Influence of Carbohydrate Intake on Caprylic Acid (C8:0)-Induced Ketogenesis-A Systematic Review and Meta-Analysis.

The ketogenic diet is used worldwide to treat various diseases, especially drug-resistant epilepsies. Medium-chain triglycerides or medium-chain fatty acids, primarily the major ketogenic compound caprylic acid (C8; C8:0), can significantly support ketogenesis. This review examines the effects of concurrent carbohydrate intake on C8-induced ketogenesis. A systematic literature search (PubMed and Web of Science) with subsequent data extraction was performed according to PRISMA guidelines and the Cochrane Handbook. Studies investigating the metabolic response to C8-containing MCT interventions with carbohydrate intake were included. The studies did not include a ketogenic diet. Three intervention groups were created. The quality of the studies was assessed using the RoB II tool, and the meta-analysis was performed using the Cochrane RevMan software. A total of 7 trials, including 4 RCTs, met the inclusion criteria. Ketone production was lower when C8 was combined with carbohydrates compared to MCT intake alone. The lower C8 dose group (11 g) did not show a significantly lower ketogenic effect than the higher dose group (19 g). Forest plot analysis showed heterogeneous data. The data suggest a non-linear relationship between C8, carbohydrate intake and ketone production. Further studies are needed to investigate the influence of different carbohydrates on C8-induced ketogenesis. Limitations include heterogeneous intervention conditions, such as different types of dispersions, caffeine intake, limited number of studies and variability in study design.

The effect of dietary sodium octanoate on Ghrelin concentration and feed intake in chickens and turkeys: a comparative study.

Active ghrelin (AG) is produced through the post-translational addition of n-octanoic acid to the amino residue Ser-3, making it the natural ligand for the ghrelin receptor. The synthesis of AG is contingent upon specific dietary fatty acids as substrates for the acylation process. Prior studies have demonstrated that AG infusion can lead to reduced feed intake (FI) in broiler chickens, suggesting that manipulating AG may serve as an alternative to quantitative feed restriction in broiler breeders. In this study, we evaluated the effect of dietary sodium octanoate (Octanoate) on FI, water intake (WI), BW, total ghrelin, and ß-hydroxybutyrate (BHB) concentration in two avian species. Broiler chickens and turkeys were reared as recommended by the industry. At 3 wk of age, birds were randomly assigned to a 2 × 3 factorial. The first factor included two species (chickens and turkeys), and the second included doses (0, 4, and 8 mg/mL) of Octanoate in drinking water for 30 d. Feed and WI were recorded daily, while body weight and blood samples were obtained weekly. In chickens, Octanoate doses increased ghrelin and BHB concentrations linearly, while FI and BW decreased linearly with rising Octanoate doses (P < 0.05). However, Octanoate doses did not affect ghrelin, BHB, FI, or BW in turkeys. In conclusion, our data indicate that sodium octanoate administration elicits a differential response in feed intake and body weight gain in chickens and turkeys.

Caprylic Acid Improves Lipid Metabolism, Suppresses the Inflammatory Response and Activates the ABCA1/p-JAK2/p-STAT3 Signaling Pathway in C57BL/6J Mice and RAW264.7 Cells.

OBJECTIVE: This study aimed to investigate the effects of caprylic acid (C8:0) on lipid metabolism and inflammation, and examine the mechanisms underlying these effects in mice and cells. METHODS: Fifty-six 6-week-old male C57BL/6J mice were randomly allocated to four groups fed a high-fat diet (HFD) without or with 2% C8:0, palmitic acid (C16:0) or eicosapentaenoic acid (EPA). RAW246.7 cells were randomly divided into five groups: normal, lipopolysaccharide (LPS), LPS+C8:0, LPS+EPA and LPS+cAMP. The serum lipid profiles, inflammatory biomolecules, and ABCA1 and JAK2/STAT3 mRNA and protein expression were measured. RESULTS: C8:0 decreased TC and LDL-C, and increased the HDL-C/LDL-C ratio after injection of LPS. Without LPS, it decreased TC in mice ( P < 0.05). Moreover, C8:0 decreased the inflammatory response after LPS treatment in both mice and cells ( P < 0.05). Mechanistic investigations in C57BL/6J mouse aortas after injection of LPS indicated that C8:0 resulted in higher ABCA1 and JAK2/STAT3 expression than that with HFD, C16:0 and EPA, and resulted in lower TNF-α, NF-κB mRNA expression than that with HFD ( P < 0.05). In RAW 264.7 cells, C8:0 resulted in lower expression of pNF-κBP65 than that in the LPS group, and higher protein expression of ABCA1, p-JAK2 and p-STAT3 than that in the LPS and LPS+cAMP groups ( P < 0.05). CONCLUSION: Our studies demonstrated that C8:0 may play an important role in lipid metabolism and the inflammatory response, and the mechanism may be associated with ABCA1 and the p-JAK2/p-STAT3 signaling pathway.

