Examples of association between vitamin E and other active molecules.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Vitamin E is the most well-known fat-soluble non-enzymatic antioxidant, mainly for its ability to inhibit the activity of pro-oxidant agents generated by reactive oxygen species (ROS). Vitamin E can eliminate free radicals induced by endogenous and/or exogenous agents such as ultraviolet radiation, drugs and pollution agents, avoiding their deleterious effects. The antioxidant activity of vitamin E is directly linked to its ability to inhibit the lipid peroxidation in unsaturated fatty acids, incorporating itself into cell membranes, which effectively inhibits lipid peroxidation [1, 2].
The antioxidant activity of vitamin E (alpha-tocopherol) has its property due to its ability to react mainly with the peroxyl radical (HOH•) and singlet oxygen (1O2), which favors lipid peroxidation. The free radical scavenging reaction occurs through the formation of a stable, low-energy radical, tocopheroxyl, which does not have the capacity to react with the free radical-forming agent [3]. Alpha-tocopherol is the main agent capable of removing peroxyl radicals from lipid membranes, such as membranes or low-density lipoproteins (LDL) [4].
It is a classic dermatological ingredient used alone in its purified form, alpha-tocopherol or by its derivatives. However, the conversion to the purified (isolated) form is required in skin to obtain the desired effects. Topical applications are designed for treating melasma, protecting against ultraviolet radiation (UVR) and improving aging damages [5, 6], The association of vitamin E with other antioxidants increase the effects in skin [7].
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in many skins’ therapies, such as: yellow nail syndrome, epidermolysis bullosa, cutaneous ulcers, pressure ulcers and burns, sub corneal pustular dermatosis, scleroderma, morphea, calcinosis cutis, Raynaud’s phenomenon, and inflammatory diseases. The oral supplementation of vitamin E could reduce the pigmentation in melasma and contact dermatitis lesions, too demonstrated remission of atopic dermatitis, prevention of sunburn reaction as well as the subsequent chronic skin damage [5]. Vitamin E combined with other antioxidants has shown positive results topically in the photoprotection, as well as delay the growth of the melanoma by promoting the apoptosis of tumor cells and inhibiting VEGF-mediated angiogenesis. Other results with alpha-tocopherol: improvement in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, collagen production and overall appearance by clinical evaluations of skin. Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB [8]. It is difficult to determine the
Skin products can be classified as medicines, cosmetics and cosmeceuticals, however, the teaching line between the categories is tenuous, being widely discussed by dermatologists, pharmacists and beauticians. Medicines and cosmetics are already widely discussed and accepted by world regulatory agencies; however, the term cosmeceutical is used as a marketing appeal and is not recognized as an official legal category. Skin products considered to be cosmetics are generally defined as products to clean, beautify, promote attractiveness, or change appearance, while medicines are intended for the diagnosis, cure, mitigation, treatment or prevention of diseases, which can affect the structure or any function of the skin. Regulatory agencies in different countries seek to organize the offer of products to ensure the safety for users.
Topical products that contain vitamin E can be classified as medicines or cosmetics, depending on their purpose. If the product is intended to lubricate the skin, it will be considered cosmetic and if it has therapeutic use as a healing agent, it will be a medicine. There are legal limits on the daily consumption of vitamin E as a supplement, however, for most international regulatory agencies, such as the NHS, FDA, Health Canada the limits for topical use are not described [10].
The antioxidant alpha-tocopherol acetate is the most common form of vitamin E in skin care products. In 2001, the Scientific Committee on Cosmetic and Non-Food Products for Consumers (SCCNFP) presented its opinion during the 18th Plenary Meeting. At the time, SCCNFP believed that alpha-tocopherol acetate did not pose a threat to consumer health and therefore did not propose any restrictions or use conditions [11].
The Cosmetic Ingredients Review Panel (CIR) in 2002 has assessed the safety of 14 tocopherols and tocotrienols and concluded that these ingredients are safe when used in cosmetics. The Panel further reviewed data from clinical and animal studies to determine the safety of tocopherols and tocotrienol ingredients and considered it appropriate to extrapolate existing information to conclude on the safety of all tocopherols and tocotrienols [12].
Since vitamin E can absorb ultraviolet light to produce free radicals, there is a possibility that strong exposure to sunlight after topical application may cause skin reactions. However, vitamin E concentrations between 0.1–1.0% are generally considered to be safe and effective for increasing vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects [8]. Vitamin E as alpha-tocopherol or tocopherol acetate is used in over-the-counter products in concentrations ranging from 1.0 to 5.0% [13, 14, 15].
Vitamin E is the main fat-soluble antioxidant in the body with biological activity and it is the collective name for the eight mains naturally occurring substances such four tocopherols and four tocotrienols. The eight analogues of vitamin E share similar chemical antioxidant activity, however, they are distinguished by their individual physico-chemical and biological effects at the molecular level in humans and higher animals. Alpha tocopherol is the most active, being considered an important asset in protecting cell membranes from lipid peroxidation promoted by free radicals [13, 14, 15].
Alpha-tocopherol is practically insoluble in water and this characteristic can difficult the development of topical products with high water content. In addition, this molecule is easily oxidized by atmospheric oxygen. Vitamin E acid acetate and succinate esters are applicable for clinical use due to their high oxidation stability but require the use of surfactants to improve the water solubility. Alpha-tocopherol is solubilized by large amounts of surfactants, but the hydrolysis of acetate is the limiting step in terms of its concentration during bioavailability [15].
The antioxidant properties of vitamin E are attributed to its free aromatic hydroxyl group; thus, the esters of vitamin E need to be hydrolyzed during absorption by the skin to exhibit this activity. In the biologically inactive esterified form, vitamin E acetate is more used because of its greater stability, acting as a prodrug, being hydrolyzed in active free vitamin E (alpha-tocopherol) after penetration into the skin. The bioconversion of vitamin E into the active form can be influenced by the technology involved in the development of formulations, by the target layer of the skin and exposure to ultraviolet rays. The stratum corneum seems to have less efficiency in the bioconversion of esters of vitamin E when compared to the nucleated epidermal layers. Thus, alpha-tocopherol should provide more efficient antioxidant protection for skin surface lipids and skin barrier constituents than vitamin E esters. However, in the nucleated epidermis the bioconversion of vitamin E acetate to active free form occurs at a much higher rate. In this sense, the choice of which vitamin E molecule to be used must consider the target layer of the skin and include product development strategies so that the activity of vitamin E is fully utilized [15, 16].
Vitamin E, more specifically alpha tocopherol, is considered one of the main fat-soluble and non-enzymatic antioxidant agents of natural origin, due to its advantages in terms of the protective activity against physical and chemical damage promoted by free radicals (FR). Vitamin E is an antioxidant capable of binding to the membrane in various tissues [17, 18]. Therefore, it is involved in several oxidative mechanisms in epidermis and dermis, catalyzed by ultraviolet radiation (UVR) and pollutants (Figure 1).
Oxidative mechanisms involving vitamin E in human skin exposed to ultraviolet radiation and pollution. ROS, reactive oxygen species.
The first studies related to the damage caused by the formation of FR on the skin, promoting lipid peroxidation, date from the 1950s and 1960s. To avoid the damages, the use of natural and synthetic substances was suggested in order to prevent the formation of FR [19, 20].
Reactive oxygen species (ROS) such as superoxide (O2−•), hydroxyl radicals (OH•), peroxyl (HOH•) and singlet oxygen (1O2), can be formed by endogenous (physiological) processes such as inflammation, physical activity in excess, nutritional disorder, hereditary issues, neoplasms, and even, by processes related to exogenous sources such as UVR and pollution agents. In the skin, the main damage related to lipid peroxidation generated by FR from exogenous sources is the activation of melanogenesis and damage to collagen fibers [19, 21, 22].
The lipid peroxidation of the epidermis cells occurs through the action of the ROS, which has the ability to bind to the unsaturated bonds present in the polyunsaturated fatty acids of the cell membrane phospholipids [22, 23]. The process starts between polyunsaturated fatty acids (PUFA) and the oxygen radical, obtaining a lipid radical, which causes a rearrangement process in the presence of molecular oxygen, becoming a peroxy lipid radical. The lipid peroxyl radical is also capable of attacking unsaturated lipids, generating new radicals, such as the lipid radical as in the first stage of the reaction and the lipid hydro peroxide radical, thus promoting a cyclic reaction. Thus, it is necessary to use substances capable of interacting with cell membranes and to extinguish the free radicals formed, such as vitamin E [24, 25].
