The role of mTORC1 in acne pathogenesis and ...

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mTORC1 signaling by a paleolithic-type diet supported with natural or synthetic mTOR inhibitors. KEYWORDS: acne • dairy • glycemic load • mechanistic target ...
Perspective

The role of mTORC1 in acne pathogenesis and treatment Expert Rev. Dermatol. 8(6), 617–622 (2013)

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Bodo C Melnik Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabru¨ck, Germany Tel.: +49 524 198 8060 [email protected]

Acne vulgaris is a common skin disease in industrialized countries with Western diet characterized by high glycemic load and milk consumption. Accumulating evidence underlines the role of Western diet as a major cause of enhanced nutrient-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling that may over-stimulate sebocyte growth and sebaceous lipogenesis resulting in sebaceous gland hyperplasia, hyperseborrhoea, Propionibacterium acnes overgrowth with biofilm formation and inflammatory follicular reactions. Substantial evidence from translational research suggests that all anti-acne agents operate by a common mechanism: the attenuation of exaggerated mTORC1 signal transduction in the pilosebaceous follicle. Future acne therapy should combine dietary and pharmacological interventions attenuating mTORC1 signaling by a paleolithic-type diet supported with natural or synthetic mTOR inhibitors. KEYWORDS: acne • dairy • glycemic load • mechanistic target of rapamycin complex 1 • milk signaling • mTOR inhibitors • paleolithic diet • treatment • Western diet

Acne is a disease of Western civilization with prevalence rates in adolescence of over 85% [1,2]. Moderate-to-severe acne affects around 20% of young people [3]. Western diet, characterized by high glycemic load and high milk and dairy protein consumption, has been recognized to be a fundamental nutritional factor promoting acne [4–8]. The placebo-controlled randomized study of Smith et al. [6] and the case-control study of Kwon et al. [7] provided evidence for the improvement of acne by a low glycemic load diet. The case control study of Di Landro et al. [8] supported the role of milk consumption as well as increased body mass index (BMI) as aggravating factors of acne. Remarkably, acne is absent in populations consuming less insulinotropic paleolithic diets [1,9], which exclude grains, milk and dairy products and thus exhibit much lower insulin/insulin-like growth factor (IGF-1)/mTORC1 signaling [4,9]. Recent evidence points to a link between acne, increased BMI and insulin resistance [9–11], explained by exaggerated nutrient-stimulated mTORC1 signaling [10]. mTORC1: the cellular sensor of nutrient signaling

At the cellular level, nutrients (glucose, essential amino acids), cellular energy (adenosine triphosphate (ATP)) as well as growth factors (insulin, IGF-1, FGFs) are sensed by the nutrientwww.expert-reviews.com

10.1586/17469872.2013.846514

sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the central cellular regulator promoting protein-, lipid- and nucleotide synthesis, cell growth and proliferation [12,13]. Recent evidence underlines that anabolic mTORC1 signaling is the pivotal regulatory pathway of lipogenesis and adipogenesis [14–16], linking enhanced mTORC1 signaling to anabolic states of metabolism resulting in increased body and fat mass, frequently associated with the development of insulin resistance. From all branched-chain amino acids (BCAAs) leucine plays a crucial role for mTORC1 activation [17]. Notably, milk proteins provide highest amounts of leucine in comparison to all other animal proteins to optimize mTORC1 activation for postnatal growth [18]. Several recent metabolomics studies underline the relationship between high plasma BCAA profiles, increased BMI and insulin resistance [19]. In fact, accumulating evidence supports the association of acne with increased mTORC1 activation, increased BMI and insulin resistance [8,11,20]. Thus, acne appears to feature over-activated mTORC1 signaling overstimulating the sebaceous follicle by nutrient signals derived from Western diet [6,21]. Acne pathogenesis: mTORC1 ‘up’

High glycemic load and dairy protein consumption both increase insulin/IGF-1 signaling that is superimposed on elevated IGF-1 signaling of

 2013 Informa UK Ltd

ISSN 1746-9872

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Palaeo diet DOXY/AzA

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sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased BMI. Enhanced androgen-, TNFa- and IGF-1 signaling due to genetic polymorphisms promoting the risk of acne are known to increase mTORC1 activation, an unfavorable genetic disposition that may be further enhanced by aberrant nutrient signaling of Western diet [20]. Acne therapy: mTORC1 ‘down’

