Yukihisa Tanaka

Siphonaxanthin, a marine carotenoid from green algae, effectively induces apoptosis in human leukemia (HL-60) cells.

BACKGROUND Bioactive marine molecules have recently received considerable attention for their nutraceutical characteristics. Considering the ever-increasing demand of nutraceuticals for anti-cancer therapy, we investigated the apoptosis-inducing effects of marine carotenoids, including siphonaxanthin, on human leukemia (HL-60) cells. METHODS Apoptotic effects were evaluated by cell viability assay, TUNEL assay, and caspase-3 activity. The expression of apoptosis-inducing death receptor-5 (DR5), Bcl-2 and Bax were assayed by Western blot analysis, and mRNA expression of GADD45α was assayed by quantitative RT-PCR analysis. RESULTS Siphonaxanthin potently inhibited the viability of HL-60 cells compared with the other carotenoids evaluated. In comparison with fucoxanthin, siphonaxanthin at a concentration of 20μM markedly reduced cell viability (p<0.05) as early as within 6h of treatment. The effective apoptotic activity of siphonaxanthin was observed by increases in TUNEL-positive cells, and by increased chromatin condensation in HL-60 cells. This induction of apoptosis was associated with the decreased expression of Bcl-2, and the subsequently increased activation of caspase-3. In addition, siphonaxanthin up-regulated the expression of GADD45α and DR5. CONCLUSIONS These data suggest that the dietary carotenoid siphonaxanthin could be potentially useful as a chemo-preventive and/or chemotherapeutic agent. GENERAL SIGNIFICANCE Our findings demonstrate for the first time the novel functional property of siphonaxanthin as a potent inducer of apoptosis in HL-60 cells.

Anti-angiogenic effect of siphonaxanthin from green alga, Codium fragile.

Since anti-angiogenic therapy has becoming a promising approach in the prevention of cancer and related diseases, the present study was aimed to examine the anti-angiogenic effect of siphonaxanthin from green alga (Codium fragile) in cell culture model systems and ex vivo approaches using human umbilical vein endothelial cells (HUVECs) and rat aortic ring, respectively. Siphonaxanthin significantly suppressed HUVEC proliferation (p<0.05) at the concentration of 2.5 μM (50% as compared with control) and above, while the effect on chemotaxis was not significant. Siphonaxanthin exhibited strong inhibitory effect on HUVEC tube formation. It suppressed the formation of tube length by 44% at the concentration of 10 μM, while no tube formation was observed at 25 μM, suggesting that it could be due to the suppression of angiogenic mediators. The ex vivo angiogenesis assay exhibited reduced microvessel outgrowth in a dose dependent manner and the reduction was significant at more than 2.5 μM. Our results imply a new insight on the novel function of siphonaxanthin in preventing angiogenesis related diseases.

The benefit of medium-chain triglyceride therapy on the cardiac function of SHRs is associated with a reversal of metabolic and signaling alterations

The spontaneously hypertensive rat (SHR) is a model of cardiomyopathy that displays a genetic defect in cardiac fatty acid (FA) translocase/CD36, a plasma membrane long-chain FA transporter. Therapy with medium-chain FAs, which do not require CD36-facilitated transport, has been shown to improve cardiac function and hypertrophy in SHRs despite persistent hypertension. However, little is known about the underlying molecular mechanisms. The aim of this study was to document the impact of medium-chain triglyceride (MCT) therapy in SHRs on the expression level and activity of metabolic enzymes and signaling pathways. Four-week-old male SHRs were administered MCT (SHR-MCT) or long-chain triglyceride (SHR-LCT) for 16 wk. We used Wistar-Kyoto (WKY) rats as controls (WKY-MCT and WKY-LCT). The SHR-MCT group displayed improved cardiac dysfunction [as assessed by left ventricular (LV) end-diastolic pressure and the positive and negative first derivatives of LV pressure/P value], a shift in the beta-myosin heavy chain (MHC)-to-alpha-MHC ratio, and cardiac hypertrophy compared with the SHR-LCT group without an effect on blood pressure. Administration of MCT of SHRs reversed the LCT-induced reduction in the cardiac FA metabolic enzymatic activities of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD). In the SHR-MCT group, the protein expression and transcriptional regulation of myocardial peroxisome proliferator-activated receptor-alpha, which regulates the transcription of LCHAD and MCAD genes, corresponded to the changes seen in those enzymatic activities. Furthermore, MCT intake caused an inhibition of JNK activation in SHR hearts. Collectively, the observed changes in the myocardial activity of metabolic enzymes and signaling pathways may contribute to the improved cardiac dysfunction and hypertrophy in SHRs following MCT therapy.

Effects of medium-chain triglyceride (MCT) application to SHR on cardiac function, hypertrophy and expression of endothelin-1 mRNA and other genes

In spontaneously hypertensive rats a decrease occurs in myocardial energy supply from long-chain triglyceride (LCT) by CD36 gene mutation-induced dysfunction. We investigated whether long-term intake of medium-chain triglyceride, which enters into cells without CD36, upregulates fatty acid metabolic capacity in the heart of spontaneously hypertensive rats, and whether this upregulation improves cardiac hypertrophy and molecular markers. Male 4-week-old spontaneously hypertensive rats were given medium-chain triglyceride (SHR-MCT) or LCT (SHR-LCT) for 16 weeks. After hemodynamic measurement, we determined myocardial fatty acid metabolic enzyme activity and mRNA expression of molecular markers (endothelin-1, α-skeletal actin, angiotensin-converting enzyme and brain natriuretic peptide) for cardiac hypertrophy. We used Wistar-Kyoto rats (WKY-MCT and WKY-LCT) as controls. When compared with SHR-LCT rats, SHRMCT rats showed an increase in myocardial fatty acid metabolic enzyme activity and improvement in cardiac function (left ventricular end-diastolic pressure and +dP/dt/P) and cardiac hypertrophy. Blood pressure did not differ between them. The mRNA expression of endothelin-1, α-skeletal actin, angiotensinconverting enzyme and brain natriuretic peptide in the heart was significantly higher in SHR-LCT than in WKY-MCT and WKYLCT rats, and there was no significant difference between SHRLCT and SHR-MCT. These findings suggest that medium-chain triglyceride application to spontaneously hypertensive rats improves decreased cardiac function and cardiac hypertrophy without affecting blood pressure and myocardial mRNA expression of molecular markers. Because mechanical stress to the heart is similar between SHR-LCT and SHR-MCT, this may be a reason for the lack of difference in expression of molecular markers.

Content and fatty acid composition of sulfoquinovosyldiacylglycerol in conifer leaves grown in Hokkaido, Japan.

Sulfoquinovosyldiacylglycerol (SQDG) contents in conifer leaves and their fatty acid (FA) compositions were determined. The SQDG content was 16–36 mg/100 g, and was high in Picea glehnii. Palmitic and α-linolenic acid were the usually predominant FAs. In Picea, the proportion of α-linolenic acid was low, and those of oleic and linoleic acid were high. The essential oil residues of Abies sachalinensis leaves were found to be a potential source of SQDG material.