Dietary Supplementation of Lauric Acid Alleviates the Irregular Estrous Cycle and the Impaired Metabolism and Thermogenesis in Female Mice Fed with High-Fat Diet (HFD).

Lauric acid (LA) has been implicated in the prevention/treatment of obesity. However, the role of LA in modulating an obesity-related female reproductive disorder remains largely unknown. Here, female mice were fed a control diet, high-fat diet (HFD), or HFD supplemented with 1% LA. The results demonstrated that the HFD-induced estrous cycle irregularity and the reduction of serum follicle-stimulating hormone (FSH) were alleviated by LA supplementation. In possible mechanisms, LA supplementation led to significant increase in serum lipid metabolites such as sphingomyelin and lysophosphatidylcholine containing LA (C12:0) and the improvement of glucose metabolism in mice fed HFD. Moreover, impaired body energy metabolism and weakened brown adipose tissue (BAT) thermogenesis of HFD-fed mice were improved by LA supplementation. Together, these findings showed that LA supplementation alleviated HFD-induced estrous cycle irregularity, possibly associated with altered serum lipid metabolites, improved glucose metabolism, body energy metabolism, and BAT thermogenesis. These findings suggested the potential application of LA in alleviating obesity and its related reproductive disorders.

Combined administration of lauric acid and glucose improved cancer-derived cardiac atrophy in a mouse cachexia model.

Cancer-derived myocardial damage is an important cause of death in cancer patients. However, the development of dietary interventions for treating such damage has not been advanced. Here, we investigated the effect of dietary intervention with lauric acid (LAA) and glucose, which was effective against skeletal muscle sarcopenia in a mouse cachexia model, on myocardial damage. Treatment of H9c2 rat cardiomyoblasts with lauric acid promoted mitochondrial respiration and increased ATP production by Seahorse flux analysis, but did not increase oxidative stress. Glycolysis was also promoted by LAA. In contrast, mitochondrial respiration and ATP production were suppressed, and oxidative stress was increased in an in vitro cachexia model in which cardiomyoblasts were treated with mouse cachexia ascites. Ascites-treated H9c2 cells with concurrent treatment with LAA and high glucose showed that mitochondrial respiration and glycolysis were promoted more than that of the control, and ATP was restored to the level of the control. Oxidative stress was also reduced by the combined treatment. In the mouse cachexia model, myocardiac atrophy and decreased levels of a marker of muscle maturity, SDS-soluble MYL1, were observed. When LAA in CE-2 diet was orally administered alone, no significant rescue was observed in the cancer-derived myocardial disorder. In contrast, combined oral administration of LAA and glucose recovered myocardial atrophy and MYL1 to levels observed in the control without increase in the cancer weight. Therefore, it is suggested that dietary intervention using a combination of LAA and glucose for cancer cachexia might improve cancer-derived myocardial damage.

Effects of intraduodenal coadministration of lauric acid and leucine on gut motility, plasma cholecystokinin, and energy intake in healthy men.

The fatty acid, lauric acid (C12), and the amino acid, leucine (Leu) stimulate gut hormones, including CCK, associated with suppression of energy intake. In our recent study, intraduodenal infusion of a combination of C12 and l-tryptophan, at loads that individually did not affect energy intake, reduced energy intake substantially, associated with much greater stimulation of CCK. We have now investigated whether combined administration of C12 and Leu would enhance the intake-suppressant effects of each nutrient, when given at loads that each suppress energy intake individually. Sixteen healthy, lean males (age: 23 ± 2 yr) received, in randomized, double-blind fashion, 90-min intraduodenal infusions of control (saline), C12 (0.4 kcal/min), Leu (0.45 kcal/min), or C12+Leu (0.85 kcal/min). Antropyloroduodenal pressures were measured continuously and plasma CCK at 15-min intervals, and energy intake from a standardized buffet-meal, consumed immediately postinfusion, was quantified. All nutrient infusions stimulated plasma CCK compared with control (P < 0.05). Moreover, C12 and C12+Leu stimulated CCK compared with Leu (P < 0.05) (mean concentration, pmol/L; control: 2.3 ± 0.3, C12: 3.8 ± 0.3, Leu: 2.7 ± 0.3, and C12+Leu: 4.0 ± 0.4). C12+Leu, but not C12 or Leu, stimulated pyloric pressures (P < 0.05). C12+Leu and C12 reduced energy intake (P < 0.05), and there was a trend for Leu to reduce (P = 0.06) energy intake compared with control, with no differences between the three nutrient treatments (kcal; control: 1398 ± 84, C12: 1226 ± 80, Leu: 1260 ± 92, and C12+Leu: 1208 ± 83). In conclusion, combination of C12 and Leu, at the loads given, did not reduce energy intake beyond their individual effects, possibly because maximal effects had been evoked.