It has recently been hypothesized that antiacne agents either enhance nuclear FoxO AAs activity or directly inhibit mTORC1 mTORC1 BPO AMP ATM ROS (FIGURE 1) [23]. Benzoyl peroxide (BPO), by mTORC1-inhibitors activation of oxidative stress-inducible kinLipin-1 EGCG ases, increases nuclear FoxO levels promotResveratrol Mitochondrial AzA TORkinibs ing Sestrin3-mediated activation of 4E-BP-1 S6K1 SREBP-1 respiration adenosine monophosphate (AMP)-actiReduced cell growth and lipogenesis vated kinase (AMPK). Furthermore, BPOderived reactive oxygen species (ROS) may Figure 1. Inhibition of mTORC1 by anti-acne agents. Oral isotretinoin, all-trans-retiactivate AMPK via ataxia-telangiectasia noic acid (ATRA), doxycycline (DOXY) and BPO increase nuclear FoxO levels, which increase the expression of Sestrin3. Sestrin3 activates AMPK and augments the inhibitory mutated. Isotretinoin and all-trans-retinoic function of TSC2 toward Rheb, thus suppresses mTORC1. BPO may stimulate ROSacid may stimulate FoxO gene expression. mediated activation of ATM, a further stimulator of AMPK-mediated mTORC1 inhibition. Doxycycline may enhance FoxOs nuclear Azelaic acid (AzA) via inhibition of mitochondrial respiration may increase ROS-mediated retention by inhibiting the expression of up-regulation of FoxOs and FoxO-induced Sestrin3 as well as cellular AMP levels activatthe nuclear export protein exportin-1. ing AMPK, like metformin, a well-known activator of AMPK. Furthermore, metformin inhibits the Rag/Ragulator-mediated amino acid (AA)-dependent activation of mTORC1. Suppression of TNFa signaling by tetracyAntiandrogens inhibit mTORC2-dependent activation of Akt, thus increase TSC1/ clines, erythromycin and other macrolides TSC2-mediated inhibition of Rheb. Antiandrogens suppress the expression of L-type may attenuate IKKb-TSC1-mediated amino acids transporter (LAT), thus interfere with AA-mediated activation of mTORC1. activation of mTORC1. Erythromycin Natural mTORC1 inhibitors like resveratrol and epigallocatechin-3-gallate (EGCG) as well attenuates ERK1/2 activity, thereby as synthetic mTOR inhibitors inhibit the ATP-dependent kinase activity of mTOR, thereby directly reducing mTORC1 activity. Vitamin D activates the expression of DNA damageincreases TSC2 activity, which inhibits inducible transcript 4 (DDIT4), which activates TSC2 inhibitory function towards mTORC1. Azelaic acid may decrease mTORC1. Thus, all anti-acne drugs directly or indirectly impair downstream mTORC1 by inhibiting mitochondrial mTORC1 signaling and attenuate cell growth, proliferation and lipogenesis. A paleolithic respiration, increasing cellular ROS and diet (paleo diet), which reduces enhanced insulin/IGF1 signaling of Western diet due to nuclear FoxO levels. Anti-androgens may high glycemic load and dairy consumption thus exerts synergistic effects with pharmacological agents in the treatment of acne. attenuate mTORC1 by suppressing Reproduced with permission from [23]. mTORC2-mediated Akt/TSC2 signaling. Thus, the mode of action of all anti-acne puberty [4]. The cell’s nutritional status is sensed by the forkhead drugs in clinical use can be explained by indirect or direct attenubox transcription factor O1 (FoxO1) and the serine/threonine ation of mTORC1 signaling [23]. kinase mTORC1. Increased insulin/IGF-1 signaling extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses Potential new anti-acne drugs attenuating hepatic IGF-1 synthesis and thus impairs somatic growth. Fur- mTORC1 activity thermore, FoxO1 attenuates androgen signaling, interacts with Remarkably, all common anti-acne drugs have been found regulatory proteins important for sebaceous lipogenesis, regulates empirically without any conclusive strategy for drug developthe activity of innate and adaptive immunity and antagonizes oxi- ment. It is thus not surprising that over more than three decadative stress [21]. Most importantly, FoxOs function as a rheostat des, the development of effective new anti-acne drugs is of mTORC1 (FIGURE 1), the master regulator of cell growth, prolif- missing. However, there is a need for future drug development eration and metabolic homeostasis [22]. Thus, FoxO1 links as therapeutically effective anti-acne drugs exhibit severe adverse nutrient availability to mTORC1-driven processes: increased effects like the teratogenic effect of systemic isotretinoin. Furprotein and lipid synthesis, cell proliferation, cell differentiation thermore, recent animal studies pointed out that systemic isoincluding hyperproliferation of acroinfundibular keratinocytes, tretinoin decreased ovarian reserve in female rats [24], an Metformin

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The role of mTORC1 in acne pathogenesis & treatment

adverse effect on fertility that can be explained by isotretinoin´s induction of FoxO1-mediated apoptosis of follicular granulosa cells [25].

