What Is The Skin?
The skin is the organ that covers our body. It is the largest organ in the human body both by area and weight—it has around 16-22 ft2 / 1.5-2 m2 of surface area and corresponds to around 15% to 20% of total body weight.
The skin is part of the integumentary system—the set of organs that form the outer layer of the body and that also include the skin’s appendages: glands, hair, and nails. The skin is a special organ that combines the body’s major systems: circulatory, nervous, muscular, immune, and endocrine. It is a barrier that protects us against the threats in our environment, but it is also a sensory organ that allows us to perceive the outside world.
What Are The Functions Of The Skin?
The skin has several functions that can be divided into a few general categories:
Protective barrier
The skin is the physical barrier that isolates and protects our body against the external environment. The skin, along with the subcutaneous fat layer, forms a shield that protects us from mechanical aggressions that can damage our tissues, such as friction or blunt trauma. The skin also shields us from radiation, blocking a deeper penetration of ultraviolet radiation (UVR) and protecting our cells from UV damage. The skin is also a chemical barrier that keeps noxious chemicals out; in parallel, it is a selective permeability barrier that allows some chemicals in and prevents excessive loss or uptake of water, maintaining internal hydration. Furthermore, the skin is an immunological barrier that blocks microbial invasion—not only physically, but also functionally—and that sets up immunological responses to microbes that manage to penetrate the skin.
Thermoregulatory barrier
The skin is a thermal barrier that insulates our body from the environment and maintains a relatively constant core body temperature. This process of temperature control is called thermoregulation. Insulation is provided not only by the skin itself, but also by the fatty layer beneath the skin (in the hypodermis) and the hair on the skin. Temperature control is managed by mechanisms of heat loss control and cooling. Heat dissipation is controlled by the vasoconstriction and vasodilation of the cutaneous microvasculature. Cooling is also achieved through sweat production—as sweat evaporates it cools down the skin because the heat of evaporation is extracted from the sweat, resulting in a cooling effect called evaporative cooling [1].
Sensory organ
The skin is a sensory organ, i.e., an organ that senses stimuli and transduces them into a neural signal that is sent to the brain. Just like the eyes are the organs of the sense of vision, the skin is the organ of the sense of touch. But this is actually a very simplified description of what the skin senses. The skin does not only sense the mechanical stimuli of touch, it also senses temperature and signals when those stimuli may become noxious through the feeling of pain. Through its sensory receptors, the skin is able to monitor the external environment and regulate our interactions with physical objects.
Metabolic organ
The skin is where vitamin D is produced through the local action of UV light on the vitamin’s precursor molecule. Vitamin D is important for skin health and needed in calcium metabolism, immune performance, and proper bone formation. Subcutaneous fat—though technically not part of the skin—is a source of cell energy fuel. It acts as a storage of fatty acids that can be mobilized to power our cells and tissues through fatty acid oxidation. The skin also participates in the elimination of excess electrolytes through sweat. Electrolytes are minerals that become electrically charged when dissolved in body fluids. Sodium, potassium, calcium, magnesium, and phosphate are examples of electrolytes. They are used in metabolic and other physiological processes in all types of cells. Balanced electrolyte levels are important for keeping the pH balance of the body, maintaining hydration, and supporting all sorts of body processes, including muscle function or neurotransmission, for example.
The skin’s major function is to simultaneously form a physical and thermal barrier that protects us from environmental aggressions and a communication interface with the outside world.
What Is The Structure Of The Skin?
The skin is organized as layers. The major division of the skin is into two layers: the epidermis, which is an epithelial layer on the surface, and the dermis, which is a layer of connective tissue underneath. Each of these is further subdivided into smaller layers.
The epidermis is the outer layer of the skin, responsible for most of its protective functions. It’s the epidermis that creates the physical barrier against the external environment and the permeability barrier that maintains internal hydration. The epidermis contains a few specialized appendages that derive from its cells: hairs and hair follicles, nails, and sebaceous and sweat glands [2].
The dermis is the layer of connective tissue that contains a network of fibers that give strength and elasticity to the skin. The dermis supports and anchors the epidermis and binds it to the subcutaneous tissue. The junction between the dermis and epidermis is irregular and made up of dermal projections called dermal papillae interdigitated with epidermal invaginations called epidermal ridges. This undulated junction increases the area of contact and strengthens the adhesion of the two layers [2].
Beneath the dermis lies the hypodermis, which is subcutaneous tissue, so, technically, not a skin layer. But the hypodermis plays an important role in skin structure and function. The hypodermis binds the skin loosely to the underlying tissues, making it possible for the skin to slide over them. It contains fat cells (called adipocytes) that vary in number in different body regions and vary in size according to the nutritional state. The hypodermis helps to thermally insulate the body, provides protective padding, and acts as an energy storage area [2].
The characteristics and size of these layers vary considerably depending on the region of the body. For example, the thickness of the skin varies from a mere 0.5 mm on the eyelids to at least 4 mm on the palms of the hands and the soles of the feet.
Another variable of the skin is the presence or absence of hair. Skin that has no hair is known as glabrous skin and it’s thicker than hairy skin; it’s found in the palms of the hands and the soles of the feet, for example. The thinner hairy skin covers around 90% of the body.
Figure 1 - Skin layers. Source: Wikimedia Commons. Author: Madhero88 and M.Komorniczak. CC BY-SA 3.0 license
Epidermal Cells And Layers
To better understand the structure and functions of the epidermis, it’s worth learning a bit about the main types of cells that can be found in this layer.
The most abundant cells of the epidermis, comprising around 95% of epidermal cells, are epithelial cells called keratinocytes. [Epithelial cells are the type of cells that line the surfaces of our body, not only the outer surface of the body, i.e., the skin, but also the outer surfaces of organs and blood vessels, as well as the inner surfaces of body cavities and organ lumens.] Keratinocytes are the producers of keratin—the set of proteins that make the skin waterproof—and vitamin D.
Several other cell types play major roles in epidermal health and function. Melanocytes are the producers of melanin, the pigment responsible for skin pigmentation and photoprotection. Langerhans cells are immune cells of the skin; they are tissue-resident dendritic cells of the skin that bind, process, and present antigens to T lymphocytes to trigger immune responses. Merkel cells are sensory cells; they are low-threshold mechanoreceptors essential for sensing gentle touch. Stem cells can also be found in relatively large numbers in the epidermis; they are found at the base of the epidermis and are the source of new skin cells.
Another characteristic of the epidermis, that is important to better understand its structure and functions, is its further division into layers.
