Plant systemic acquired resistance (SAR) signaling pathway
Induces the expression of AZELAIC ACID INDUCED 1 (AZI1) gene[1]
The exact mechanism of action of azelaic acid is not fully known. It possesses antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis, which may be due to inhibition of microbial cellular protein synthesis. Azelaic acid also exhibits antitryrosinase and antimitochondrial enzymatic activities, and may reduce hyperpigmentation through free radical scavenging. [2]

Azelaic acid (0.5 M, 48 h-7 D) exerts bacteriostatic properties [3]. < br /> Azelaic acid (5 M, 24 h) can lower intracellular reactive oxygen species (ROS) levels and boost antioxidant capacity [5] ]. < br /> Azelaic acid (1-100 nM, 24 hours) suppresses the transitory ability of B16, HMB2 and SK23 cells in a dose-regulated manner [6]. < br />

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Azelaic acid has been shown to possess antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis. Electron microscopic and immunohistochemical evaluation of skin biopsy specimens from human subjects treated with azelaic acid cream demonstrated a reduction in stratum corneum thickness, reduction in number and size of keratohyalin granules, and reduction in the amount and distribution of filaggrin in epidermal layers. [2]

For mild papulopustules, azelaic acid (15% Conductive, applied twice daily) is beneficial [4].

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Azelaic acid accumulates in the vascular sap of Arabidopsis after bacterial infection and confers both local and systemic resistance against Pseudomonas syringae[1]
Treatment with azelaic acid primes plants to accumulate higher levels of salicylic acid (SA) upon subsequent pathogen infection[1]
Azelaic acid treatment increases expression of the SA-associated defense marker gene PRI upon infection[1]
The mobility of azelaic acid within the plant was demonstrated, and its accumulation is increased in biologically active petiole exudates[1]
Azelaic acid requires functional SA biosynthesis and signaling pathways, as well as the DIR1 protein, to confer disease resistance[1]
Loss of the AZI1 gene abolishes systemic immunity triggered by azelaic acid and the priming of SA induction[1]
In patients with papulopustular rosacea, topical application of azelaic acid (20% cream or 15% gel) resulted in significant decreases in mean inflammatory lesion count and erythema severity compared to vehicle in four out of five randomized controlled trials. No significant improvement in telangiectasia severity was observed. [2]

Cell viability assay[6]
Cell Types: B16, HMB2 and SK23, CHO
Tested Concentrations: 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM
Incubation Duration: 24 hour
Experimental Results: Dramatically diminished amounts of B16, HMB2 and SK23 compared to CHO.

Animal/Disease Models: Human Rosacea 12 Weeks[4]
Doses: 15% Gel Application: Smear
Experimental Results: 78% of azelaic acid patients demonstrated excellent improvement.

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Arabidopsis thaliana plants (wild-type Col and mutant lines) were used[1]
For local immunization, leaves were infiltrated with Pseudomonas syringae pv. maculicola DG3 (PmaDG3) or the avirulent strain PmaDG6/avrPtz2[1]
Azelaic acid (concentration not specified) was infiltrated into leaves to test its ability to induce systemic resistance[1]
Petiole exudates (Pex) were collected from infected leaves over 72 hours and used for transfer experiments[1]
For systemic challenge, distal leaves were inoculated with PmaDG3 bacteria 2 days after primary treatment or exudate injection[1]
Bacterial growth was measured to assess resistance[1]
SA levels and PRI gene expression were analyzed in distal leaves after infection[1]