In a more detailed way, the mechanism involved in the lipid peroxidation process occurs through a chain reaction of the polyunsaturated fatty acids (PUFA) of biological membranes, which due to the large amount of unsaturation, become extremely susceptible to attack by free radicals. The process begins with the activity of the free radical like OH*, which extracts H from PUFA resulting in the radical PUFA*. After the molecular rearrangement of a conjugated diene, the molecule is susceptible to attack by O2, resulting in a peroxyl radical (PUFAOO*). PUFAOO* can extract H from the adjacent PUFA, thus propagating a chain reaction. Self-oxidation occurs continuously, which can seriously affect the functionality of the tissue [26].
The action of pollutants and UV radiation (UVR) on the skin has already been studied, but the mechanisms involved are still uncertain, knowing that the damage is initially related to the composition of the skin’s sebum and the quality of the stratum corneum, which may lead to the formation of wrinkles, hyperchromies (spots), wrinkles and accelerated extrinsic aging and dermatological diseases such as atopic dermatitis, related to lipid peroxidation [27, 28, 29].
The chronic and acute damage to the skin caused by UVR (UVB and UVA) are related to the direct absorption of rays and indirectly through photosensitization reactions. Mostly (> 95%), UVA radiation, more specifically UVAI (340–400 nm), has the major ability to penetrate the skin and it causes deeper damage. The aggression of UVA radiation targets collagen and supporting fibers, in addition to cellular DNA. The DNA damage is related to the mutagenic power of UVA radiation, which can act directly or indirectly through photosensitization reactions [30].
Studies prove the mutagenic power of UVA through direct oxidation reactions of DNA nucleic acids with ROS, which can lead to simple disruptions of the DNA strands or to disruptions in symmetrical positions in the two strands. Several studies (
As the UVR, polluting agents have harmful effects on the skin by increasing the oxidative stress and decreasing the physiological enzymatic and non-enzymatic antioxidant capacity. With the formation of FR and ROS, an interaction occurs with the lipid layer membrane, initiating the cascade reactions of lipid peroxidation and the release of pro-inflammatory mediators, which result in the accumulation of neutrophils and phagocytic cells, that also generate radicals free, thus promoting a cyclical reaction. Oxidative stress initiates a series of quite complex biological processes that result in DNA damage, activation of transcription factors such as activating protein 1 (AP1) and the nuclear factor Kappa-B (NF-KB) and even some pathways of signaling involved in cell growth and differentiation and degradation of dermal connective tissue. Pollutants are also capable of inducing functional changes in lipids, DNA, skin proteins, favoring the acceleration of skin aging, inflammatory processes and dermatological pathologies [33, 34].
Melanogenesis can be considered as the first skin defense, being directly influenced by the skin phototype and, consequently, by the amount and type of melanin present. Melanocytes are particularly vulnerable to excessive oxidative stress from ROS due to their pro-oxidant state and the melanin synthesis involves oxidation reactions and generation of superoxide anion (O2−) and hydrogen peroxide (H2O2), promoting oxidative stress. The initiation of melanin synthesis occurs by a single route, with the conversion of tyrosine to dopa by the catalytic activity of the enzyme tyrosinase, releasing O2−, which also oxidizes dopa to dopaquinone with the release of O2−. From the obtaining of dopaquinin, a specific orthoquinone, capable of reacting with nucleophilic compounds, the synthesis follows two distinct pathways, eumelanogenesis and pheomelanogenesis, which respectively produce the darkest and lightest melanin monomers (red-yellow) [35, 36].
The homeostasis of human melanocytes in the epidermis is maintained mainly through a complex paracrine network, involving growth factors and cytokines synthesized by epidermal keratinocytes and dermal fibroblasts and modulated by UV radiation. Keratinocyte-derived endothelin-1 is a potent mitogen and a melanogenic factor capable of reducing H2O2 generation and apoptosis in human UV-irradiated melanocytes [37]. The α-MSH melanocortin and adrenocorticotropic hormone (ACTH) are synthesized by keratinocytes and melanocytes and stimulate the synthesis of eumelanin, as well as the survival and proliferation of melanocytes by binding and activating the melanocortin 1 receptor (MC1R). The MC1R is a receptor located on the surface of melanocytes with the ability to bind to protein G. Studies show that the treatment of human melanocytes in culture with α-MSH, results in a decrease in the generation of H2O2, due to exposure to UV rays [35].
With the production of ROS, oxidative stress formed can interrupt melanocyte homeostasis, compromising their survival or even leading to malignant pathogens. Thus, the balance between the pro and antioxidant properties of melanin in the skin is mainly determined by the proportions of eumelanin and pheomelanin, the levels of melanin intermediates and the concentrations of reactive metals in the melanosome microenvironment. The generation of H2O2 in response to the action of UV radiation is inversely proportional to the constitutive pigmentation, suggesting a natural antioxidant effect of melanin [35, 38]. The inhibition of melanogenesis occurs in several stages, such as the inhibition of the enzyme tyrosinase that acts in several phases of the melanin production cascade, and also influences the post-transcriptional concentration of tyrosinase and other enzymes related to melanogenesis, such as tyrosinase-related protein 1 (TRP1) and DOPA chrome tautomerase (TRP2) [39].
The mechanism of action of vitamin E (Figure 2) regarding the antioxidant activity in the skin is directly related to the chemical mediation of the phenolic hydroxyl (OH) of its structure, capable of donating H to the peroxyl radical (PUFAOO*), resulting in the formation of a stable lipid species (PUFAOOH). Thus, when donating the hydroxyl H, vitamin E becomes a relatively non-reactive free radical, as the unpaired electron moves to the aromatic ring. Thus, with electronic displacement, incorporation occurs in biological membranes, being located awfully close to the polyunsaturated fatty acids of the cell membrane phospholipids, interrupting the chain reaction. Vitamin E stops the reaction by the ability to donate hydrogen from the OH group to the unsaturated lipid or to the lipid peroxyl radical (PUFOO *), forming the low-energy tocopheroxyl stable radical (VE-O *), which in turn does not present the ability to act as a free radical forming agent [40, 41]. Vitamin E also has antioxidant activity involving other lipid radicals, acting directly on the radical’s singlet oxygen and superoxide anion [19].
Mechanism of lipid peroxidation and vitamin E in cells. PUFA, polyunsaturated fatty acids; PUFA*, lipid radical; PUFAOO*, Peroxy lipid radical; OH*, oxygen radical - hydroxyl; O2, oxygen; VE-OH, Vitamin E, alpha-tocopherol; VE-O*, radical tocopheroxyl.
Studies have shown the activity of vitamin E in the modulation of damage caused by FR mediated by the action of UVR on the skin, such as lipid peroxidation, photoaging, immunosuppression and photocarcinogenesis [42]. Vitamin E is able to reduce the inflammatory reactions of the skin, attenuating the production of prostaglandin involved in the process, pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) and NADPH oxidase [43, 44, 45].
In addition to its anti-inflammatory capacity, vitamin E is also able to modulate the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways and to reduce the increase in collagenase expression. PKC modulation may be representative in terms of cell growth control, however, the interaction between vitamin E (alpha-tocopherol) and PKC protein does not occur directly, assuming that it occurs preventively to its action at the cellular level [45, 46].
Vitamin E has the ability to significantly suppress collagen degradation by inhibiting metalloprotein 1 (MMP-1), involved in the initial process of collagen hydrolysis [44]. It can be identified in deeper layers of the skin, supposing its activity to minimize the photocarcinogenesis process, being considered as one of the main antioxidants of the human epidermis. Another characteristic of vitamin E is its use as an early and very sensitive marker for oxidative damage promoted by the environment [47, 48]. Thus, vitamin E prevents the lipoperoxidation of cell membranes and the degradation of fatty acids that are essential for the proper functioning of the body and skin [8, 49, 50].
Vitamin E can eliminate FR induced by UVA radiation, protect endogenous antioxidants from degrading processes, prevent lipid peroxidation and reduce immunosuppression caused by UVR. To increase protection against erythema and sunburn, the association of vitamins E and C is indicated, presenting potential against skin aging and skin cancer. Another activity of vitamin E on the skin is its application before sun exposure, avoiding the formation of the cyclobutane pyrimidine dimer (CPD) induced by UVB [46].
In general, exposure excessive to pollution and ultraviolet radiation promotes a greater production of free radicals, thus requiring an oral and/or topical supplementation of antioxidant substances, such as vitamin E, thus, the endogenous mechanism is not sufficient to prevent deleterious skin damage [51].
