Niacinamide is a member of the vitamin B3 family and is an important functional ingredient in topical skin care and cosmetics. From a pharmaceutical perspective, niacinamide can be used to treat conditions such as acne vulgaris, melasma, and psoriasis. From a cosmeceutical perspective, niacinamide is a multi-purpose anti-aging ingredient. This review delves into the mechanisms associated with nicotinamide as a drug and cosmeceuticals. The evolving role of niacinamide in skincare products was evaluated, with a focus on its biochemical mechanisms. Finally, new indications and potential applications of nicotinamide in dermal fillers and alternative injectable formulations are prospected.
Mechanistic studies on the function and activity of nicotinamide
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1. Regulatory effect of nicotinamide on NAD+-dependent enzymes
Nicotinamide is essential for the formation of nicotinamide adenine dinucleotide (NAD+) and influences the activity of several enzymes that are essential for basic cellular activities, such as NAD+-dependent deacetylase (sirtuins) and poly(adp-ribose) polymerase (PARP). Both sirtuins and PARP are part of the fundamental cellular biochemical pathways with intertwined functions and effects. For example, nicotinamide exerts anti-inflammatory effects by inhibiting sirtuin1 (SIRT-1), increasing the activity of PARP-1. Therefore, nicotinamide can be considered as a PARP-1 agonist. In addition to reducing the expression levels of pro-inflammatory cytokines, the PARP-1 enzyme also plays an important role in DNA repair.
2. Antioxidant activity of niacinamide
Oxidative stress (i.e., the production of reactive oxygen species [ROS] and free radicals) is often thought to be a core driver of skin aging. The production pathways of ROS and free radicals are complex and involve a variety of enzymes, such as reduced coenzyme II (NADPH) oxidase and nitric oxide synthase (NOS). Nicotinamide is associated with a lower NADP/NADPH ratio, so the use of nicotinamide may reduce the expression and activity of NADPH oxidase. Nicotinamide interferes with the activity of NOS, but the exact mechanism is not well understood. In addition to regulating the action of NADPH oxidase and NOS, nicotinamide increases the encodematic activity of catalase, which converts hydrogen peroxide into oxygen and water. In addition, niacinamide is able to directly neutralize ROS and free radicals. In vitro and in vivo studies have demonstrated that nicotinamide protects against protein oxidation and lipid peroxidation (Figure 1), an antioxidant function that protects cell membrane integrity.
Figure 1: Overview of the intracellular antioxidant mechanism of nicotinamide in the ROS cascade. The key enzymes involved in the cascade are indicated by gray boxes. The inhibitory effect of nicotinamide on the enzyme is indicated in red. The stimulating effect of niacinamide is indicated by a green arrow.
3. Anti-inflammatory activity of niacinamide
Oxidative stress can exacerbate inflammatory responses, and niacinamide has strong antioxidant activity to reduce inflammatory responses. In addition to reducing ROS levels, nicotinamide can also inhibit the secretion of pro-inflammatory cytokines through PARP regulation. Nicotinamide can directly inhibit PARP, reducing NOS expression and thus reducing nitric oxide (NO) synthesis. In addition, the inhibition of PARP by nicotinamide can also reduce the secretion of prostaglandin E2 (PGE2) and the activity of myeloperoxidase, which helps to exert anti-inflammatory effects. Nicotinamide inhibits the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, PGE2, interleukin (IL)-1, IL-6, and IL-8 by inhibiting NFκB-mediated transcription, and increases the production of anti-inflammatory mediators such as IL-10 and macrophage scavenger receptor (MRC)-1). By reducing the level of inflammatory mediators, niacinamide prevents keratinocyte senescence, thereby reducing the production of senescence-associated secretory phenotype (SASP). The anti-inflammatory effects of nicotinamide also stabilize mast cells (i.e., mast cells in the dermis) and inhibit mast cell degranulation and allergic reactions in mice.
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4. Antimicrobial activity of niacinamide
Niacinamide has been shown to have antibacterial, antifungal, and antiviral activity, a property that makes niacinamide an effective substance for the treatment of acne. Nicotinamide does not directly kill bacteria, and its antimicrobial activity is mainly attributed to the stimulating effect on neutrophils and the synthesis of antimicrobial peptides (AMP). AMPs are part of the skin's innate immune system and have broad antimicrobial activity against gram-positive and gram-negative bacteria, as well as antifungal and antiviral activity. In vitro studies have shown that nicotinamide solution stimulates the synthesis of AMPs, thereby protecting the skin from infection. In addition, nicotinamide selectively enhances the killing effect of neutrophils against Staphylococcus aureus and rodent citrobacterium.
5. Niacinamide reduces the activity of sebum production
Topical formulations of 2% to 5% niacinamide have been shown to be effective in reducing sebum production and are more effective in Asians and Caucasians. However, the mechanism of sebum inhibition of niacinamide is not well understood. Niacin in the vitamin B3 family activates the niacin receptor (HCA2), which regulates sebum secretion in the body's sebum cells. Niacinamide does not bind to HCA2 receptors, but it has been suggested that niacinamide can be converted to niacin, which indirectly reduces sebum production.
6. Skin anti-yellowing activity of niacinamide
Glycation is a spontaneous oxidative cross-linking reaction that occurs between proteins (e.g., dermal collagen) and endogenous sugars, resulting in the formation of advanced glycation end products (AGEs) that affect different structural and physiological functions of the skin. AGEs can make the skin yellow, but antioxidants prevent the formation of AGEs. The antioxidant activity of niacinamide makes it a natural antioxidant that reduces yellowing/yellowing of the skin.
