Geranic Acid Research Articles

Choline geranate (CAGE): A multifaceted ionic liquid for drug delivery

Ionic liquids, organic salts in a liquid state below 100 °C, have traditionally been associated with industrial applications. Recent research has introduced a new generation of ionic liquids, designed from biocompatible ions, to enable applications in drug delivery. Here, I provide a historical perspective, development status and applications of a leading example of biocompatible ionic liquids, a salt of Choline And Geranic acid (CAGE). Since its first report in 2014, CAGE has opened multiple drug delivery applications including transdermal, oral, buccal, sustained release, tissue ablation, periodontitis and hand hygiene, among others. CAGE-based products have been tested in more than 200 patients through multiple Phase 1 and Phase 2 clinical studies, including successful use in a Phase 2 clinical study in Atopic Dermatitis patients. CAGE became the first ‘drug delivery ionic liquid’ to enter into clinical trials. This article summarizes the key fundamental and translational aspects of CAGE as pertained to its use in drug delivery.

Phenolic content, volatile composition and sensory profile of red wines macerated with toasted woods from different South American botanical species

The use of wood species from South American origin was not previously considered for wine aging. Thus, this work focuses on the comparative analysis of phenolic content, volatile composition and sensory characteristics of a red wine macerated with woods, in form of toasted cubes, from jequitibá, jaqueira, ipê, amburana and lenga species. All wines macerated with these woods showed a tendency for an increase of the phenolic parameters evaluated. This tendency was more evident in wine chromatic characteristics, especially for the wine macerated with jequitibá wood, where significantly higher color intensity and total color difference values was detected. For volatile composition, the different wood species induced significant changes on wine volatile profile. Thus, 3-hydroxy-4-phenyl-2-butanone was only detected in wine macerated with jaqueira wood, while benzophenone, ethyl pentadecanoate, D-citronellol, linalool, geranic acid and isovainillic acid were only detected in wine macerated with amburana wood. For sensory profile, wine macerated with amburana wood showed significantly higher scores for “coconut”, “toasted” and “floral” aroma descriptors, while for taste and overall appreciation this wine also showed a tendency for a slightly higher score. The outcomes of this research improved the knowledge of the use of several South American wood species on red wine characteristics.

Development of biocatalysts for high-value-added compounds.

High-value-added compounds, such as monoterpenoids, are an important industrial targets because they are an essential group of compounds for pharmaceutical and industrial applications. Meanwhile, the depletion of natural resources and climate change demands sustainable production methods. In recent years, biocatalysis, which allows microbial bioproduction by regio- and stereo-selective reaction under mild conditions, has been attracted researchers' attention as a possible alternative to conventional methods. In this mini-review, we focus on the identification of biotransformation pathways in the non-model microorganism Acinetobacter sp. Tol 5 using geraniol, a representative monoterpenoid, and on the construction of an unconventional bioproduction method for high-value-added monoterpenoid (E)-geranic acid, which has great potential for industrial applications. This method offers a more environmentally friendly approach and insights contribute to optimizing biotransformation and bioproduction strategies for high-value-added compounds.

Mechanism and performance of choline-based ionic liquids in enhancing nasal delivery of glucagon

Proteins and peptides have been increasingly developed as pharmaceuticals owing to their high potency and low side effects. However, their administration routes are confined to injections, such as intra-muscular and intra-venous injections, making patient compliance a challenge. Hence, non-injectable delivery systems are crucial to expanding the clinical use of proteins and peptides. In this context, two choline-based ionic liquids (ILs), namely, choline geranic acid ([Ch][Ger]) and choline citric acid ([Ch][Cit]), have been identified as promising agents for enhancing the permeation and prolonging the retention time of glucagon (GC) after intra-nasal administration. Notably, intra-nasal delivery of GC via ILs (GC/ILs) elicited rapid and smooth reversal of acute hypoglycaemia without leading to rebound hyperglycaemia in type 1 diabetic rats subjected to insulin induction. In addition, ILs could improve the transcellular transport of GC through electrostatic interaction. ILs could also transiently open inter-cellular tight junctions transiently to facilitate the paracellular transport of GC. Safety tests indicated that continuous intra-nasal delivery of ILs led to reversible changes, such as epithelial cell inflammation, goblet cell overgrowth, and impacts on the distribution of nasal cilia. However, these changes could be alleviated by the innate self-repair ability of mucosal epithelial cells. This study highlights the considerable potential of ILs for long-term nasal delivery of biomacromolecules.