After vitamin E depletion, oral intake is the best way to replenish the stock of this antioxidant in skin. In fact, oral supplementation brings cosmetic effects after 8–12 weeks. For alpha-tocopherol alone, a photoprotection effect by reduction of human skin malondialdehyde concentration was observed [52]. The combination of vitamin E with other antioxidants is very beneficial for skin treatments. Alpha-tocopherol in combination with ascorbic acid increased UVB photoprotection in the human epidermis [53, 54]. The same combination showed a reduction in UV-induced inflammation [55]. Good outcomes for treating chloasma were seen with the same mixture during double blinded clinical trials [56]. When more antioxidants act together, strong outcomes are seen, such as reduction of UVB-induced wrinkle and increased collagen synthesis [57] and treatments of melasma [58, 59]. Despite the benefits to skin appearance, oral intake is not considered cosmetic treatment for its systemic effects.
Topical delivery also plays an important role in restock vitamin E. It is widely used in its purified forms or indirectly using vegetable seed oils [60]. It is a classical ingredient in dermatology and still used in cosmetics worldwide in a recent growth tendency. Cosmetics containing vitamin E are most valuable in the USA, UK and France. The top cosmetic claims used in labels and the categories are in Figure 3 [61].
Evolution of the most explored categories using tocopherol in cosmetics’ labels between 2016 and 2020 (A). Claims used in cosmetics’ labels containing tocopherol between 2016 and 2020(B).
The lipophilic nature of vitamin E requires an oily or alcoholic phase at the topical formulation. In cosmetics, the main drivers capable of delivering this type of molecule are serums, tonics, oils and especially emulsions. For vitamin E alone, hydro-alcoholic solution of alpha-tocopherol showed a reduction of UV-induced erythema in the epidermis [62] and the reduction on the number of epidermal sunburn cells. While O/W and W/O emulsions containing alpha-tocopherol acetate increased skin hydration and water-binding capacity in the stratum corneum [63]. Vitamin E is also used as coadjutant in other topical products to improve physical–chemical characteristics or to donate different effects. One of the most studied associations is with vitamin C, due its primary replenisher of vitamin E mechanism in skin. Vitamin C regenerates the oxidized form of vitamin E to its reduced form [64, 65]. A similar mechanism is expected using other antioxidants. Table 1 shows examples of associations of vitamin E and other molecules. The type of molecule and/or type of formulation is chosen depending on the target to address.
Vitamin E | Combined molecule | Effect | Model | Reference |
---|---|---|---|---|
Alpha-tocopherol (1%) | L-ascorbic acid (15%) | Synergic protection against erythema and sunburn cell formation | Aqueous solution applied to pig skin | [66] |
Tocopheryl acetate (1%) | L-ascorbic acid (20%) + | Improved the appearance of aging skin (Skin color, elasticity, radiance, smoothness, scaliness and wrinkles) | Commercial serum applied | [67] |
Tocopheryl acetate | Bioflavanoids from | Protected the skin from UV damage by reduction on the number of sunburn cells | Emulsion containing 5% of the mixture | [68] |
Vitamin E | A good antibacterial activity against | Dressing | [69] | |
Vitamin E 5 IU | vitamin A (10 000 IU) + vitamin D (1000 IU) + vitamin B1 (50 mg) + vitamin B2 (12.7 mg) + vitamin B6 (15 mg) + vitamin C (500 mg) + nicotinamide (100 mg) + dexpanthenol (vitamin B5) (25 mg) | Reduction of age spots and melasma | [70] | |
Vitamin E | Resveratrol + Baicalin | Improvement on the periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance | [71] | |
Vitamin E | Photostable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor) + vitamins A (1,700,000 UI/g) and C [2% (w/w) ascorbyl tetraisopalmitate] | The formulation with filters showed better stability comparing with the vitamins alone | In mouse skin | [72] |
Vitamin E | Amniotic membrane mesenchymal stem cell | Decreased the diameter of lesions | In chronic leprosy | [73] |
Vitamin E | Ferulic acid + Vitamin C | Suggests preventing skin cancer | Topically solution in the skin of white Yorkshire pigs | [74] |
Vitamin E | Vitamin C | Prevention of inflammation due lipid peroxidation caused by | [5] | |
Alpha-tocopherol | Ferulic acid | Inhibition of melanization | [75, 76] | |
Delta-tocopherol glucoside (0.05%) | Retinaldehyde (0.05%) + glycylglycine oleamide (0.1%) | Improvement on the elastin fiber production and a protection effect of the elastin and fibrillin fiber network against UV-induced alterations | [77] |
Examples of association between vitamin E and other active molecules.
The metabolization of derivatives into the active form of vitamin E (alpha-tocopherol) occurs at a far extend in the nucleated epidermis [6]. Therefore, the conversion is highly dependent on the delivery system of cosmetic preparations into controlling skin permeation [14]. To address this issue, several innovations on cosmetic formulations have appeared during the last decade.
The use of chemical permeation enhancers (e.g. alcohol, surfactants, terpenoids) is a good strategy to change stratum corneum polarity and fluidity. Likewise, the use of devices that create micron-scale pores in skin (e.g. iontophoresis, microneedles) is also available in clinics [78]. The benefits of using those techniques is to maintain the original formulation. However, adaptations may be needed to maintain stability in the case of adding chemical agents. Another strategy is to change the formulation completely by using new delivery systems to encapsulate vitamin E.
Micro and nanoemulsions are strong candidates for its permeation capacity. Nevertheless, reduced sizes may have systemic effects, which is not allowed for cosmetics. Regulatory issues must be address in controlling the particle size. Vitamin E microemulsions (256 nm) reach dermis, however with the aid of surfactants [79]. More recently, bigels are a viable cosmetic formulation. These biphasic systems formed by hydrogels and organogels show good spreadability and emollient and moisturizing effect, besides its transdermal capacity [80]. However, bigels containing alpha-tocopherol showed no difference against regular emulsions for hyperpigmentation and inflammatory markers in in vivo tests [81]. More tests are required to evaluate the benefits and safety of new cosmetic formulations.
Many products in the cosmetic market have vitamin E in its composition. The definition of optimal dosage of vitamin E in cosmetics products depends on the derivative molecule and the type of formulation.
Studies with animals to evaluate safety is common in many countries, especially in oral products. In animal experiments, 200 mg/kg was administered orally to frogs, rabbits, cats, dogs, and monkeys, with repeated application to mice over a period of 10–61 days. In food of rats, 4.000 mg/kg of Vitamin E was added and, in these experiments, was not mutagenic, teratogenic nor carcinogenic properties [82].
The toxicity of vitamin E is very low, because in clinical studies, a daily dosage of 100–300 mg of vitamin E was considered harmless, even when their use extends over a long period of time. Double-blind studies demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. They mentioned that the optimal human plasma concentration of vitamin E is between 1.0 and 1.5 mg/dl [82].
Numerous genotoxicity studies were conducted with tocopherol, tocopheryl acetate, tocopheryl phosphate (MTP), and tocopheryl succinate. The only remarkable result was tocopheryl succinate with only a weak positive in a sister chromatid exchange assay in the presence of metabolic activation [12].
Tocopherol and tocopheryl acetate are generally recognized as safe food ingredients [12]. According to Brigelius-Flohe et al. [83], vitamin E supplements for pregnancy usually contain only small doses of vitamin E, although adverse effects have not been observed at higher doses. The original report on tocopherols indicated that tocopheryl succinate, up to 75 mg/d in the diet did not have reproductive or developmental effects in rats. In relation to tocopheryl acetate, 1.6 g/kg/d, generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice [84]. There is no published report documenting adverse fetal effects due to use of topical vitamin products. Topical application of vitamin E can rarely cause contact dermatitis, erythema multiforme, and xanthoma [5].
Vitamin E and its derivatives are widely used in many cosmetic and dermatologic products, in general, papers with side effects such as allergic or irritant skin reactions are rare. In clinical studies, tocopherol and tocopherol acetate were found to be safe for use in topical skin formulation since irritant or sensitizing reactions were found only in very small percentages [85]. Tocopheryl acetate was not irritating to rabbit eyes in one study, but it produced weak-to-moderate conjunctival irritation in another study [86]. Positive patch test results of alfa-tocopherol are rare and need to be critically reviewed. However, the derivative (alpha-tocopheryl linoleate), demonstrated allergic popular and follicular contact dermatitis in 1000 cases, reported in Switzerland by a line cosmetic in 1992. This compound was easily oxidized under the storage condition [8]. According to Baumann and Spencer [87], 33% of the patients studied developed a contact dermatitis to the vitamin E. The ingredients considered safe to use in cosmetics were Ascorbyl tocopheryl acetate, Ascorbyl tocopheryl maleate, Dioleyl tocopheryl methylsilanol, Potassium ascorbyl tocopheryl phosphate, Sodium tocopheryl phosphate, Tocopherol, Tocophersolan, Tocopheryl acetate, Tocopheryl linoleate, Tocopheryl linoleate/oleate, Tocopheryl nicotinate, Tocopheryl phosphate, Tocopheryl succinate and Tocotrienols. remembering that the concentrations and conditions of use in the safety tests must be observed [12].