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Plant-derived mTORC1 inhibitors

Resveratrol is a polyphenolic flavonoid that down regulates mTORC1 signaling [26,27]. Indeed, topical treatment of facial acne vulgaris in 20 patients with a resveratrol-containing gel (0.01% weight/volume) significantly reduced the number of microcomedones, papules and pustules compared with vehicle control [28]. Furthermore, resveratrol inhibited Propionibacterium acnes growth and eradicated P. acnes biofilm formation [29,30]. Epigallocatechin-3-gallate (EGCG), the major green tea catechin, is regarded as the active anti-inflammatory and antiproliferative compound of green tea extracts. EGCG functions directly as an ATP-competitive inhibitor of mTORC1 [31]. It has been demonstrated that topical 2% green tea lotion was effective in the treatment of mild-to-moderate acne vulgaris [32]. After 6 weeks, the mean total lesion count and mean severity index of acne showed significant reductions of 58 and 39%, respectively. Furthermore, a 3% green tea emulsion significantly reduced sebum production in 10 healthy male volunteers after 8 weeks of treatment [33]. Most recently, it has been demonstrated that topical application of EGCG to rabbit auricles reduced the size of sebaceous glands [34]. When applied to cultured human SZ95 sebocytes, EGCG strongly suppressed sebocyte proliferation and lipogenesis [34]. Importantly, EGCG in a dose-dependent manner decreased IGF-1-stimulated mTORand S6K phosphorylation of SZ95 sebocytes [34]. Thus, direct experimental evidence underlines that the EGCG attenuates IGF-1-stimulated mTORC1 activity of sebocytes. As mTORC1 regulates the activity and expression of sterol response element binding protein 1 (SREBP-1), the most important transcription factor of lipogenesis [14], it should be expected that EGCG treatment of sebocytes would reduce sebocyte SREBP-1 expression. In fact, EGCG has been shown to inhibit SREBP-1 in SEB-1 sebocytes and improved acne in an 8-week randomized split-face clinical trial with and without EGCG [35]. EGCGmediated activation of AMPK is another inhibitory mechanism attenuating mTORC1-SREBP1 signaling, which explains EGCG-mediated suppression of sebaceous lipogenesis (FIGURE 1) [35]. Synthetic mTORC1 inhibitors

Recently, a new generation of mTOR inhibitors, called mTORkinibs, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed [36]. These inhibitors bind to the ATP binding site of the kinase domain of mTOR and as a result inhibit the mTOR complexes, mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycinresistant) [37,38]. The small molecular weight mTOR inhibitors applied in submaximal doses have the potential for the development of new synthetic anti-acne drugs attenuating enhanced mTORC1 signaling up-regulated by Western diet or genetic www.expert-reviews.com

Perspective

polymorphisms converging into increased downstream mTORC1 signaling [23]. Combination of nutrition therapy and pharmacotherapy of acne

Increased mTORC1 signaling induced by Western diet appears to represent the major pathogenic mechanism of diseases of civilization [13]. Accumulating evidence links acne to the family of diseases of civilization [1], characterized by exaggerated mTORC1 signaling [4]. Thus, the primary focus of causal acne therapy should eliminate the nutrient-derived stimuli that induce or aggravate acne [4,5,39]. Nutritional therapy of acne should (1) normalize total calorie intake, (2) lower glycemic load [5–7] and (3) restrict total dairy protein consumption, especially whey protein abuse [40,41]. The ideal nutrition therapy of acne should favor a paleolithic-type diet containing less insulinotropic carbohydrates and reduced consumption of milk and dairy products to attenuate mTORC1 activity and should reduce the undesirable intake of androgen precursors present in milk and dairy products [42]. The paleolithic-type diet offers a higher amount of natural plant-derived mTORC1 inhibitors (EGCG, resveratrol and other natural polyphenols) by higher consumption of vegetables, fruits and green tea. Moreover, a paleolithic-type diet increases the consumption of fish protein, which exhibits a lower insulinaemic index than dairy protein and represents a favorable source of anti-inflammatory w-3 fatty acids [8,43]. Patients exhibiting an increased genetic disposition for acne for instance by gene polymorphisms of TNFa, IGF1, TLR2, mutated FGFR2 or androgen receptor (AR) polymorphism with shorter CAG repeats may feature persistently elevated mTORC1 signaling. These individuals most likely belong to the group of patients with moderatesevere acne as well as therapy-resistant acne, which may not be cured by sole dietary intervention. Certainly, these patients need prolonged and sufficient pharmacological treatment but may still benefit from dietary attenuation of mTORC1 signaling by a paleolithic-type diet. Conclusion

