Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation.

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity. OBJECTIVES: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-(hCGα) and beta-subunits (hCGß), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex. METHODS: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression. RESULTS: Perfluorohexane sulfonic acid (PFHxS) [hCGß: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: -0.09; 95% CI: -0.16, -0.02) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with hCGα and positively with hCGß. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with hCGß only in Black participants (-0.23; 95% CI: -0.37, -0.09) and in participants with high school education or less (-0.14; 95% CI: -0.26, -0.02); conversely, perfluorononanoic acid (PFNA) was negatively associated with hCGα only in White participants (-0.15; 95% CI: -0.27, -0.03) and with hCGß only in participants with a college education or greater (-0.19; 95% CI: -0.36, -0.01). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was <100%. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with hCGα, and PFNA with h-hCG. CONCLUSIONS: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with hCGα and hCGß differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

Parallel electromembrane extraction of peptides with monoterpene and medium-length fatty acid deep eutectic solvents.

BACKGROUND: Electromembrane extraction (EME) involves the process of mass transfer of charged analytes from an aqueous sample through an organic liquid membrane into an aqueous acceptor medium under the influence of an electrical field. Successful solvation of the analyte within the liquid membrane is of paramount importance and involves molecular interactions with the liquid membrane. In this comprehensive investigation, parallel EME was examined using a training set of 13 model peptides employing deep eutectic solvents as the liquid membrane. These deep eutectic solvents were formulated by mixing specific monoterpenes (thymol, menthol, camphor) with medium-chain fatty acids (1-octanoic acid and 1-decanoic acid). RESULTS: From an array of different liquid membrane compositions explored, it was revealed that the combination of camphor and 1-decanoic acid (in a 1:1 w/w ratio) with 2% di (2-ethylhexyl) phosphate (DEHP) delivered the most efficient extraction system. The solvation of the model peptides within this liquid membrane predominantly relied on ionic interactions between protonated basic functionalities and DEHP, along with hydrogen bond interactions between the deprotonated acid functionalities (hydrogen bond acceptor) and 1-decanoic acid (hydrogen bond donor). Selectivity was modulated by the pH of the sample and acceptor solutions, with a direct correlation to the polarity and net charge of the model peptides. The ionization of 1-decanoic acid in the interfacial region between the sample and liquid membrane emerged as an important factor influencing the selectivity. SIGNIFICANCE AND NOVELTY: Although parallel EME of peptides has been reported previously, the current liquid membrane provides an extraction system with sufficient stability for the first time. Selective extraction of peptides through EME holds substantial promise within the realm of next-generation environmentally-friendly sample preparation methodologies. The findings presented in this paper contribute significantly to our fundamental understanding of these processes, and may serve as an important reference for the development of future methods in this field.

The interaction of perfluoroalkyl acids and a family history of diabetes on arthritis: analyses of 2011-2018 NHANES.

Whether a family history of diabetes (FHD) and exposure to perfluoroalkyl acids (PFAAs) are correlated with an increased risk of developing arthritis remains unclear. This cross-sectional study was conducted to explore the correlations between FHD or exposure to PFAAs and arthritis as well as their interaction using the National Health and Nutrition Examination Survey (NHANES). In total, 6,194 participants aged ≥ 20 years from the 2011-2018 NHANES were enrolled. PFAAs are a cluster of synthetic chemicals, including perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS). FHD was evaluated using self-reported questionnaires. Arthritis was classified into three types, rheumatoid arthritis (RA), osteoarthritis (OA), and others, which were diagnosed using questionnaires. Generalized linear models (GLMs) were used to test the correlation between FHD and arthritis. To examine the joint effects of PFAAs and FHD on arthritis, interaction terms were applied in the GLM. Arthritis incidence was 26.7% among all participants. FHD was associated with both RA [OR = 1.70 (95% CI: 1.15-2.50)] and other types of arthritis [OR = 1.62 (95% CI: 1.21-2.16)]. However, the relationship between FHD and OA was not significant after adjustment (P = 0.18). Interaction outcomes indicated that higher PFDA levels increased the association between FHD and arthritis. FHD is associated with an increased incidence of arthritis, which may be increased by PFDA. Given the heavy burden of arthritis, preventive measures for arthritis and reduction of PFAAs exposure for patients with FHD are required.