Absorption, Distribution and Excretion
Approximately 4% of azelaic acid is absorbed systemically after topical application. Azelaic acid is primarily excreted unchanged in the urine, but some undergoes β-oxidation to form short-chain dicarboxylic acids. Azelaic acid (AA, C9 dicarboxylic acid)…when administered orally, even at the same concentration as other dicarboxylic acids (DA), its serum and urinary concentrations are significantly higher. Following intravenous or arterial infusion of azelaic acid, serum concentrations and urinary excretion are significantly higher than with oral administration. In addition to azelaic acid, varying amounts of its metabolites, primarily pimelic acid, are present in serum and urine, indicating the involvement of mitochondrial β-oxidases in this process. One hour after a single intravenous infusion, serum azelaic acid (AA) concentrations transiently increase; however, with continuous infusion at similar concentrations over extended periods, serum AA concentrations continue to rise during administration. These concentrations are consistent with AA concentrations that produce cytotoxic effects on tumor cells in vitro. Azelaic acid (AA) can cross the blood-brain barrier: its concentration in cerebrospinal fluid is typically 2-5% of its serum concentration. Azelaic acid is the first dicarboxylic acid proposed as an alternative energy substrate for total parenteral nutrition. This study investigated the pharmacokinetics of azelaic acid in 12 healthy volunteers, with 7 receiving continuous infusion (10 g over 90 minutes) and 5 receiving a single bolus injection (1 g). 24-hour urinary excretion and plasma concentration in periodically collected blood samples were determined using gas chromatography. Experimental data were analyzed using a two-compartment nonlinear model, which describes renal tubular secretion and cellular uptake using the Michaelis-Menten equation. Results showed high urinary excretion (mean 76.9% of the infused dose) and a mean clearance of 8.42 L/hr, indicating renal tubular secretion. Population mean estimates of the pharmacokinetic model parameters yielded a maximum cellular uptake of 0.657 g/hr. This model predicted that at a constant infusion rate of 2.2 g/hr, a plateau phase of 90% of the maximum uptake would occur. The large and rapid urinary excretion and the low estimated maximum cellular uptake suggest that azelaic acid is unsuitable as an energy substrate for total parenteral nutrition. To determine whether the in vitro antimicrobial activity observed in previous studies has an in vivo relevance, this study employed a rapid, non-invasive method to determine the concentration of azelaic acid (AzA) in hair follicles after a single topical application of 20% (w/w) azelaic acid cream. Pre-weighed 20% (w/w) azelaic acid cream was applied to specific areas of the forehead and back of nine young adults, and samples were collected within 5 hours. Azelaic acid was removed from the skin surface by washing with acetone, and hair follicle casts were collected using cyanoacrylate gel. Samples were centrifuged to remove particulate matter, and the supernatant was derivatized and then analyzed by high-performance liquid chromatography (HPLC). Although the results showed considerable variability, the hair follicle concentration increased with decreasing surface content. The maximum follicular concentrations of AzA in samples collected from the back and forehead ranged from 7.5 to 52.5 ng/μg follicular casts and 0.5 to 23.4 ng/μg follicular casts, respectively. Assuming an average density of follicular material of 0.9 g/mL, the average maximum follicular concentrations reached on the back ranged from 36 to 251 mmol/L, while those on the forehead ranged from 2 to 112 mmol/L. This indicates that the concentration of azelaic acid (AzA) in follicular casts after a single topical application is comparable to the concentration required to inhibit the growth of Propionibacterium acnes and Staphylococcus epidermidis in vitro. Six healthy male volunteers received a single topical treatment, applying 5 g of an anti-acne cream containing 20% azelaic acid (AzA) to the face, chest, and upper back. One week later, the same group of subjects orally administered 1 g of an aqueous microcrystalline suspension of AzA. Renal excretion of the unchanged compound was measured after both treatments. Analytical methods included urinary ether extraction, extract derivatization, and high-performance liquid chromatography-ultraviolet detection. Following topical application, 2.2 ± 0.7% of the dose was excreted unchanged in the urine; after oral administration, 61.2 ± 8.8% of the dose was excreted unchanged in the urine. By comparing the two methods, the dermal absorption of AzA from the cream was assessed to be 3.6% of the dermal dose. For more complete data on the absorption, distribution, and excretion of 1,7-heptanedicarboxylic acid (7 metabolites), please visit the HSDB record page. Metabolites/Metabolites are primarily excreted unchanged in the urine, but some is metabolized by β-oxidation to short-chain dicarboxylic acids. Approximately 60% of the oral dose is excreted unchanged in the urine within 12 hours, with some metabolized by β-oxidation. Eight hours later, after rats received a tracer dose of [14C]azelic acid, 6% of the radioactivity was recovered as 14CO2. Azelaic acid undergoes a series of β-oxidative cleavages to produce pimelic acid and glutaric acid, followed by malonyl-CoA and acetyl-CoA. Therefore, azelaic acid is incorporated into fatty acid biosynthesis and the citric acid cycle. Pimelic acid is primarily excreted unchanged in humans and dogs; the amount excreted varies with dosage. Dicarboxylic acids also undergo some degree of β-oxidation, producing dicarboxylic acids with two fewer carbon atoms than the parent acid. Pimelic acid has been identified as a metabolite of azelaic acid in microorganisms. It is primarily excreted unchanged in urine, but some undergoes β-oxidation to produce short-chain dicarboxylic acids. Elimination pathway: Azelaic acid is primarily excreted unchanged in urine, but some undergoes H-oxidation to produce short-chain dicarboxylic acids. Half-life: The half-life observed in healthy subjects after oral administration is approximately 45 minutes, and after topical administration, it is approximately 12 hours, indicating limited transdermal absorption.

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Biological half-life
The half-life observed after oral administration in healthy subjects was approximately 45 minutes, and after topical administration, approximately 12 hours, indicating that its transdermal absorption rate is limited.
The half-life observed after oral administration in healthy subjects was approximately 45 minutes, and after topical administration, approximately 12 hours. In terms of dosage, azelaic acid is described as a metabolite that can move within the vascular system of plants[1].
Its concentration in vascular sap increases after local bacterial infection[1].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
No studies have been conducted on the topical use of azelaic acid during lactation. Since only 4% of the applied dose is absorbed, and azelaic acid is a chemical normally found in food, blood, and breast milk, the risk to breastfeeding infants is considered low. If the mother needs to use azelaic acid, breastfeeding does not need to be discontinued. Do not apply azelaic acid to the breasts or nipples, and ensure that the infant's skin does not come into direct contact with areas where azelaic acid has been applied. Only water-soluble creams or gels should be applied to the breasts, as ointments may expose the infant to high concentrations of mineral oil through licking.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Common treatment-related adverse reactions associated with the use of azelaic acid include local skin irritation symptoms such as burning and stinging sensations, which are usually transient and mild to moderate in severity. [2]

[1]. Priming in systemic plant immunity. Science. 2009 Apr 3;324(5923):89-91.

[2]. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol. 2006 Aug;142(8):1047-52.

[3]. The in vitro antimicrobial effect of azelaic acid. Br J Dermatol. 1986 Nov;115(5):551-6.

[4]. Azelaic acid 15% gel in the treatment of rosacea.

[5]. Azelaic Acid Exerts Antileukemia Effects against Acute Myeloid Leukemia by Regulating the Prdxs/ROS Signaling Pathway. Oxid Med Cell Longev. 2020 Dec 23:2020:1295984.

[6]. Effect of azelaic acid on melanoma cells in culture. Exp Dermatol. 1995 Apr;4(2):79-81.

Azelaic acid is an α,ω-dicarboxylic acid with a structure in which heptane is substituted with carboxyl groups at positions 1 and 7. It possesses various functions, including antibacterial, antitumor, dermatological, and plant metabolic effects. Azelaic acid is a dicarboxylic acid fatty acid and also an α,ω-dicarboxylic acid. It is the conjugate acid of azelaic acid (2-) and azelaic acid. Azelaic acid is a saturated dicarboxylic acid naturally found in wheat, rye, and barley. It is also produced by Malassezia furfur (also known as Malassezia furfur), a fungus commonly found on human skin. When applied topically as a 20% cream, azelaic acid is effective against various skin conditions, such as mild to moderate acne. Its mechanism of action is partly through inhibiting the growth of acne-causing skin bacteria and keeping pores open. The antibacterial effect of azelaic acid may be attributed to its inhibition of protein synthesis in microbial cells. Azelaic acid is a metabolite found in or produced by Escherichia coli (K12 strain, MG1655 strain). Azelaic acid's physiological effects are achieved by reducing protein synthesis and sebaceous gland activity. It has been reported to be found in Truffles in India, Streptomyces niger, and several other microorganisms with relevant data. Azelaic acid is a naturally occurring dicarboxylic acid produced by Malassezia furfur and found in whole grains, rye, barley, and animal products. Azelaic acid possesses antibacterial, keratolytic, comedolytic, and antioxidant activities. It exhibits bactericidal activity against Propionibacterium acnes and Staphylococcus epidermidis due to its inhibitory effect on microbial cell protein synthesis. Azelaic acid exerts its keratolytic and comedolytic effects by reducing the thickness of the stratum corneum and decreasing the content and distribution of filaggrin in the epidermis, thereby reducing the number of keratinocytes. Azelaic acid also has free radical scavenging activity, thus possessing a direct anti-inflammatory effect. Topical application of this drug can reduce inflammation associated with acne and rosacea. Azelaic acid is a saturated dicarboxylic acid naturally found in wheat, rye, and barley. It is a natural substance produced by Malassezia furfur (also known as Malassezia furfur spores), a yeast that lives on normal skin. Azelaic acid cream (20%) is effective in treating a variety of skin conditions, such as mild to moderate acne, when applied topically. Part of its mechanism of action is by inhibiting the growth of acne-causing skin bacteria and keeping pores open. The antibacterial effect of azelaic acid may be attributed to its inhibition of microbial cell protein synthesis.
See also: Azelaic acid; Niacinamide (ingredient)...See more...
Drug indications
For the treatment of mild to moderate inflammatory acne vulgaris.
FDA label
Mechanism of action
The exact mechanism of action of azelaic acid is not known. It is believed that azelaic acid exerts its antibacterial effect by inhibiting the cellular protein synthesis of anaerobic and aerobic bacteria, particularly Staphylococcus epidermidis and Propionibacterium acnes. In aerobic bacteria, azelaic acid reversibly inhibits a variety of redox enzymes, including tyrosinase, mitochondrial respiratory chain enzymes, thioredoxin reductase, 5α-reductase, and DNA polymerase. In anaerobic bacteria, azelaic acid inhibits glycolysis. In addition to these effects, azelaic acid can improve acne vulgaris by regulating keratinogenesis and reducing microcomedone formation. Azelaic acid may be effective for both inflammatory and non-inflammatory lesions. Specifically, azelaic acid can reduce stratum corneum thickness, shrink keratinocytes (components of keratinocytes) by reducing their content and distribution in the epidermis, and reduce their number. Azelaic acid and other saturated dicarboxylic acids (C9-C12) have been shown to be competitive inhibitors of tyrosinase (Ki = 2.73 × 10⁻³ M for azelaic acid) and membrane-bound thioredoxin reductase (Ki = 1.25 × 10⁻⁵ M for azelaic acid). Monomethyl azelaate does not inhibit thioredoxin reductase, but it does inhibit tyrosinase, albeit at twice the concentration of azelaate (Ki = 5.24 × 10⁻³ M). When catechol is used instead of L-tyrosine as the substrate, neither azelaate nor its monomethyl ester inhibits tyrosinase. Therefore, the weak inhibitory effect of azelaate on tyrosinase appears to be due to competition between the single carboxylic acid group on the inhibitor and the α-carboxylic acid binding site of the L-tyrosine substrate at the enzyme's active site. Based on the inhibition constant for tyrosinase, if this mechanism is responsible for depigmentation in hyperpigmentation disorders such as freckles and melasma, then at least cytotoxic concentrations of azelaate would be required to directly inhibit melanin biosynthesis in melanosomes. Alternatively, only 10⁻⁵ M of azelaate would be needed to inhibit thioredoxin reductase. This enzyme has been shown to regulate tyrosinase through a feedback mechanism involving electron transfer to intracellular thioredoxin, followed by a specific interaction between reduced thioredoxin and tyrosinase. Furthermore, the thioredoxin reductase/thioredoxin system has been shown to be the primary electron donor for ribonucleotide reductase, which regulates DNA synthesis. The exact mechanism of action of topical azelaic acid in treating acne vulgaris is not fully elucidated; however, its efficacy appears to stem in part from the drug's antibacterial activity. Azelaic acid inhibits the growth of susceptible microorganisms (primarily Propionibacterium acnes) on the skin surface by inhibiting protein synthesis. Additionally, the drug may inhibit follicular keratosis, thereby preventing or maintaining comedone formation. Azelaic acid generally has antibacterial activity, but at high concentrations it may have bactericidal effects against Propionibacterium acnes and Staphylococcus epidermidis. Azelaic acid also has an antiproliferative effect on overactive and abnormal melanocytes, but has no significant depigmenting effect on normally pigmented skin.

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Azelaic acid is a nine-carbon dicarboxylic acid[1]
It is considered a component of plant systemically acquired resistance (SAR)[1]
It plays an upstream role in salicylic acid (SA) accumulation and DIR1-dependent signaling pathways, downstream of SFD1 and FAD7 genes or independently of SFD1 and FAD7 genes[1]
It does not cause major transcriptional reprogramming; microarray analysis showed no significant changes in the expression of defense-related genes after treatment[1]
The AZI1 gene encodes a predicted secretory protein that can be induced by azelaic acid and is crucial for the generation/transport of SAR signals[1]
Azelaic acid is used to treat papulopustular rosacea and acne vulgaris. It appears to be as effective as, or even more effective than, topical metronidazole in reducing inflammatory lesions and erythema. This review suggests the need for a standardized scoring system for assessing the severity of rosacea.[2]

C9H16O4

188.22

188.104

123-99-9

Azelaic acid-d14;119176-67-9

2266

White to off-white solid powder

1.1±0.1 g/cm3

286 ºC (100 mmHg)

98-103 ºC

215 ºC

0.0±1.8 mmHg at 25°C

1.475

1.33

2

4

8

13

147

0

BDJRBEYXGGNYIS-UHFFFAOYSA-N

InChI=1S/C9H16O4/c10-8(11)6-4-2-1-3-5-7-9(12)13/h1-7H2,(H,10,11)(H,12,13)

nonanedioic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~531.29 mM)
H2O : ~2 mg/mL (~10.63 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)