, for two weeks prior to and three days after exercise may be a useful nutritional strategy for attenuating exercise-induced DOMS and muscle damage.