Tocopheryl acetate, 0.2 mL applied under an occlusive patch for 24 hours prior to irradiation, was not phototoxic in a study in 11 participants [84]. According to ECHA [86], animal and clinical testing concluded that tocopheryl acetate was not photoallergenic or phototoxic. The dermal LD50 of tocopheryl acetate is >3 g/kg bw in albino rats. Five animals per group were dosed with 1 or 3 g/kg bw undiluted tocopheryl acetate in vegetable oil under an occlusive patch for 24 hours. Slight erythema was observed 24 to 48 hours after exposure. Slight abrasion was observed in one low dose female, two high-dose females, and two high-dose males [86]. The acute dermal toxicity of mixed tocopheryl phosphates (MTPs) was determined in New Zeal and rabbits; the dermal LD50 was greater than 1,130 mg/kg bw MTP in female rabbits [88].
An aqueous gel containing 1,130 mg/kg bw MTP (918 mg/kg bw a-tocopherol equivalents) was applied to the clipped dorsal skin of 5 male and 5 female rabbits for 24 hours using surgical gauze. At 24 hours, slight-to-well-defined erythema was observed in 4 of 5 males and all females, and slight-to-moderate edema was observed in 2 of 5 males and all females. Signs of irritation were not observed at days 7 and 14 [12].
According to Costa [89], vitamin E has a wetting action and in an
An
Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB. Magnetic resonance images showed that there was no increase in skin thickness associated with edema. However, the cytotoxic effects of UV exposure as measured in Chinese hamster embryo cells can also be reversed by the presence of other antioxidants as well as a-tocopherol, ascorbic acid, butylated hydroxytoluene (BHT) and GSH. However, before exposure UV these components do not protect against cytotoxicity. In this study, it was observed that high dietary levels of vitamin E can restore the level of incorporation of thymidine dimers into DNA, in UV-exposed epidermal cells in relation to control non irradiated cells. The DNA was isolated and determined by the method of Gendominico Record et al. 1991 [90].
Gaspar and Campos [72], evaluated photoprotective formulations with a combination of photostable (octyl methoxycinnamate, benzophenone-3 and octocrylene or photoinstable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor), both in addition to A, C and E. vitamins The combination of photostable filters showed a better response compared to the others. The filter components and vitamins were quantified by HPLC analysis and spectrophotometry. The formulation containing only vitamins, showed irritation and hairless in mouse skin, this was observed by histopathology.
Ferulic acid, by protecting vitamins C and E, can prevent UV-induced thymine dimer formation when applied topically to skin evaluated by fluorescence microscope coupled with a camera. Studies mentioned a presence of mutations in thymine dimer in keratoses and squamous cell carcinomas of skin, so this result requires that this combination can prevent skin cancer [74]. The photoprotective actions demonstrated by the topical application of alpha-tocopherol in mice may not be restricted to the action of itself [91]. It is likely that the dimers formed from UVB photo-oxidation of alpha-tocopherol, and perhaps the trimers as well, may themselves confer photoprotection, this was observed by similarities in the UV absorbance spectrum. Vitamin E slowed melanoma growth by promoting tumor cell apoptosis and inhibiting VEGF-mediated angiogenesis. The mechanism of the
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in therapy of yellow nail syndrome in a dosage of 1000 IU once a day for a period of 6 months; epidermolysis bullosa (300–600 IU/day); in cutaneous ulcers with treatment of pressure sores in doses of 800 IU/L gradually increasing to 1600 IU/L; in wound healing with zinc and vitamin C for pressure ulcers and burns; in subcorneal pustular dermatosis (d-alpha-tocopheryl acetate) 100 IU/day, gradually increasing to 400 IU/day for 4 weeks; in scleroderma, morphea, calcinosis cutis, and Raynaud’s phenomenon respond to vitamin E in a range from 200 to 1200 IU per day; in Hailey–Hailey disease with derivative of vitamin E
Vitamin E has been reported to be effective in inflammatory diseases with attenuation of pro-inflammatory cytokine TNF, evaluated by a section of skin mice by quantitative ELISA kit [64]. In a combination of oral vitamins, A, C, and E with or not proanthocyanidin there was a significant reduction of pigmentation in melasma and pigmented contact dermatitis lesions in two randomized clinical double-bind study [5, 92]. Oral vitamin E (400 IE/day) for 8 months, improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels [93]. In oral combination with carotenoids (ß-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins there was decreases the UV-induced expression of Metalloproteinases 1 and 9, that means prevention of sunburn reaction as well as subsequent chronic skin damage, evaluated by clinical trials [94].
In chronic leprosy a topical combination of vitamin E and with an amniotic membrane mesenchymal stem cell decreased the diameter of these lesions, evaluated by randomized controlled trial and monitored weekly [73]. In a dressing based on the association of Vitamin E and
Chung
Studies show that there was an improvement in the healing of wounds in diabetic rats by topical vitamin E [95]. According to Kuriyama et al. [9], some animal’s studies even suggest that topical vitamin E at a concentration of 20% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to 0.5% prednisone ointment. Those skin conditions are generally self-reported as dry skin [96].
With the onset of xerosis, several inappropriate situations can arise, such as the release of inflammatory mediators, hyperproliferation of keratinocytes and interruption of epidermal differentiation, in addition to changes in lipid structure and enzymatic activity [97]. Skin aging, specifically after age 65, presents several constitutional and functional changes in all layers of the skin, such as cellular senescence, decreased proliferative capacity, decreased ability to repair cellular DNA, abnormalities related to chromosomes, loss of telomeres, DNA extranuclear related mutations, oxidative stress and genetic mutations, promoting the formation of wrinkles, loss of elasticity and dryness of the skin [98, 99]. According to Rhie et al., 2001, the alpha-tocopherol concentration in the epidermis is negatively affected with aging and especially with photoaging, in this case the levels found are even lower when compared to young skin [100].
Over the years, the main histological changes occur with the basal cells, which suffer from dyscrasia, presenting an increase in volume and size, which can be accentuated by the action of UV radiation. As for the functionality of the basal cells, there is a decrease in mitotic activity and an increase in the cell cycle time and the cell migration time, which can promote changes in the outermost layer of the skin. The horny extract does not change its thickness, however, the replacement of lipids happens slowly, which significantly affects the function of barrier, protection and maintenance of natural hydration [101, 102].
Thus, the topical use of vitamin E is adequate for its recognized antioxidant and protective activities, favoring the improvement of the skin barrier due to its lipophilic character and also, effectively avoiding lipid peroxidation by protecting cell membranes from the action of free radicals [103]. Gehring et al. [63] evaluated the hydration capacity of the stratum corneum by the use of vitamin E (5%) in water/oil and oil/water emulsions, demonstrating moisturizing activity in the stratum corneum, in addition to providing indications that indicate retention of water in the stratum corneum. Gonullu and collaborators [104] also report that the topical use of vitamin E for a period of two to four weeks can improve the ability of water to retain in the skin, favoring hydration.
While aging decreases keratinocyte proliferation, the abnormal hyperproliferation those cells are seen in psoriasis. Psoriasis is a chronic inflammatory process of the skin which affects 1–2% of the population and can affect the quality of life. It is most characterized by the presence of erythematous plaques with silvery scale on various regions of the body including the scalp, extensor regions of the extremities, and intertriginous areas of the skin [19, 105, 106]. Studies on the influence of vitamin E on psoriasis include oral and topical treatment evaluation of the vitamins combination, minerals, among others (vitamins A, C, D, E, B1, B2, B3, B5, B6, B12, magnesium, zinc, selenium, folic acid, copper, lysine and proline), that act on oxidative stress, energy metabolism, the immune system and optimized collagen formation. The consumption of olive oil, a vitamin E source, is also associated with improvement in psoriasis symptoms, acting positively in the suppression of serum levels of metalloproteinase-3 (MMP-3), protein of the cartilage olimeric matrix (COMP) as well as the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) [107]. Topical treatments include the application of products added with plant extracts containing vitamin E and other derivatives, the results are representative in relieving the symptoms of psoriasis induced in the mouse model, suppressing the levels of Interleukin-22 involved in extensive proliferation of keratinocytes and pathogenesis of psoriasis. The critical importance of the interleukin axis for the pathogenesis of psoriatic disease has resulted in new biological treatments targeting these cytokines, indicating that vitamin E is a component of interest in the treatment of psoriasis [106, 107, 108, 109].