At the base of the epidermis, there is the stratum basale, a single layer of cells in contact with the basement membrane of the epidermis where new keratinocytes are generated from stem cells; melanocytes and Merkel cells are also found in this layer. The next layer (i.e., from the inner to the outer layer) is the stratum spinosum, made up of several layers of keratinocytes all tightly joined by specialized cell-to-cell adhesion structures (desmosomes) that strengthen the epidermis and contribute to its barrier properties; Langerhans cells are mainly found in this layer. Above it is the stratum granulosum, which consists of 3 to 5 layers of keratinocytes containing distinct kerato-hyaline granules that give this layer its name. Next is the stratum lucidum, consisting of 2 to 3 layers of anucleate, dead cells. This layer is seen only in thick skin. The outermost layer is the stratum corneum, made up of 20 to 30 layers of dead, flattened, anucleate, keratin-filled keratinocytes; this is the layer that confers most protection against friction and water loss.
Figure 2: Layers of the epidermis. Source: OpenStax, Anatomy and Physiology. 5.1 Layers of the skin. CC BY 4.0 license.
Keratinocytes And Skin Barrier Function
The layers of the epidermis are formed as an outcome of the process of keratinization—the aggregation and accumulation of keratin, which is produced by keratinocytes. Keratin is a fibrous structural protein that, with the aid of a protein called filaggrin, aggregates into bundles to form tough filaments. It’s keratin that’s responsible for the physical properties and resistance of the skin.
Keratinocytes originate from skin stem cells in the innermost layer of the epidermis, the basal layer or stratum basale. As they differentiate, they are pushed outwards by newer keratinocytes that are constantly being born in the basal layer. While they migrate and differentiate, keratinocytes accumulate keratin in their cytosol and become tougher.
Outer layers of the epidermis are heavily keratinized and accumulate a lipid-rich, impermeable layer around the cells. In the end stage of keratinization, known as cornification, keratinocytes contain only amorphous, fibrillar proteins with plasma membranes surrounded by the lipid-rich layer. These fully keratinized (or cornified) cells are called corneocytes; they are dead cells and they make up the stratum corneum, the outermost layer of the epidermis.
The epidermis is fully renewed about every 15-30 days (depending on age, the region of the body, and other factors). Corneocytes are continuously shed at the epidermal surface as the lipid-rich cell envelopes break down. In healthy skin, corneocytes are shed individually and imperceptibly, but changes in hydration and lipid content can result in abnormal corneocyte desquamation, such as scaling and cracked skin [3].
Keratinization and the production of the lipid-rich layer have a sealing effect on the skin, contributing to its barrier function and to the water-retaining properties of the skin. The major lipids of the epidermis (specifically of the stratum corneum) consist of 50% ceramides, 25% cholesterol, and about 15% fatty acids (by mass). It is estimated that the epidermis synthesizes 100–150 mg of lipids per day to replace lipids lost in corneocyte shedding, thereby being one of the most active sites of lipid production in the body [4].
Intercellular lipids of the stratum corneum are essential to the barrier function of the skin. They help to maintain skin hydration by blocking transepidermal water loss (TEWL), they help to block the entry of foreign substances (xenobiotics) through the skin, and they regulate corneocyte desquamation, for example [3].
Maintaining a healthy epidermal structure and skin barrier function is essential for the maintenance of the skin’s selective permeability and physical shield functions, as well as for skin hydration and skin smoothness. Qualia Skin includes a set of ingredients that support these properties of the skin.
Zinc (from inactive Aspergillus oryzae culture) is a necessary mineral for epidermal proliferation and keratinocyte differentiation and plays a major role in keratinocyte cell survival and skin morphogenesis, repair, and maintenance [5–7]. Selenium (from inactive Aspergillus oryzae culture) is part of selenoproteins that play important roles in keratinocyte function [2]; Selenium protects keratinocyte stem cells against senescence [8]. Iron (from inactive Aspergillus oryzae culture) has an important role in the regulation of mitochondrial DNA synthesis in the highly metabolically active cells of the basal epidermis, which undergo a continuous sequence of maturation and loss at the skin surface [9].
Aloe Vera Inner Leaf Juice Powder supports skin barrier function by restoring epidermal tight junctions [10]. Sea Buckthorn (Hippophae rhamnoides) Fruit Extract influences the fatty acid composition of epidermal lipids [11]. AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract supports healthy epidermal structure [12] by regulating corneocyte desquamation [13] and supporting healthy skin lipid content, thus supporting barrier function [13]. Lycopene (from Tomato Fruit Extract) supports sebum production [14] and epidermal structure [14].
HydroPeach™ Ceramides (Peach Fruit Extract) provides ceramides, which are the major lipids of the skin barrier [4,15]. Ceramides are necessary for maintaining barrier and water-retaining properties of the skin. In addition to providing ceramides for the skin, HydroPeach™ Ceramides (Peach Fruit Extract) supports skin ceramide synthesis [16–19] and stratum corneum ceramide levels [20], thereby supporting stratum corneum structure [21–23], and skin barrier function [19,22,24]. The outcome of these actions is the support of skin hydration [25–28] and healthy transepidermal water loss (TEWL) levels [16,21–23,28–32], along with the support of skin texture/smoothness [28,32].
Healthy transepidermal water loss (TEWL) is further supported by Aloe Vera Inner Leaf Juice Powder [33,34] and AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [35,36]. In line with this action, skin hydration is also supported by Aloe Vera Inner Leaf Juice Powder [33,34,37,38] and AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [39–41], as well as by Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [42], Pomanox® Pomegranate Fruit Extract [43], and Silicon (in Bamboo Stem & Leaf Extract) [44].
A smooth skin texture is further supported by AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [39] Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [42], Pomanox® Pomegranate Fruit Extract [43,45], and Silicon (in Bamboo Stem & Leaf Extract) [44,46].
How Are Hair And Nails Formed?
Hairs are elongated keratinized structures formed within hair follicles, which are epidermal invaginations that extend deep into the dermis. The base of hair follicles forms a bulb—the hair bulb—that contains a dermal papilla with a capillary network that nourishes the hair follicle. Keratinocytes that cover the dermal papilla form the matrix of the elongating hair. These keratinocytes are formed from stem cells that are found within the hair follicle.
Keratinocytes of the hair bulb divide rapidly in the matrix and undergo keratinization, melanin accumulation, and migration as they are pushed outward by new keratinocytes. As elsewhere in the skin (as we’ll see below), melanin is produced by melanocytes present in the hair bulb and transferred to keratinocytes. Keratinocytes in the hair root matrix produce a hard and compact form of keratin that will form the heavily keratinized hair shaft that extends beyond the skin surface and which is able to maintain its structure for long periods of time [2].