No Effects of Decanoic Acid on Locomotor Activity and Antioxidant Defences in an Experimental Animal Model of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Medium-chain triglycerides such as decanoic acid (C10), which is one of the fatty acids that constitute dietary fats, are of substantial interest for their potential therapeutic effects on neuropsychiatric disorders. However, the effects of C10 on attention-deficit/hyperactivity disorder (ADHD) remain to be studied. We explored the effects of C10 on behavioural activity and antioxidant defences in an experimental animal model of ADHD. METHODS: To establish an experimental animal model of ADHD, neonatal rats were subjected to unilateral striatal lesions using 6-hydroxydopamine (6-OHDA). The rats sequentially underwent open-field and Y-maze tests before treatment [postnatal day 25 (PN25)]. After the subcutaneous administration of either vehicle or C10 solution (250 mg/kg) for 14 days, the behavioural tests were repeated on PN39. Next, we examined the effects of C10 on the expression of the constitutive antioxidant enzymes catalase and glutathione peroxidase-1/2 and the phase II transcription factor nuclear factor erythroid 2-related factor 2 in four different regions of the rat brain. RESULTS: Injection of 6-OHDA unilaterally into the striatum resulted in elevated locomotor activity on PN39. The administration of C10 for a period of 14 days did not alter the locomotor hyperactivity. Moreover, the administration of C10 had no significant effects on the expression of proteins related to antioxidant defences in the hippocampus, prefrontal cortex, striatum or cerebellum of both control and lesioned rats. CONCLUSIONS: The lack of significant effects of C10 in our study may depend on the dose and duration of C10 administration. Further exhaustive studies are needed to verify the efficacy and effects of different doses and treatment durations of C10 and to explore the underlying mechanisms.

[Determination of seven perfluoroalkyl and polyfluoroalkyl substances in serum of pregnant women and evaluation of neonatal neurobehavior based on high performance liquid chromatography-tandem mass spectrometry].

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been extensively used as synthetic fluorine-containing compounds in various consumer products, including surfactants, cookware, lubricants, clothing, and food packaging, since the 1950s. Evidence has shown that PFASs cross the placental barrier and interfere with fetal thyroid hormone homeostasis, which is crucial for fetal growth and neurobehavioral development in children aged 2-9 years. However, no epidemiological data on the association between prenatal PFAS exposure and neonatal neurobehavioral development are available. In this study, we explored the association between prenatal PFAS exposure and neonatal neurobehavioral development based on the Ezhou cohort study. Blood samples (10 mL) were collected during the third trimester of pregnancy (28-36 weeks) at the Ezhou maternal and child health hospital. The blood specimens were centrifuged at 4000 r/min for 15 min immediately after collection, separated, stored at -80 ℃. The samples were analyzed for seven PFASs, namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonamide (PFOSA). The PFASs were separated using a C18 column (100 mm×2.1 mm, 1.7 µm) at an oven temperature of 40 ℃, injection volume of 10 µL, and flow rate of 0.4 mL/min via gradient elution with methanol and ammonium acetate aqueous solution. The instrument was operated in negative electrospray ionization mode with multiple reaction monitoring. The correlation coefficients (r2), limits of detection (LODs) and quantification (LOQs), and spiked recoveries of the seven PFASs were 0.993-0.999, 0.006-0.020 ng/mL, 0.020-0.066 ng/mL, and 84.6%-116.8%, respectively. Neonatal behavioral neurological assessment (NBNA) was used to evaluate newborn cognitive development 72 h after birth; this tool consisted of five clusters, including behavior (six items), passive muscle tone (four items), active muscle tone (four items), primitive reflexes (three items), and general assessment (three items). Each item was rated on a three-point scale (0, 1, or 2), with the 20 items having a maximum score of 40. A total of 379 mother-newborn pairs were included in the analysis. The PFASs with the highest exposure levels was PFOA, with median levels of 19.4 ng/mL. Linear regression models were used to test the effects of ln-converted PFAS levels in newborns. After adjusting for confounding factors, the linear regression model showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(ß(95% CI): 0.36(-0.64, 0.08)) and general assessment(ß(95% CI): 0.34(-0.61, 0.07)) in all newborns. Furthermore, PFNA exposure was associated with decreased passive muscle tone(ß(95% CI): 0.38(-0.74, 0.01)) and total NBNA(ß(95% CI): 0.37(-0.68, 0.06)). PFDA exposure was associated with decreased behavior(ß(95% CI): 0.28(-0.54, 0.01)), while PFHxS exposure was associated with elevated total NBNA(ß(95% CI): 0.27(0.05-0.48)). Gender stratification analysis showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(ß(95% CI): 0.54(-0.73, 0.35)) and general assessment(ß(95% CI): 0.50(-0.88, 0.13)), PFNA exposure during pregnancy was associated with decreased passive muscle tone(ß(95% CI): 0.67(-1.2, 0.14)) and total NBNA(ß(95% CI): 0.45(-0.91, 0.01)), PFDA exposure during pregnancy was associated with decreased behavior(ß(95% CI): 0.44(-0.71, 0.17)), PFHxS exposure was associated with elevated total NBNA(ß(95% CI): 0.41(0.02-0.80)) in male newborns, and PFOA exposure was associated with decreased general assessment(ß(95% CI): -0.27(-0.51, 0.02)), and PFDA exposure was associated with elevated behavior(ß(95% CI): 0.46(0.40-0.52)) in female newborns. The proposed method separates and detects various PFASs without the need for cumbersome pretreatment processes, and has the advantages of low LODs, satisfactory recoveries, and accurate precision. Thus, it allows for the simultaneous analysis of trace PFASs in microserum samples from pregnant women. Our results also showed that prenatal PFAS exposure can lead to neurobehavioral disorders in offspring, with male newborns showing greater sensitivity than female newborns.