Open-Label, Phase I, Pharmacokinetic Studies in Healthy Chinese Subjects to Evaluate the Bioequivalence and Food Effect of a Novel Formulation of Abiraterone Acetate Tablets.

PURPOSE: Abiraterone acetate tablets (I)(N-AbA) is a novel tablet co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). This study aimed to compare the pharmacokinetics, bioequivalence, safety, and food effects of N-AbA with the reference ZYTIGA® (R-AbA) in healthy Chinese male subjects. PATIENTS AND METHODS: This study was conducted in three parts. Part I was an open, dose-escalation trial conducted in 16 Chinese healthy males; Part II was a randomized, open-label, 2 × 4 crossover, single-dose bioequivalence trial conducted in 36 subjects; Part III was a randomized, 3 × 3 crossover trial conducted on 24 volunteers to investigate the effect of food on the pharmacokinetics of N-AbA. RESULTS: The exposure (AUC0-∞) and maximum concentration (Cmax) of abiraterone and excipient SNAC were linear in the range of 75-450 mg dose. The bioavailability of N-AbA 300 mg was equivalent to that of R-AbA 1000 mg. The drug exposure of prednisone and prednisolone was not affected by SNAC co-administration. The Cmax of orally administered abiraterone as R-AbA in a modified fed state was 5.9 times and AUC0-∞ was 4.3 times, respectively, higher than those in of orally administered abiraterone as N-AbA in a high-fat diet. The Cmax and AUC0-∞ of orally administered abiraterone as N-AbA on a high-fat diet were 2.2 times and 2 times, respectively, higher than those on a fasting state. All adverse events reported in the three parts of the study were grade 1 or 2, and no serious adverse events were reported. CONCLUSION: These three Phase I trials showed that N-AbA and excipient SNAC had excellent linear pharmacokinetic characteristics. A single dose of N-AbA 300 mg was bioequivalent to R-AbA 1000 mg in healthy subjects under fasting conditions. Meanwhile, SNAC had no effect on the pharmacokinetics of prednisone and prednisolone. The effect of food on N-AbA was significantly lower than that on R-AbA.

Propanediol (and) Caprylic Acid (and) Xylitol as a New Single Topical Active Ingredient against Acne: In Vitro and In Vivo Efficacy Assays.

In addition to dermatological complications, acne can affect the quality of life of individuals in numerous ways, such as employment, social habits and body dissatisfaction. According to our expertise, caprylic acid and propanediol would not have a direct action on Cutibacterium acnes. Despite this, we investigated the existence of a synergistic effect among xylitol, caprylic acid and propanediol as a mixture of compounds representing a single topical active ingredient that could benefit the treatment against acne. In vitro and in vivo assays were performed to challenge and to prove the efficacy of propanediol, xylitol and caprylic acid (PXCA) against acne. PXCA had its MIC challenged against C. acnes (formerly Propionibacterium acnes) and Staphylococcus aureus, resulting in concentrations of 0.125% and 0.25%, respectively, and it also developed antimicrobial activity against C. acnes (time-kill test). PXCA was able to reduce the 5-alpha reductase expression in 24% (p < 0.01) in comparison with the testosterone group. By the end of 28 days of treatment, the compound reduced the skin oiliness, porphyrin amount and the quantity of inflammatory lesions in participants. According to the dermatologist evaluation, PXCA improved the skin's general appearance, acne presence and size.

Transcriptional effects of binary combinations of PFAS in FaO cells.