Ionic Liquid-Mediated Transdermal Delivery of Organogel Containing Cyclosporine A for the Effective Treatment of Psoriasis.

The dermal delivery of peptide therapeutics that are of high molecular weight is a challenge. Cyclosporine A (CsA) is a cyclic undecapeptide with poor aqueous solubility and high molecular weight (1202 Da) indicated for psoriasis. The objective of the study was to evaluate the effect of ionic liquids mixed with the Pluronic F127 matrix in skin permeation of CsA and its efficacy in psoriasis treatment. Choline and geranic acid (CAGE) ionic liquids in a 1:2 molar ratio were mixed with Pluronic F127 (22.7%) and PEG 400 (45%) to prepare an organogel formulation. The CsA-loaded CAGE (CsA-CAGE) and CAGE-Pluronic F127 gels (CsA-CAGE-P gel) were characterized for physical and rheological characteristics. The skin transport studies showed that free CsA did not permeate across the excised porcine skin after 48 h. The amount of CsA permeated across the oleic acid (0.25% v/v) and palmitic acid (0.25% w/v) cotreated skin was found to be 244 ± 4 and 1236 ± 17 μg/cm2, respectively. The application of CsA-CAGE and CsA-CAGE-P gel enhanced CsA flux by 110- and 135-fold, respectively, compared with the control. The thermal analysis and biophysical studies changed the barrier property of the skin significantly (p < 0.05) after incubation with CAGE and CAGE-P gel. The pharmacokinetic studies in the rat model showed that topical application of CsA-CAGE-P gel provided 2.6- and 1.9-fold greater C max and AUC0-t, respectively, compared to the control group. In vitro-in vivo level A correlations were established with R 2 values of 0.991 and 0.992 for both linear and polynomial equations for the CsA-CAGE-P gel formulation using the Wagner-Nelson method. The topical application of CsA-CAGE-P gel (10 mg/kg) on an imiquimod-induced plaque psoriatic model reduced the area of the psoriasis and severity index (PASI) score significantly for erythema and scaling, reversing the changes to skin thickness, blood flow rate, and transepidermal water loss. Together, CAGE-Pluronic F127 organogel was developed as an effective topical formulation for the local and systemic delivery of CsA for the treatment of psoriasis.

Biotransformation of Geraniol to Geranic Acid Using Fungus Mucor irregularis IIIMF4011.

Geraniol is an important component in essential oils of aromatic plants such as lemongrass, rosa grass, and many others. It can be converted to different high-value products by using microbes/enzymes. The present study aims at the isolation and screening of microbes showing efficient production of geranic acid (a high-value product) from geraniol (a low-value monoterpene). Mucor irregularis IIIMF4011, isolated from the soil sample of Cymbopogon citratus (Lemongrass), showed biotransformation of geraniol to geranic acid. After optimization of reaction parameters, 97-100% conversion of geraniol to geranic acid was obtained after 72 h of incubation at 28 °C. Furthermore, the biotransformation reaction was also carried out in a 3 L fermentor (working volume 1.5 L), and 98.89% conversion was observed. Therefore, an efficient process of geranic acid production using M. irregularis IIIMF4011 was developed.

