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Extracts of Artocarpus communis decrease α-melanocyte stimulating hormone-induced melanogenesis through activation of ERK and JNK signaling pathways.

ABSTRACT: Artocarpus communis is an agricultural plant that is also used in folk medicine to prevent skin diseases, including acne and dermatitis. Extracts of A. communis have been used to effectively inhibit melanogenesis; however, the antimelanogenesis mechanism of these extracts has not yet been investigated. The present study utilized a cell-free tyrosinase assay as well as α-melanocyte stimulating hormone- (-MSH-) induced tyrosinase assay conducted in B16F10 cells, performed a cytotoxicity assay, and determined cellular melanin content to examine the effects of a methanolic extract of A. communis (ACM) and various organic partition fractions of A. communis on melanogenesis. In addition, we performed western blot analysis to elucidate the mechanism of their antimelanogenesis effect. Our results indicated that, except for the n-hexane extract, ACM and the various partition extracts at noncytotoxic concentrations effectively decreased melanin content and tyrosinase activity by downregulating microphthalmia-associated transcription factor (MITF) and phosphorylated cAMP response element-binding protein (p-CREB). Moreover, ACM and the partition fractions activated phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) to inhibit the synthesis of MITF and finally to decrease melanin production. In conclusion, we suggest that noncytotoxic concentrations of ACM and the various partition fractions may be useful as references for developing skin-lighting agents for use in medicines or cosmetics.

SUBMITTER: Fu YT

PROVIDER: S-EPMC3967707 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Oleoylethanolamide inhibits α-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells.

Project description:The present study aimed to examine the potential inhibitory activity of oleoylethanolamide (OEA) on α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis and the molecular mechanism(s) involved in the process in B16 mouse melanoma cells. Our data demonstrated that OEA markedly inhibited melanin synthesis and tyrosinase activity in α-MSH-stimulated B16 cells. In addition, the expression of melanogenesis-related proteins, such as melanocortin-1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and tyrosinase, was suppressed in a concentration-dependent manner by OEA. In addition, OEA may suppress melanogenesis through a peroxisome proliferator-activated receptor α (PPARα)-independent pathway. Moreover, OEA activated ERK, Akt, p38 pathways and inhibits CREB pathway in α-MSH-stimulated B16 cells. The specific ERK inhibitor PD98059 partly blocked OEA-inhibited melanin synthesis and tyrosinase activity and partly abrogated the OEA-suppressed expression of melanogenic proteins. Furthermore, OEA presented remarkable inhibition on the body pigmentation in the zebrafish model system. Our findings demonstrated that OEA is an effective inhibitor of hyperpigmentation through activation of ERK, Akt and p38 pathways, inhibition of the CREB pathway, and subsequent down-regulation of MITF, TRP-1 and tyrosinase production.

| S-EPMC5593609 | biostudies-literature

Tyrosol and its analogues inhibit alpha-melanocyte-stimulating hormone induced melanogenesis.

Project description:Melanin is responsible for skin color and plays a major role in defending against harmful external factors such as ultraviolet (UV) irradiation. Tyrosinase is responsible for the critical steps of melanogenesis, including the rate-limiting step of tyrosine hydroxylation. The mechanisms of action of skin hypopigmenting agents are thought to be based on the ability of a given agent to inhibit the activity of tyrosinase and, hence, down regulate melanin synthesis. Tyrosol and its glycoside, salidroside, are active components of Rhodiola rosea, and in our preliminary study we found that Rhodiola rosea extract inhibited melanogenesis. In this study, we examined the effects of tyrosol and its analogues on melanin synthesis. We found that treatment of B16F0 cells to tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), 2-hydroxyphenylacetic acid (7), or salidroside (11) resulted in a reduction in melanin content and inhibition of tyrosinase activity as well as its expression. Tyrosol (1), 4-hydroxyphenylacetic acid (5) and 2-hydroxyphenylacetic acid (7) suppressed MC1R expression. Tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), and 2-hydroxyphenylacetic acid (7) inhibited α-MSH induced TRP-1 expression, but salidroside (11) did not. All the compounds did not affect MITF and TRP-2 expression. Furthermore, we found that the cell viability of tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), and 2-hydroxyphenylacetic acid (7) at concentrations below 4 mM and salidroside (11) at concentrations below 0.5 mM were higher than 90%. The compounds exhibited metal-coordinating interactions with copper ion in molecular docking with tyrosinase. Our results suggest that tyrosol, 4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 2-hydroxyphenylacetic acid, and salidroside are potential hypopigmenting agents.

| S-EPMC3876054 | biostudies-literature

Desacetyl-?-melanocyte stimulating hormone and ?-melanocyte stimulating hormone are required to regulate energy balance.