Figure 3 - Hair follicle structure. Source: OpenStax, Anatomy and Physiology. 5.2 Accessory Structures of the Skin. CC BY 4.0 license.
Nails are formed by a similar process of keratinization. They are formed at the nail root, which is the area covered by a fold of skin from which the epidermal stratum corneum extends as the cuticle. The nail root forms from the nail matrix in which cells divide and become keratinized in a process somewhat similar to hair formation. As cells become heavily keratinized and hardened, the nail plate is formed. Continuous growth in the nail matrix pushes the nail plate forward over an epidermal nail bed containing only the basal and spinous epidermal layers [2].
Figure 4 - Nail structure. Source (adapted): OpenStax, Anatomy and Physiology. 5.2 Accessory Structures of the Skin. CC BY 4.0 license.
Hair and nails are skin appendages—specialized structures that derive from epidermal cells. Both are formed through processes of keratinization.
Qualia Skin provides two minerals and a vitamin that have been shown to nutritionally support hair and nail structure and health: Iron (from inactive Aspergillus oryzae culture) provides important support for mitochondrial DNA synthesis; it therefore provides essential support for the continued turnaround of new cells for the growth, maintenance and normal physiology of hair and nails [9]. Silicon (in Bamboo Stem & Leaf Extract) is one of the main minerals in nails and is therefore important for nail health [46,47]. Hair health—thickness, tensile strength, elasticity, break load—is also supported by silicon, and hair strands with higher silicon content tend to have lower falling rates and higher brightness [46–48]. Vitamin B7, or Biotin, also supports nail structure and health [49–51] and hair health [52]. In addition to these nutrients, Qualia Skin includes Aloe Vera Inner Leaf Juice Powder, which has also been shown to support nail structure and health [34].
Melanocytes And Skin Pigmentation
Skin color is determined by several factors (e.g., carotenoid levels, number of blood vessels in the dermis), but the most significant is the content of melanin in keratinocytes. Melanin is a pigment (i.e., a colored molecule that absorbs light) that is also responsible for hair and eye color, for example [2]. There are two types of melanin: dark brown or black eumelanin, the most common form, and pale red or yellowish pheomelanin, found in red hair.
Skin color is determined by the quantity and relative amounts of eumelanin and pheomelanin and by melanocytes' activity level. Dark-skinned individuals have higher melanin levels in their skin than those with paler skin. Melanin production in the skin is under hormonal regulation by a pituitary gland hormone called melanocyte-stimulating hormone (MSH). Melanin synthesis is also stimulated by UV light, which is why sun exposure darkens the skin. In fact, the main function of melanin is precisely to protect against UV radiation.
Melanin is produced by a specialized type of epithelial cell called melanocytes. They are found at the base of the epidermis from where they send branched cytoplasmic extensions, or dendrites, to outer layers of the skin. Through these branches, melanocytes distribute melanin to keratinocytes, where it accumulates and creates skin color. Melanocytes are also found in hair follicles.
Melanin is produced from the amino acid tyrosine by the enzyme tyrosinase, in a process known as melanogenesis. Tyrosinase first converts tyrosine into 3,4-dihydroxyphenylalanine (DOPA), which is then further transformed and polymerized into the different forms of melanin. Once synthesized, melanin is stored in special cellular organelles called melanosomes which are transported through the cellular branches of melanocytes to nearby keratinocytes [2].
Qualia Skin provides a few ingredients that support melanocyte function and melanin synthesis, thereby contributing to the maintenance of a uniform pigmentation of the skin and supporting natural skin responses to sun exposure. Copper (from inactive Aspergillus oryzae culture) is a cofactor of tyrosinase [53] and Sea Buckthorn (Hippophae rhamnoides) Fruit Extract influences melanin synthesis [54]. Healthy melanin synthesis and uniform skin pigmentation are also supported by Pomanox® Pomegranate Fruit Extract [55,56], Red Orange Complex® (Citrus sinensis Fruit Extract) [57], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [58,59], BioVin® French Red Grapes Extract [60–65], and HydroPeach™ Ceramides (Peach Fruit Extract) [32].
Figure 5 - Melanin synthesis and skin pigmentation. Source: OpenStax, Anatomy and Physiology. 5.1 Layers of the skin. CC BY 4.0 license.
Melanin accumulates around the nucleus of keratinocytes to protect their DNA against UV radiation.
Dermal Cells And Extracellular Matrix
The dermis is a layer of connective tissue with an extracellular matrix (ECM) composed of collagen, elastic fibers, proteoglycans, and other components that give it a fibrous structure.
Fibroblasts are the main cell type in the dermis (and in all other types of connective tissue). Fibroblasts are the cells that produce collagen and other ECM components and are therefore responsible for the structural integrity of the dermis. Type I Collagen is the most abundant ECM protein in the dermis, making up around 90% of the skin’s dry weight. Dermal collagen is responsible for the skin’s tensile strength and mechanical properties [66].
The outer region of the dermis (the papillary layer) consists of loose connective tissue, with type I and III collagen fibers, fibroblasts and scattered mast cells, dendritic cells, and lymphocytes. From this layer, anchoring fibrils of type VII collagen insert into the base of the epidermis, helping to bind the dermis to the epidermis. The underlying region (the reticular layer) is much thicker and consists of dense irregular connective tissue (mainly bundles of type I collagen), with more fibers and fewer cells than the papillary layer. A network of elastic fibers is also present, giving elasticity to the skin. Abundantly found among the collagen and elastic fibers are glycosaminoglycans and proteoglycans [2].
Other structures that can be found in the dermis include glands (e.g., sweat glands and sebaceous glands, i.e., oil glands). The dermis also contains a rich network of blood and lymphatic vessels. The dermis is also richly innervated with sensory and autonomic nerve fibers. Sensory afferent nerve fibers form a network in the papillary dermis and around hair follicles, ending at epithelial and dermal sensory receptors. Sensory receptors in the skin include mechanoreceptors that sense touch and other mechanical stimuli (pressure, vibration, stretching, and distortion, for example), nociceptors that sense painful stimuli, thermoreceptors that sense temperature, and chemoreceptors that sense chemical substances. Autonomic sympathetic effector nerves control the activity of dermal sweat glands and smooth muscle fibers in the skin; no parasympathetic innervation is present in the skin [2].
