4-TERPINEOL

In order to devise more effective penetration enhancers, 4- O -acylterpineol derivatives which were expected to be hydrolyzed into nontoxic metabolites by esterase in the living epidermis, were synthesized from 4-terpineol (4-TER) enantiomers and straight chain fatty acids. Their promoting activities on the SR -flurbiprofen and its enantiomers were tested across full-thickness rabbit skin, as well as to correlate under in vitro and in vivo conditions. The permeation studies indicated that both d -4- O -acylterpineol and l -4- O -acylterpineol had significant enhancing effects, interestingly, d -4- O -aclyterpineol had higher enhancing effects than l -4- O -aclyterpineol with the exception of d -4-methyl-1-(1-methylethyl)-3-cyclohexen-1-yl octadec-9-enoate ( d -4-T-dC18). The mechanism of 4- O -acylterpineol facilitating the drug penetration across the skin was confirmed by Attenuated total reflection-Fourier transformed infrared spectroscopy (ATR-FTIR) and molecular simulation. The mechanism of penetration enhancers promoting drug release was explored by the in vitro release experiment. Finally, a relative safety skin irritation of enhancers was also investigated by in vivo histological evaluation. The present research suggested that d -4- O -aclyterpineol and l -4- O -aclyterpineol could significantly promote the penetration of SR -flurbiprofen and its enantiomers both in vitro and in vivo , with the superiorities of high flux and low dermal toxicity.

Natural terpenes found in essential oils (EOs) have shown promise as penetration enhancers (PEs) in pharmaceutical and cosmetic formulations. This study compared the skin penetration enhancement properties of sesquiterpenes and monoterpenes from galangal EO (GEO), e.g. δ-cadinene, β-caryophyllene, caryophyllene oxide (CPO), 4-terpineol, β-pinene, and 1,8-cineole. Results indicated that the sesquiterpenes, particularly δ-cadinene, significantly improved the skin permeation of rhodamine B compared to monoterpenes. Electrical resistance measurements of the skin, DSC and XRD analysis revealed that the sesquiterpenes notably disturbed the ordered arrangement of stratum corneum (SC) components including lipids and keratins. Additionally, the results of molecular docking also revealed that sesquiterpenes were easily combined with transient receptor potential vanilloid 4 (TRPV4) ion channel. The cutaneous TRPV4 ion channel, which played a role in tight junction (TJ) formation in keratinocytes, were abundantly expressed in rat abdominal skin. δ-Cadinene, specifically, exhibited an agonistic effect on the cutaneous TRPV4 ion channel, significantly enhancing its SC retention and facilitating in vivo skin permeation of rhodamine B. In summary, the penetration enhancement mechanism of sesquiterpenes from GEO, particularly δ-cadinene, includes acting on SC components and activating the cutaneous TRPV4 ion channel.

Acne vulgaris is a chronic inflammatory skin disorder predominantly caused by Cutibacterium acnes and its virulence-associated CAMP (Christie-Atkins-Munch-Petersen) factors, particularly CAMP1 and CAMP2, which contribute to inflammation and bacterial survival. With increasing antibiotic resistance and concerns over microbiome disruption from conventional treatments, probiotic-derived postbiotics present a promising alternative. This study aimed to investigate the anti-acne potential of fatty acids produced by Pediococcus acidilactici BCBH1, targeting CAMP1 and CAMP2 proteins of C. acnes using a network pharmacology-guided approach. Metabolite profiling via GC-MS identified vaccenic acid as a major fatty acid metabolite (4.88 mg/L at 48 h under 10% linoleic acid stress). Virulence prediction confirmed high pathogenicity of CAMP1 (score 0.9055) and CAMP2 (score 0.9927). Molecular docking revealed strong binding affinities of vaccenic acid to CAMP1 and CAMP2 with binding energies of -9.6 kJ/mol and -9.3 kJ/mol, respectively, outperforming traditional anti-acne compound 4-terpineol (-9.0 kJ/mol and -8.7 kJ/mol). Molecular dynamics simulations further validated the stable interaction of vaccenic acid with CAMP proteins over 100 ns. Pharmacokinetic analyses indicated vaccenic acid's favorable absorption and safety profiles with no blood-brain barrier permeability. These findings highlight vaccenic acid as a potent, microbiome-friendly therapeutic candidate for acne management. Future work should focus on experimental validation, formulation development, and combinatorial strategies to enhance clinical efficacy and safety.