In vitro and In silico studies of terpenes extracted from Cymbopogon flexuous leaves against human myeloid leukemia as an inhibitor of NF-κB activation signaling pathway

Despite recent progress in treating myeloid leukemia (ML) challenges such as the emergence of drug resistance and the persistence of minimal residual disease pose significant obstacles in treating these patients. This highlights the importance of devising novel and innovative strategies to enhance therapeutic outcomes. Citral, myrcene and geranic acid are the major bio-actives of Cymbopogon flexuosus volatile oil (CFVO) that possess strong anticancer potential. This study explored the cytotoxic potential, chemical profiling, and the inhibitory effect of CFVO on nuclear factor-κB (NF-κB) activation pathways. The 3-(4–5-dimethylthiazol-2- yl) 2–5-diphenyl-tetrazolium (MTT) protocol was employed to assess the cell viability. Flow cytometry analysis was performed for assessing the cell cycle and conducting apoptosis assays. Western blot analysis showed that CFVO triggered apoptosis in cancer cells via activating caspases which led to proteolysis of poly ADP ribose polymerase (PARP). Furthermore, electrophoretic mobility shift assay (EMSA) showed that CFVO was capable of suppressing the activation of NF-kB triggered by TNF-α and also resulted in decrease in NF-κB-dependent proteins such as antiapoptotic(cFLIP, Bcl-xL and XIAP) proliferative (Cyclin E1, Cyclin D, C-myc) and invasion (ICAM-1) proteins. Our in sililco study also revealed the binding of anticancer phytochemicals with the P50 protein of NF-kB that favors the downregulation of this protein. Inclusively CFVO inhibits the proliferation and metastasis of tumor cells and we can suggest that it will be an effective therapy in fighting against cancer.

Prostate tissue ablation and drug delivery by an image-guided injectable ionic liquid in ex vivo and in vivo models.

Benign prostatic hyperplasia and prostate cancer are often associated with lower urinary tract symptoms, which can severely affect patient quality of life. To address this challenge, we developed and optimized an injectable compound, prostate ablation and drug delivery agent (PADA), for percutaneous prostate tissue ablation and concurrently delivered therapeutic agents. PADA is an ionic liquid composed of choline and geranic acid mixed with anticancer therapeutics and a contrast agent. The PADA formulation was optimized for mechanical properties compatible with hand injection, diffusion capability, cytotoxicity against prostate cells, and visibility of an x-ray contrast agent. PADA also exhibited antibacterial properties against highly resistant clinically isolated bacteria in vitro. Ultrasound-guided injection, dispersion of PADA in the tissue, and tissue ablation were tested ex vivo in healthy porcine, canine, and human prostates and in freshly resected human tumors. In vivo testing was conducted in a murine subcutaneous tumor model and in the canine prostate. In all models, PADA decreased the number of viable cells in the region of dispersion and supported the delivery of nivolumab throughout a portion of the tissue. In canine survival experiments, there were no adverse events and no impact on urination. The injection approach was easy to perform under ultrasound guidance and produced a localized effect with a favorable safety profile. These findings suggest that PADA is a promising therapeutic prostate ablation strategy to treat lower urinary tract symptoms.

Aromatic Characterisation of Moscato Giallo by GC-MS/MS and Validation of Stable Isotopic Ratio Analysis of the Major Volatile Compounds.

