COX-2; Autophagy; Mitophagy; Apoptosis

At far lower concentrations than those necessary to prevent NF-κB activation (20 mg/mL), salicylic acid has strong COX-2 activating properties. After a 24-hour period, interleukin E2 can be stimulated by salicylic acid and leukocyte hormone 1β, with an IC50 value of 5 μg/mL. NF-κB activation, COX-2 modulation, or translation are unrelated to this effect. By contrast, when exogenous arachidonic acid is raised to 30 μM, salicylic acid becomes a relatively poor COX-2 inhibitor. Activity inhibition: >100 μg/mL for the IC50. Salicylic acid inhibited PGE2 release in a concentration-dependent manner when combined with IL-1β for a full day; an IC50 value of roughly 5 μg/mL was observed. We evaluated salicylic acid's capacity to directly suppress COX-2 activity in A549 cells by exposing the cells for 30 minutes and then adding varying doses of exogenous arachidonic acid (1, 10, and 30 μM). either in the presence of 1 or 10 μM exogenous substrate, or in the absence of additional arachidonic acid. Here, COX-2 activity was inhibited by salicylic acid in a concentration-dependent manner; an IC50 value of roughly 5 μg/mL was reported. Salicylic acid, on the other hand, was an inefficient COX-2 reactive dye when the same experiment was run with 30 μM arachidonic acid; apparent IC50 values exceeded 100 μg/mL, and maximum inhibition was less than 50% [1].

Salicylic acid tended to lower postprandial and fasting blood glucose levels in C57Bl/6 DIO samples. Additionally, there was a trend toward decreased blood glucose levels following salicylic acid treatment in C57Bl/6 DIO samples (P=0.059). In the omental adipose tissue of C57Bl/6 DIO mice, salicylic acid significantly decreased 11β-HSD1 mRNA, and there was a similar tendency in the mesenteric fat (P=0.057). Salicylic treatment also decreased the activity of the 11β-HSD1 enzyme in the omental fat of C57Bl/6 DIO mice [2].

Human purified COX-2 are and the cofactors Glutathione (5 mM), Adrenaline (5 mM), and Hematin (1 μM) are dissolved in 50 mM Tris buffer (pH 7.5). Hematin is first dissolved in a concentrated stock of 100 mM in 1 M NaOH before being further diluted in Tris buffer. Enzyme reactions are carried out in individual wells of 96-well plates with a final reaction volume of 200 μL. Different concentrations of Salicylic acid are added to the plate, followed by the addition of 10 units of enzyme (180 μL). The plates are incubated at 37° for 30 min before Arachidonic acid (10 nM to 30 μM) is added for a further 15 min. The reaction is stopped by heating the plate to 100°C for 5 min. The 96-well plate is then centrifuged at 10,000× g for 10 min, and appropriated samples are removed and added into the radioimmunoassay[1].

To assess the direct effect of Salicylic acid on COX-2 activity after induction has occurred, A549 cells are first treated with IL-1β for 24 hr, and the culture medium is replaced with DMEM containing different concentrations of Salicylic acid(10, 100 and 1000 μg/mL). Cells are incubated at 37°C for 30 min. Arachidonic acid (1-30 μM) is then added for 15 min, and the medium is removed for the measurement of PGE2[1].

Adult male C57Bl/6 mice are at age 12 weeks. Diet-induced obese C57Bl/6 mice (C57Bl/6 DIO) are given 10 weeks of high-fat diet (58% fat, 12% sucrose) before treatment. Salicylic acid (120 mg/kg/day) is administered from 1 week after arriving (C57Bl/6 Lean), after 10 weeks of high-fat feeding (C57Bl/6 DIO), or after achieving target weight (HSD1KO-DIO) for 4 weeks to groups of n=8 via osmotic minipumps implant subcutaneously between the scapulae. [2]