Distinct bile acid alterations in response to a single administration of PFOA and PFDA in mice.

Per- and polyfluoroalkyl substances (PFASs), a group of synthetic chemicals that were once widely used for industrial purposes and in consumer products, are widely found in the environment and in human blood due to their extraordinary resistance to degradation. Once inside the body, PFASs can activate nuclear receptors such as PPARα and CAR. The present study aimed to investigate the impact of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) on liver structure and functions, as well as bile acid homeostasis in mice. A single administration of 0.1 mmole/kg of PFDA, not PFOA, elevated serum ALT and bilirubin levels and caused cholestasis in WT mice. PFDA increased total and various bile acid species in serum but decreased them in the liver. Furthermore, in mouse livers, PFDA, not PFOA, down-regulated mRNA expression of uptake transporters (Ntcp, Oatp1a1, 1a4, 1b2, and 2b1) but induced efflux transporters (Bcrp, Mdr2, and Mrp2-4). In addition, PFDA, not PFOA, decreased Cyp7a1, 7b1, 8b1, and 27a1 mRNA expression in mouse livers with concomitant hepatic accumulation of cholesterol. In contrast, in PPARα-null mice, PFDA did not increase serum ALT, bilirubin, or total bile acids, but produced prominent hepatosteatosis; and the observed PFDA-induced expression changes of transporters and Cyps in WT mice were largely attenuated or abolished. In CAR-null mice, the observed PFDA-induced bile acid alterations in WT mice were mostly sustained. These results indicate that, at the dose employed, PFDA has more negative effects than PFOA on liver function. PPARα appears to play a major role in mediating most of PFDA-induced effects, which were absent or attenuated in PPARα-null mice. Lack of PPARα, however, exacerbated hepatic steatosis. Our findings indicate separated roles of PPARα in mediating the adaptive responses to PFDA: protective against hepatosteatosis but exacerbating cholestasis.

Enzymatic production process of capric acid-rich structured lipids: Development of formulation as a new therapeutic approach.

The present work reports an optimization of the synthesis of MLM-type (medium, long, medium) structured lipids (SL) through an acidolysis reaction of grape seed oil with capric acid catalyzed by Rhizopus oryzae lipase immobilized. At first, tests were carried out by preparing the biocatalysts using enzyme loadings (0.15 to 1 g of enzymatic powder) for each gram of support. Enzyme loading was used 0.3 g of enzymatic powder, and hydrolytic activity of 1860 ± 23.4 IU/g was reached. Optimized conditions determined by the Central Composite Rotatable Design (CCRD) revealed that the acidolysis reaction reached approximately 59 % incorporation degree (%ID) after 24 h, in addition to the fact that the biocatalyst could maintain the incorporation degree in five consecutive cycles. From this high incorporation degree, cell viability assays were performed with murine fibroblast cell lines and human cervical adenocarcinoma cell lines. Concerning the cytotoxicity assays, the concentration of MLM-SL to 1.75 and 2 % v/v were able to induce cell death in 56 % and 64 % of adenocarcinoma cells, respectively. Human cervical adenocarcinoma cells showed greater sensitivity to the induction of cell death when using emulsions with MLM-SL > 1.75 % v/v compared to emulsions with lower content indicating a potential for combating carcinogenic cells.