Among the Moscato grapes, Moscato Giallo is a winegrape variety characterised by a high content of free and glycosylated monoterpenoids, which gives wines very intense notes of ripe fruit and flowers. The aromatic bouquet of Moscato Giallo is strongly influenced by the high concentration of linalool, geraniol, linalool oxides, limonene, α-terpineol, citronellol, hotrienol, diendiols, trans/cis-8-hydroxy linalool, geranic acid and myrcene, that give citrus, rose, and peach notes. Except for quali-quantitative analysis, no investigations regarding the isotopic values of the target volatile compounds in grapes and wines are documented in the literature. Nevertheless, the analysis of the stable isotope ratio represents a modern and powerful tool used by the laboratories responsible for official consumer protection, for food quality and genuineness assessment. To this aim, the aromatic compounds extracted from grapes and wine were analysed both by GC-MS/MS, to define the aroma profiles, and by GC-C/Py-IRMS, for a preliminary isotope compound-specific investigation. Seventeen samples of Moscato Giallo grapes were collected during the harvest season in 2021 from two Italian regions renowned for the cultivation of this aromatic variety, Trentino Alto Adige and Veneto, and the corresponding wines were produced at micro-winery scale. The GC-MS/MS analysis confirmed the presence of the typical terpenoids both in glycosylated and free forms, responsible for the characteristic aroma of the Moscato Giallo variety, while the compound-specific isotope ratio analysis allowed us to determine the carbon (δ13C) and hydrogen (δ2H) isotopic signatures of the major volatile compounds for the first time.

The mechanism of low temperature enhances dough aromas during fermentation by Pichia kudriavzevii: Sugar and amino acid metabolism, acid utilization and alcohol production

In order to investigate the impact of low temperature on enhancing aromas in fermented dough by Pichia kudriavzevii CGMCC 17607 (EP), the study initially utilized gas chromatography to detect volatile organic compounds (VOCs), followed by analyzing basal metabolites derived from these VOCs. Metabolomics was employed to monitor metabolic changes during fermentation, while proteomics was used to examine protein expression related to these changes. Results indicated notable increases in VOCs such as 3-methyl-1-butanol and 2-phenylethanol. Essential metabolites exhibited decreases in sugars (e.g., sucrose, maltose), organic acids (e.g., lactic acid, acetic acid), and amino acids (e.g., leucine, histidine). Particularly, low temperature fermentation led to raised levels of NAD+, NADH, acyltransferases, and ATP, excluding pyruvic acid and glucose-6-phosphate dehydrogenase. These outcomes suggested that low temperature fermentation boosted acid utilization and alcohol production. Metabolomics and proteomics highlighted decreased glycolysis influencing energy metabolism. Moreover, metabolomics revealed elevated levels of flavor substances like octanoic acid and its derivatives with aromatic properties, as well as geranic acid with terpenoid aroma. Furthermore, key intermediates like chorismite and phenylpyruvic acid, along with the pivotal enzyme chorismate synthase, illustrated the biosynthesis pathway of shikimic acid instead of phenylalanine. In summary, at low temperature, EP showed weakened glycolysis, with sugars and amino acids metabolizing into desirable flavor substances like alcohols, which promoted acidity reduction and aroma enhancement of dough.

Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III.

Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to identify metabolic markers in the cerebrospinal fluid (CSF) of children with SMA types II and III. CSF samples were collected from 40 patients with SMA (27 with type II and 13 with type III) and analyzed for metabolites. We identified 135 metabolites associated with SMA types II and III. These were associated with lysine degradation and arginine, proline, and tyrosine metabolism. We identified seven metabolites associated with the Hammersmith Functional Motor Scale: 4-chlorophenylacetic acid, adb-chminaca,(+/-)-, dodecyl benzenesulfonic acid, norethindrone acetate, 4-(undecan-5-yl) benzene-1-sulfonic acid, dihydromaleimide beta-d-glucoside, and cinobufagin. Potential typing biomarkers, N-cyclohexylformamide, cinobufagin, cotinine glucuronide, N-myristoyl arginine, 4-chlorophenylacetic acid, geranic acid, 4-(undecan-5-yl) benzene, and 7,8-diamino pelargonate, showed good predictive performance. Among these, N-myristoyl arginine was unaffected by the gene phenotype. This study identified metabolic markers are promising candidate prognostic factors for SMA. We also identified the metabolic pathways associated with the severity of SMA. These assessments can help predict the outcomes of screening SMA classification biomarkers.

The Development and Characterization of Novel Ionic Liquids Based on Mono- and Dicarboxylates with Meglumine for Drug Solubilizers and Skin Permeation Enhancers.