: The present work evaluates for the first time two Lavandin ( Lavandula × intermedia Emeric ex Loisel.) aromatic waters obtained from different plant organs, the flowers and the stems. Both extracts were analysed by GC-MS, which indicates semi-quantitative differences between the major metabolites including linalool, 1,8-cineole, camphor, linalyl acetate and 4-terpineol. 1 H-NMR and LC-MS investigation confirmed the presence of these compounds. Moreover, behavioural tests with the food insect pest Tribolium confusum (Coleoptera Tenebrionidae) showed a good repellency for both hydrosols extracts with RD 50 values of 3.6 and 3.3 µL cm - 2 for the flowers and stems, respectively; at the higher concentrations, however, the hydrosol extract from the flowers is expected to be more effective than the one from the stems. The effect of the flowers and stems aromatic water of Lavandin on seed germination of Raphanus sativus was also evaluated. Results showed that seed germination was completely inhibited by flowers hydrolate, having a possible application as natural herbicide. The overall experience with these Lavandin extracts indicates the potential of improved hydrolates to become the main distillation products, rather than by-products, of the aromatic plants manufacturing; this stimulates further discussions about the potential positive impacts that such a shift could have in the context of ecopharmacognosy.

It has been reported that natural transdermal permeation enhancers (TPEs) are superior in safety compared with synthetic TPEs. The essential oil (EO) of Ledum palustre L. var. angustum N. Busch had a strong enhancement effect on drug skin permeation based on previous studies. However, their enhancement mechanisms and safety were still unclear. The composition of the EO was determined using GC-MS. By using donepezil (DNP) as a model drug, the enhancement effect of the constituents of the EO and the EO were evaluated by in vitro skin permeation test. Confocal laser scanning microscopy (CLSM), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and molecular docking were used to investigate the interaction among drug, enhancers and skin. Skin retention amount, apparent partition coefficient (K') and molecular simulation were used to reflect the effect of the enhancers on drug partition into skin. The skin irritation potential was evaluated using in vivo skin erythema analysis. The results showed that the main constituents of the EO were sabinene (SA), 4-terpineol (TE), p-cymene (CY) and cuminaldehyde (CU). CU was the main active constituent of the EO, which facilitated skin permeation of DNP. CU improved the skin permeation of DNP by increasing the mobility of the stratum corneum (SC) intercellular lipids, decreasing the interaction between DNP and the SC intercellular lipids, and improving the partition of DNP into the SC layer. Besides the superior enhancement effect, CU also showed a lower skin irritation potential compared with the EO. This work gave us some enlightenment that the effectiveness and safety of the natural transdermal permeation enhancers could be improved by understanding their composition and the enhancement mechanisms.

Microbial infection has been reported to cause blepharitis, conjunctivitis and keratitis. We evaluated the safety and efficacy of a foam formulation of 2% 4-terpineol (T4O) against common ocular microorganisms. The antimicrobial effect of a 2% T4O formulation was evaluated by the United States Pharmacopeia 51 (USP <51>) antimicrobial effectiveness test for 14 and 28 days, as well as by a Time Kill Study (ASTM E2315) with a 60 s exposure time. Its potential of causing skin and ocular irritation was evaluated by the Repeated Insult Patch Test and the Hen's Egg Chorioallantoic Membrane Test, respectively. It was seen that 2% T4O formulation did not cause ocular irritation, skin irritation, sensitisation or allergic contact dermatitis in human subjects. Most importantly, it killed microorganisms listed in USP <51> at both 14 and 28 days and exerted a rapid killing effect within 60 s against 13 bacteria, 1 fungus and Acanthamoeba castellanii . The above finding suggests that 2% T4O formulation is safe and effective in killing microorganisms related to common ocular and skin infective diseases. Although the clinical efficacy in treating ocular disease was not directly studied; this foam formulation containing 2% T4O, based on the in vitro results of this work, demonstrated that it can potentially be used as a preservative-free cleansing agent for ocular hygiene maintenance due to its ability to exert a broad-spectrum antimicrobial effect without causing ocular or skin irritation.