Absorption, Distribution and Excretion
Approximately 10% is excreted unchanged in the urine. The volume of distribution is approximately 170 mL/kg body weight. A single-center, single-sequence, two-period crossover study compared systemic exposure to salicylic acid in nine healthy male and female subjects 5 minutes after facial application of a 30% salicylic acid cosmetic exfoliant and after oral administration of 650 mg aspirin. The mean (standard deviation) maximum salicylic acid concentration (C_max) was 0.81 (0.32) μg/mL and 56.4 (14.2) μg/mL, respectively. The safety margin based on AUC was 50:1. A drug storage effect was observed during topical application of the exfoliant solution, meaning that salicylic acid absorption continued even after the 5-minute application time. Peak plasma salicylic acid concentrations (Cmax) were reached 1.4 to 3.5 hours after topical application of salicylic acid and 0.5 to 1.5 hours after oral administration of aspirin. The plasma concentrations (30%; 5 minutes) in this study were similar to those of a low-concentration (2%) residual product applied to the same body surface area. This study investigated the absorption of reagent-grade salicylic acid through the abdominal skin of guinea pigs. After shaving the abdominal hair of the guinea pigs, the absorption rate was determined using a circulation device. At pH 3.0, the absorption rate of salicylic acid at concentrations of 250, 400, and 1000 μg/mL was constant (approximately 4%). The relationship between absorption rate and pH was investigated using a 500 μg/mL salicylic acid solution. At pH 2, 3, 4, and 5, the absorption rates at 1 to 6 hours were 6.1%, 3.3%, 0.6%, and 0%, respectively; at pH 7, 8, 9, and 10, the absorption rates were 0%, 1.8%, 8.0%, and 15.5%, respectively. Salicylic acid can be rapidly absorbed by intact skin, especially when applied in oily liniments or ointments… This study used a circulating apparatus to investigate the transdermal absorption of salicylic acid through damaged guinea pig skin. Male guinea pigs were shaved and their keratinized skin removed, then connected to a glass container for continuous circulation. The absorption of 500 μg/mL salicylic acid at pH 3.0 was calculated based on the remaining concentration in the solution. Furthermore, the effects of concentration and pH on absorption were determined using salicylic acid solutions at concentrations of 250, 500, and 1000 μg/mL (pH 3.0) and a 500 μg/mL solution (pH 2, 3, 4, 5, or 6). For damaged skin, the absorption rate of 500 μg/mL salicylic acid in the circulating solution was 79.4%; the disappearance of salicylic acid from the solution showed a linear relationship from the start of exposure. (This is 10 times the absorption rate of intact skin; the disappearance of salicylic acid in intact skin is linear after 1 hour of exposure.) The absorption rate of the circulating solution is concentration-independent but increases with the proportion of unionized form. The residual amount of the drug in damaged guinea pig skin was then determined after different exposure times. Animals were euthanized after being exposed to a salicylic acid solution of 500 μg/mL at pH 3.0 for 0.5, 1.0, 3.0, 4.5, or 6.0 hours. The test area was wiped, and the skin was dissected to the dermis. Peak salicylic acid residues in the skin were observed between 0.5 and 1 hour. …These results are attributed to increased transdermal absorption and a rapid decrease in salicylic acid concentration in the test solution due to stratum corneum removal, which in turn leads to a rapid decrease in salicylic acid concentration in the skin. Increasing the salicylic acid concentration from 250 μg/mL to 1000 μg/mL showed a similar retention pattern. As the pH value changes from 3 to 6, the peak accumulation decreases and the peak shape broadens as the proportion of nonionized salicylic acid decreases, and the time required to reach the peak value also shows a delayed trend. For more data on the absorption, distribution, and excretion (complete) of salicylic acid (16 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Salicylic acid is widely metabolized. At low doses, approximately 80% of salicylic acid is metabolized in the liver. It combines with glycine to form salicyluric acid, and with glucuronic acid to form acyl and phenolic glucuronides. Small amounts of salicylic acid can also be hydroxylated to form gentianic acid. At high doses, the pharmacokinetics change from first-order to zero-order. Administer 1 gram (14)C-salicylic acid (containing 10 microcuries) dissolved in sodium bicarbonate solution intravenously to dogs. Collect urine over 30 to 36 hours. The urinary metabolites recovered from a representative animal were: 50% unmetabolized salicylic acid, 25% glucuronic acid, 10% salicyluric acid, and 4%–5% gentic acid. The total recovery rate was >90% of the administered dose. The major urinary metabolites identified after topical administration differed from those after oral administration of salicylates; the transdermal derivatives contained more salicylate glucuronide (42%) and less salicyluric acid (52%) and salicylic acid (6%). O-carboxyphenyl-BD-glucuronide was generated in humans; O-carboxyphenyl sulfate was generated in rabbits; and O-carboxyphenyl sulfate was generated in rats. /Excerpt from Tables/ For more complete data on the metabolism/metabolites of salicylic acid (6 in total), please visit the HSDB record page. Known human metabolites of salicylic acid include 5-hydroxylated products.

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Biological Half-Life
Male Fischer 344 rats aged 3 months and 25 months were intravenously injected with 5 or 50 mg/kg (14)C-salicylic acid… The half-lives for 3-month-old animals were 4.08 hours and 30.1 hours, respectively, at doses of 5 mg/kg and 50 mg/kg; for 25-month-old animals, these values were 21.3 hours and 21.9 hours, respectively.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no clinical information regarding the skin use of salicylic acid during lactation. Since salicylic acid is unlikely to be significantly absorbed or pass into breast milk, its use during lactation is considered safe. Avoid applying to body parts that may come into direct contact with the infant's skin or to areas where the infant may ingest the drug through licking.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
The plasma protein binding rate of salicylic acid is approximately 90%.