Per- and polyfluoroalkyl substances (PFAS) represent a large class of structurally diverse chemicals of increasing public concern, mostly due to their chemical stability and undetermined toxicity profiles. In laboratory animals, adverse effects implicated for certain PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in particular, include liver toxicity and the associated metabolic dysregulation, immune and thyroid alterations, reproductive toxicity, and selected tumors. The broad commercialization and environmental distribution of PFAS has drawn attention to the need for understanding risks associated with combined exposure to multiple PFAS in complex mixtures. The purpose of this investigation is to determine whether binary combinations of PFAS elicit a molecular response that is either greater than or less than the sum of the individual responses. Exposure of FaO rat hepatoma cells for 24 h to 25 µM-200 µM of the 4- and 8-carbon perfluorocarboxylic acids (PFBA and PFOA) or the 4, 6, and 8-carbon perfluorosulfonic acids (PFBS, PFHxS, and PFOS, respectively) individually caused a dose-dependent increase in PPARα-regulated expression of peroxisomal bifunctional enzyme (Ehhadh). Potency increased with carbon number, with the carboxylates eliciting a greater transcriptional response than the corresponding sulfonates. Combined exposure to PFOA and PFBA produced an effect that was significantly less than the sum of the individual responses. The response to the combination of PFOA and PFOS produced a summative effect at concentrations that were not cytotoxic. Combined exposures to PFOS and either PFBS or PFHxS at low noncytotoxic concentrations produced a transcriptional effect that was significantly less than the sum of the individual effects. The results demonstrate that among the five structurally related perfluoroalkyl acids included in this investigation, PPARα transcriptional activation in response to combined binary exposures is consistently at or below that predicted by the sum of the individual effects.

Acetylcholine and Royal Jelly Fatty Acid Combinations as Potential Dry Eye Treatment Components in Mice.

Dry eye is a multifactorial disease characterized by ocular discomfort and visual impairment. Our previous studies have shown that royal jelly (RJ) has restored the capacity for tear secretion by modulating muscarinic calcium signaling. RJ contains acetylcholine, which is a major cholinergic neurotransmitter, and a unique set of fatty acids with C 8 to 12 chains, which are expected to be associated with health benefits. The purpose of the present study was to investigate the active components involved in tear secretion capacity, focusing on acetylcholine and fatty acids in RJ. Using the stress-induced dry-eye model mice, it was confirmed that acetylcholine with three fatty acids (10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, and (R)-3,10-dihydroxydecanoic acid) was essential for tear secretion. In ex vivo Ca2+ imaging, these three fatty acids suppressed the decrease in intracellular modulation of Ca2+ in the lacrimal gland by acetylcholine when treated with acetylcholinesterase, indicating that the specific type of RJ fatty acids contributed to the stability of acetylcholine. To our knowledge, this study is the first to confirm that a specific compound combination is important for the pharmacological activities of RJ. Our results elucidate the active molecules and efficacy mechanisms of RJ.

Clinical Features of Essential Voice Tremor and Associations with Tremor Severity and Response to Octanoic Acid Treatment.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to characterize the clinical features, tremor variability, and factors related to octanoic acid (OA) treatment response in essential voice tremor (EVT). STUDY DESIGN: Prospective, double blind, placebo-controlled, crossover study with secondary analysis. METHODS: Clinical tremor features in 16 individuals with EVT were comprehensively assessed, and correlations with acoustic tremor severity were determined. Intrasubject and intersubject variability measures were analyzed from 18 repeated measures for each acoustic tremor variable. Clinical correlates of treatment response were evaluated, and cumulative effects over a 2-week period of OA drug dosing were assessed. RESULTS: Participants with EVT were 90% female with a mean age of 70.31 (±8.68) years at the time of testing. Neurologist-rated body tremor beyond the vocal tract region was present in 69% of participants, and multiple vocal tract regions contributed to the voice tremor. The mean frequency of amplitude tremor was 4.67 Hz (±0.88). Respiratory tremor was evident in 50% of participants. Participants experienced moderate voice-related disability as assessed on the Voice Handicap Index-10 (19.38, ±8.50), and increased speaking effort. Acoustic tremor severity was significantly associated with severity of tremor affecting vocal tract structures. Overall intrasubject consistency was strong (single measures intraclass correlation coefficient = 0.701, P < .01), with high intersubject variability. Acoustic tremor severity was significantly, positively associated with treatment response, and results suggested a cumulative OA benefit for magnitude of amplitude tremor. CONCLUSIONS: This study identified common clinical correlates of EVT and demonstrated positive associations between acoustic tremor severity, severity of affected vocal tract structures, and response to treatment. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:E2792-E2801, 2021.

Effect of Ingestion of Medium-Chain Triglycerides on Substrate Oxidation during Aerobic Exercise Could Depend on Sex Difference in Middle-Aged Sedentary Persons.

