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Hyaluronic Acid (HA), also called hyaluronan, is a carbohydrate, more specifically a high molecular weight biopolysacharide. In the body, HA is found in a salt form (hyaluronate), in high concentrations in several soft connective tissues, including skin, umbilical cord, synovial fluid, and vitreous humour. Significant amounts of HA are also found in lung, kidney, brain, and muscle tissues. It is naturally synthesized by a class of integral membrane proteins called hyaluronan synthases; and degraded by a family of enzymes called hyaluronidases (Necas et al., 2008). It can be several thousands of sugars (carbohydrates) long; and when not bound to other molecules, it binds to water giving it a stiff viscous quality similar to “Jello”.
Because of this, Hyaluronic acid is considered as one of the most hydrophilic (water-loving) molecules in nature and can be described as nature’s moisturizer. The biological functions of HA include maintenance of the elastoviscosity of liquid connective tissues such as joint synovial and eye vitreous fluid, control of tissue hydration and water transport, supramolecular assembly of proteoglycans in the extracellular matrix; and also has numerous receptor-mediated roles in cell detachment, mitosis, migration, and inflammation (Toole et al., 2002; Turley et al., 2002; Hascall et al., 2004). Its function in the human body is to bind water and lubricate movable parts of the body, such as joints and muscles. Moreover, its consistency and tissue-friendliness allows it to be used in skin-care products as an excellent moisturizer.
Figure 1. Chemical structure of Hyaluronic Acid (Necas et al., 2008).
Hyaluronic Acid homeostasis changes with age. The most dramatic histochemical change observed in the senescent skin is the marked disappearance of epidermal HA, while HA is still present in the dermis. The synthesis of epidermal HA is influenced by the underlying dermis and is under separate controls from the synthesis of dermal HA (Papakonstantinou et al., 2012). Thus, the epidermis loses the principle molecule responsible for binding and retaining water molecules, resulting in loss of skin moisture. In the dermis, the major age-related change is the increasing avidity of HA with tissue structures with the concomitant loss of HA extractability (Papakonstantinou et al., 2012). This parallels the progressive cross-linking of collagen and the steady loss of collagen extractability with age.
All of the above age related phenomena contribute to the apparent dehydration, atrophy and loss of elasticity that characterizes aged skin. This indicates the hygroscopic property of HA and its importance in modulating tissue hydration and osmotic balance (Dechert et al., 2006). However, skin aging is triggered not only by intrinsic factors but also extrinsic factors such as daily environmental exposure to pollutants and UV light.
Being a hydrator, when taken orally in the form of supplement, HA can demonstrate significant moisturizing effect, finer skin texture and improved skin elasticity. Moreover, studies have also found that daily topical application of HA can also demonstrate a significant improvement in skin hydration, wrinkle appearance and elasticity (Dechert et al., 2006). This is because there are multiple sites in the skin involved in the control of Hyaluronic Acid synthesis, deposition, cell and protein association and degradation (Dechert et al., 2006).
Hyaluronan also supports dermal regeneration and its content in the skin is further elevated during the wound healing process. Broun & Jones (2005) found that cross-linked HA hydrogel films accelerate the healing of full-thickness wounds, presumably by providing a highly hydrated and non-immunogenic environment that is conducive to tissue repair.
Hyaluronic acid is found in all bones, connecting tissue, joints, tendons and cartilage structures throughout the body — especially a type called hyaline cartilage, which covers the ends of bones and provides cushioning. Moreover, HA plays a vital role in the development of cartilage, the maintenance of the synovial fluid and the regeneration of tendons (Toole, 2001). High concentrations of HA are mainly predominant in the extracellular matrix (ECM) of all adult joint tissues, including the synovial fluid and the outer layer cartilage (Leach & Schmidt, 2004). In part because of its viscoelastic nature and ability to form highly hydrated matrices, HA acts in the joint as a lubricant and shock absorber.
Because it helps buffer bones and provides resistance to wear and tear, HA is useful for lowering pains and tenderness associated with degenerative joint diseases, and is quickly becoming a go-to approach for the treatment of osteoarthritis. This is because HA could bind to specific receptors expressed in many cells, such as the cluster determinant 44 (CD44), the intracellular adhesion molecule-1 (ICAM-1) and the receptor for hyaluronate-mediated motility (RHAMM). Chondrocytes (cells found in cartilage connective tissue) express the glycoprotein CD44 on their cell surface (Akmal et al., 2005). This has the capacity to function as a HA receptor and so may be involved in biochemical interactions with chondrocytes.
In 2015, Nelson et al. (2015) treated 40 patients with knee OA, with an oral HA mixture at 80 mg/day or placebo for 3 months. In this study, an analysis of serum and synovial fluid illustrated that inflammatory cytokine levels were significantly increased in the placebo group and significantly decreased in the HA group. Furthermore, bradykinin levels which are related to inflammation and pain, and leptin, which is related to OA caused by obesity, the levels of both substances were significantly lower in the HA group than in the placebo group (Nelson et al., 2015).
Figure 2. Oral administration of hyaluronan modulates inflammation by upregulating suppressor of cytokine signaling-3 expression and down-regulating pleiotrophin expression via Toll-like receptor-4 in intestinal epithelial cells (Nelson et al., 2015)
According to a recent study, HA has been found to be a helpful in reducing osteoarthritic symptoms (Santilli et al., 2016). In this study, Santilli et al. (2016) demonstrated an ability of HA to reduce the production of pro-inflammatory mediators and matrix metalloproteinases, and reduce nerve impulses and nerve sensitivity associated with osteoarthritic pain. Santilli et al. (2016) further suggested that HA therapy could lead to modulation of nociceptors, reduction of synovial/capsular fibrosis, increased synthesis of higher molecular weight endogenous HA and reduction in inflammatory mediators including prostaglandin-E2, IL-1 and IL-6.
Another study by Moriña et al. (2016) reported a meta-analysis of two randomized, controlled, double-blind, placebo-controlled trials involving a total of 148 patients with mild knee pain. In both studies, patients were administered an oral HA mixture at 80 mg/day (HA content, 48 mg/day) or placebo for 3 months and outcomes were evaluated using an isokinetic dynamometer. The studies further demonstrated that the knee pain was significantly improved in the HA group compared with the placebo group.
Several foods are known to have good sources of hyaluronic acid, while others can help boost its production.
Grass fed meats: Most livestock meats such as beef, turkey, pork, lamb and chicken contain high levels of hyaluronic acid.
Vitamin C-rich foods: Ascorbic acid is believed to play a critical role in the production of hyaluronic acid.
Magnesium-rich foods: This mineral can help synthesize the production of hyaluronic acid.
BSc Herbal Medicine; MSc Pharmacology
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