Controlling anticancer drug activity and release on demand is very significant in cancer therapy. The photoactivated platinum(IV) pro-drug is stable in the dark and can be activated by UV light. In this study, we develop a multifunctional drug delivery system combining upconversion luminescence/magnetic resonance/computer tomography trimodality imaging and NIR-activated platinum pro-drug delivery. We use the core–shell structured upconversion nanoparticles to convert the absorbed NIR light into UV to activate the trans-platinum(IV) pro-drug, trans,trans,trans-[Pt(N3)2(NH3)(py)(O2CCH2CH2COOH)2]. Compared with using the UV directly, the NIR has a higher tissue penetration depth and is less harmful to health. Meanwhile, the upconversion nanoparticles can effectively deliver the platinum(IV) pro-drugs into the cells by endocytosis. The mice treated with pro-drug-conjugated nanoparticles under near-infrared (NIR) irradiation demonstrated better inhibition of tumor growth than that under direct UV irradiation. ...

In Vivo Multimodality Imaging and Cancer Therapy by Near-Infrared Light-Triggered trans-Platinum Pro-Drug-Conjugated Upconverison Nanoparticles

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.

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m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade.

Peels and edible pulp from three species of citrus including Citrus aurantifolia (varieties pica and sutil) and Citrus x lemon var. Genova widely cultivated and consumed in Northern Chile (I and II region) were analyzed for phenolic compounds and antioxidant activity for the first time. A high performance electrospray ionization mass spectrometry (HPLC-UV-ESI-MS) method was developed for the rapid identification of phenolics in extracts from peels and juices of all species. Several flavonoids including one kaempferol-O-hexoside (peak 16) and one hesperidin derivative (peak 22) three quercetin derivatives (peaks 4, 19 and 36), five isorhamnetin derivatives (peaks 5, 23, 24, 26 and 29) four luteolin derivatives (peaks 14, 25, 27 and 40), seven apigenin derivatives (peaks 2, 3, 12, 20, 34, 35 and 39), seven diosmetin derivatives (peaks 7-9, 17, 21, 31 and 37), three chrysoeriol derivatives (peaks 10, 18 and 30), and four eryodictiol derivatives (peaks 6, 13, 15 and 38) were identified in negative and positive mode using full scan mass measurements and MSn fragmentations. Ascorbic acid content was higher in the pulps of the varieties Genova and Sutil (60.13 ± 1.28 and 56.53 ± 1.06 mg ascorbic acid per g dry weight, respectively) while total phenolic content was higher in Pica peels followed by Sutil peels (34.59 ± 0.81 and 25.58 ± 1.02 mg/g GAE dry weight, respectively). The antioxidant capacity was also higher for Pica peels (10.34 ± 1.23 µg/mL in the DPPH assay and 120.63 ± 2.45 µM trolox equivalents/g dry weight in the FRAP assay). The antioxidant features together with the high polyphenolic contents can support at least in part, the usage of the peel extracts as nutraceutical supplements, especially to be used as anti-ageing products.

HPLC-UV-MS profiles of phenolic compounds and antioxidant activity of fruits from three citrus species consumed in Northern Chile.

Skin cancer and new treatment perspectives: a review.

As ultraviolet (UV) radiation is naturally and ubiquitously emitted by the sun, almost everyone is exposed to it on a daily basis, and it is necessary for normal physiological function. Human exposure to solar UV radiation thus has important health implications. The generation of reactive oxygen species (ROS) by UV radiation is one of the mechanisms through which UV light can manifest its possible detrimental effects on health. When an imbalance develops due to ROS generation exceeding the body’s antioxidant defence mechanisms, oxidative stress can develop. Oxidative stress can lead to cellular damage (e.g. lipid peroxidation and DNA fragmentation), apoptosis and cell death. Broadly UV can induce ROS by affecting the cellular components directly or by means of photosensitization mechanisms. More specifically UV light can induce ROS by affecting the enzyme catalase and up-regulating nitric oxide synthase (NOS) synthesis. It may also cause a decrease in protein kinase C (PKC) expression leading to increased ROS production. UVR is capable of modifying DNA and other chromophores resulting in elevated ROS levels. The effects of raised ROS levels can vary based on the intracellular oxidant status of the cell. It is therefore important to protect yourself against the potentially harmful effects of UV light as it can lead to pathological UV-induced ROS production.

Ultraviolet Light Induced Generation of Reactive Oxygen Species.

UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

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UV Radiation and the Skin

Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, impaired wound healing and DNA damage that promotes cellular senescence and carcinogenesis. Melanoma is the deadliest form of skin cancer and among the malignancies of highest increasing incidence over the last several decades. Melanoma incidence is directly related to age, with highest rates in individuals over the age of 55 years, making it a clear age-related disease. In this review, we will focus on UV-induced carcinogenesis and photo aging along with natural protective mechanisms that reduce amount of "realized" solar radiation dose and UV-induced injury. We will focus on the theoretical use of forskolin, a plant-derived pharmacologically active compound to protect the skin against UV injury and prevent aging symptoms by up-regulating melanin production. We will discuss its use as a topically-applied root-derived formulation of the Plectranthus barbatus (Coleus forskolii) plant that grows naturally in Asia and that has long been used in various Aryuvedic teas and therapeutic preparations.