Antioxidants consumed orally or topically may impact several organs in the body and among them, the skin. Systemic or centralized effects of these molecules can be modulated by the administration pathway and cellular machinery involved in their metabolization. When compared with other natural bioactive compounds, vitamin E has a specific mechanism of activation in skin due its lipophilicity. Alpha-tocopherol is the active molecule, but several derivatives are available in the market to address solubility, cost and pharmacotechnical necessities. The acetate and succinate esters exhibit better oxidation stability and are often associated with surfactants to improve water-solubility. The hydrolyzation of those molecules is mandatory to achieve biological effects and is mainly driven by enzymatic complexes in skin. The application of derivatives is an interesting alternative for slow delivery of this vitamin since the necessity of activation may lead to accumulation and a reservoir effect [110].
The natural lipophilicity of vitamin E impacts also its biological effects in skin. Vitamin E structure forms complexes with lipids in the cellular membrane and therefore acts promptly against the ROS formation due UV or pollution exposure [111]. The reduction/blockage of oxidative stress’ cascade protects skin against several damages visible as wrinkles, melasma and cancer. Besides the lipid peroxidation, vitamin E has an important role in DNA integrity and epigenetic gene modulation [112]. As a natural component of the healthy tissue, vitamin E is associated with impaired skin treatments, such as psoriasis, dry skin, atopic dermatitis and other skin disorders related to oxidative stress and inflammation [5].
The presence of vitamin E is expected in skin, which makes permeation experiments, bioavailability studies and quantification analysis more challenging. Raman confocal spectroscopy showed good sensibility to evaluate the health benefits and safety of vitamin E in human skin
The cosmetic market is always releasing innovative products despite vitamin E is considered a very classic dermatological active. New delivery systems focused on better absorption, deeper permeation or simpler hydrolysis are the R&D main targets. Since vitamin E is generally recognized as safe (GRASA) food ingredient and used in over-the-counter products with broader concentration range (1.0 to 5.0%), there is little regulatory concern about the exploration of this molecule in cosmetics and supplements. The focus of this chapter is topical applications and therefore, the oral toxicity data was not extensively covered. Safety assessment of alpha-tocopherol and its most used esters showed no phototoxicity, no genotoxicity and no ocular and dermal sensibilization [12]. The use of vitamin E in topical applications is a safe, effective and well accepted worldwide, especially in association with other antioxidants.
Vitamin E, more specifically alpha-tocopherol, can be considered a substance with antioxidant activity with the ability to protect long-chain unsaturated fatty acids. It is also capable of playing an important role in a wide variety of physiological and biochemical functions, mediated by the antioxidant function or by its stabilizing effect on cell membranes, breaking down the peroxyl chain propagation reactions and eliminating the efficient lipid peroxyl radicals. Is has been used for decades and is still a very good a widespread ingredient for dermatological products and formulations, especially when associated with other antioxidants such as vitamin C. However, it is important to emphasize the need for more in-depth studies on the use of its derivatives and associations, regarding the conversion speed and the converted amount of vitamin E in skin. There are few studies related to the topical safety and efficacy of vitamin E in the literature, although it is widely used in cosmetics and dermatologic products. A low incidence of contact dermatitis has been reported. However, more studies would be needed for a conclusive answer regarding its topical safety. The definition of optimal dosage in cosmetics depends on the derivative molecule and the type of cosmetic formulation.
Breast cancer is one of the most common neoplasia in women, representing about 25% of all most cancer instances in women, and is the second main purpose of most cancer deaths in advanced countries [1]. The search for therapies for this pathology is an expanding field in medical research.
Melatonin is an indoleamine secreted in particular with the aid of using the pineal gland with circadian rhythmicity. Melatonin represents one of the links between circadian disruption and cancer development. The role of this hormone in the regulation of cancer cell growth has been extensively investigated and many studies have pointed out the oncostatic properties of melatonin against different neoplasia, including breast cancer, ovarian, skin, lymphomas, leukemia, sarcoma, hepatocarcinoma, colorectal cancer, melanoma, lung cancer, endometrial and cervical cancer, prostate cancer, larynx carcinoma, neural tumors, and pancreatic cancer [2]. Melatonin production takes place mainly during the night in the pineal gland. However, its synthesis is also produced in other parts of the body, including gastrointestinal tract [3]. Specifically, gut cells synthesize great quantities of this indoleamine [4]. Apart from this, melatonin can be produced by gut microbiota directly or indirectly, since microbiota produces short-chain fatty acids (SCFAs), which stimulate serotonin production. Serotonin by the action of two enzymes (arylalkylamine-N-acetyltransferase (AANAT) together with 14–3-3 proteins for its stabilization, and acetylserotonin O-methyltransferase (ASMT)) is converted into melatonin [5].
The melatonergic pathway starts with the uptake of tryptophan (Trp) [6]. This important amino acid is needed for lifestyle and growth, however, is not synthesized via way of means of the organism. In the body, Trp is transported around the periphery either bounded to albumin (90%) or in free form (10%) [7]. Trp can act as a precursor of different pathways once in the central nervous system (CNS). First, kynurenine pathway constitutes the major catabolism route (95% of whole Trp dietary intake) [8]. In second place, 3% of Trp is converted into tryptamine by decarboxylation or into indol-3-pyruvic acid by transamination. Thirdly, about 1% of Trp is used for protein synthesis, and finally, the melatonergic pathway is over 1% of whole Trp intake, being this route through which serotonin and melatonin synthesis is done [9].
The kynurenine pathway begins with the action of the rate-limiting enzymes Trp-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO-1 and IDO-2) [10]. TDO is an enzyme that is mainly expressed in the liver, apart from other organs such as the brain, where it is found in low quantities. TDO expression is induced by oxidative stress [9, 10]. In contrast, IDO-1 is found primarily in extrahepatic tissues such as the lungs, brain, or kidneys [9, 10]. IDO-1 expression is induced by lipopolysaccharides (LPS), amyloid peptides, human immunodeficiency virus (HIV) proteins [10], tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ), and by different proinflammatory cytokines, including interleukin-1beta (IL-1 β), IL-6, and IL-18 [8]. Thanks to the action of TDO and IDO, Trp is converted into kynurenine (KYN), which activates the aryl hydrocarbon receptor (AhR) [9]. After this activation, AhR/cytochrome P450 (CYP1B1) pathway starts, being this pathway fundamental in breast cancer [11]. After, CYP1B1 stimulates N-acetylserotonin (NAS) conversion from melatonin, causing an increase in NAS/melatonin ratio and a reduction in melatonin levels [12]. NAS induces the dimerization and activation of tyrosine kinase B receptors (TrkB) and the stimulation of the AKT and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways [13], which are implicated in the survival, proliferation, invasion, and migration of breast cancer cells and their resistance to the different therapies.
As previously described, the kynurenine pathway is implicated in the development of breast cancer. Apart from this, it has been implicated in a wide range of diseases and disorders, including inflammatory processes, infectious diseases, neurological disorders, Huntington’s disease, affective disorders, autoimmune diseases, peripheral conditions, and cancer progression. A key indicator of cancer progression is often the upregulation in IDO-1, resulting in an accelerated and sustained degradation in Trp [8]. Tryptophan degradation products through the kynurenine pathway exhibit neuromodulatory and inflammatory effects and have been related to cancer development and tumor progression [9]. Glioblastoma sufferers with a high-ratio KYN/Trp had a bad evolution and occasional survival as compared with sufferers with a decrease ratio [14].
The importance of the kynurenine pathway during cancer development has encouraged recent studies on the use of IDO inhibitors as a therapeutic strategy for treatment of breast, lung, and ovarian cancer [9]. Suppression of IDO and TDO would lead to a decrease in kynurenine production [15]. It is a novel therapeutic target in cancer research and the results have been positive. Using transgenic mouse model of breast cancer, IDO-1 inhibitors, 1-methyltryptophan (1-MT), and methyl-thiohydantoin-tryptophan were able to potentiate the efficacy of chemotherapy drugs, promoting tumor regression without increasing the side effects [16]. 1-MT, a competitive IDO inhibitor, has been tested and approved in phase I clinical trials in patients with metastatic neoplasms as well as in lung, ovarian, Fallopian tube, and breast cancers displaying sickness stabilization in many cases [17, 18, 19, 20].
In addition, the alterations in the melatonergic pathway that occurred in breast cancer cells produce changes in gut permeability and microbiome composition accompanied by a reduction in butyrate levels and an increase in LPS, leading to a pro-inflammatory response, and increasing the production of Trp catabolites, thus decreasing the melatonin production [21].
