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【Sudachitin】Main Citrus Flavonoids with Antidiabetic Effects



【Sudachitin】Main Citrus Flavonoids with Antidiabetic Effects

Sudachitin (5,7,4′-trihydroxy-6,8,3′-trimethoxyflavone), also known as menthocubanone, is a polymethoxylated flavone originally found in the skin of Citrus sudachi Hort. fruit. Sudachitin belongs to the class of organic compounds known as 8-O-methylated flavonoids and has been detected commonly in citrus fruits, such as mandarin oranges and bitter oranges. It exhibits diverse biological activities, such as the suppression of inflammatory bone destruction, induction of apoptosis in human keratinocyte HaCaT cells, enhancement of antigen-specific cellular and humoral immune responses, and inhibition of matrix metalloproteinase (MMP)-1 and MMP-3 production in TNF-α-stimulated human periodontal ligament cells.

The effects of sudachitin on glucose, lipid, and energy metabolism in an HFD experimental obesity model using C57BL/6J mice and diabetic db/db mice fed a normal diet were investigated by Tsutsumi et al. , and it was found that sudachitin reduced the weight gain in the HFD mice without changing the food intake. It also ameliorated the elevated adipose tissue mass, increased subcutaneous fat deposits, and elevated visceral fat composition, and normalized adipocyte size and function. In addition, it reduced hyperinsulinemia and hyperglycemia, improved glucose tolerance, ameliorated plasma leptin levels, decreased visceral fat content, increased plasma adiponectin levels, and improved insulin sensitivity. A possible explanation for these effects could be the ability of sudachitin to modulate metabolism-related genes, such as by modulating the mRNA expression of GLUT4 and transcripts of uncoupling protein 1 and 3 (UCP1 and UCP3) in white adipose tissue and the liver, which were significantly increased in the white adipose tissue of the diabetic animals. Besides, it was able to decrease the levels of the mRNA transcripts encoding FAS ligand, ACC1, and ACC2 in the liver. Tsutsumi et al. also reported that sudachitin promoted energy expenditure by activating the sirtuin (Sirt)1–PGC1α pathway, increased basal muscle skeletal adenosine triphosphate (ATP) contents, and increased mitochondrial citrate synthase activity. Sudachitin also improved insulin sensitivity and reduced fasting blood glucose and TG levels in diabetic db/db mice. Finally, an important in vitro study carried out by Tsutsumi et al. showed that sudachitin influenced the mitochondrial biogenesis by activating vital signaling pathways in myocytes, increasing the expression of genes such as nuclear respiratory factor 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (mtTFA). Sudachitin treatment increased the mitochondrial number and activity. Therefore, these observations indicate that sudachitin has good potential for managing obesity and diabetes and its associated complications.

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