The appreciation of acne vulgaris as an mTORC1-driven disease of civilization mediated by Western diet and the recently proposed concept that the mode of commonly used anti-acne agents attenuates enhanced mTORC1 signaling allows the development of new strategies for acne treatment. The primary causal strategy correcting exaggerated diet-induced mTORC1 signaling in acne should consider a dietary intervention by a paleolithic-type diet restricting hyperglycemic carbohydrates as well as high intake of milk and dairy products [44]. The presented mTORC1 concept of acne pathogenesis and therapy allows the rational development of new anti-acne agents. Natural plant-derived topical or systemic mTORC1 inhibitors like resveratrol and EGCG could be combined with a paleolithictype diet. Furthermore, there is the opportunity to develop various synthetic small molecular weight mTOR kinase inhibitors (TORkinibs), which may open new avenues for the pharmacological treatment of acne. 619

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Five-year view

The recent awareness of acne belonging to the family of anabolic mTORC1-driven metabolic diseases provides the rationale for mTORC1 down-regulation by nutrition therapy as well as pharmacological intervention. Two major acne-aggravating or acne-inducing components of Western diet have been identified: high glycemic load and milk consumption. Whereas the adverse effects of high glycemic load on acne have convincingly been demonstrated, placebo-controlled randomized studies investigating the effect of milk and various dairy products as well as studies investigating high glycemic load in combination with increased milk/dairy consumption still have to be performed in corporation with nutrition science and dermatology. Future studies should clarify the pathways of milk-driven mTORC1 signaling. Recently identified exosomal microRNA in commercial milk may be an important acneigenic stimulus. Milk-derived microRNA-21 may attenuate the expression of important cell cycle inhibitors and tumor suppressor proteins like PTEN, Sprouty and PDCD4, thus further enhancing mTORC1 signaling promoting the development of acne. The recent view of acne as an mTORC1-driven disease allows the implementation of various new pharmaceutical strategies to target increased mTORC1 signaling at various levels. It should be kept in mind that inflammatory signals and nutrient

signaling are all integrated by mTORC1. In acne patients, not only sebocytes and acroinfundibular keratinocytes are metabolically over-activated but also immune cells creating the inflammatory environment of acne. mTORC1 plays a major role in the regulation immune responses and inflammation. Due to its strong immunosuppressive and anti-proliferative effects the allosteric mTORC1 inhibitor rapamycin is already in use for immunosuppressive therapy and cancer treatment. Plant-derived natural mTORC1 inhibitors like resveratrol and EGCG have already demonstrated promising clinical effects in the treatment of acne and reduction of sebum synthesis and need be studied in more detail. Synthetic mTORC1 inhibitors, which have been recently developed for the treatment of various cancers, may in a moderate non-lethal concentration be successful for the topical treatment of acne. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Acne is an mTORC1-driven anabolic and inflammatory skin disease. • High glycemic load and milk/dairy consumption as well as pro-inflammatory signals enhance mTORC1 signaling. • Anti-acne agents in clinical use operate by indirect or direct mTORC1 inhibition. • Future anti-acne drugs are either natural or synthetic mTOR-inhibitors. • Future acne therapy should be a combination of nutrition therapy with a paleolithic-type diet supported by pharmacological attenuation of enhanced mTORC1 signaling.

References

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Papers of special note have been highlighted as: • of interest •• of special interest

Burris J, Rietkerk W, Woolf K. Acne: The role of medical nutrition therapy. J. Acad. Nutr. Diet. 113 (3), 416–430 (2013).