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid-base neutralization reactions. The successful synthesis was validated by attenuated total reflection-Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of -43.4 °C--13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs.

Production of geraniol and geranic acid: High value compounds of citral biosynthetic pathway from lemongrass oil using Aspergillus niger AUD-C2 as catalyst

Microbial biotransformation of lemongrass oil to geraniol and geranic acid, high value compounds of citral biosynthetic pathway has been reported. Biotransformation studies were carried out using a fungus Aspergillus niger strain AUD-C2 isolated from the rhizospheric soil of lemongrass, as catalyst. Three different methodologies using culture broth, spore suspension and cell-free extract, have been utilized for biotransformation and successfully demonstrated at litre scale in bioreactors. Overall 55% geraniol and 75% geranic acid were obtained by biotransformation of lemongrass oil in 48 h using spore suspension and cell free extract, respectively.

Efeito do óleo essencial de Mentha piperita na conservação de carne refrigerada do peixe híbrido tambatinga

Abstract The search for safer foods has led to increased research attention to discover natural alternatives to synthetic additives that are used in the food industry. Natural preservatives, such as essential oils (EOs) from plants, could increase fish conservation and even positively affect human health. Therefore, the objective of the study was to evaluate the effect of Mentha piperita EO on the physicochemical characteristics and concentration of microorganisms in chilled tambatinga (Colossoma macropomum × Piaractus brachypomum) meat. Mentha piperita EO was prepared at three concentrations (0%, 0.25% and 0.50%) in a solution containing distilled water, propylene glycol and Tween. The meat samples remained immersed in this solution for 60 min; then, they were packed in plastic packages and stored under refrigeration (± 0.4 °C) for 14 days. During this storage, pH, total volatile nitrogenous bases (TVB-N), peroxides, thiobarbituric acid reactive substances (TBARS) and counts of strict and facultative aerobic mesophilic microorganisms were determined. The major constituents found in M. piperita EO were geranial (32.28%), neral (18.64%) and geranic acid (6.98%). None of the EO concentrations affected TVB-N, but there were some changes to the pH. Both 0.25% and 0.50% EO reduced the formation of peroxides and TBARS. The growth of microorganisms was reduced by treatment with 0.50% EO. Based on the findings, 0.50% EO was more effective in reducing the deterioration of meat kept refrigerated for up to 14 days.

Levofloxacin-Fatty Acid Systems: Dual Enhancement Through Deep Eutectic Formation and Solubilization for Pharmaceutical Potential and Antibacterial Activity.

Fatty acids, including medium-chain saturated and polyunsaturated fatty acids, are known for their broad health benefits, including antimicrobial activity. Through their green properties, deep eutectic systems have been heralded as having the potential to be at the forefront of pharmaceutical applications. In this work, capric acid and geranic acid, two examples of medium-chain saturated and polyunsaturated fatty acids, were employed to enhance the pharmaceutical properties and the antibacterial activity of levofloxacin. To this end, levofloxacin formulations with either capric or geranic acid were prepared and characterized using appropriate techniques. Levofloxacin was utilized to create innovative deep eutectic systems in conjunction with capric acid at three different molar ratios: 1:9, 2:8 and 3:7. This was confirmed through a rigorous analysis involving nuclear magnetic resonance, infrared spectroscopy and differential scanning calorimetry. Furthermore, it is noteworthy that geranic acid demonstrated an impressive threefold improvement in levofloxacin's solubility compared to its solubility in aqueous solutions. The antibacterial activity of the novel combinations of levofloxacin with either fatty acid was evaluated using a checkerboard titration assay. Gratifyingly, both formulations exhibited synergistic effects against a panel of levofloxacin-sensitive and resistant Gram-negative bacteria. In conclusion, the observed superior antibacterial activity of levofloxacin illuminates the potential use of fatty acid-based formulations and deep eutectic systems as green and innovative strategies to combat the global antimicrobial resistance problem.