The ingredients in Qualia Skin support dermal function and structure through several mechanisms. Copper (from inactive Aspergillus oryzae culture) supports the synthesis of collagen and elastin fiber components by fibroblasts and supports signaling by TGF-β, an inducer of collagen synthesis [67]. Manganese (from inactive Aspergillus oryzae culture) is required for the activation of prolidase, an enzyme that can provide the amino acid proline for collagen synthesis in human skin cells [68,69]; glycosaminoglycan synthesis also requires manganese-activated enzymes [70]. Silicon (in Bamboo Stem & Leaf Extract) is important for collagen synthesis, glycosaminoglycan synthesis, and the activation of enzymes that support skin strength and elasticity [47]; accordingly, silicon supports skin collagen levels [71] and skin firmness [44]. L-Ornithine is a precursor for the synthesis of L-proline, which is one of the primary amino acids in collagen. Accordingly, L-Ornithine (as L-ornithine hydrochloride) supports skin levels of collagen-constituting amino acids [72] and collagen deposition [73].
Fibroblast function and ECM structural molecule levels are supported by several other ingredients: Aloe Vera Inner Leaf Juice Powder supports collagen and hyaluronic acid levels [33,34,37,38,74–80]; Amla (Emblica officinalis) Fruit Extract supports fibroblast proliferation [81] and collagen and hyaluronic acid synthesis [81–85]; Pomanox® Pomegranate Fruit Extract supports dermal collagen and hyaluronan levels [43,45,55,86]; SoyLife™ Soy Germ Extract supports fibroblast renewal and collagen, elastic fiber, and hyaluronic acid levels [87–93]; AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract supports collagen levels [12,94,95]. Healthy dermal ECM structure in general is also supported by BioVin® French Red Grapes Extract [96–99] and Lycopene (from Tomato Fruit Extract) [100,101].
One of the main outcomes of supporting fibroblast cell function and the synthesis of ECM structural molecules is the support of the mechanical properties of the skin, particularly skin elasticity. This is an outcome that several ingredients in Qualia Skin have been shown to support, namely Aloe Vera Inner Leaf Juice Powder [33,74,80,102], Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [42], SoyLife™ Soy Germ Extract [103], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [35,41], and HydroPeach™ Ceramides (Peach Fruit Extract) [26,104].
The Dermis And Skin Blood Flow
The epidermis is avascular—it does not have any blood vessels, not even microvasculature. Therefore, epidermal cells must receive nutrients and oxygen by diffusion from the dermis, which has a rich vascular network [105].
The cutaneous vasculature forms two plexuses in the dermis. Between the papillary and reticular layers of the dermis, there is a microvascular plexus from which capillaries branch into the dermal papillae to form a nutritive capillary network just beneath the epidermis. Another plexus with larger blood vessels is found between the dermis and the hypodermis, from which arterioles and venules branch out to connect with the outer plexus and to supply hair bulbs and glands.
In addition to the nutritive function, the cutaneous vasculature also has an important role in thermoregulation. The cutaneous vasculature allows the dissipation of heat. The amount of heat that is lost is controlled by the dilation and constriction of blood vessels. Vasodilation increases blood flow in the skin and increases the dissipation of heat, whereas vasoconstriction decreases blood flow and minimizes heat loss, thus helping to maintain a constant body temperature. Vasoconstriction and vasodilation are controlled by the sympathetic nervous system [106].
Qualia Skin supports healthy skin blood flow by supporting dermal vascularity, through the action of Aloe Vera Inner Leaf Juice Powder [75], SoyLife™ Soy Germ Extract [90], and AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [12].
Skin Microbiome
The skin, like the gut, acts simultaneously as a barrier and as a neurological and immunological interface between the internal human body and the external environment. Also like the gut, the skin is home to a large community of microbes known as the skin microbiota. These microbes, their genes, and their products, by-products, and metabolites, collectively called the skin microbiome, have an important role in maintaining skin homeostasis, i.e., a state of balance in the skin’s biology and physiological processes [107,108].
The microbes found in the skin include bacteria, fungi, and viruses. The skin microbiota is not only present at the surface of the skin, it also reaches deeper layers in the dermis—around 25% of skin microbes grow at the level of the dermis in sebum glands and within hair follicles [109].
Resident microbes that make up an individual’s skin microbiota contribute to skin health by modulating different aspects of skin physiology. An important role of the skin microbiota is to support the skin’s function as a physical barrier by processing skin proteins, free fatty acids, and sebum, for example. Importantly, the skin microbiota collaborates with the skin’s immune system in supporting the detection and elimination of pathogenic microbes [107,108,110,111].
The skin microbiome is akin to the gut microbiome. In fact, as barriers and interfaces of the human body with the exterior, and as home to the largest symbiotic microbial communities in the human body, the skin and the gut are interactive and complementary [112,113].
Qualia Skin supports a healthy skin microbiome through the action of AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [13], Pomanox® Pomegranate Fruit Extract [13], and Lycopene (from Tomato Fruit Extract) [14].
The skin and the gut form a complex communication network of reciprocal influence that involves the immune, endocrine, metabolic, and nervous systems—the skin-gut axis.
Skin Immunity
The skin is an immune organ [114,115]. Not only does the skin form a physical immune barrier that blocks the entry of external substances and microorganisms, it also forms a functional immune barrier that senses threats and devises responses against pathogens. The skin has its own immune system—a set of innate and adaptive immune cells, both resident and recruited, that populate the dermis and the epidermis. [If you want to learn more about the immune system, take a look at our overviews of the innate immune system and the adaptive immune system].
The epidermis has its own specific type of resident dendritic cells called Langerhans cells. Like other dendritic cells, Langerhans cells recognize microbial molecules and signal their presence to other immune cells. They release signaling molecules and capture and present microbial protein antigens to T lymphocytes, the main cells of cell-mediated adaptive immunity, thereby acting as antigen-presenting cells (APCs). This triggers complex adaptive immune responses that eliminate threats. The epidermis has resident T cells ready to devise an adaptive immune response.
Keratinocytes also carry out immune functions. In addition to creating a physical barrier that also acts as an innate immune barrier, they are the first sensors of pathogen invasion—they recognize pathogens and signal their presence through immune signaling molecules. Keratinocytes also produce antimicrobial peptides that are able to block the invasion of microorganisms by killing pathogens, activating immune cells, or influencing cytokine signaling. Melanocytes also have a role in the immune system. They are able to phagocytize pathogens, produce and release cytokines in response to microbes, and present microbial antigens to T-cells to activate them.