Dietary Saturated Fatty Acids Modulate Pain Behaviour in Trauma-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) is a degenerative condition of joints, causing pain and swelling, and can be caused or worsened by trauma and obesity. The objectives of this study were to determine whether pain behaviour and progression of OA were increased in rats with trauma-induced OA fed dietary saturated fatty acids (SFA). Male Wistar rats were fed either a corn starch diet (C) or high-carbohydrate high-fat diet (H) with either 20% beef tallow or SFA (lauric (HLA), myristic (HMA), palmitic (HPA) or stearic (HSA) acids) for 16 weeks prior to and 8 weeks after excision of the medial meniscus of right knee joint to initiate OA when pain behaviour, glial activity, progression of knee OA, inflammatory mediators and signs of metabolic syndrome were assessed. Rats fed beef tallow, palmitic or stearic acids showed increased pain symptoms characterised by decreased hind paw/limb withdrawal thresholds and grip strengths and increased spinal astrogliosis and microgliosis compared to rats fed lauric or myristic acids. However, the severity of OA joint damage was unchanged by these dietary manipulations. We conclude that pain symptoms of trauma-induced OA in rats worsen with increased dietary beef tallow or palmitic or stearic acids, but improve with lauric or myristic acids, despite unchanged OA cartilage damage.

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.

Effects of Duodenal Infusion of Lauric Acid and L-Tryptophan, Alone and Combined, on Fasting Glucose, Insulin and Glucagon in Healthy Men.

The fatty acid, lauric acid ('C12'), and the amino acid, tryptophan ('Trp'), when given intraduodenally at loads that individually do not affect energy intake, have recently been shown to stimulate plasma cholecystokinin, suppress ghrelin and reduce energy intake much more markedly when combined. Both fatty acids and amino acids stimulate insulin secretion by distinct mechanisms; fatty acids enhance glucose-stimulated insulin secretion, while amino acids may have a direct effect on pancreatic ß cells. Therefore, it is possible that, by combining these nutrients, their effects to lower blood glucose may be enhanced. We have investigated the potential for the combination of C12 and Trp to have additive effects to reduce blood glucose. To address this question, plasma concentrations of glucose, insulin and glucagon were measured in 16 healthy, lean males during duodenal infusions of saline (control), C12 (0.3 kcal/min), Trp (0.1 kcal/min), or C12+Trp (0.4 kcal/min), for 90 min. Both C12 and C12+Trp moderately reduced plasma glucose compared with control (p < 0.05). C12+Trp, but not C12 or Trp, stimulated insulin and increased the insulin-to-glucose ratio (p < 0.05). There was no effect on plasma glucagon. In conclusion, combined intraduodenal administration of C12 and Trp reduced fasting glucose in healthy men, and this decrease was driven primarily by C12. The effects of these nutrients on postprandial blood glucose and elevated fasting blood glucose in type 2 diabetes warrant evaluation.

Giving combined medium-chain fatty acids and glucose protects against cancer-associated skeletal muscle atrophy.

Skeletal muscle volume is associated with prognosis of cancer patients. Maintenance of skeletal muscle is an essential concern in cancer treatment. In nutritional intervention, it is important to focus on differences in metabolism between tumor and skeletal muscle. We examined the influence of oral intake of glucose (0%, 10%, 50%) and 2% medium-chain fatty acid (lauric acid, LAA, C12:0) on tumor growth and skeletal muscle atrophy in mouse peritoneal metastasis models using CT26 mouse colon cancer cells and HT29 human colon cancer cells. After 2 weeks of experimental breeding, skeletal muscle and tumor were removed and analyzed. Glucose intake contributed to prevention of skeletal muscle atrophy in a sugar concentration-dependent way and also promoted tumor growth. LAA ingestion elevated the level of skeletal muscle protein and suppressed tumor growth by inducing tumor-selective oxidative stress production. When a combination of glucose and LAA was ingested, skeletal muscle mass increased and tumor growth was suppressed. Our results confirmed that although glucose is an important nutrient for the prevention of skeletal muscle atrophy, it may also foster tumor growth. However, the ingestion of LAA inhibited tumor growth, and its combination with glucose promoted skeletal muscle integrity and function, without stimulating tumor growth. These findings suggest novel strategies for the prevention of skeletal muscle atrophy.

Effects of intraduodenal administration of lauric acid and L-tryptophan, alone and combined, on gut hormones, pyloric pressures, and energy intake in healthy men.