6

Smith RN, Mann NJ, Braue A et al. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial. J. Am. Acad. Dermatol. 57(2), 247–256 (2007).

1

2

3

Cordain L, Lindeberg S, Hurtado M et al. Acne vulgaris: a disease of Western civilization. Arch. Dermatol. 38(12), 1584–1590 (2002). Collier CN, Harper J C, Cafardi JA et al. The prevalence of acne in adults 20 years and older. J. Am. Acad. Dermatol. 58(1), 56–59 (2008). Bhate K, Williams HC. Epidemiology of acne vulgaris. Br. J. Dermatol. 168 (3), 474–485 (2012).

4

Melnik B. Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 4(1), 20–32 (2012).



Explains the role of Western diet in enhancing mTORC1 signaling.

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A valuable randomized, controlled study demonstrating the beneficial effect of low glycemic load diet in the treatment of acne. Kwon HH, Youn JY, Hong JS et al. The clinical and histological effect of low glycaemic load diet in the treatment of acne vulgaris in Korean patients: a randomized, controlled trial. Acta Derm. Venereol. 92(3), 241–246 (2012).

8

Di Landro A, Cazzaniga S, Parazzini F et al. Family history, body mass index, selected dietary factors, menstrual history, and risk of moderate to severe acne in adolescents and young adults. J. Am. Acad. Dermatol. 67(6), 1129–1135 (2012).

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An important case control study demonstrating the association of acne and milk consumption.

9

Lindeberg S, Eliasson M, Lindahl B et al. Low serum insulin in traditional Pacific Islanders: the Kitava Study. Metabolism 48(10), 1216–1219 (1999).

10

Melnik BC, John SM, Plewig G. Acne: risk indicator for increased body mass index and insulin resistance. Acta Derm. Venereol. doi: 10.2340/00015555-1677 (2013) (Epub ahead of print).



Explains the metabolic relationship between increased mTORC1 signaling, increased BMI, insulin resistance and acne.

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12

Expert Review of Dermatology Downloaded from informahealthcare.com by 79.208.113.223 on 01/12/14 For personal use only.

13

Kumari R, Thappa DM. Role of insulin resistance and diet in acne. Indian J. Dermatol. Venereol. Leprol. 79(3), 291–299 (2013). Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J. Biol. Chem. 285(19), 14071–14077 (2010). Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell. Biol. 12(1) 21–35 (2011).

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An excellent state of the art review on mTORC1 signaling.

14

Bakan I, Laplante M. Connecting mTORC1 signalling to SREBP-1 activation. Curr. Opin. Lipidol. 23(3), 226–234 (2012).

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A well-written paper showing the pivotal role of mTORC1 in lipogenesis.

15

Yoon MS, Zhang C, Sun Y et al. Mechanistic target of rapamycin (mTOR) controls homeostasis of adipogenesis. J. Lipid Res. 54(8), 2166–2173 (2013).

16

Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 126(8), 1713–1719.

mTORC1 signaling in the pathogenesis of acne. 22

Hay N. Interplay between FOXO, TOR, and Akt. Biochim. Biophys. Acta 1813(11), 1965–1970 (2011).

23

Melnik BC, Schmitz G. Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? Exp. Dermatol. 22(7), 502–504 (2013).

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A viewpoint on acne treatment that shows for the first time that all anti-acne drugs have a common mode of action: the attenuation of mTORC1 signaling.

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Abali R, Yuksel MA, Aktas C et al. Decreased ovarian reserve in female Sprague-Dawley rats induced by isotretinoin (retinoic acid) exposure. Reprod. Biomed. Online. 27(2), 184–191 (2013).



Important experimental work demonstrating that isotretinoin impairs follicular reserve and thus fertility of female rats.

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Melnik BC. Isotretinoin and FoxO1: A scientific hypothesis. Dermatoendocrinol. 3(3), 141–165 (2011).



Scientific hypothesis suggesting that isotretinoin up-regulates FoxO expression and reduces mTORC1 signaling.



A most recent update on mTORC1-mediated gene regulation.

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Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am. J. Physiol. Endocrinol. Metab. 302(11), E1329–E1342 (2012).

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Fro¨jdo¨ S, Cozzone D, Vidal H et al. Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem. J. 406(3), 511–518 (2007).

18

Melnik BC, John SM, Schmitz G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr. J. 12, 103 (2013).