Zanthoxylum bungeanum, as a crucial "dual-purpose resource for food and medicine", has been proven to possess a wide range of biological activities, including antimicrobial, anti-inflammatory, analgesic, and antioxidant effects. In the traditional application of Traditional Chinese Medicine, external use of Zanthoxylum bungeanum exhibits antipruritic efficacy and is commonly used to alleviate pruritus caused by eczema and mosquito bites. However, its underlying mechanism of action has not yet been systematically elucidated. This study aims to identify the compounds in Zanthoxylum bungeanum essential oil (ZO), preliminarily analyze the pathways and targets related to its alleviation of acute pruritus using network pharmacology and molecular docking, and verify the findings through in vivo experiments. The compounds of ZO was analyzed using GC-MS. Pathways and targets related to acute pruritus were screened through databases including GenGards, OMIM, DrugBank, TTD, and Disgenet. Molecular docking was employed to examine the interactions between active compounds and potential targets. A rat model of acute pruritus was induced by subcutaneous injection of 5 mg/mL histamine phosphate solution into the nape of the neck. After 14 days of topical application of the test substance, behavioral observations were conducted; the levels of IL-4, IL-7,IgE, and IgM in serum were determined; and skin and spleen tissues were collected for pathological examination and detection of other relevant indicators. In total,21 compounds were identified from ZO. Among the identified compounds, linalool (81.60 %), 4-terpineol (3.18 %), D-limonene (3.12 %), and sabinene (3.07 %) being confirmed as the major bioactive constituents. Network pharmacology predicted that ZO alleviates acute itch potentially through targeting JAK1, STAT3, and STAT6, which was further supported by molecular docking simulations demonstrating strong binding affinity between these targets and the corresponding compounds. In vivo experiments revealed that ZO significantly alleviated acute itch in rats by: Downregulating serum levels of IL-4, IL-7, IgM, and IgG; Reducing CD3 + , CD4 + , and CD8 + T-cell populations in the spleen; Inhibiting phosphorylation of JAK1, STAT3, and STAT6 proteins in the skin. ZO demonstrated significant efficacy in alleviating acute itch in rats, It may alleviate skin pruritus in rats by down-regulating the levels of IL-4, IL-7, IgE, and IgM in serum, reducing the contents of CD3 + , CD4 + , and CD8 + in the spleen, inhibiting the expression of JAK1, STAT3, and STAT6 proteins, and weakening their immune capacity.

Rhodococcus globerulus (R. globerulus) was isolated from the soil beneath a Eucalypt tree. Metabolic growth studies revealed that R. globerulus was capable of living on certain monoterpenes, including 1,8-cineole and p-cymene, as sole sources of carbon and energy. Multiple P450 genes were identified in the R. globerulus genome that shared homology to known bacterial, monoterpene hydroxylating P450s. To date, two of these P450s have been expressed and characterised as 1,8-cineole (CYP176A1) and p-cymene (CYP108N12) monooxygenases that are believed to initiate the biodegradation of these terpenes. In this work, another putative P450 gene (CYP108N14) was identified in R. globerulus genome. Given its amino acid sequence identity to other monoterpene hydroxylating P450s it was hypothesised to catalyse monoterpene hydroxylation. These include CYP108A1 from Pseudomonas sp. (47 % identity, 68 % similarity) which hydroxylates α-terpineol, and CYP108N12 also from R. globerulus (62 % identity, 77 % similarity). Also present in the operon containing CYP108N14 were putative ferredoxin and ferredoxin reductase genes, suggesting a typical Class I P450 system. CYP108N14 was successfully over-expressed heterologously and purified, resulting in a good yield of CYP108N14 holoprotein. However, neither the ferredoxin nor ferredoxin reductase could be produced heterologously. Binding studies with CYP108N14 revealed a preference for the monoterpenes p-cymene, (R)-limonene, (S)-limonene, (S)-α-terpineol and (S)-4-terpineol. An active catalytic system was reconstituted with the non-native redox partners cymredoxin (from the CYP108N12 system) and putidaredoxin reductase (from the CYP101A1 system). CYP108N14 when supported by these redox partners was able to catalyse the hydroxylation of the five aforementioned substrates selectively at the methyl benzylic/allylic positions.