7. Whitening activity of niacinamide
Niacinamide can be used to treat pigmentation. Studies have shown that a 4% nicotinamide solution is successful in reducing underarm pigmentation. Niacinamide can significantly improve pigmentation, which is related to the anti-melanin production effect of niacinamide. Regarding the anti-melanin production effect of nicotinamide, studies have shown that nicotinamide molecules do not affect the catalytic activity of tyrosinase or melanin production in melanocytes, which means that nicotinamide does not appear to affect melanin synthesis. However, nicotinamide has been shown to block the transfer of melanosomes from melanocytes to peripheral keratinocytes. Therefore, nicotinamide has anti-melanogenesis effect, which is dose-dependent and reversible, but the exact inhibition mechanism of melanosome transfer needs to be further explored.
8. Niacinamide enhances the extracellular matrix (EMC) and skin barrier of the skin
The decrease in protein synthesis is associated with an increase in ROS, which induces cellular senescence and degradation of ECM components, leading to premature aging of the skin. The intrinsic antioxidant activity of niacinamide contributes to cellular balance and maintains the integrity of the skin's ECM. Mast cell degranulation leads to fibroblast senescence, and nicotinamide helps maintain normal activity of fibroblasts by stabilizing mast cells (i.e., mast cells in the dermis) through a variety of mechanisms.
Fibroblasts secrete matrix metalloproteinases (MMPs), which lead to collagen degradation. ROS and inflammatory cytokines stimulate the synthesis of MMP, and niacinamide has antioxidant and anti-inflammatory activities that inhibit the synthesis of MMP. Collagen glycosylation can negatively affect the ECM molecular organization, and the antioxidant effect of niacinamide prevents collagen glycosylation, thereby contributing to the integrity of the skin's ECM.
Nicotinamide promotes ceramide synthesis by activating mRNA expression of serine palmitoyltransferase, a key enzyme in sphingolipid synthesis, and accelerating keratinocyte differentiation. Niacinamide prevents keratinocyte senescence caused by photoaging and oxidative stress. In summary, niacinamide affects both fibroblasts and keratinocytes, improving ECM quality and skin barrier integrity, thereby improving overall skin health.
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9. Skin anti-aging activity of niacinamide
Nicotinamide prevents cell senescence, and its anti-aging activity is mainly due to its anti-inflammatory effects, such as reducing inflammatory mediators and inhibiting mast cell degranulation, in addition to reversing the accumulation of DNA damage caused by oxidative stress. Senescence of fibroblasts and keratinocytes is associated with decreased synthesis of collagen, elastin, and keratin. Several studies have shown that niacinamide stimulates collagen, elastin, and ceramide production. As a result, niacinamide significantly improves the quality of the skin's ECM at the cellular level, reversing visible signs of aging. Nicotinamide is a precursor of NAD+, which regulates the redox state of cells and balances the levels of various cellular metabolites. The anti-aging effects of niacinamide may not be a specific feature, but rather a combined result of its overall activity (Figure 2).
Figure 2: Overview of the main processes by which niacinamide affects the skin and the biological functions it produces
Challenges and opportunities for nicotinamide formulations
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Niacinamide acts primarily in the epidermis or dermis, and most nicotinamide preparations (i.e., those sold on the market) are topical. These formulations must be transdermally administered in order to realize the full potential of nicotinamide activity. But transdermal administration is challenging because the molecule needs to penetrate the stratum corneum, the outermost layer of the skin.
The stratum corneum is mainly composed of dead keratinocytes, and the intercellular matrix is mainly composed of ceramides, cholesterol, and free fatty acids. Nicotinamide is a class I drug, which has high water solubility and high permeability, and is difficult to administer transdermally. The permeation and deposition of niacinamide is highly dependent on specific permeation promoters. Encapsulation of nicotinamide molecules into oil bladders and then suspension in hydrogels for topical use has been shown to increase nicotinamide deposition and decrease permeation (i.e., low systemic distribution).
A convenient method for transdermal administration is to inject niacinamide directly into the dermis. In addition to cosmetic applications, nicotinamide injections can also be used to treat vitamin deficiencies and as an absorption regulator for rapid-acting subcutaneous insulin formulations. Cross-linked hyaluronic acid (HA) dermal fillers are among the most popular injectable formulations in cosmetics due to their quality, efficacy, and reversibility. HA dermal fillers containing niacinamide may improve the stability of the product and thus its residence time. In addition, the addition of niacinamide to HA fillers promotes the effect of vitamins on the dermis. Studies have shown that cross-linked HA-based hydrogels can effectively load and release nicotinamide, and these dermal fillers may be ideal carriers for future nicotinamide delivery modalities (Figure 3).
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Figure 3: Nicotinamide formulations and their penetration/administration in the skin. The penetration of aqueous preparations (A) in the stratum corneum is very limited. The oil-in-water formulation (B) nicotinamide has enhanced permeability in the epidermis. Intradermal injection of aqueous solution (C) and hydrogel (D) increases the bioavailability and effectiveness of niacinamide.
Conclusions
Niacinamide is well tolerated by the skin and is essential for NAD+ synthesis, PARP and sirtuin regulation. Nicotinamide can act on basic biochemical reactions in cells,