Interesting Behavior of Geranic Acid during the Beer Brewing Process: Why Could Geranic Acid Remain at a Higher Level Only in the Beer Using Sorachi Ace Hops?

Hops are among the most important ingredients in beer that contribute to beer flavor. Consequently, novel types of hops have been bred and widely used worldwide. For example, the Sorachi Ace hop imparts characteristic varietal aromas, including woody, pine-like, citrus, dill-like, and lemongrass-like aromas, to the finished beer. In our previous study, the unique volatile compound geranic acid was significantly detected only in the test beer brewed with the Sorachi Ace hop; moreover, the coexistence of geranic acid and other hop-derived flavor compounds could result in the characteristic aroma of the Sorachi Ace beers. In this study, selected hop-derived flavor compounds, including geranic acid, were compared among 17 hop varieties. The geranic acid content in the Sorachi Ace hop was the highest among the studied hops. We also investigated the behavior of geranic acid and related flavor compounds throughout the fermentation process. The content of geranic acid was higher than those of the other compounds during fermentation. Next, we compared the concentrations of these compounds in kettle-, late-, and dry-hopped beers using Sorachi Ace hop. The results revealed that geranic acid remained at higher concentrations from the worts to finished beers despite the decrease in the content of other hop-derived flavor compounds as a result of evaporation and/or other factors during brewing. Further, geranic acid could remain at high levels in the test-brewed beers with Sorachi Ace hops because of its behavior as an acid throughout the brewing process, including during wort boiling and fermentation.

Human Metabolism and Urinary Elimination Kinetics of the Fragrance Geraniol after Oral Dosage.

Geraniol is a fragrance with a characteristic rose-like smell, naturally occurring in terpene oil and also chemically synthesized on a large scale. Geraniol is widely used in consumer products such as cosmetics, personal care products, and household cleaners and as an additive in foods. An experimental study in human volunteers was carried out to investigate the metabolism and elimination kinetics of geraniol. Three subjects were orally exposed to geraniol in two different dosages (25 or 250 mg). In each case, one pre-exposure urine sample and all urine voids for 72 h after exposure were collected separately. The geraniol metabolites Hildebrandt acid, geranic acid, 3-hydroxycitronellic acid, and 8-carboxygeraniol were analyzed in every sample after enzymatic hydrolysis and liquid-liquid extraction using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Maximum urinary concentrations of the metabolites were measured between 1 and 5 h after oral dosing, and elimination half-lives were determined to be about 2-4 h. The predominant metabolite found in urine was Hildebrandt acid with 34.4 ± 5.6% of the ingested dose, followed by geranic acid (12.7 ± 5.6%), 3-hydroxycitronellic acid (2.2 ± 0.4%), and 8-carboxygeraniol (0.19 ± 0.09%). In total, the four metabolites determined represent 41.7-55.5% of the ingested dose. Only 8-carboxygeraniol is, however, a specific metabolite, while the other three target analytes are also formed from other terpenes like citral. Within this study, conversion factors were calculated, which allow for a rough estimate of the total geraniol uptake by back-calculation from metabolite concentrations of spot urine samples. Taking the conversion factor for all four metabolites into account, a mean daily uptake of geraniol of 1.43 mg was estimated from 41 urine samples of occupationally nonexposed adults. The metabolites Hildebrandt acid, geranic acid, 3-hydroxycitronellic acid, and 8-carboxygeraniol in urine are suitable biomarkers of exposure for geraniol and can be used for human biomonitoring studies.