Juniperus plants are considered important sources of cedar-wood oil which is used widely in folk medicine as antiseptic and in treatment of inflammatory disorders such as, rheumatoid arthritis but there is not enough scientific evidence to support the claimed uses and there is no specification of a certain Juniperus species as the most active. The aim of this study is volatiles profiling of three Juniperus species; J. communis, J. horizontalis and J. chinensis in addition to efficacy-directed discrimination of the three studied essential oils based on their antimicrobial, and anti-inflammatory activities in LPS (lipopolysaccharide)-stimulated WBCs (White blood cells) to investigate the inter-specific variability effect on the biological activities of each oil. Volatile components profiling of the three studied plants volatile oils was achieved using GC-FID (Gas chromatography - flame ionization detector) and GC-MS (Gas chromatography - mass spectrometry). The antimicrobial activity of the studied essential oils was investigated and the minimum inhibitory concentration (MIC) was determined for oils. The production of the pro-inflammatory cytokines was evaluated by ELISA (Enzyme linked immunosorbent assay). Identification of the biomarkers responsible for each activity was attempted through construction of orthogonal projection to latent structures model using multivariate statistical analysis. Forty five components were identified in the volatile oils of the three studied plants. J. horizontalis oil displayed the highest activity against E. coli while J. communis showed the highest activity against S. aureus. OPLS model biplot showed the in-between class discrimination of J. chinensis oil sample from J. communis and J. horizontalis. The three oils were found to significantly decrease the production of the pro-inflammatory cytokines tumour necrosis factor (TNF)- α, interleukin (IL)-1β, and gamma interferon (INF- γ) in lipopolysaccharide-activated white blood cells. All studied oils were similar in reduction of TNF-α, and INF-γ, while J. chinensis oil possessed the highest potency against IL-1β. The coefficient plots of TNF-α and INF-γ pro-inflammatory mediators showed that 1-terpineol, 4-terpineol, bornyl acetate, dl-limonene and α-pinene positive contributors to both activities while β-thujone, 3-carene and γ-muurolene were the positive contributors to IL-1β inhibitory activity. The differences observed in the volatile profiles among the three studied oils demonstrate the effect of inter-specific variability on the biological activities of the tested oils. It was shown that the tested oils possessed good antibacterial activities against E.coli and S. aureus justifying its folk use as an a topical antiseptic while the observed anti-inflammatory effects in human WBCs is due at least in part to their inhibitory effect on the production of pro-inflammatory cytokines.