Project description:ObjectiveRegulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (?-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-?-MSH, the precursor for ?-MSH, is present in brain and blood. Desacetyl-?-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with ?-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-?-MSH is still unclear.MethodsWe created a novel mouse model to determine whether desacetyl-?-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-?-MSH and ?-MSH from adrenocorticotropin (ACTH1-39).ResultsThe mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-?-MSH or ?-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-?-MSH and ?-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-?-MSH.ConclusionsBased on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-?-MSH and ?-MSH.

| S-EPMC5869732 | biostudies-literature

?-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways.

Project description:Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied ?-Melanocyte-stimulating hormone (?-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that ?-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-?, IL-1?, and IFN-?, in ocular surface of the dry eye rats. Moreover, ?-MSH, at 10(-4)??g/?l, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, ?-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished ?-MSH's protective effects, suggesting that both pathways are necessary for ?-MSH's protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of ?-MSH warrant translation of the ?-MSH-containing eye drop into a novel and effective intervention to DED.

| S-EPMC4685655 | biostudies-literature

MicroRNA-141-3p and microRNA-200a-3p regulate ?-melanocyte stimulating hormone-stimulated melanogenesis by directly targeting microphthalmia-associated transcription factor.

Project description:In recent years, it has been reported that non-coding RNAs, especially microRNAs (miRNAs) and long non-coding RNAs, act as melanogenesis-regulating molecules in melanocytes. We found that the expression levels of miR-141-3p and miR-200a-3p were decreased significantly by ?-melanocyte-stimulating hormone (?-MSH) stimulation in mouse melanocyte B16-4A5 cells, as demonstrated by a miRNA array. Overexpression of miR-141-3p and miR-200a-3p in B16-4A5 cells suppressed melanogenesis and tyrosinase activity. Moreover, both miR-141-3p and miR-200a-3p showed direct targeting of microphthalmia-associated transcription factor using a luciferase reporter assay. Furthermore, topical transfection of miR-141-3p and miR-200a-3p to three-dimensional reconstructed human skin tissue inhibited ?-MSH-stimulated melanin biosynthesis. Taken together, our findings indicate that downregulation of miR-141-3p and miR-200a-3p during the ?-MSH-stimulated melanogenesis process acts as an important intrinsic signal. This result is expected to lead to the development of miRNA-based whitening therapeutics.

| S-EPMC7005774 | biostudies-literature

Effect of 3,6-anhydro-l-galactose on α-melanocyte stimulating hormone-induced melanogenesis in human melanocytes and a skin-equivalent model.

Project description:3,6-Anhydro-l-galactose (l-AHG) is a bioactive sugar that is a major component of agarose. Recently, l-AHG was reported to have anti-melanogenic potential in human epidermal melanocytes (HEMs) and B16F10 melanoma cells; however, its underlying molecular mechanisms remain unknown. At noncytotoxic concentrations, l-AHG has been shown to inhibit alpha-melanocyte-stimulating hormone-induced melanin synthesis in various cell models, including HEMs, melan-a cells, and B16F10 cells. Although l-AHG did not inhibit tyrosinase activity in vitro, reverse transcription-polymerase chain reaction results demonstrated that the anti-melanogenic effect of l-AHG was mediated by transcriptional repression of melanogenesis-related genes, including tyrosinase, tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and microphthalmia-associated transcription factor (MITF) in HEMs. Western blot analysis showed that l-AHG effectively attenuated α-melanocyte-stimulating hormone-induced melanogenic proteins by inhibiting cyclic adenosine monophosphate/cyclic adenosine monophosphate-dependent protein kinase, mitogen-activated protein kinase, and Akt signaling pathways in HEMs. Topical application of l-AHG significantly ameliorated melanin production in a 3D pigmented human skin model. Collectively, these results suggest that l-AHG could be utilized as novel cosmetic compounds with skin-whitening efficacy.

| S-EPMC6175185 | biostudies-literature

7,3',4'-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses α-Melanocyte-Stimulating Hormone-Induced Melanogenesis by Targeting Melanocortin 1 Receptor.