BACKGROUND: The fatty acid, lauric acid ('C12'), and the amino acid, L-tryptophan ('Trp'), modulate gastrointestinal functions including gut hormones and pyloric pressures, which are important for the regulation of energy intake, and both potently suppress energy intake. OBJECTIVE: We hypothesized that the intraduodenal administration of C12 and Trp, at loads that do not affect energy intake individually, when combined will reduce energy intake, which is associated with greater modulation of gut hormones and pyloric pressures. DESIGN: Sixteen healthy, lean males (age: 24 ± 1.5 y) received 90-min intraduodenal infusions of saline (control), C12 (0.3 kcal/min), Trp (0.1 kcal/min), or C12 + Trp (0.4 kcal/min), in a randomized, double-blind, cross-over study. Antropyloroduodenal pressures were measured continuously, and plasma cholecystokinin (CCK), ghrelin, and glucagon-like peptide-1 (GLP-1) concentrations, appetite perceptions, and gastrointestinal symptoms at 15-min intervals. Immediately after the infusions, energy intake from a standardized buffet meal was quantified. RESULTS: C12 + Trp markedly reduced energy intake (kcal; control: 1,232 ± 72, C12: 1,180 ± 82, Trp: 1,269 ± 73, C12 + Trp: 1,056 ± 106), stimulated plasma CCK (AUC(area under the curve)0-90 min, pmol/L*min; control: 21 ± 8; C12: 129 ± 15; Trp: 97 ± 16; C12 + Trp: 229 ± 22) and GLP-1 (AUC0-90 min, pmol/L*min; control: 102 ± 41; C12: 522 ± 102; Trp: 198 ± 63; C12 + Trp: 545 ± 138), and suppressed ghrelin (AUC0-90 min, pg/mL*min; control: -3,433 ± 2,647; C12: -11,825 ± 3,521; Trp: -8,417 ± 3,734; C12 + Trp: -18,188 ± 4,165) concentrations, but did not stimulate tonic, or phasic, pyloric pressures, compared with the control (all P < 0.05), or have adverse effects. C12 and Trp each stimulated CCK (P < 0.05), but to a lesser degree than C12 + Trp, and did not suppress energy intake or ghrelin. C12, but not Trp, stimulated GLP-1 (P < 0.05) and phasic pyloric pressures (P < 0.05), compared with the control. CONCLUSION: The combined intraduodenal administration of C12 and Trp, at loads that individually do not affect energy intake, substantially reduces energy intake, which is associated with a marked stimulation of CCK and suppression of ghrelin. The study was registered as a clinical trial at the Australian and New Zealand Clinical Trial Registry (www.anzctr.org.au,) as 12613000899741.

Inhibition of soluble epoxide hydrolase regulates monocyte/macrophage polarization and improves neurological outcome in a rat model of ischemic stroke.

It is generally understood that continuing neuroinflammation after ischemic stroke can exacerbate the brain damage. During the inflammatory hematogenous recruitment process, the monocytes and macrophages are activated into proinflammatory M1 and anti-inflammatory M2 cell types. Inhibition of soluble epoxide hydrolase (sEH) activity has been reported to regulate monocytes/macrophages, and attenuates neuroinflammation. This study aimed to evaluate whether a selective sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), can regulate monocyte/macrophage polarization and improve motor function in the rats with ischemic stroke induced by middle cerebral artery occlusion. We measured the infarct volume with 2,3,5-triphenyltetrazolium chloride staining and used the rotarod test to assess motor performance in rats. The monocyte/macrophage activation and mRNA expression of proinflammatory mediators were measured by flow cytometry and reverse-transcription quantitative PCR, respectively. Our results showed better neurological function and less infarct volume in the rats treated with AUDA. Compared with the vehicle group, the AUDA-treated group showed a reduction in M1 monocyte/macrophage activation and proinflammatory mRNA expressions in the infarct cortex of rats. Our data suggest that the sEH inhibition may regulate monocyte/macrophage polarization and improve neurological outcome after ischemic stroke.

Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: Roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair.