Melaleuca alternifolia essential oil (tea tree oil) is widely used as an ingredient in skin care products because of its recognized biological activities. The European Scientific Committee on Consumer Products constantly promotes research and collection of data on both skin distribution and systemic exposure to tea tree oil components after the application of topical formulations. This study quantitatively evaluates permeation, skin layer distribution ( stratum corneum , epidermis, and dermis), and release into the surrounding environment of bioactive tea tree oil markers (i.e., α -pinene, β -pinene, α -terpinene, 1,8-cineole, γ -terpinene, 4-terpineol, α -terpineol) when a 5% tea tree oil formulation is applied at a finite dosing regimen. Permeation kinetics were studied in vitro on pig ear skin using conventional static glass Franz diffusion cells and cells ad hoc modified to monitor the release of markers into the atmosphere. Formulation, receiving phases, and skin layers were analyzed using a fully automatic and solvent-free method based on headspace solid-phase microextraction/gas chromatography-mass spectrometry. This approach affords, for the first time, to quantify tea tree oil markers in the different skin layers while avoiding using solvents and overcoming the existing methods based on solvent extraction. The skin layers contained less than 1% of each tea tree oil marker in total. Only oxygenated terpenes significantly permeated across the skin, while hydrocarbons were only absorbed at trace level. Substantial amounts of markers were released into the atmosphere.

Headspace nanofiber sheet microextraction together with GC-MS and chemometrics resolution techniques were implemented to separate and identify the volatiles emitted by intact marjoram (Origanum majorana L.) and their relative concentrations. A novel polyaniline-nylon-6 nanofiber composite was applied for headspace microextraction. Characteristics such as high surface-to-volume ratio and π-π functional groups in polyaniline together with the NH and C=O functional groups in nylon-6 make the polyaniline-nylon-6 nanofiber composite a suitable candidate for the extraction of volatiles and semivolatiles. The extracted constituents were desorbed and injected into the GC-MS system under the optimum conditions. Chemometric resolution techniques were utilized to solve the baseline offset, asymmetric peaks, and overlapped peaks problems that arise from GC-MS analysis. By means of these techniques and resolving the overlapped peak clusters, the number of identified constituents was increased to 67 compounds. The major released constituents from the intact marjoram leaves are 4-terpineol, β-linalool, cis-sabinol, and trans-geraniol.

The relationships between physicochemical parameters of majority components of Eucalyptus essential oils and their insecticide effect were evaluated on Aedes aegypti (L.) (Diptera: Culicidae). The octanol-water partition coefficients of the monoterpenes were estimated by the atom/fragment contribution method and the vapor pressures were determined by our laboratory in previous studies. The larvicidal activity (LC50 (ppm)) and knockdown effect (KT50 (min)) of each component was determined. The results show that the toxicity of EOs main components of Eucalyptus on adults and larvae of A. aegypti is strongly related to their physicochemical properties (vapor pressure and Log P). However, the interaction of both variables (vapor pressure * Log P) explains the toxicological phenomenon more precisely. The regression models were expressed as follows: KT 50(min) =  - 10.9 + 3.7 * Log P + 1.9 * 1/Pvapor (R(2) = 0.80; F = 42.5) and LC 50(ppm) =  - 94.3 + 438.6 *  1/Log P + 2.8 *  1/Pvapor (F = 57.8; R(2) = 0.85). The six evaluated components present different functional groups. Therefore, it was considered to evaluate the monoterpenes as a group and separated in two groups: oxygenated monoterpenes (α-terpineol, 4-terpineol, and 1,8-cineole) and terpene hydrocarbons (γ-terpinene, p-cymene, and α-pinene). The results show the regression models for each group as follows: (A) oxygenated terpenes: KT 50(min) = - 515.3 + 1613.2 * 1/Log P + 5, 2 * 1/Pvapor (F = 3176.7 R(2) = 0.99) and LC 50(ppm)  =  - 1679.4 + 5402.1 * 1/Log P + 12.7 *  1/Pvapor (F = 282.9; R(2) = 0.99). (B) Hydrocarbons terpenes: KT 50(min) = 18.2 - 58.3 * 1/Log P + 2.7 * 1/Pvapor (F = 171.7;  R(2) = 0.97) and LC 50(ppm) = - 21.1 + 174.9 * 1/Log P - 14.3 * 1/Pvapor (F = 410.0; R(2) = 0.99). The association between the toxic effect of the evaluated monoterpenes against A. aegypti and the physicochemical properties can be better described when they are separated into functional groups (hydrocarbons vs. oxygenated terpenes).