Therefore, a bidirectional flow is observed between alterations in the composition of the microbiota (dysbiosis), the production of melatonin levels (circadian disruption), and breast cancer. Thus, in this chapter, we will deal with the properties of melatonin, highlighting its antiestrogenic properties, and its relationship with the microbiota and breast cancer.
Melatonin has different actions depending on its binding to specific receptors. On the one hand, melatonin activates MT1, MT2, and MT3 cell membrane receptors coupled to Gi protein [22]. This hormone binds to these receptors, reducing cAMP levels, thus counteracting the estrogen-induced estrogen receptor alpha (ERα) transcriptional activity by interacting with the cAMP signaling cascade [22] and thus suppressing adenylate cyclase [23].
On the other hand, melatonin binds to calmodulin (CaM), behaving as an antagonist capable of binding and inactivating the Ca2+/CaM complex. CaM is important in the activation of ERα, by facilitating its association with other coactivators and binding to the estrogen response element (ERE) [24]. Melatonin inactivates the Ca2+/CaM complex, inhibiting CAM-dependent estradiol-induced transactivation of the ER [25].
Besides, melatonin interacts with the retinoic Z receptor/retinoid, receptor-related orphan nuclear receptor alpha and beta (RZR/RORα and RORβ) superfamily. The estrogen-induced transcriptional activity of ERα is due to the overexpression of these receptors and its effects can be inhibited by melatonin by the activation of MT1 or by inhibiting CaM [26].
Finally, melatonin is described as an antioxidant. It transfers electrons to hydroxyl radicals, superoxide anions, hydrogen peroxide, hypochlorous acid, nitric oxide, and peroxynitric anions [27]. Furthermore, melatonin stimulates the expression of antioxidant enzymes, being a powerful free radical scavenger [28, 29].
Melatonin has been widely described in the literature as a potential antitumor agent due to its several antitumoral properties [30]. Firstly, melatonin is a powerful antioxidant molecule that neutralizes the free radicals that induce carcinogen modifications in the DNA and cause cell nuclear damage, preventing the appearance of cancer [31].
Secondly, melatonin is known to prevent circadian disruption that occurs frequently in women who work night shifts by exposure to artificial light at night (ALAN) [32]. Therefore, this hormone synchronizes the circadian rhythms with ambient light [33].
Furthermore, melatonin regulates fat metabolism since it prevents the linoleic acid adsorption. This fatty acid activates the epidermal growth factor (EGF), mitogen-activated kinases (MAPK), and ERK1/2 pathways, promoting the proliferation and growth of the tumor. Thus, melatonin can prevent cancer by inhibiting the acid linoleic adsorption [30].
On the other hand, melatonin is known to regulate cell cycle. The Trp-derivated causes the arrest of cell cycle by lengthening the GAP1 (G1) growth phase, thus delaying the entrance to the synthesis (S) and mitosis (M) phases [34]. For this reason, melatonin has antiproliferative actions. Besides, melatonin stimulates apoptosis process of the tumoral cells by increasing p53 expression [35, 36].
Also, low levels of melatonin are related to alterations in the immune system [33]. Melatonin stimulates immune system mediated by interleukins and other cytokines in monocytes and lymphocytes, reducing tumor cell survival and proliferation [28].
Apart from these antitumoral actions, melatonin inhibits angiogenesis by avoiding the different steps in this process. In fact, this hormone inhibits invasion, migration [37], and metastasis of tumoral cells [38], thus preventing tumoral cells from entering to the vascular system and inhibiting tumoral angiogenesis [39].
Additionally, melatonin also inhibits telomerase activity, which is stimulated in breast cancer cells [40]. Telomerase activity is responsible to maintain the DNA stability, contributing to the cancer cells’ immortality, and providing an unlimited capacity for the division of neoplastic cells [30]. Melatonin prevents the action of estrogen, cadmium, or estradiol-induced telomerase reverse transcriptase (hTERT) transcription in the breast cancer cells and reduces the transactivation of hTERT initiated by ERα [41].
Finally, melatonin is known to be a potent antiestrogenic molecule by acting on the neuroendocrine-reproductive axis and preventing the estrogen actions that at last will cause breast cancer [30]. In the next section, we will deal with the actions of melatonin behaving as a selective estrogen modulator (SERM) or selective estrogen enzyme modulator (SEEM) in detail.
Melatonin is a molecule that modifies the estrogen levels by altering the estrogen synthesis pathway preventing breast cancer. This hormone has direct actions at the level of the tumoral cell, behaving as a SERM [42]. On the one hand, it counteracts the effects of estrogen acting as a natural antiestrogen. Besides, melatonin binds to the MT1 receptor and avoids the binding between the estradiol (E2)-ERα complex to ERE and the initiation of transcription [25]. In addition, the literature has described another mechanism by which melatonin binds to calmodulin (CaM), preventing the binding of the E2-ERα complex to ERE and thus its transcription [25].
On the other hand, melatonin modulates the expression and activity of the different enzymes implies in the synthesis of estrogens (SEEM), thus reducing its levels. In concrete, melatonin reduces the expression and activity of aromatase, sulfatase (STS), and 17β-hydroxysteroid dehydrogenase (17βHSD) enzymes and enhances the expression and activity of estrogen sulfotransferase (EST). Aromatase is the enzyme responsible to convert the androgens into estrogens by the stimulation of its different promoters (promoter II, I.3 and I.4) [43]. Melatonin is able to inhibit this enzyme by inhibiting cyclooxygenase-2 (COX-2) and decreasing the production of prostaglandin E2 (PGE2), which reduces the levels of cAMP and indirectly decreases the activation of aromatase promoters and finally decreases the aromatase expression and activity, which will reduce the estrogen levels [44]. 17βHSD and sulfatase enzymes are the responsible for the conversion of biologically inactive estrogens into their active form. EST is the enzyme responsible to do the opposite action, converting the steroids into the active form [45]. Therefore, melatonin by modulating the expression and activity of these enzymes can prevent the development of breast cancer by reducing theestrogen levels [43].
Finally, melatonin has indirect actions on the hypothalamus-hypophysis-gonads axis, lowering the synthesis of ovarian estrogens and prolactin, which are fundamental in mammary growth [28].
Cohen et al. proposed that a reduction in melatonin levels induced an increase in estrogen levels, being the cause of the development of breast cancer [46]. Since then, there are numerous research that display the association between melatonin levels, estrogens and cancer progression [39]. There are studies in which women with low levels of circulating melatonin, suffer from breast cancer [28]. Specially, women with tumors with positive receptors to estrogen or progesterone, have lower nocturnal levels of melatonin than those with negative hormone receptors [47]. Furthermore, lower levels of 6-sulfatexymelatonin in the urine of breast cancer patients are observed, in comparison with women with benign pathologies [48]. Apart from this, it is described that shift work produces circadian disruption, reducing the production of melatonin and thus increasing the risk of breast cancer [30].
The uses of melatonin are demonstrated
The link between obesity and breast cancer has been widely described in the literature. Obesity consists of excessive fat accumulation in white adipose tissue (WAT) in addition to hyperplasia and hypertrophy of adipocytes. These events cause chronic inflammation of WAT, constituting an important adipokines and triglycerides source which will be related with breast cancer development [52]. There are several adipokines secreted by adipose tissue that are implied with breast cancer [53]. Specially, increased leptin levels are related not only with breast cancer but also with obesity [54]. Leptin is the responsible for the mammary glands development and lactation, in addition to the breast cancer proliferation and invasion [55]. In fact, higher levels of leptin have been observed in women with breast cancer compared to healthy women. On the other hand, it has been described that adiponectin levels are inversely proportional to adiposity, exerting an inhibitory action on tumor growth and proliferation as well as stimulating apoptosis [56]. That is why lower levels of this adiponectin have been observed in patients with obesity [52]. Regarding insulin, obese and breast cancer women present higher circulating levels. Insulin induces proliferation of the breast cancer cells with ER+ by realizing growth factors that stimulate mitosis and inhibit apoptosis [57]. Finally, it should be noted that obese women with breast cancer have low levels of sex hormone-binding globulin (SHBG) [58]. This protein binds to sex steroids, regulating their bioavailability in the bloodstream. Therefore, this is the reason by which obese women with breast cancer have elevated levels of estrogen in their breast tissues.
While the principle supply of estrogen in premenopausal women is the ovaries, in postmenopausal women estrogen synthesis is located in peripheral tissues along with WAT (which include mammary glands) and endothelial tissue [59]. In this case, estrogens are synthesized by transformation of androgenic precursors of adrenal origin or biologically inactive estrogens. Adipose tissue from mammary glands is composed of fibroblasts and endothelial cells. Breast cancer risk is correlated to the increased amount of adipose tissue, particularly in undifferentiated fibroblasts, due to this tissue has high aromatase activity, responsible for stimulating the synthesis of estrogens, and its promoters [60]. In normal breast tissue there is a high concentration of inactive steroids and the expression and activity of EST tend to be increased. In contrast, in breast tumor tissue, aromatase, 17βHSD, and steroid sulfatase (STS) tend to be overexpressed while EST expression and activity is decreased, resulting in an accumulation of 17beta-estradiol in breast tumor tissues [61, 62].