Effect of different drying methods on color difference, microorganisms and volatile metabolites profiles of Ganpu Tea

In this study, sunlight drying, low temperature drying and hot air drying were used to investigate the effects of different drying methods on color difference, microorganisms and volatile metabolites profiles of Ganpu Tea. The results suggested that the L*, a* and b* values of sunlight drying Ganpu Tea (GPTS) in the traditional drying process were significantly lower than those of low temperature drying Ganpu Tea (GPTL) and hot air drying Ganpu Tea (GPTH). It indicated that sunlight drying could decrease the lightness, redness and yellowness values compared with low temperature drying and hot air drying. 16S rDNA amplicon sequencing analysis showed that GPTS, compared with GPTL and GPTH, significantly increased the abundances of Cyanobacteria while significantly decreasing the abundances of Staphylococcus, Bacillus, Brevibacterium and Brachybacterium. At the genus level, Cyanobacteria was the core functional flora in GPTS, while Brevibacterium and Staphylococcus were the core functional flora in GPTL, and Bacillus was the core functional flora in GPTS. In addition, volatile metabolites profile analysis showed that GPTS significantly increased the volatile metabolites levels of Butanoic acid, 3-hexenyl ester, (E)- and Geranic acid compared with GPTL and GPTH. The research on the effects of different drying methods on the aroma, microorganisms and color of Ganpu tea would provide new strategies for improving the quality and enhancing the aroma of Ganpu Tea.

Interactions of Choline and Geranate (CAGE) and Choline Octanoate (CAOT) Deep Eutectic Solvents with Lipid Bilayers

AbstractMixtures between choline and geranic acid (CAGE) have previously been shown to insert into lipid bilayers. This may be useful for the transdermal delivery of larger pharmaceuticals, however, little is known about the mechanism of activity. By comparing the interactions between CAGE and lipid bilayers with those of a less‐active, yet closely‐related analogue, choline octanoic acid (CAOT), a chemical basis can be investigated. Overall, six systems are studied here by neutron reflectivity, where d54‐1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) solid‐supported phospholipid bilayers are first formed on SiO2 substrates before exposure to the deep eutectic solvent (DES). Components of the DES could be identified within the bilayer by exploiting contrast variation and selective deuteration. CAGE is shown to be a mild disruptive agent, free to insert and diffuse across the bilayer, preserving much of the bilayer integrity. Experiments identify co‐mingling of geranate ions inhibits the efficient packing of lipid tails, increasing hydration across the bilayer. Conversely, CAOT is found to both exchange and remove lipid molecules to achieve incorporation, inducing swelling and the formation of solvent patches. It appears these behaviors derive from the structures of the anions and thus amphiphilicity of the DES, laying the foundations for the rational design and optimization of these candidates toward transdermal delivery.

Ligand-independent Activation of Aryl Hydrocarbon Receptor and Attenuation of Glutamine Levels by Natural Deep Eutectic Solvent.

Natural deep eutectic solvents (NADESs) are emerging sustainable alternatives to conventional organic solvents. Beyond their role as laboratory solvents, NADESs are increasingly explored in drug delivery and as therapeutics. Their increasing applications notwithstanding, our understanding of how they interact with biomolecules at multiple levels - metabolome, proteome, and transcriptome - within human cell remain poor. Here, we deploy integrated metabolomics, proteomics, and transcriptomics to probe how NADESs perturb the molecular landscape of human cells. In a human cell line model, we found that an archetypal NADES derived from choline and geranic acid (CAGE) significantly altered the metabolome, proteome, and transcriptome. CAGE upregulated indole-3-lactic acid and 4-hydroxyphenyllactic acid levels, resulting in ligand-independent activation of aryl hydrocarbon receptor to signal the transcription of genes with implications for inflammation, immunomodulation, cell development, and chemical detoxification. Further, treating the cell line with CAGE downregulated glutamine biosynthesis, a nutrient rapidly proliferating cancer cells require. The ability of CAGE to attenuate glutamine levels is potentially relevant for cancer treatment. These findings suggest that NADESs, even when derived from natural components like choline, can indirectly modulate cell biology at multiple levels, expanding their applications beyond chemistry to biomedicine and biotechnology.