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Melnik BC. Western diet-mediated mTORC1-signaling in acne, psoriasis, atopic dermatitis, and related diseases of civilization: Therapeutic role of plant-derived natural mTORC1 inhibitors. In: Bioactive Dietary Factors and Plant Extracts in Dermatology, Watson RR, Zibadi S (Eds.). Springer New York Heidelberg Dordrecht London, chapter 37, 397–419, (2013).

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The first comprehensive review demonstrating that milk is an endocrine system of mammalian evolution promoting mTORC1 signaling.

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Morris C, O´Grada C, Ryan M et al. The relationship between BMI and metabolomics profiles: a focus on amino acids. Proceed. Nutr. Soc. 71(4), 634–638 (2012).

20

Melnik BC. Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Acta Derm. Venerol. 92(3), 228–231 (2012).

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Melnik BC, Zouboulis CC. Potential role of FoxO1 and mTORC1 in the pathogenesis of Western-diet induced acne. Exp. Dermatol. 22(5), 311–315 (2013). Updated viewpoint providing information on the interaction of diet, FoxO- and

www.expert-reviews.com

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Fabbrocini G, Staibano S, De Rosa G et al. Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. Am. J. Clin. Dermatol. 12(2), 133–141 (2011).



First clinical study that demonstrates clinical efficacy of reseveratrol in the treatment of acne.

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Docherty JJ, McEwen HA, Sweet TJ et al. Resveratrol inhibition of Propionibacterium acnes. J. Antimicrob. Chemother. 59(6) 1182–1184 (2007).

30

Coenye T, Brackman G, Rigole P et al. Eradication of Propionibacterium acnes biofilms by plant extracts and putative

Perspective

identification of icariin, resveratrol and salidroside as active compounds. Phytomedicine 19(5), 409–412 (2012). 31

Huang CH, Tsai SJ, Wang YJ et al. EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol. Nutr. Food Res. 53(9), 1156–1165 (2009).

32

Elsaie ML, Abdelhamid MF, Elsaaiee LT, Emam HM. The efficacy of topical 2% green tea lotion in mild-to-moderate acne vulgaris. J. Drugs Dermatol. 8(4), 358–364 (2009).



First paper showing beneficial effects of topical green tea lotion in acne.

33

Mahmood T, Akhtar N, Khan BA et al. Outcomes of 3% green tea emulsion on skin sebum production in male volunteers. Bosn. J. Basic. Med. Sci. 10(3), 260–264 (2010).

34

Im M, Kim SY, Sohn KC et al. Epigallocatechin-3-gallate suppresses IGF-I-induced lipogenesis and cytokine expression in SZ95 sebocytes. J. Invest. Dermatol. 132(12) 2700–2708 (2012).

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Important paper which provides evidence that epigallocatechin-3-gallate suppresses Akt/mTORC1 signaling in SZ95 sebocytes.

35

Yoon JY, Kwon HH, Min SU et al. Epigallocatechin-3-gallate improves acne in humans by modulating intracellular targets and inhibiting P. acnes. J. Invest. Dermatol. 133(2), 429–440 (2013).

36

Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med. Chem. 10(7), 571–581 (2010).

37

Feldman ME, Shokat KM. New inhibitors of the PI3K-Akt-mTOR pathway: insights into mTOR signaling from a new generation of Tor kinase domain inhibitors (TORKinibs). Curr. Top. Microbiol. Immunol. 347, 241–262 (2010).

38

Liu Q, Kang SA, Thoreen CC et al. Development of ATP-competitive mTOR inhibitors. Methods Mol. Biol. 821, 447–460 (2012).

39

Danby FW. Turning acne on/off via mTORC1. Exp. Dermatol. 22(7), 505–506 (2013).

40

Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athlethes. Cutis 90(2), 70–72 (2012).

41

Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology 225(3), 256–258 (2012).

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Perspective

Melnik

Danby FW. Acne, dairy and cancer: the 5alpha-P link. Dermatoendocrinol. 1(1), 12–16 (2009).



Important paper on the potential acneigenic role of androgen precursors in

commercial milk produced by pregnant cows. 43

44

Cordain L. The Dietary Cure for Acne. Paleo Diet Enterprises, CO, USA (2006).

Rubin MG, Kim K, Logan AC. Acne vulgaris, mental health and omega-3-fatty acids: a report of cases. Lipids Health Dis 7, 36 (2008).

Expert Review of Dermatology Downloaded from informahealthcare.com by 79.208.113.223 on 01/12/14 For personal use only.

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