In the dermis, other types of immune cells can also be found, including dendritic cell subpopulations, macrophages, neutrophils, mast cells, natural killer cells, B cells, and different types of T cells [114–116].
Figure 6 - Immune cells of the skin. Source (adapted): Chong SZ, et al. Front Immunol 4:286 (2013) CC BY 3.0 license
Qualia Skin supports skin immunity through the action of Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [117] and Pomanox® Pomegranate Fruit Extract [118]. Other ingredients in Qualia Skin that are known to support general immune function and thereby contribute to the skin’s immune health include Zinc (from inactive Aspergillus oryzae culture) [119–121] and Selenium (from inactive Aspergillus oryzae culture) [122–125].
Vitamin D Production
One of the most important metabolic functions of the skin is the production of vitamin D. Vitamin D is a fat-soluble vitamin with an essential role in regulating calcium and phosphate homeostasis in the human body. Vitamin D is therefore vital for bone health, the role for which it is most known. But vitamin D has important roles in many other functions of the human body, including immunity, muscle activity, neuronal function, antioxidant defenses, and skin health [126].
Vitamin D is actually the collective name of the set of steroid molecules with vitamin D activity. The major forms include vitamin D3, or cholecalciferol, which is produced in the skin, and ergocalciferol, or vitamin D2, which is not produced in humans.
Vitamin D3 is produced by keratinocytes in the human skin upon exposure to sunlight. Cholecalciferol is synthesized from the provitamin D sterol 7-dehydrocholesterol by a two-step process involving the action of ultraviolet light (UVB, 290–310 nm). The first step is a photoactivation reaction in which the absorption of light causes the conversion of 7-dehydrocholesterol to previtamin D3. Once formed, previtamin D3 undergoes thermal rearrangement to form cholecalciferol [126].
Vitamin D that comes from the skin or diet is biologically inert and requires a hydroxylation in the liver to 25-hydroxycholecalciferol, (calcidiol), the primary form of circulating vitamin D. A further hydroxylation in the kidneys then forms the biologically active form of vitamin D 1,25-dihydroxycholecalciferol (calcitriol).
Calcitriol acts by binding the vitamin D receptor (VDR), a nuclear receptor and ligand-dependent transcription factor that regulates the expression of hundreds of genes involved in many important physiological functions.
In addition to producing vitamin D3, keratinocytes can also metabolize it to calcitriol. Furthermore, they express VDR in their nucleus, meaning that vitamin D can act locally. In the skin, vitamin D regulates the proliferation and differentiation of keratinocytes and protects from UV-induced DNA damage, inflammation, and cell death. VDR activation in the skin can also induce the synthesis of cathelicidins, a type of innate immune system peptide that enhances skin immunity by participating in the direct killing of pathogens and in cellular inflammatory and immune responses [126–128].
The Importance Of Healthy Skin
Considering the fundamental role of the skin in shielding our body from environmental aggressions, keeping our body temperature constant, maintaining our body properly hydrated, and blocking the entry of microbes, it seems obvious that skin health is an essential element of our general health.
Skin health is the result of many intersecting elements, including biological and genetic factors, environmental challenges, and lifestyle patterns such as nutrition. Many of these factors are out of our control—we can’t change our genes nor what the exterior world throws at us; but we do have control over some elements of skin health, particularly over our lifestyle options. Maintaining healthy skin—for example, by exercising and following a healthy diet—can help to maintain the functional and structural integrity of our skin, and consequently, maintain the functional and structural integrity of our whole body.
Qualia Skin was formulated to promote beauty from within. It can add another level of support to skin health by providing a set of scientifically studied ingestible ingredients that have been shown to support some of the main processes underlying healthy skin structure and function.
References
[1] E.A. Tansey, C.D. Johnson, Adv. Physiol. Educ. 39 (2015) 139–148.
[2] L. Junqueira, J. Carneiro, in: A.L. Mescher (Ed.), Junqueira’s Basic Histology Text and Atlas, McGraw-Hill Education, 2018.
[3] G.E. Pierard, V. Goffin, T. Hermanns-Le, C. Pierard-Franchimont, Int. J. Mol. Med. 6 (2000) 217–221.
[4] H.J. Cha, C. He, H. Zhao, Y. Dong, I.-S. An, S. An, Int. J. Mol. Med. 38 (2016) 16–22.
[5] D.L. Vollmer, V.A. West, E.D. Lephart, Int. J. Mol. Sci. 19 (2018).
[6] M. Richelle, M. Sabatier, H. Steiling, G. Williamson, Br. J. Nutr. 96 (2006) 227–238.
[7] Y. Ogawa, T. Kawamura, S. Shimada, Arch. Biochem. Biophys. 611 (2016) 113–119.
[8] L. Jobeili, P. Rousselle, D. Béal, E. Blouin, A.-M. Roussel, O. Damour, W. Rachidi, Aging 9 (2017) 2302–2315.
[9] A.B. Lansdown, Int. J. Cosmet. Sci. 23 (2001) 129–137.
[10] K. Na, E. Lkhagva-Yondon, M. Kim, Y.-R. Lim, E. Shin, C.-K. Lee, M.-S. Jeon, Scand. J. Immunol. 91 (2020) e12856.
[11] B. Yang, K.O. Kalimo, R.L. Tahvonen, L.M. Mattila, J.K. Katajisto, H.P. Kallio, J. Nutr. Biochem. 11 (2000) 338–340.
[12] X. Li, T. Matsumoto, M. Takuwa, M. Saeed Ebrahim Shaiku Ali, T. Hirabashi, H. Kondo, H. Fujino, Biomedicines 8 (2020).
[13] N.E. Chalyk, V.A. Klochkov, T.Y. Bandaletova, N.H. Kyle, I.M. Petyaev, Nutr. Res. 48 (2017) 40–48.
[14] M. Wiese, Y. Bashmakov, N. Chalyk, D.S. Nielsen, Ł. Krych, W. Kot, V. Klochkov, D. Pristensky, T. Bandaletova, M. Chernyshova, N. Kyle, I. Petyaev, Biomed Res. Int. 2019 (2019) 4625279.
[15] M.H. Meckfessel, S. Brandt, J. Am. Acad. Dermatol. 71 (2014) 177–184.
[16] H. Shimoda, S. Terazawa, S. Hitoe, J. Tanaka, S. Nakamura, H. Matsuda, M. Yoshikawa, J. Med. Food 15 (2012) 1064–1072.
[17] J. Ishikawa, S. Takada, K. Hashizume, Y. Takagi, M. Hotta, Y. Masukawa, T. Kitahara, Y. Mizutani, Y. Igarashi, J. Dermatol. Sci. 56 (2009) 220–222.