Fat oxidation (FAO) during aerobic exercise and whole-body FAO via lipid intake are thought to be important for the maintenance of health, such as the prevention of type 2 diabetes and obesity in sedentary persons in their 40s and 50s. Medium-chain triglycerides (MCTs) ingestion has been attracting attention. However, the effects of difference of sex and the composition of medium-chain fatty acids (MCFAs) are unclear, so we examined the effects of these factors on FAO during aerobic exercise. We conducted a randomized, double-blind, placebo-controlled, 3-arm, within-participants crossover trial. FAO during low- to moderate-intensity exercise was compared when octanoate-rich MCTs (C8R), decanoate-rich MCTs (C10R), or carbohydrate (control) was ingested. Three 2-week interventions were separated by two 2-week washout periods. An increase of FAO during exercise after the C8R diet was found in males, but not in females. An increase of carbohydrate oxidation (CAO) and oxygen uptake during exercise after the C10R diet was found in females, but not in males. In a pooled estimate of the effect of MCTs (C8R and C10R) in women and men, FAO increased during exercise. In conclusion, short-term ingestion of MCTs by middle-aged sedentary persons could increase FAO during aerobic exercise compared to carbohydrate ingestion, but the enhancing effect of MCTs on substrate utilization and oxygen uptake might vary, depending on sex and the composition of MCFAs.

Perfluoroalkyl acids potentiate glutamate excitotoxicity in rat cerebellar granule neurons.

Perfluoroalkyl acids (PFAAs) are persistent man-made chemicals, ubiquitous in nature and present in human samples. Although restrictions are being introduced, they are still used in industrial processes as well as in consumer products. PFAAs cross the blood-brain-barrier and have been observed to induce adverse neurobehavioural effects in humans and animals as well as adverse effects in neuronal in vitro studies. The sulfonated PFAA perfluorooctane sulfonic acid (PFOS), has been shown to induce excitotoxicity via the N-methyl-D-aspartate receptor (NMDA-R) in cultures of rat cerebellar granule neurons (CGNs). In the present study the aim was to further characterise PFOS-induced toxicity (1-60 µM) in rat CGNs, by examining interactions between PFOS and elements of glutamatergic signalling and excitotoxicity. Effects of the carboxylated PFAA, perfluorooctanoic acid (PFOA, 300-500 µM) on the same endpoints were also examined. During experiments in immature cultures at days in vitro (DIV) 8, PFOS increased both the potency and efficacy of glutamate, whereas in mature cultures at DIV 14 only increased potency was observed. PFOA also increased potency at DIV 14. PFOS-enhanced glutamate toxicity was further antagonised by the competitive NMDA-R antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at DIV 8. At DIV 8, PFOS also induced glutamate release (9-13 fold increase vs DMSO control) after 1-3 and 24 h exposure, whereas for PFOA a large (80 fold) increase was observed, but only after 24 h. PFOS and PFOA both also increased alanine and decreased serine levels after 24 h exposure. In conclusion, our results indicate that PFOS at concentrations relevant in an occupational setting, may be inducing excitotoxicity, and potentiation of glutamate signalling, via an allosteric action on the NMDA-R or by actions on other elements regulating glutamate release or NMDA-R function. Our results further support our previous findings that PFOS and PFOA at equipotent concentrations induce toxicity via different mechanisms of action.

Antibacterial effects of hydrogen peroxide and caprylic acid on selected foodborne bacteria.

Bactericidal activity of caprylic acid (CA) and hydrogen peroxide (HP) was investigated in this study in order to design a suitable formulation for use in the food-processing industry. Antibacterial effects of the two chemicals were tested in vitro against the reference strains of Salmonella enterica subsp. enterica serotype Enteritidis CCM 4420, Escherichia coli CCM 3988, Listeria monocytogenes CCM 5578 and Staphylococcus aureus CCM 4223, as well as against the wild bacterial strains obtained from various food commodities (poultry meat, rabbit meat, raw milk sheep cheese 'Bryndza') and potable water. First, suspension test was carried out to determine the minimum bactericidal concentrations for individual chemical compounds. While most Gram-negative bacteria tested were effectively inhibited by HP at a 0.5% concentration, the growth of Gram-positive bacterial strains was stopped by a 2% solution. CA showed similar antibacterial effect on all bacterial strains tested except for Staph. aureus showing the same sus-ceptibility as Gram-negative bacteria. The wild strains generally had higher resistance to both chemicals than the reference strains. Combination of HP and CA at concentrations of 0.01%; 0.05% and 0.1% was further tested by the suspension test, carrier test, and carrier test with simul-taneous exposure to UV light. The total bactericidal activity against selected foodborne pathogens was already observed at a concentration of 0.1% and the efficiency was significantly increased by the use of UV radiation. A novel disinfectant based on the combination of HP with CA appears to be a suitable binary formulation for potential use in the food sector.