/pdf/ultraviolet-radiation-aging-and-the-skin-prevention-of-2pbifbrzxj.pdf

Ultraviolet radiation, aging and the skin: prevention of damage by topical cAMP manipulation.

Fairness of skin, UV sensitivity and skin cancer risk all correlate with the physiologic function of the melanocortin 1 receptor, a Gs-coupled signaling protein found on the surface of melanocytes. Mc1r stimulates adenylyl cyclase and cAMP production which, in turn, up-regulates melanocytic production of melanin in the skin. In order to study the mechanisms by which Mc1r signaling protects the skin against UV injury, this study relies on a mouse model with "humanized skin" based on epidermal expression of stem cell factor (Scf). K14-Scf transgenic mice retain melanocytes in the epidermis and therefore have the ability to deposit melanin in the epidermis. In this animal model, wild type Mc1r status results in robust deposition of black eumelanin pigment and a UV-protected phenotype. In contrast, K14-Scf animals with defective Mc1r signaling ability exhibit a red/blonde pigmentation, very little eumelanin in the skin and a UV-sensitive phenotype. Reasoning that eumelanin deposition might be enhanced by topical agents that mimic Mc1r signaling, we found that direct application of forskolin extract to the skin of Mc1r-defective fair-skinned mice resulted in robust eumelanin induction and UV protection (1). Here we describe the method for preparing and applying a forskolin-containing natural root extract to K14-Scf fair-skinned mice and report a method for measuring UV sensitivity by determining minimal erythematous dose (MED). Using this animal model, it is possible to study how epidermal cAMP induction and melanization of the skin affect physiologic responses to UV exposure.

Pharmacologic induction of epidermal melanin and protection against sunburn in a humanized mouse model.

OF DISSERTATION PHARMACOLOGIC INDUCTION OF THE MELANOCORTIN 1 RECEPTOR (MC1R) PATHWAY PROVIDES PROTECTION AGAINST SUNBURN AND ENHANCES EXPRESSION OF ANTIOXIDANT ENZYMES IN THE SKIN. The inability to tan properly after sun exposure strongly correlates with increased incidence of skin cancer. The melanocortin 1 receptor (MC1R) is a transmembrane Gscoupled cell surface receptor found on epidermal melanocytes that transmits pro-survival and pro-differentiation signals mediated by the second messenger cAMP. Humans carrying loss-of-function polymorphisms in MC1R signaling exhibit higher incidences of skin cancers including melanoma. This study focused on the physiologic effects of topical application of forskolin, an adenylate cyclase activator, in extension (Mc1re/e) K14-SCF animals, which model the fairskinned UV-sensitive human. Twice daily application of the drug promoted accelerated pigmentation, increased skin darkening due to epidermal deposition of melanin pigment, and induced epidermal melanin, which protected the skin against UV injury as judged by “minimal erythematous dose” (MED). Moreover, MC1R signaling regulated the expression of antioxidant enzymes at the transcriptional level. The human melanoma cell line A375, known to harbor a loss-of-function signaling mutation in MC1R, was used to determine effects of cAMP stimulation on the expression of antioxidant enzymes. We observed increases in expression of genes that control the biosynthesis and regulation of glutathione including the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione peroxidase, GPX, and glutathione reductase GSR. In addition, there is an increase in manganese superoxide dismutase (MnSOD) at the protein level. There was accumulation of MnSOD in the mitochondria after pharmacologic induction of cAMP with forskolin. Addition of the oxidative agent H2O2 enhanced the expression of MnSOD at the protein level as early as one hour after MC1R stimulation. Oxygen consumption rate on mitochondria was measured using Seahorse analysis; pharmacologic activation of MC1R/cAMP signaling did not affect mitochondrial metabolism. In addition, topical application of a crude extract of Solidago inhibited UV-induced inflammation in K14-SCF mice. Several UV-induced cytokines, including TNF-α, were down-regulated at the transcriptional level after topical application of Solidago extract. Together, these results indicate that MC1R signaling protects melanocytes from UV damage by regulating antioxidant enzyme expression and suggest that pharmacologic cAMP induction may be a useful preventive mechanism against UV-mediated skin sunburn and oxidative injury.

/pdf/pharmacologic-induction-of-the-melanocotin-1-receptor-mc1r-yco2dusfka.pdf

Pharmacologic induction of the melanocotin 1 receptor (mc1r) pathway provides protection against sunburn and enhances expression of antioxidant enzymes in the skin

Alexandra Amaro-Ortiz

Papers

UV Radiation and the Skin

Ultraviolet radiation, aging and the skin: prevention of damage by topical cAMP manipulation.

Pharmacologic induction of epidermal melanin and protection against sunburn in a humanized mouse model.

Pharmacologic induction of the melanocotin 1 receptor (mc1r) pathway provides protection against sunburn and enhances expression of antioxidant enzymes in the skin

169 – The Melanocortin 1 Receptor (MC1R) Pathway Enhances Expression of MnSOD and Protects againstROS-Induced Oxidative Stress in Human Melanocytes