Project description:7,3',4'-Trihydroxyisoflavone (7,3',4'-THIF) is a metabolite of daidzein which is a representative isoflavone found in soybean. Recent studies suggested that 7,3',4'-THIF exerts a hypopigmentary effect in B16F10 cells, however, its underlying molecular mechanisms and specific target protein remain unknown. Here, we found that 7,3',4'-THIF, but not daidzein, inhibited α-melanocyte-stimulating hormone (MSH)-induced intracellular and extracellular melanin production in B16F10 cells by directly targeting melanocortin 1 receptor (MC1R). Western blot data showed that 7,3',4'-THIF inhibited α-MSH-induced tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) expressions through the inhibition of Microphthalmia-associated transcription factor (MITF) expression and cAMP response element-binding (CREB) phosphorylation. 7,3',4'-THIF also inhibited α-MSH-induced dephosphorylation of AKT and phosphorylation of p38 and cAMP-dependent protein kinase (PKA). cAMP and Pull-down assays indicated that 7,3',4'-THIF strongly inhibited forskolin-induced intracellular cAMP production and bound MC1R directly by competing with α-MSH. Moreover, 7,3',4'-THIF inhibited α-MSH-induced intracellular melanin production in human epidermal melanocytes (HEMs). Collectively, these results demonstrate that 7,3',4'-THIF targets MC1R, resulting in the suppression of melanin production, suggesting a protective role for 7,3',4'-THIF against melanogenesis.

| S-EPMC7747307 | biostudies-literature

Orexin expression is regulated by alpha-melanocyte-stimulating hormone.

Project description:The hypothalamic melanocortin system plays a fundamental role in the regulation of energy homeostasis. Orexins (hypocretins) are also involved in a diverse range of physiological processes, including food intake. Previous evidence has suggested that hypothalamic orexin expression may be influenced by the central melanocortin system. Here, we studied orexin mRNA levels in pro-opiomelanocortin-deficient (Pomc(-/-)) mice, a mouse model lacking all endogenously produced melanocortin peptides. Orexin expression in the lateral hypothalamus was significantly increased in corticosterone deficient Pomc(-/-) mice. Furthermore, when circulating glucocorticoids were restored to levels within the physiological range, orexin expression remained elevated. However, i.c.v. administration of the melanocortin alpha-melanocyte-stimulating hormone (MSH) to Pomc(-/-) mice reduced orexin expression back down to wild-type levels. This was independent of the effects of alpha-MSH on food intake because elevated orexin expression persisted in Pomc(-/-) mice pairfed to alpha-MSH-treated animals. These data indicate that alpha-MSH may play a role in the regulation of orexin expression in Pomc(-/-), with an elevation in orexin levels contributing to the hyperphagia seen in these animals.

| S-EPMC2637479 | biostudies-literature

?-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors.

Project description:ObjectiveCentral melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral ?-melanocyte stimulating hormone (?-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting ?-MSH.MethodsWe established glucose-stimulated ?-MSH secretion using humans, non-human primates, and mouse models. Continuous ?-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of ?-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of ?-MSH via the melanocortin 5 receptor (MC5R)-PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and ?-MSH was adopted to restore glucose tolerance in obese mice.ResultsHere we demonstrate that pituitary secretion of ?-MSH is increased by glucose. Peripheral ?-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of ?-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores ?-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice.ConclusionThese data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary ?-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.

| S-EPMC5034615 | biostudies-literature

Rewired ERK-JNK signaling pathways in melanoma.

Project description:Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.

| S-EPMC1978100 | biostudies-literature

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