Please consult your physician first (especially if you have a medical condition). Do not use if you are pregnant/lactating or under the age of 18. Remember that an adequate state of hydration must be maintained when using this product. Have at least 8 - 12 large glasses of water per day. Do not exceed the recommended daily intake. Taking more than the recommended dose will not improve results and may cause adverse reactions. For best results an appropriate weight gain eating plan and training programme should be followed. High intake of free-form amino acids may initially cause gastric discomfort in sensitive individuals - if this prolongs, reduce dosage or discontinue. Nutritional supplements should not replace a balanced, varied diet. Tolerance to lactose is variable - please seek advice as to the role of lactase in the diet.
Reduced SIRT1 activity and levels during osteoarthritis (OA), promotes gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase of matrix metalloproteinase 13 (MMP13), partially due to enhanced LEF1 transcriptional activity. Here we assess the role of SIRT1 in LEF1-mediated MMP13 gene expression in human osteoarthritic chondrocytes. Results show that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1β, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression, however, overexpression of SIRT1 during IL-1β challenge impeded LEF1 levels and MMP13 gene expression. While previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mice articular cartilage from Sirt1 nulls presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.
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