[18] Y. Shirakura, K. Kikuchi, K. Matsumura, K. Mukai, S. Mitsutake, Y. Igarashi, Lipids Health Dis. 11 (2012) 108.
[19] J. Duan, T. Sugawara, M. Hirose, K. Aida, S. Sakai, A. Fujii, T. Hirata, Exp. Dermatol. 21 (2012) 448–452.
[20] Y. Tokudome, N. Masutani, S. Uchino, H. Fukai, Nutrients 9 (2017).
[21] T. Hasegawa, H. Shimada, T. Uchiyama, O. Ueda, M. Nakashima, Y. Matsuoka, Lipids 46 (2011) 529–535.
[22] R. Ideta, T. Sakuta, Y. Nakano, T. Uchiyama, Biosci. Biotechnol. Biochem. 75 (2011) 1516–1523.
[23] K. Tsuji, S. Mitsutake, J. Ishikawa, Y. Takagi, M. Akiyama, H. Shimizu, T. Tomiyama, Y. Igarashi, J. Dermatol. Sci. 44 (2006) 101–107.
[24] C. Kawada, T. Hasegawa, M. Watanabe, Y. Nomura, Biosci. Biotechnol. Biochem. 77 (2013) 867–869.
[25] S. Guillou, S. Ghabri, C. Jannot, E. Gaillard, I. Lamour, S. Boisnic, Int. J. Cosmet. Sci. 33 (2011) 138–143.
[26] J. Kawamura, S. Kotoura, T. Okuyama, M. Furumoto, H. Fuchuu, K. Miake, M. Sugiyama, M. Ohnishi, Journal of The Japanese Society for Food Science and Technology 60 (2013) 218–224.
[27] M. Yeom, S.-H. Kim, B. Lee, J.-J. Han, G.H. Chung, H.-D. Choi, H. Lee, D.-H. Hahm, J. Dermatol. Sci. 67 (2012) 101–110.
[28] T. Koikeda, Y. Tokudome, M. Okayasu, Y. Kobayashi, K. Kuroda, J. Yamakawa, K. Niu, K. Masuda, M. Saito, Immunol. Endocr. Metab. Agents Med. Chem. 17 (2017).
[29] T. Uchiyama, Y. Nakano, O. Ueda, H. Mori, M. Nakashima, A. Noda, C. Ishizaki, M. Mizoguchi, J. Health Sci. 54 (2008) 559–566.
[30] K.-I. Kawano, K. Umemura, Phytother. Res. 27 (2013) 775–783.
[31] K. Miyanishi, N. Shiono, H. Shirai, M. Dombo, H. Kimata, Allergy 60 (2005) 1454–1455.
[32] S. Fukunaga, S. Wada, T. Sato, M. Hamaguchi, W. Aoi, A. Higashi, J. Nutr. Sci. Vitaminol. 64 (2018) 265–270.
[33] M. Tanaka, Y. Yamamoto, E. Misawa, K. Nabeshima, M. Saito, K. Yamauchi, F. Abe, F. Furukawa, Skin Pharmacol. Physiol. 29 (2016) 309–317.
[34] C. Kaminaka, Y. Yamamoto, M. Sakata, C. Hamamoto, E. Misawa, K. Nabeshima, M. Saito, M. Tanaka, F. Abe, M. Jinnin, J. Dermatol. 47 (2020) 998–1006.
[35] K. Tominaga, N. Hongo, M. Karato, E. Yamashita, Acta Biochim. Pol. 59 (2012) 43–47.
[36] T. Komatsu, S. Sasaki, Y. Manabe, T. Hirata, T. Sugawara, PLoS One 12 (2017) e0171178.
[37] M. Tanaka, E. Misawa, K. Yamauchi, F. Abe, C. Ishizaki, Clin. Cosmet. Investig. Dermatol. 8 (2015) 95–104.
[38] E. Misawa, M. Tanaka, M. Saito, K. Nabeshima, R. Yao, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, Photodermatol. Photoimmunol. Photomed. 33 (2017) 101–111.
[39] N. Ito, S. Seki, F. Ueda, Nutrients 10 (2018) 817.
[40] K. Tominaga, N. Hongo, M. Fujishita, Y. Takahashi, Y. Adachi, J. Clin. Biochem. Nutr. 61 (2017) 33–39.
[41] L. Phetcharat, K. Wongsuphasawat, K. Winther, Clin. Interv. Aging 10 (2015) 1849–1856.
[42] B. Yang, A. Bonfìgli, V. Pagani, L.T. von-Knorring Asa, A.V.-P.J. Jutila, Journal of Applied Cosmetology 27 (2009) 13–35.
[43] S.-J. Kang, B.-R. Choi, S.-H. Kim, H.-Y. Yi, H.-R. Park, C.-H. Song, S.-K. Ku, Y.-J. Lee, Exp. Ther. Med. 14 (2017) 1023–1036.
[44] C.L. Petersen Vitello Kalil, V. Campos, S. Cignachi, J. Favaro Izidoro, C. Prieto Herman Reinehr, C. Chaves, J. Cosmet. Dermatol. 17 (2018) 814–820.
[45] J.-Y. Bae, J.-S. Choi, S.-W. Kang, Y.-J. Lee, J. Park, Y.-H. Kang, Exp. Dermatol. 19 (2010) e182–90.
[46] A. Barel, M. Calomme, A. Timchenko, K. De Paepe, N. Demeester, V. Rogiers, P. Clarys, D. Vanden Berghe, Arch. Dermatol. Res. 297 (2005) 147–153.
[47] L.A. de Araújo, F. Addor, P.M.B.G.M. Campos, An. Bras. Dermatol. 91 (2016) 331–335.
[48] R.R. Wickett, E. Kossmann, A. Barel, N. Demeester, P. Clarys, D. Vanden Berghe, M. Calomme, Arch. Dermatol. Res. 299 (2007) 499–505.
[49] V.E. Colombo, F. Gerber, M. Bronhofer, G.L. Floersheim, J. Am. Acad. Dermatol. 23 (1990) 1127–1132.
[50] G.L. Floersheim, Z. Hautkr. 64 (1989) 41–48.
[51] L.G. Hochman, R.K. Scher, M.S. Meyerson, Cutis 51 (1993) 303–305.
[52] D.P. Patel, S.M. Swink, L. Castelo-Soccio, Skin Appendage Disord 3 (2017) 166–169.