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers.

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.

Enhancing the oral bioavailability of simvastatin with silica-lipid hybrid particles: The effect of supersaturation and silica geometry.

Silica-lipid hybrid (SLH) microparticles are a solidified lipid-based drug delivery system under investigation for their aptitude to enhance the oral bioavailability of poorly water-soluble drugs. The cholesterol-lowering agent, simvastatin (SIM), is poorly water-soluble and undergoes extensive first pass metabolism, resulting in a low oral bioavailability of approximately 5%. Hence, the current pre-clinical studies investigated the application of SLH technology to SIM with a supersaturation approach, aiming to enhance bioavailability and drug loading capacity. Additionally, the effect of silica was explored by evaluating the performance of SLH fabricated with silica of different particle geometries. SLH microparticles with supersaturated SIM loading levels ranging from 100% to 400% above the equilibrium solubility were successfully fabricated using either Aerosil® 300 or Syloid® 244 silica. All SLH formulations existed as white free-flowing powders, consisting of spherical porous microparticles for Aerosil® 300, and aggregated irregular microparticles for Syloid® 244. During in vitro dissolution in pH 7.0 media, the SLH formulations performed up to 4.4-fold greater than pure SIM powder. Furthermore, in vivo oral pharmacokinetics in male Sprague-Dawley rats revealed that the SLH formulations enhanced the oral bioavailability of SIM up to 6.1-fold and 2.9-fold, in comparison to pure SIM powder and a commercially available formulation (Simvastatin Sandoz®), respectively. The greatest in vivo performance enhancement was observed for the SLH formulation manufactured with Syloid® 244 silica with a supersaturation level of 200%. SLH technology demonstrated to be a successful formulation strategy to significantly improve the oral bioavailability of SIM in rodents and therefore, has a strong potential to also improve the oral bioavailability of SIM in humans.

Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System.

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

Enhancement of Fat Oxidation during Submaximal Exercise in Sedentary Persons: Variations by Medium-Chain Fatty Acid Composition and Age Group.

Previous studies in recreational and trained athletes aged mostly in their 20s have reported that short-term ingestion of medium-chain triacylglycerols (MCT) enhances fat oxidation (FAO) during submaximal exercise. However, whether the FAO-enhancing effect of MCT with a different composition of medium-chain fatty acids (MCFA) occurs in older sedentary persons is unclear. The present study investigated the effect of MCT ingestion with different proportions of MCFA in sedentary participants in their 40's and 50's. Participants ingested 0 g of MCT (control), 6 g of octanoic acid-rich MCT (OAR), or 6 g of decanoic acid-rich MCT (DAR) for 14 days separated by a 14-day washout period in random order. Cumulative FAO (Fcv ) during submaximal, fixed, and incremental exercise was evaluated at workload from 20 W to the appearance of a ventilation threshold (VT). During the 20 W fixed-load exercise, Fcv was significantly (p < 0.05) higher in the OAR than in the control. At appearance of VT, intervention effect of power output was significantly higher in the OAR and DAR than in the control. In a subgroup analysis by age, intervention effects of maximal FAO rate and oxygen uptake in the upper age subgroup were higher in the OAR and DAR than in the control. In a pooled analysis with age subgroup and diet, the integrated pooled estimate of Fcv during submaximal exercise was significantly higher in 6 g of MCT ingestion than 0 g ingestion. Our data show that the effect of MCT might differ depending on the age group and the proportion of MCFA, while MCT could enhance FAO during submaximal exercise.

Effects of Medium Chain Fatty Acids on Intestinal Health of Monogastric Animals.

Medium-chain fatty acids (MCFAs) are the main form of Medium Chain Triglycerides (MCTs) utilized by monogastric animals. MCFAs can be directly absorbed and supply rapid energy to promote the renewal and repair of intestinal epithelial cells, maintain the integrity of intestinal mucosal barrier function, and reduce inflammation and stress. In our review, we pay more attention to the role of MCFAs on intestinal microbiota and mucosa immunity to explore MCFA's positive effect. It was found that MCFAs and their esterified forms can decrease pathogens while increasing probiotics. In addition, being recognized via specific receptors, MCFAs are capable of alleviating inflammation to a certain extent by regulating inflammation and immune-related pathways. MCFAs may also have a certain value to relieve intestinal allergy and inflammatory bowel disease (IBD). Unknown mechanism of various MCFA characteristics still causes dilemmas in the application, thus MCFAs are used generally in limited dosages and combined with short-chain organic acids (SOAs) to attain ideal results. We hope that further studies will provide guidance for the practical use of MCFAs in animal feed.