Occurrence and pattern of legacy and emerging per- and Poly-FluoroAlkyl substances (PFAS) in eggs of loggerhead turtle Caretta caretta from western Mediterranean.

Per-and Poly-FluoroAlkyl Substances (PFAS) are a class of persistent, toxic, and mobile and chemicals both from industrial sources and from the use and disposal of Consumers products containing PFAS, whose concentration in marine food webs could pose a toxicological risk for biota and humans. In 2021, unhatched eggs were sampled from 41 loggerhead turtle Caretta caretta nests from the Italian shores of the Campania Region (Southern Italy). Whole eggs were analysed for the presence of 66 legacy and emerging PFAS with Liquid Chromatography coupled to Hybrid High Resolution Mass Spectrometry. A median Σ66 Per- and Poly-FluoroAlkyl Substances value of 3.34 ng/g egg fresh weight was found; perfluoroctane sulfonate (PFOS) represented the most contributing congener (47%), followed by perfluoro-n-undecanoic acid, perfluoro-n-tridecanoic acid, perfluoro-n-decanoic acid, perfluoro-n-decanoic acid, and perfluoro-n-tetradecanoic acid, respectively. Such compounds showed a log-norm distribution, suggesting found concentrations could represent the baseline levels in the considered sampling area. Emerging ChloroPolyFluoroPolyEthers Carboxylic Acids (ClPFECAs) were found in 20 out of 41 samples in the range 0.01-1.59 ng/g. Four samples had 20-100 fold higher concentration compared to that of other samples, suggesting the presence of hot spot areas possibly related to presence of fluoropolymer-based marine litter turtles may ingest. The analysis of two paired eggs/liver samples recovered from stranded animals revealed PFAS concentration in the same order of magnitude, supporting the role of vitellogenin in their selective transfer to yolk. Significant (P = 0.0155) Kendall negative correlation coefficient of -0.2705 among PFOS content in eggs and the recorded hatching success prompts for further investigation on associated exposure assessment and related eco-toxicity risk. This work reports for the first time PFAS presence in georeferenced loggerhead turtle eggs of the Mediterranean Sea and results represent a starting point to study PFAS time-trends in this vulnerable species.

Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio).

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.

Fatty acids-modified liposomes for encapsulation of bioactive peptides: Fabrication, characterization, storage stability and in vitro release.

The fragile membranes of liposomes limit their application by the food industry. In this study, we hypothesized that interactions between fatty acids with different chain lengths and phospholipids might enhance liposome stability. Decanoic acid modified liposomes (Lipo-DA) and stearic acid modified liposomes (Lipo-SA) were fabricated for encapsulation of hydrophilic peptides. Fluorescence spectroscopy and FTIR analysis showed molecular interactions existed between alkyl chains and phospholipids, resulting in greater compactness and hydrophobicity of the membranes in Lipo-DA and Lipo-SA. This led to a reduction in melting point characterized by differential scanning calorimetry analysis. Lipo-DA and Lipo-SA could delay the release of hydrophilic peptides compared with unmodified liposomes in simulated digestion. Moreover, Lipo-DA showed better stability during storage, while Lipo-SA exhibited precipitation, resulting in the lowest peptide retention. Our study showed that decanoic acid is suitable to enhance the stability of liposomes, although this approach has yet to be tested in food products.

(-)-Epigallocatechin-3-Gallate Reduces Perfluorodecanoic Acid-Exacerbated Adiposity and Hepatic Lipid Accumulation in High-Fat Diet-Fed Male C57BL/6J Mice.

Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase-1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes.

Liposomes are considered as advanced drug delivery systems for cancer treatment. A generation of pH-sensitive liposomes is being developed that use fatty acids (FAs) as a trigger for drug release in tumor tissues. However, FAs are also known to enhance permeability, and it is unclear whether FAs in liposomes may cause drug leakage or premature drug release. The passive permeability of the drug through the membrane of the liposome is thus a crucial factor for timely drug delivery. To investigate how the curvature and lipid composition of liposomes affect their passive permeability, coarse-grained molecular dynamics were performed. The permeability was determined with a counting method. Flat bilayers and three liposomes with varying diameters were studied, which had varying lipid compositions of dipalmitoylphosphatidylcholine, cholesterol, and deprotonated or neutral saturated FAs. The investigated permeants were water and two other small permeants, which have different free energy profiles (solubility) across the membrane. First, for the curvature effect, our results showed that curvature increases the water permeability by reducing the membrane thickness. The permeability increase for water is about a factor of 1.7 for the most curved membranes. However, a high curvature decreases permeability for permeants with free energy profiles that are a mix of wells and barriers in the headgroup region of the membrane. Importantly, the type of experimental setup is expected to play a dominant role in the permeability value, i.e., whether permeants are escaping or entering the liposomes. Second, for the composition effect, FAs decrease both the area per lipid (APL) and the membrane thickness, resulting in permeability increases of up to 55%. Cholesterol has a similar effect on the APL but has the opposite impact on membrane thickness and permeability. Therefore, FAs and cholesterol have opposing effects on permeability, with cholesterol's effect being slightly stronger in our simulated bilayers. As all permeability values were well within a factor of 2, and with liposomes usually being larger and less curved in experimental applications, it can be concluded that the passive drug release from a pH-sensitive liposome does not seem to be significantly affected by the presence of FAs.

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.

Perfluorodecanoic acid promotes high-fat diet-triggered adiposity and hepatic lipid accumulation by modulating the NLRP3/caspase-1 pathway in male C57BL/6J mice.

Perfluorodecanoic acid (PFDA), a chemical contaminant, may casue became obesity, which makes it a public health concern. In this study, we investigated the effects of PFDA on adiposity development and hepatic lipid accumulation in mice fed with a high-fat diet (HFD). Animals were assigned to two diet treatments (low-fat and high-fat); and PFDA was administered through drinking water for 12 weeks. The contaminant promoted body weight gain and adiposity in HFD-fed mice. Moreover, HFD-fed mice exposed to PFDA had impaired glucose metabolism, inflammation and hepatic lipid accumulation compared to mice fed HFD alone. PFDA activated the expression of hepatic NLRP3 and caspase-1, and induced that of SREBP-1c expression in the liver of HFD-fed mice. PFDA exposure in HFD-fed mice significantly inhibited hepatic AMPK expression than animals fed HFD without PFDA exposure. Furthermore, MCC950, an NLRP3 inhibitor, suppressed the upregulation of NLRP3 and caspase-1 expression, and inhibited the expression of SREBP-1c and the accumulation of hepatic lipid in mice exposed to PFDA. Thus, PFDA may enhance HFD-induced adiposity and hepatic lipid accumulation through the NLRP3/caspase-1 pathway. This contaminant may be a key risk factor for obesity development in individuals consuming high-fat foods, particularly Western diet.

Coconut fatty acids exhibit strong repellency and week-long efficacy against several urban pest arthropods of the southwestern United States.

BACKGROUND: The southwestern United States is home to a variety of arthropods including Turkestan cockroaches, Blatta lateralis (Walker); hematophagous kissing bugs, Tritoma rubida (Uhler); and Arizona bark scorpions, Centruroides sculpturatus Ewing. These arthropods cause medical concern when they become established around homes and/or invade indoors. Traditionally, the management of these pests has relied primarily on the use of chemical insecticides; however, they offer poor prospects for control owing to their lack of efficacy as well as the effects of insecticides on humans and the environment. Botanical repellents are an option that has not been fully investigated for the management of these pests. Here, we investigated the behavioral responses of common urban pests of the southwestern USA to recently discovered coconut fatty acids (CFAs), to establish the potential use of these compounds as repellents. RESULTS: Fresh residues of CFA mixture (CFAm) and their constituents caprylic acid, capric acid, capric acid methyl ester, lauric acid, and lauric acid methyl ester, tested at a concentration of 1 mg cm-2 , strongly repelled all arthropods. The repellent activity of CFAm lasted for at least 7 days, and the addition of lavender oil, used as an odor-masking agent, did not decrease this effect. Concentrations of CFAm ten times lower (0.1 mg cm-2 ) still repelled Turkestan cockroaches, and concentrations 100 times lower (0.01 mg cm-2 ) repelled T. rubida and scorpions. CONCLUSIONS: CFAm and some of their constituents are efficacious, economical, and logistically feasible for inclusion in integrated pest management programs for these important urban pests of the southwestern USA. © 2023 Society of Chemical Industry.

Impact of de-branched starch molecules and fatty acid complexes on the attenuation of ageing-induced cognitive impairment.

BACKGROUND: Ageing and associated cognitive impairments are becoming serious issues around the world. In this study, the physiological properties of three kinds of complexes of fatty acid (capric, stearic and oleic acid, respectively) and de-branched starch molecules were investigated via a d-galactose-induced ageing model. This study revealed differences in the regulation of cognitive impairment and brain damage following intervention of different complexes, which might highlight a potent approach for the prevention of this chronic disease. RESULTS: Data indicated that three complexes improved response time and cognitive function and the bio-parameter markers associated with oxidative stress in ageing rats. Among them, the complexes prepared from de-branched starch-oleic acid showed a greater improvement compared to others. In addition, de-branched starch-capric acid complex showed a higher improvement in the morphology of colon cells and hippocampal neuronal cells. The consumption of de-branched starch-capric acid and -oleic acid complexes generated more short-chain fatty acids in the gut. More importantly, the complexation of de-branched starch with either caprate or stearate enhanced gut Akkermansia. Therefore, it was proposed that the richness in Akkermansia and gut metabolites might be associated with reduced damage of the hippocampal neuronal cells induced by the ageing progress. Moreover, the AMPK (AMP-activated protein kinase) pathway was activated in liver in de-branched starch-capric acid complex diet. In summary, de-branched starch-capric acid complex exhibited a greater effect on the attenuation of ageing-induced cognitive impairment. CONCLUSION: This study might highlight a new approach for intervening in the cognitive impairment during the ageing progress via a food supply. © 2023 Society of Chemical Industry.

Protocell Self-Assembly Driven by Sodium Trimetaphosphate.

The co-evolution of peptide formation and membrane self-assembly is considered an essential step in the origin of life. However, more research is required on both processes, particularly on the interaction between prebiotic simple fatty-acid membranes and peptide synthesis. In this study, the sodium trimetaphosphate (P3 m)-activated peptide formation reaction of phenylalanine (Phe) in an alkaline decanoic acid-decanol vesicle system was systematically investigated. The experimental results showed that peptide formation could competitively occur with N-acyl amino acid (NAA) formation. NAA formation did not follow the traditional P3 m-activated peptide formation reaction involving the intermediate cyclic acylphosphoramidate (CAPA). Decanoic acid was activated by P3 m to form a mixed anhydride, which then reacted with an amino acid to form the amide NAA. As a kind of membrane-forming amphiphile, NAA can form vesicles independently and reduce the critical vesicle concentration of the fatty-acid vesicles. Moreover, 11 other representative amino acids, namely alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), glycine (Gly), isoleucine (Ile), leucine (Leu), proline (Pro), serine (Ser), threonine (Thr), valine (Val), and arginine (Arg), were selected for investigation. All of them reacted with decanoic acid to form NAA via the activation effect of P3 m. The abovementioned mechanism involving P3 m-activated carboxylic acid has not been reported in the literature. Our experimental results indicate that the participation of decanoic acid in the P3 m activation-based peptide formation reaction system plays a significant role in the emergence of functionalized protocells. The P3 m activation effect can provide diversified raw membrane materials to form and stabilize protocell membranes; moreover, the small peptides, such as Phe-Leu, formed in the same reaction system can induce the amplification of primitive cells. This implies that synergistic symbiosis between membrane and peptide can be realized via the P3 m activation effect.

In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide.

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

Efficacy Evaluation of Medium-Chain Fatty Acids as Skin and Spatial Repellents Against Aedes aegypti (Diptera:Culicidae) Mosquitoes.

Fatty acids derived from natural oils are considered as perspective products for adoption as repellents. Fatty acids derived from coconut oil have shown promise as repellents. This study consisted of an olfactometer evaluation of new formulations containing medium-chain fatty acids for spatial repellency and an in laboratory arm-in cage study for contact repellency against Aedes aegypti L. mosquitoes. Six formulations each of capric acid and lauric acid were evaluated for spatial repellency. These formulations contained 0.28-10% of either capric acid or lauric acid as the active ingredients in a consumer friendly skin care formulation. Base formula without fatty acids was evaluated as control in spatial repellency evaluation. For the arm-in cage evaluations, six formulations of capric acid, one base formulation, and a 7% N,N-diethyl-m-toluamide (DEET) product were tested for contact repellency. For contact repellency, United States Department of Agriculture (USDA) standard repellent test cages were used to determine the complete protection time (CPT) of the different formulated repellents. Among all capric acid formulations tested, the concentration of 2.25% (wt) indicated the best level of spatial repellency, but not significantly different from other concentrations. None of the lauric acid concentrations showed any level of spatial repellency. In the arm-in-cage evaluations, the highest contact repellency resulted from 4.5% capric acid, which was significantly higher than 7% DEET and base formula.