[53] C. Olivares, F. Solano, Pigment Cell Melanoma Res. 22 (2009) 750–760.
[54] J. Zhang, C. Wang, C. Wang, B. Sun, C. Qi, Food Funct. 9 (2018) 5402–5416.
[55] S.J. Kang, B.R. Choi, S.H. Kim, H.Y. Yi, H.R. Park, S.J. Park, C.H. Song, J.H. Park, Y.J. Lee, S. Kwang, J. Cosmet. Sci. 66 (2015) 145–159.
[56] M. Kanlayavattanakul, W. Chongnativisit, P. Chaikul, N. Lourith, Planta Med. 86 (2020) 749–759.
[57] C. Puglia, A. Offerta, A. Saija, D. Trombetta, C. Venera, Journal of Cosmetic Dermatology 13 (2014) 151–157.
[58] T. Niwano, S. Terazawa, H. Nakajima, Y. Wakabayashi, G. Imokawa, Cytokine 73 (2015) 184–197.
[59] H. Nakajima, K. Fukazawa, Y. Wakabayashi, K. Wakamatsu, K. Senda, G. Imokawa, Arch. Dermatol. Res. 304 (2012) 803–816.
[60] J. Yamakoshi, A. Sano, S. Tokutake, M. Saito, M. Kikuchi, Y. Kubota, Y. Kawachi, F. Otsuka, Phytother. Res. 18 (2004) 895–899.
[61] J. Yamakoshi, F. Otsuka, A. Sano, S. Tokutake, M. Saito, M. Kikuchi, Y. Kubota, Pigment Cell Res. 16 (2003) 629–638.
[62] Y.-S. Lin, H.-J. Chen, J.-P. Huang, P.-C. Lee, C.-R. Tsai, T.-F. Hsu, W.-Y. Huang, Biomed Res. Int. 2017 (2017) 5232680.
[63] T.H. Lee, J.O. Seo, S.-H. Baek, S.Y. Kim, Biomol. Ther. 22 (2014) 35–40.
[64] Q. Liu, C. Kim, Y.H. Jo, S.B. Kim, B.Y. Hwang, M.K. Lee, Molecules 20 (2015) 16933–16945.
[65] R.A. Newton, A.L. Cook, D.W. Roberts, J.H. Leonard, R.A. Sturm, J. Invest. Dermatol. 127 (2007) 2216–2227.
[66] T. Quan, G.J. Fisher, Gerontology 61 (2015) 427–434.
[67] N. Philips, P. Samuel, H. Parakandi, S. Gopal, H. Siomyk, A. Ministro, T. Thompson, G. Borkow, Connect. Tissue Res. 53 (2012) 373–378.
[68] R. Besio, M.C. Baratto, R. Gioia, E. Monzani, S. Nicolis, L. Cucca, A. Profumo, L. Casella, R. Basosi, R. Tenni, A. Rossi, A. Forlino, Biochim. Biophys. Acta 1834 (2013) 197–204.
[69] A. Lupi, R. Tenni, A. Rossi, G. Cetta, A. Forlino, Amino Acids 35 (2008) 739–752.
[70] (2014).
[71] M.R. Calomme, D.A. Vanden Berghe, Biol. Trace Elem. Res. 56 (1997) 153–165.
[72] D. Harada, S. Nagamachi, K. Aso, K. Ikeda, Y. Takahashi, M. Furuse, Biochem. Biophys. Res. Commun. 512 (2019) 712–715.
[73] H.P. Shi, R.S. Fishel, D.T. Efron, J.Z. Williams, M.H. Fishel, A. Barbul, J. Surg. Res. 106 (2002) 299–302.
[74] S. Cho, S. Lee, M.-J. Lee, D.H. Lee, C.-H. Won, S.M. Kim, J.H. Chung, Ann. Dermatol. 21 (2009) 6–11.
[75] A. Atiba, M. Nishimura, S. Kakinuma, T. Hiraoka, M. Goryo, Y. Shimada, H. Ueno, Y. Uzuka, Am. J. Surg. 201 (2011) 809–818.
[76] P. Chithra, G.B. Sajithlal, G. Chandrakasan, J. Ethnopharmacol. 59 (1998) 179–186.
[77] P. Chithra, G.B. Sajithlal, G. Chandrakasan, Mol. Cell. Biochem. 181 (1998) 71–76.
[78] F. Ali, N. Wajid, M.G. Sarwar, A.M. Qazi, Curr. Pharm. Biotechnol. (2020).
[79] R. Yao, M. Tanaka, E. Misawa, M. Saito, K. Nabeshima, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, J. Food Sci. 81 (2016) H2849–H2857.
[80] M. Saito, M. Tanaka, E. Misawa, R. Yao, K. Nabeshima, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, Biosci. Biotechnol. Biochem. 80 (2016) 1416–1424.
[81] T. Fujii, M. Wakaizumi, T. Ikami, M. Saito, J. Ethnopharmacol. 119 (2008) 53–57.
[82] S. Pientaweeratch, V. Panapisal, A. Tansirikongkol, Pharm. Biol. 54 (2016) 1865–1872.
[83] M.D. Adil, P. Kaiser, N.K. Satti, A.M. Zargar, R.A. Vishwakarma, S.A. Tasduq, J. Ethnopharmacol. 132 (2010) 109–114.
[84] P. Chanvorachote, V. Pongrakhananon, S. Luanpitpong, B. Chanvorachote, S. Wannachaiyasit, U. Nimmannit, J. Cosmet. Sci. 60 (2009) 395–403.
[85] M. Majeed, B. Bhat, S. Anand, A. Sivakumar, P. Paliwal, K.G. Geetha, J. Cosmet. Sci. 62 (2011) 49–56.
[86] H.M. Park, E. Moon, A.-J. Kim, M.H. Kim, S. Lee, J.B. Lee, Y.K. Park, H.-S. Jung, Y.-B. Kim, S.Y. Kim, Int. J. Dermatol. 49 (2010) 276–282.
[87] S.-Y. Kim, S.-J. Kim, J.-Y. Lee, W.-G. Kim, W.-S. Park, Y.-C. Sim, S.-J. Lee, J. Am. Coll. Nutr. 23 (2004) 157–162.
[88] E. Duchnik, J. Kruk, I. Baranowska-Bosiacka, A. Pilutin, R. Maleszka, M. Marchlewicz, Postepy Dermatol Alergol 36 (2019) 760–766.
[89] K. Miyazaki, T. Hanamizu, R. Iizuka, K. Chiba, Skin Pharmacol. Appl. Skin Physiol. 16 (2003) 108–116.