Estrogens are necessary to the malignant epithelial cells’ growth. These cells produce antiadipogenic cytokines (IL-6, IL-11 and TNF-α and PGE2), that increase the cAMP levels which stimulate the aromatase promoters, giving place an up-regulation of aromatase expression in the preadipocytes. This is the reason why there are a great number of estrogens in adipose tissue fibroblasts. Furthermore, the antiadipogenic cytokines are responsible for the inhibition of the adipogenic cytokines, PPARγ and C/EBPα, stopping the differentiation of preadipocytes into mature adipocytes [63]. All these processes are known as desmoplastic reaction [64].
Melatonin stimulates the adipogenic cytokines, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPα), promoting the differentiation of preadipocytes into mature adipocytes [65]. Besides, melatonin inhibits the expression of aromatase promoters lowering the estrogen circulating levels [64]. This hormone is able to inhibit cyclooxygenase activity, thus reducing PGE2 levels, and decreasing intracellular cAMP. This fact will inhibit the aromatase promoters in peritumoral fibroblasts, reducing the expression and activity of aromatase and, therefore, the local estrogen levels in breast tissue [66]. Finally, melatonin reduces the antiadipogenic cytokines production in malignant epithelial cells, being related this with the aromatase expression.
As already has been described in a previous section, melatonin acts as a SEEM and SERM, reducing the estradiol concentrations in tumors, and therefore reducing the risk of breast cancer [42, 43, 67, 68].
Finally, melatonin is associated with a reduction in the risk of obesity related to breast cancer because increases adiponectin secretion; inhibits aromatase expression; inhibits leptin levels; reduces blood glucose and insulin resistance; and decreases body fat mass [57].
It is known that both changes in the production of melatonin (circadian disruption) and the imbalance in the composition of the microbiota (dysbiosis) produce alterations in estrogen levels, which is one of the main risk factors for the development of breast cancer. Therefore, since a relationship between circadian disruption and breast cancer and between dysbiosis and breast cancer have been described, here we claim to describe the link between gut microbiota, melatonin, and breast cancer.
Bacterial composition of estrobolome in turn is probably affected by different factors, which can exert selective pressures on bacterial populations and can cause an imbalance or dysbiosis, which increases the risk of breast cancer due to elevated levels of circulating estrogens in postmenopausal women [69]. Melatonin modulates the composition of the microbiota and suppresses pathogenic bacteria in the gut due through its antioxidant activities [70]. Additionally, significantly, enteric cells and gut microbiota produce large amounts of melatonin. Circadian disruption, caused by sleep deprivation or exposure to constant light, causes an alteration in the composition of intestinal bacteria (dysbiosis) and affects the levels of melatonin [70]. Some authors demonstrated that exogenous melatonin supplementation restores microbiota composition [71] by reducing oxidative stress and the inflammatory response by suppressing toll-like receptor 4 (TLR4) expression, suggesting that melatonin may interact directly with gut microbiota. Thus, since melatonin modulates microbiota composition, involved in the pathogenesis of various cancers, a link exists between melatonin, microbiota, and the pathogenesis of cancer caused by dysbiosis [70].
Regarding breast cancer, gut microbiome is fundamental for the regulation of steroid hormone metabolism. It is crucial in the development of hormone receptor-positive breast cancer, whose circulating estrogen levels are the most important risk factor. Alterations in the bacterial composition of the estrobolome favor bacteria with β-glucuronidase activity, which deconjugate estrogens, favoring their enterohepatic circulation, causing their reabsorption and increasing the total estrogen load, and therefore increasing the risk of breast cancer [72].
On the other hand, melatonin increases the expression and activity of EST and reduces the expression and activity of STS, increasing the concentration of conjugated estrogens (biologically inactive) that are excreted in the bile and reducing the amount of deconjugated (biologically active) estrogens [44]. Therefore, this neurohormone exerts an activity opposite to the β-glucuronidase activity of intestinal bacteria, reducing the number of estrogens and lowering the risk of developing breast cancer [21].
Apart from this effect, changes in the intestinal microbiota activate the kynurenine pathway, moving Trp away from the melatonergic pathway and reducing the amount of melatonin and thus increasing the risk of breast cancer. In addition, butyrate favors the melatonergic pathway, so a reduction in this SCFA will produce a decrease in melatonin, increasing the NAS/melatonin ratio. NAS activates TrkB, activating the PI3K/AKT, MAPK, and PLC/PKC pathways, which are involved in cancer cell survival, migration, invasion, and metastasis. Therefore, dysbiosis leads to lower concentrations of butyrate and melatonin, which can result in inflammation and an increase in estrogens in the bloodstream and, therefore, an increase in breast cancer risk [73].
Dysbiosis and circadian disturbances induce the appearance of various diseases, including cancer. These disorders are characterized by an increase in gut permeability, which allows the passage of compounds such as LPS that interact with the immune system, causing inflammatory gut diseases [74].
A diet rich in fats and sugars causes an imbalance in bacteria composition, favoring the appearance of pathologies that are further pronounced by the circadian disruption [74]. This kind of diet has been shown to increase the abundance of Firmicutes, Proteobacteria, and Verrucomicrobia, and decrease the abundance of Bacteroidetes [74]. This dysbiosis is associated with a reduction in SCFAs production (especially butyrate) and an increase in the LPS levels, inducing gut permeability. Butyrate is related to the maintenance of gut barrier and the increased natural killer cytotoxicity, allowing the removal of viruses and cancer cells [75].
Increase in intestinal permeability is related to a reduction of calcium absorption produced by a vitamin D decreased [76], which produces a reduction in intestinal motility. This situation will allow the transfer of LPS to the circulation, which will activate the CD14/TLR2/4/MD2 pathogen recognition system [77]. The activation of this complex activates the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFkβ), activating the inflammatory cytokines and thus triggering strong autoimmune inflammatory activity that will be associated with cancer [76, 77]. Melatonin reduces the levels of these proinflammatory cytokines and inhibits NFkβ, modulating inflammation and reducing permeability [75, 78]. Furthermore, melatonin is able to reduce permeability by preserving mitochondrial-function mechanism [79] and releasing acetylcholine in the vagus nerve, which activates α7nAChR in intestinal cells [75, 80]. Apart from this, melatonin inhibits NOD-like Receptor 3 (NLRP3) and NOD-like Receptor pyrin domain-containing-6 (NLRP6), decreasing permeability [77]. Butyrate may also act as NLRP3 inhibitor, behaving similarly to melatonin [73].
On the other hand, circadian disruption induces an increase in proinflammatory cytokines, causing the loosening of tight junctions in intestinal epithelial cells and also increasing permeability [75]. When circadian disruption occurs, a significant increase in de abundance of Firmicutes is observed and this abundance was even higher when this situation is combined with a diet rich in fats and sugars. In addition, an increase in Ruminococcus and Sporosarcina was observed, accompanied by a reduction in Desulfosporosinus and Desulfotomocalum. Alternatively, melatonin can restore microbiota composition, reducing Clostridiales abundance and increasing Lactobacillus [81]. It is important to highlight that when circadian disruption occurs, there is an increase in the pro-inflammatory bacteria Ruminococcus and a reduction in the antiinflammatory bacteria Lactobacillus, which is associated with the NFkβ inhibition. All this suggests that circadian disruption favors inflammation and permeability, which are characteristics of cancers [74].
Clinical trials suggest that melatonin, due to its antioxidant, immunomodulatory, antiestrogenic, proapoptotic, and antiproliferative properties [82], can have a protective effect when administered along with other treatments such as chemotherapy or radiotherapy in patients suffering from advanced solid tumors [83]. The most outstanding results have been particularly obtained in breast cancer. Melatonin is an antitumor agent that enhances the beneficial effects of chemotherapy and radiotherapy and, on the other hand, it protects against the side effects of these therapies [83].
Melatonin has been shown to have anticancer actions in both
Finally, melatonin has been shown to behave as an adjuvant agent that prevents the side effects of breast cancer treatments. In particular, melatonin has been studied for the improvement of sleep and life quality [93]. A prospective phase II trial showed that melatonin improves quality of sleep and life, social functions, reduces fatigue, and increases clock genes expression [93]. Another randomized, placebo-controlled, and double-blind clinical trial in postmenopausal breast cancer survivors showed that melatonin improved the quality of sleep but had no effect on hot flashes [94]. Melatonin as an adjuvant of anti-aromatase therapies prevents the osteoporosis induced by these treatments since this hormone promotes osteoblasts proliferation [95].
