Acne vulgaris is an inflammatory disease in sebaceous glands and pilosebaceous units in the skin, and is characterised by excess sebum production, hypercornification of the follicular wall epidermis, local infection with Propionibacterium acnes, and local inflammatory events such as the augmentation of proinflammatory cytokine production and the formation of papules and pustules . Treatments for acne include: benzoyl peroxide, retinoic acids such as tretinoin and isotretinoin, and adapalene; antibiotics are also widely prescribed [2-4]. In addition, herbal medicines are well known to be effective for the prevention and/or remission of various diseases including acne [5-10]. Flavonoids from medicinal plants have also been reported to possess various pharmacological effects including anti-inflammatory and anti-ageing effects against skin disorders [11-13]. We recently found a citrus polymethoxy flavonoid, nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), that exhibits multiple pharmacological actions in both in vivo and in vitro models of rheumatoid arthritis, tumorigenesis, tumour invasion and metastasis, and photoageing [14-21]. This review describes the novel effects of nobiletin and related citrus polymethoxy flavonoids on sebaceous lipogenesis and sebum excretion , and discusses their application as acne therapies.
The pathogenesis of acne is characteristic of: (1) excess sebum production and hyperplasia of sebaceous glands; (2) formation of microcomedones closely associated with hyperkeratinisation of follicular walls and infundibulum; and (3) induction of inflammatory reactions such as the enhancement of cytokine production and arachidonic acid metabolism in keratinocytes, sebocytes, and invading inflammatory cells . Androgens such as testosterone and 5 [alpha]-dihydrotestosterone (5 [alpha] -DHT), insulin, prostaglandin J2, and peroxisome-proliferation stimulating factors have been reported to augment lipogenesis in sebaceous glands [23-28]. P. acnes, a Gram-positive anaerobe microbial species, contributes to the development of acne vulgaris in sebaceous glands and pilosebaceous units in the skin . P. acnes lipase degrades triacylglycerols, a major component of sebum and a nutritional element of P. acnes, to produce free fatty acids, which are in turn associated with the hyperkeratinisation of follicular walls and infundibulum . In addition, P. acnes-derived factor(s) have been reported to induce inflammatory reactions such as the augmentation of inflammatory cytokine production and extracellular matrix remodelling [30-33]. Furthermore, recent studies suggest a possibility that the skin flora of Gram-negative bacteria take part in the appearance and increase in deterioration of acne by locally enhancing inflammatory events in concert with P. acnes [29,34,35].
Application of nobiletin for acne therapy
Flavonoids have many pharmacological actions in vivo and in vitro. They are antioxidants, free radical scavengers and have anti-inflammatory, antitumourigenic and antitumour metastatic activities [16,17,36,37]. In the regulation of lipid synthesis, a common dietary flavonoid, quercetin, has been reported to exhibit the suppressive action of de novo triacylglycerol synthesis in human intestinal cells . In addition, a citrus flavonoid, hesperetin, has been shown to inhibit triacylglycerol synthesis in rat hepatocytes . Although the formulation of herbal medicines has been effective in improving the constitution of acne patients , there is little evidence on the regulation of sebaceous lipogenesis by herbal medicines. In this context, wogonin, a flavonoid derived from Japanese-Chinese traditional...