Immunotoxicity and allergenic potential induced by topical application of perfluorooctanoic acid (PFOA) in a murine model.

Perfluorooctanoic acid (PFOA) is a per- and polyfluoroalkyl substance (PFAS) once used as a surfactant in the polymerization of chemicals. Because of its ubiquitous nature and long half-life, PFOA is commonly detected in the environment, wildlife, and humans. While skin exposure to PFOA is of concern, studies evaluating the immunotoxicity of dermal exposure are lacking. These studies evaluated the immunotoxicity of PFOA (0.5-2% w/v, or 12.5-50 mg/kg/dose) following dermal exposure using a murine model. PFOA (0.5-2%) was not identified to be an irritant or sensitizer using the local lymph node assay. The IgM antibody response to sheep red blood cell. was significantly reduced in the spleen following 4-days of dermal exposure (2%). PFOA exposure produced a significant decrease in thymus (1 and 2%) and spleen (0.5-2%) weight along with an increase in liver weight (0.5-2%). Immune cell phenotyping identified a reduction in the frequency (1 and 2%) and number (0.5-2%) of splenic B-cells. To further define the mechanism of immunotoxicity, gene expression was also evaluated in the skin. The findings support a potential involvement of the nuclear receptor PPARα. These results demonstrate that dermal exposure to PFOA is immunotoxic and raise concern about potential adverse effects from dermal exposure.

Altered expression and activity of phase I and II biotransformation enzymes in human liver cells by perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS).

Human exposure assessments for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) have been mostly limited to the quantification of these chemicals in different environmental matrices, but only a few studies have addressed toxicological aspects associated with them. It has been suggested that both PFOA and PFOS are highly stable chemicals that are not metabolized, yet previous reports have described abnormal activity of important biotransformation pathways. Therefore, the goal of the present study was to investigate the effects of PFOA and PFOS on phase I and II biotransformation enzymes at the gene expression and activity levels, and by using the well-established human liver HepaRG cell line. Cells were exposed to a wide range of PFOA and PFOS concentrations for 24 or 48 h, prior to cytotoxicity measurements, and quantification of expression and activity of three cytochrome P450 enzymes (CYP1A2, CYP2C19 and CYP3A4) and two conjugation enzymes (glutathione-S-transferase (GST-M1) and UDP-glucuronosyltransferase (UGT-1A1)). Expression of all CYP enzymes was significantly reduced from exposure to both PFOA and PFOS after 48 h and from concentrations as low as 40-50 ng/L, with CYP3A4 also presenting the lowest activity. Among the conjugation enzymes, the expression of UGT was significantly reduced only by PFOA after 48 h of exposure, yet no significant alterations in its activity were observed. While the specific chemico-biological interactions of these compounds with gene expression and biotransformation pathways is not clear, the results from this study suggest that the interference of PFOA and PFOS with phase I and II biotransformation enzymes could potentially lead to adverse outcomes resulting from the inability of biotransformation pathways to function as needed.

Blockade of astrocytic activation delays the occurrence of severe hypoxia-induced seizure and respiratory arrest in mice.

Seizures are induced when subjects are exposed to severe hypoxia. It is followed by ventilatory fall-off and eventual respiratory arrest, which may underlie the pathophysiology of death in patients with epilepsy and severe respiratory disorders. However, the mechanisms of hypoxia-induced seizures have not been fully understood. Because astrocytes are involved in various neurological disorders, we aimed to investigate whether astrocytes are operational in seizure generation and respiratory arrest in a severe hypoxic condition. We examined the effects of astrocytic activation blockade on responses of EEG and ventilation to severe hypoxia. Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording. After recording EEG and ventilation by whole body plethysmography in room air, the gas in the recording chamber was switched to 5% oxygen (nitrogen balanced) until a seizure and ventilatory depression occurred, followed by prompt switch back to room air. Severe hypoxia initially increased ventilation, followed by a seizure and ventilatory suppression in all mice examined. Fourteen mice without arundic acid showed respiratory arrest during loading of hypoxia. However, 22 mice pretreated with arundic acid did not suffer from respiratory arrest. Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest.