Ima Nirwana Soelaiman

OSTEOPOROSIS is a generalised, degenerative disorder of the skeleton. As a person ages, the bone will lose its density and become thinner and more porous. This will make the bone more susceptible to fractures.  There are many causes of osteoporosis, such as lack of the sex hormones oestrogen and testosterone, which occurs  as a woman or a man ages, heavy smoking, calcium and vitamin D deficiency, as well as excess of thyroid and steroid hormones.

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γ-Tocotrienol attenuates TNF-α-induced changes in secretion and gene expression of MCP-1, IL-6 and adiponectin in 3T3-L1 adipocytes

Matsunaga T, Shoji A, Gu N, Joo E, Li S, Adachi T, Yamazaki H, Yasuda K, Kondoh T, Tsuda K.

Mol Med Report. 2012 Apr;5(4):905-9. Epub 2012 Jan 30.

Tocotrienols, members of the vitamin E family, have been shown to possess anti-inflammatory properties and display activity against a variety of chronic diseases, such as cancer, cardiovascular and neurological diseases. However, whether tocotrienols contribute to the prevention of inflammatory responses in adipose tissue remains to be elucidated. In this study, we examined the effects of γ-tocotrienol, the most commontocotrienol isomer, on tumor necrosis factor-α (TNF-α)-induced inflammatory responses by measuring the expression of the adipokines, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes. Exposure to TNF-α (10 ng/ml) for 24 h increased MCP-1 and IL-6 secretion, and decreased adiponectin secretion and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA expression. γ-tocotrienoleffectively improved the TNF-α-induced adverse changes in MCP-1, IL-6 and adiponectin secretion, and in MCP-1, IL-6, adiponectin and PPARγ mRNA expression. Furthermore, TNF-α-mediated IκB-α phosphorylation and nuclear factor-κB (NF-κB) activation were significantly suppressed by the γ-tocotrienol treatment. Our results suggest that γ-tocotrienol may improve obesity-related functional abnormalities in adipocytes by attenuating NF-κB activation and the expression of inflammatory adipokines.

The objective of this study was to optimize a novel tocotrienol (TRF)-rich Self Emulsified Drug Delivery System (SEDDS). In the first part, an unusual phenomenon was investigated. It was observed that by sub-stituting Tween® 80 with Cremophor® EL in the SEDDS it was possible to emulsify > 55% TRF (by weight of the formulation) into submicron (<200 nm) emulsion. With Tween®, only 17.5% of the loaded TRF could be emulsified into crude emulsion. The superiority of Cremophor® was attributed to the special arrange-ment of the surfactant at the oil/water interface, which was confirmed by modelling and docking studies. In the second part of this study, the composition of the secondary ingredients in the TRF-rich SEDDS were optimized by the modified Multisimplex® approach. SEDDS were manufactured at pre-defined step-size and tested for their dissolution behavior. Testing was performed sequentially until the optimum compo-sition that can emulsify 50% of the loaded TRF into a stable < 150 nm submicron emulsion was obtained. Optimization end-point was identified when the “membership value” approached 1, which was con-firmed by a second Multisimplex® run. Overall, this study demonstrated the utility of docking studies and the Multisimplex® approach in product development when little is known about the experimental “design space”.

γ-Tocotrienol has attracted much attention owing to its multiple health benefits. This study developed and validated a simple, specific, sensitive and reliable LC/MS/MS method to analyze γ-tocotrienol in rat plasma. Plasma samples (50mL) were extracted with internal standard solution (25 ng/mL of itraconazole) in acetonitrile (200mL) with an average recovery of 44.7% and an average matrix effect of -2.9%. The separation of γ-tocotrienol and internal standard from the plasma components was achieved with a Waters XTerraW MS C18 column with acetonitrile–water as mobile phase. Analysis was performed under positive ionization electrospray mass spectrometer via the multiple reaction monitoring. The standard curve was linear over a concentration range of 10–1000 ng/mL with correlation coefficient values >0.997. The method was validated with intra- and inter-day accuracy (relative error) ranging from 1.79 to 9.17% and from 2.16 to 9.66%, respectively, and precision (coefficient of variation) ranged from 1.94 to 9.25% and from 2.37 to 10.08%, respectively. Short-term stability, freeze–thaw stability and the processed sample stability tests were performed. This method was further applied to analyze γ-tocotrienol plasma concentrations in rats at various time points after administration of a 2 mg/kg single intravenous dose, and a pharmacokinetic profile was successfully obtained.

“First evidence that gamma-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-kappaB pathway.”

Manu, K. A., Shanmugam, M. K., Ramachandran, L., Li, F., Fong, C. W., Kumar, A. P., Tan, P., Sethi, G.

Clin Cancer Res. 2012 Apr 15;18(8):2220-9.

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether gamma-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.

Experimental Design: The effect of gamma-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kappaB activation by DNA-binding assay, and gene expression by Western blotting. The effect of gamma-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.

Results: gamma-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kappaB, and suppressed the NF-kappaB-regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of gamma-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and gamma-tocotrienol. As compared with vehicle control, gamma-tocotrienol also suppressed the NF-kappaB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.

Conclusions: Overall our results show that gamma-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kappaB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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