[90] A. Accorsi-Neto, M. Haidar, R. Simões, M. Simões, J. Soares Jr, E. Baracat, Clinics 64 (2009) 505–510.
[91] R. Gopaul, H.E. Knaggs, E.D. Lephart, Biofactors 38 (2012) 44–52.
[92] E.D. Lephart, Pharm. Biol. 51 (2013) 1393–1400.
[93] P. Sienkiewicz, A. Surazyński, J. Pałka, W. Miltyk, Acta Pol. Pharm. 65 (2008) 203–211.
[94] H.-Y. Chou, C. Lee, J.-L. Pan, Z.-H. Wen, S.-H. Huang, C.-W.J. Lan, W.-T. Liu, T.-C. Hour, Y.-C. Hseu, B.H. Hwang, K.-C. Cheng, H.-M.D. Wang, Int. J. Mol. Sci. 17 (2016).
[95] J. Meephansan, A. Rungjang, W. Yingmema, R. Deenonpoe, S. Ponnikorn, Clin. Cosmet. Investig. Dermatol. 10 (2017) 259–265.
[96] J. Kim, J. Oh, J.N. Averilla, H.J. Kim, J.-S. Kim, J.-S. Kim, J. Food Sci. 84 (2019) 1600–1608.
[97] E.D. Lephart, M.B. Andrus, Exp. Biol. Med. 242 (2017) 1482–1489.
[98] E.D. Lephart, J.M. Sommerfeldt, M.B. Andrus, J. Funct. Foods 10 (2014) 377–384.
[99] J. Wittenauer, S. Mäckle, D. Sußmann, U. Schweiggert-Weisz, R. Carle, Fitoterapia 101 (2015) 179–187.
[100] M. Rizwan, I. Rodriguez-Blanco, A. Harbottle, M.A. Birch-Machin, R.E.B. Watson, L.E. Rhodes, Br. J. Dermatol. 164 (2011) 154–162.
[101] S. Grether-Beck, A. Marini, T. Jaenicke, W. Stahl, J. Krutmann, Br. J. Dermatol. 176 (2017) 1231–1240.
[102] M. Tanaka, Y. Yamamoto, E. Misawa, K. Nabeshima, M. Saito, K. Yamauchi, F. Abe, F. Furukawa, Clin. Cosmet. Investig. Dermatol. 9 (2016) 435–442.
[103] T. Izumi, M. Saito, A. Obata, M. Arii, H. Yamaguchi, A. Matsuyama, J. Nutr. Sci. Vitaminol. 53 (2007) 57–62.
[104] M. Hori, S. Kishimoto, Y. Tezuka, H. Nishigori, K. Nomoto, U. Hamada, Y. Yonei, Anti-Aging Med 7 (2010) 129–142.
[105] I.M. Braverman, J. Investig. Dermatol. Symp. Proc. 5 (2000) 3–9.
[106] N. Charkoudian, Mayo Clin. Proc. 78 (2003) 603–612.
[107] E.A. Grice, J.A. Segre, Nat. Rev. Microbiol. 9 (2011) 244–253.
[108] A.L. Byrd, Y. Belkaid, J.A. Segre, Nat. Rev. Microbiol. 16 (2018) 143–155.
[109] B. Lange-Asschenfeldt, D. Marenbach, C. Lang, A. Patzelt, M. Ulrich, A. Maltusch, D. Terhorst, E. Stockfleth, W. Sterry, J. Lademann, Skin Pharmacol. Physiol. 24 (2011) 305–311.
[110] Y.E. Chen, M.A. Fischbach, Y. Belkaid, Nature 553 (2018) 427–436.
[111] R.R. Roth, W.D. James, Annu. Rev. Microbiol. 42 (1988) 441–464.
[112] A.R. Vaughn, M. Notay, A.K. Clark, R.K. Sivamani, WJD 6 (2017) 52–58.
[113] C.A. O’Neill, G. Monteleone, J.T. McLaughlin, R. Paus, Bioessays 38 (2016) 1167–1176.
[114] S. Eyerich, K. Eyerich, C. Traidl-Hoffmann, T. Biedermann, Trends Immunol. 39 (2018) 315–327.
[115] J.A.S. Quaresma, Clin. Microbiol. Rev. 32 (2019).
[116] F. Abdallah, L. Mijouin, C. Pichon, Mediators Inflamm. 2017 (2017) 5095293.
[117] X. Wang, S. Li, J. Liu, D. Kong, X. Han, P. Lei, M. Xu, H. Guan, D. Hou, BMC Complement Med Ther 20 (2020) 263.
[118] F. Afaq, N. Khan, D.N. Syed, H. Mukhtar, Photochem. Photobiol. 86 (2010) 1318–1326.
[119] J. Duchateau, G. Delepesse, R. Vrijens, H. Collet, Am. J. Med. 70 (1981) 1001–1004.
[120] S. Sazawal, S. Jalla, S. Mazumder, A. Sinha, R.E. Black, M.K. Bhan, Indian Pediatr. 34 (1997) 589–597.
[121] A.S. Prasad, F.W.J. Beck, B. Bao, J.T. Fitzgerald, D.C. Snell, J.D. Steinberg, L.J. Cardozo, Am. J. Clin. Nutr. 85 (2007) 837–844.
[122] C.S. Broome, F. McArdle, J.A.M. Kyle, F. Andrews, N.M. Lowe, C.A. Hart, J.R. Arthur, M.J. Jackson, Am. J. Clin. Nutr. 80 (2004) 154–162.
[123] W.C. Hawkes, D.S. Kelley, P.C. Taylor, Biol. Trace Elem. Res. 81 (2001) 189–213.
[124] J.C. Avery, P.R. Hoffmann, Nutrients 10 (2018).
[125] O.M. Guillin, C. Vindry, T. Ohlmann, L. Chavatte, Nutrients 11 (2019).
[126] G.F. Combs, J.P. McClung, in: G.F. Combs, J.P. McClung (Eds.), The Vitamins (Fifth Edition), Academic Press, 2017, pp. 161–206.
[127] C. Gordon-Thomson, W. Tongkao-on, E.J. Song, S.E. Carter, K.M. Dixon, R.S. Mason, Adv. Exp. Med. Biol. 810 (2014) 303–328.
[128] K. Kwiecien, A. Zegar, J. Jung, P. Brzoza, M. Kwitniewski, U. Godlewska, B. Grygier, P. Kwiecinska, A. Morytko, J. Cichy, Cytokine Growth Factor Rev. 49 (2019) 70–84.
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