[1]. Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. Mol Pharmacol. 1997 Jun;51(6):907-12.

[2]. Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. Diabetes. 2012 Apr;61(4):790-6.

Salicylic acid is an odorless white to light brown solid that sinks to the bottom and dissolves slowly in water. (USCG, 1999)
Salicylic acid is a monohydroxybenzoic acid, meaning benzoic acid has a hydroxyl group at the ortho position. It is extracted from white willow bark and holly leaves. Salicylic acid has various functions, including anti-infective, antifungal, keratolytic, EC 1.11.1.11 (L-ascorbic acid peroxidase) inhibitor, plant metabolite, algal metabolite, and plant hormone. It is the conjugate acid of salicylates.
Salicylic acid is a compound extracted from white willow bark and holly leaves, and can also be synthesized artificially. It has antibacterial, antifungal, and keratolytic effects. Salicylic acid salts, namely salicylates, can be used as analgesics.
Salicylic acid is present in or produced by Escherichia coli (K12 strain, MG1655 strain).
It has been reported that salicylic acid is found in tea trees, Taiwan astilbe, and other organisms with relevant data.
Salicylic acid is a β-hydroxy acid that naturally occurs in plants. It has direct anti-inflammatory activity and can be used as a topical antibacterial agent due to its ability to promote exfoliation.
Salicylic acid is a compound extracted from the bark of white willow and the leaves of holly, and can also be synthesized artificially. It has antibacterial, antifungal, and keratolytic effects. Salts of salicylic acid, namely salicylates, can be used as analgesics.
Salicylic acid is a compound extracted from the bark of white willow and the leaves of holly. It has antibacterial, antifungal, and keratolytic effects.
See also: benzoic acid (containing the active moiety); methyl salicylate (active moiety); benzyl salicylate (active moiety)... See more...
Pharmaceutical Indications

A key additive in many skin care products used to treat acne, psoriasis, calluses, corns, keratosis pilaris, and warts.

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Mechanism of Action
Salicylic acid directly and irreversibly inhibits COX-1 and COX-2, thereby reducing the conversion of arachidonic acid into prostaglandin and thromboxane precursors. Salicylate is used to treat rheumatic diseases due to its analgesic and anti-inflammatory activities. Salicylic acid is a key ingredient in many skin care products used to treat acne, psoriasis, calluses, corns, keratosis pilaris, and warts. Salicylic acid promotes epidermal cell shedding. Due to its effects on skin cells, salicylic acid is also used in various anti-dandruff shampoos. Salicylic acid is also used as the active ingredient in gels for removing plantar warts (foot warts). Salicylic acid competitively inhibits the oxidation of uridine-5-bisphosphate glucose (UDPG) with nicotinamide adenosine dinucleotide (NAD), rather than competitively inhibiting it with UDPG. It also competitively inhibits the transfer of the glucuronic acid group of uridine-5-phosphate glucuronic acid (UDPGA) to phenol receptors. Inhibition of mucopolysaccharide synthesis may be the reason why salicylate slows wound healing. Salicylic acid, when applied topically, has potent keratolytic activity and mild antibacterial properties. At low concentrations, the drug exhibits keratolytic activity (correcting abnormal keratinization), while at high concentrations (e.g., 1% or higher, depending on the excipients), it exhibits keratolytic activity (leading to skin exfoliation). Salicylic acid softens and disrupts the stratum corneum by increasing endogenous moisture (water concentration), likely due to a decrease in pH, causing the keratinized epithelium (stratum corneum) to swell, soften, and then shed.

C7H6O3

138.12

138.031

69-72-7

Sodium Salicylate;54-21-7;Salicylic acid-d6;285979-87-5;Salicylic acid-13C6;1189678-81-6

338

Off-white to light brown solid

1.44

211 ºC (20 mmHg)

158-161 °C(lit.)

157 ºC

0.0±0.7 mmHg at 25°C

1.616

2.06

2

3

1

10

133

0

O([H])C1=C([H])C([H])=C([H])C([H])=C1C(=O)O[H]

YGSDEFSMJLZEOE-UHFFFAOYSA-N

InChI=1S/C7H6O3/c8-6-4-2-1-3-5(6)7(9)10/h1-4,8H,(H,9,10)

Benzoic acid, 2-hydroxy-

NSC-180; NSC180; NSC 180; Salicylic acid; 2-hydroxybenzoic acid

2918211000

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ≥ 50 mg/mL (~362.00 mM)
H2O : ~1 mg/mL (~7.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (18.10 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 (18.10 mM) 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; with ultrasonication.
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 (18.10 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
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.)