Besides, melatonin has been studied as the treatment of depressive symptoms and anxiety [96]. In particular, a study on women undergoing breast cancer surgery showed that melatonin reduced the risk of depressive symptoms [96]. Patients treated not only with tamoxifen but also con melatonin, felt an improvement in anxiety, asthenia, and symptoms of depression in comparison with those treated with tamoxifen alone [97].
In addition, melatonin is described as the prevention of breast radiation dermatitis [98]. Topical applications of melatonin emulsions to the management of skin toxicity during radiotherapy have been proposed [99]. In this sense, A phase II, prospective, double-blind randomized trial was designed to evaluate the efficacy of melatonin-containing cream (twice daily) in breast cancer patients during radiation treatment. In conclusion, patients in the melatonin group experimented a significantly reduced radiation dermatitis compared to those women receiving placebo [98].
On the other hand, melatonin is able to decrease the toxicity and increase the efficacy of chemotherapy [100]. It has been demonstrated that melatonin may protect patients against side effects such as stomatitis, asthenia, cardiotoxicity, and neurotoxicity caused by chemotherapy [101]. Melatonin reduces the hepatotoxicity induced by anti-aromatase therapies, such as letrozole [33]. Besides, melatonin decreases damage caused for chemotherapy drugs in blood cells [102]. In breast, lung, and gastrointestinal cancer patients, melatonin preserved against thrombocytopenia, stomatitis, asthenia, and neuropathy [103]. A hybrid compound of melatonin and tamoxifen has been patented (US8785501) to combine antiestrogenic properties of these compounds and reduce the side effects of tamoxifen, reducing the hyperproliferation uterine risk [104, 105]. Previous studies have also demonstrated that the percentage of 1-year survival in patients with advanced non-small-cell lung cancer treated with cisplatin and melatonin and in breast cancer treated with tamoxifen and melatonin increased in comparison with patients treated only with chemotherapy [97].
Despite the promising experimental results about the radioprotective role of melatonin, few clinical trials to verify the therapeutic usefulness of melatonin in humans have been conducted. In this sense, a preliminary study suggests that adjuvant melatonin plus radiotherapy may prolong the 1-year survival rate and improve the quality of life of patients affected by untreatable glioblastoma [106].
Thus, it exists a plethora of applications of melatonin, which could be a promising future target of study in the pathology of breast cancer.
Breast cancer is a multifactorial disease. However, an explanation for the mechanism, which triggers this pathology remains unclear, and there lacks a hypothesis that can link all the mechanisms together. Over the years, researchers have studied the enormous range of biological activities of melatonin and its potential applications, including its effects as anticancer molecule. Recently, this indolamine has been described as a promising adjuvant in ER breast cancer prevention and treatment because of its antiestrogenic properties.
Herein we have proposed that a link between gut microbiota and melatonin levels exists, as well as between dysbiosis and circadian disruption, leading to an increase in the circulation of estrogen levels that is able to induce the development of breast cancer. On the other hand, butyrate is an SCFA synthesized by the intestinal microbiota that stimulates the melatonergic pathway by promoting the production of melatonin. Nevertheless, proinflammatory cytokines, stress, and diet factors stimulate the kynurenine pathway, moving Trp away from melatonergic pathway. This situation contributes to reducing melatonin levels and favoring NAS levels, increasing the NAS/melatonin ratio in breast cancer patients. It is important to highlight that NAS is implicated in survival, proliferation, and metastasis of breast cancer cells. In addition, this generates changes in gut microbiome and intestinal permeability caused by butyrate reduction and LPS levels increasing, inducing the inflammatory response, and decreasing melatonin production. All the foregoing contribute to breast cancer development.
Regarding changes in estrobolome composition as well as chronodisruption, favor the presence of deconjugated state of estrogens, which are the active form that increases breast cancer risk. We described the opposite action that melatonin exerts, unlike gut microbiome-derived β-glucuronidase activity. Melatonin is able to reduce the expression and activity of enzymes important in the biosynthesis of estrogens, reducing the estrogens levels and preventing breast cancer appearance.
On the other hand, melatonin regulates the desmoplastic reaction inducing the differentiation of preadipocytes into mature adipocytes, which do not express aromatase, lowering levels of estrogens and then reducing breast cancer risk. Melatonin achieves this differentiation through the stimulation of adipogenic cytokines (PPARγ and C/EBPα) and the inhibition of antiadipogenic cytokines (TNFα, IL-6, IL-11).
Although many in vitro and in vivo studies have been described, more clinical trials will be needed to describe the sensitizing properties of melatonin to the different treatments used to treat breast cancer, as well as to avoid their side effects. In addition, it will be important to explore the relationship between melatonin and the intestinal microbiota, since measuring the levels of this hormone together with the determination of the composition of the estrobolome of patients with breast cancer could constitute a promising tool for the development of biomarkers that help predict the development of breast cancer earlier. In conclusion, it will be crucial to maintain adequate levels of melatonin and a balanced composition of the microbiota to avoid developing breast cancer.
This work was funded in part by PE-0106-2019 from the Consejería de Salud de la Junta de Andalucía, C19047-2018 from Fundación Unicaja and UMA18-FEDERJA-042 from UMA-FEDER & ALIANZA MIXTA ANDALUCÍA-ROCHE. María Isabel Queipo Ortuño is recipient of a “Miguel Servet Type II” program (CPI13/00003) from ISCIII, co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, Madrid, Spain and also belongs to the regional “Nicolas Monardes” research program of the Consejería de Salud (C-0030-2018, Junta de Andalucía, Spain. Alicia González González is recipient of a postdoctoral grant Margarita Salas (RMS-08) from European Union-NextGenerationEU, Spanish Ministry of Universities and Recovery Transformation and Resilience Plan, through a call from University of Cantabria. Aurora Laborda Illanes is recipient of a predoctoral grant, PFIS-ISCIII (FI19-00112), co-funded by the Fondo Social Europeo (FSE). Lidia Sanchez Alcoholado is recipient of a predoctoral grant (PE-0106-2019) from the Consejería de Salud y Familia (co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, Andalucía, Spain). Daniel Castellano Castillo is recipient of a postdoctoral grant Sara Borrell (CD21/00164) from Instituto de Salud Carlos III.
The authors declare no conflict of interest.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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The CC BY 3.0 and CC BY 4.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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Therefore, a multiaxial classification gives a more comprehensive description of a child with CP. The recent WHO International Classification of Functioning, Disability and Health (ICF) emphasizes the importance of focusing on the functional consequences of various states of health and has stimulated the development of newer functional scales in CP. It is widely accepted that the functional classification is the best classification for the patient because it guides management. The objectives of this chapter are to review the various classifications of CP, to highlight the clinical features used in the various classifications, to outline the recent functional classifications of CP and to highlight how these recent classifications guide current management. It is expected that at the end of this chapter, the reader should be able to understand the difficulties in classifying CP, enumerate and discuss the various classifications of CP, understand the merits and shortcomings of each classification scheme, clinically evaluate and classify a child with CP multiaxially and understand how functional scales predict current and future needs of children with CP.",book:{id:"7072",slug:"cerebral-palsy-clinical-and-therapeutic-aspects",title:"Cerebral Palsy",fullTitle:"Cerebral Palsy - Clinical and Therapeutic Aspects"},signatures:"Christian Chukwukere Ogoke",authors:[{id:"250398",title:"Dr.",name:"Christian",middleName:"Chukwukere",surname:"Ogoke",slug:"christian-ogoke",fullName:"Christian Ogoke"}]},{id:"70770",title:"Ambulatory Devices: Assessment and Prescription",slug:"ambulatory-devices-assessment-and-prescription",totalDownloads:1203,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Injuries or disabilities associated with the lower extremities and aging frequently result in ambulation difficulty and this usually necessitates the prescription of ambulatory assistive device (e.g., cane, crutch and walker) in an attempt to restore locomotory function. Ambulatory devices are orthotic devices that provide support, stability and balance for users to able to move from one point to another. Users can progress or retrogress from one ambulatory device to another while some are permanently fit on a particular device throughout lifetime. The progression is dependent on the medical condition, user’s abilities, user’s anthropometric and environment. Physiotherapist prescribes ambulatory device to users and helps with the fitting and proper use of the ambulatory device. A correct prescription and well fitted ambulatory device minimize functional limitation and promote functional ability and improve quality of life. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. 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