Though ion-pair strategy has been employed as an effective and promising method for controlling transdermal delivery of drugs, investigations into the underlying mechanisms involved in the controlled release process of ion-pairs are still limited. In the present study, a brand-new controlled release system combining acrylic pressure sensitive adhesive containing carboxyl group (carboxylic PSA) with ion-pair strategy was developed, and the molecular mechanism of ion-pair releasing from carboxylic PSA was systemically elucidated. Bisoprolol (BSP) and bisoprolol-lauric acid ion-pair (BSP-C12) were chosen as model drugs. Carboxylic PSA was designed and synthesized. Effect of ion-pair on controlling BSP release from carboxylic PSA was evaluated by in vitro drug release study, in vitro skin permeation study and pharmacokinetic study. Molecular mobility of PSA, along with the strength of drug-PSA interaction was evaluated by thermal analysis and dielectric spectroscopy. Molecular details of drug-PSA interaction were identified by FTIR, XPS and Raman. Roles of drug-PSA interaction in the controlled release process were clarified by molecular modeling. Results showed that BSP-C12 patch demonstrated a controlled release drug plasma profile, with lower Cmax (193 ±â€¯63 ng/mL) and longer MRT (19.9 ±â€¯3.4 h) compared to BSP patch (Cmax,BSP = 450 ±â€¯28 ng/mL, MRTBSP = 7.9 ±â€¯0.9 h). Besides, there was no significant difference between the AUC of BSP-C12 and BSP patch. It turned out that instead of PSA molecular mobility, molecular interaction between ion-pair and PSA played a dominant role in the controlled release process of BSP: as illustrated by FTIR, Raman and molecular docking, the ionic interaction between BSP-C12 and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP-C12 and PSA-COO- controlled the release rate, which was the kinetic process. In conclusion, it was found that the doubly ionic hydrogen bond formed between carboxylic PSA and ion-pair controlled the release profile of BSP, which broadened our understanding about the molecular mechanisms involved in ion-pair controlled release transdermal patches and contributed to the design of controlled release TDDS.

A preclinical evaluation of cytarabine prodrug nanofibers assembled from cytarabine-lauric acid conjugate toward solid tumors.

Cytarabine (Ara-C) has become cornerstones for the treatment of hatmatological malignancies for several decades; however, it still faces serious challenges in clinical applications due to its side effects such as hand foot syndrome (HFS) and stomatitis. Therefore, considerable researchers have devoted to looking for the new derivative with desirable activity and low toxicity. A new prodrug based on the conjugation of cytarabine with lauric acid (LA-Ara) was synthesized in our group, and it could self-assemble into nanofibers (NFs) in aqueous solution with high drug loading (57 wt%). The lauric acid moiety protects NH2 group of from the enzymatic attachment and simultaneously raises the lipophilicity of Ara-C, thus obviously prolongs its plasma half-life. The oil/water partition coefficient (lg P) and the permeability of cell membrane of LA-Ara were obviously increased compared with Ara-C. Furthermore, the in vitro gastrointestinal stability results indicated the prodrug was suitable to be administrated orally. In the current study, the in vitro cytotoxicity and in vivo anti breast cancer experimental results indicate LA-Ara markedly improved antitumor activity compared with free Ara-C. The favorable safety evaluations elucidated its potentiality for oral alternative treatment to Ara-C. Importantly, LA-Ara can effectively decrease the incidence of toxic effects (HFS and stomatitis) of Ara-C, thereby exhibiting favorable skin safety profile. Overall, these results indicated the LA-Ara would be an excellent candidate for further clinical investigation and simultaneously highlight the prospects of Ara-C prodrug strategies in solid tumors therapy.

Influence of lauric acid on the susceptibility of chickens to an experimental Campylobacter jejuni colonisation.

Among the organic acids, lauric acid has shown a high level of in vitro activity against Campylobacter jejuni. The prevalence and intensity of C. jejuni excretion at slaughter often becomes lower with increasing age. In higher-aged broilers on organic farms which often use other breeds, in turn, the prevalence of C. jejuni is sometimes higher at slaughter. The question then arises as to whether a diet with higher lauric acid concentrations, the age alone or the genetic breed might have an effect in the spread and intensity of an experimental C. jejuni infection in vivo. Therefore, two complete diets with or without 2% lauric acid from palm kernel fatty acids were offered to 450 chickens (ten subgroups à 15 birds, repetitions: n = 3) of two broiler and two layer breeds (Ross 308, Hubbard JA 757, Lohmann Dual and Lohmann Brown-Classic). All breeds were reared for 42 days, Lohmann Brown-Classic also for about 98 days. Twenty-one days before dissection, three seeder birds per subgroup were orally infected with a 1 mL inoculum of C. jejuni (4.46±0.35 log10 CFU/mL). Qualitative detection of C. jejuni in cloacal swabs was performed at days 2, 4, 7, 14 after inoculation and at dissection in all birds. Quantitative detection was performed on excreta samples of seeder birds at days 2, 11 and 17 after experimental challenge and on caecal samples of all birds at dissection. Two days after experimental inoculation, C. jejuni prevalence was higher in control birds without lauric acid supplementation (48.9% vs. 39.6%; P = 0.0462). Depending on age, two days after inoculation the C. jejuni prevalence in young Lohmann Brown-Classic chickens was significantly lower (37.8% vs. 61.1%) whereas at dissection it was higher (99% vs. 67%). At day 2 after inoculation C. jejuni counts in the excreta of young Lohmann Brown-Classic were lower in comparison to those in old ones (log10 CFU/g: 3.30±2.68 vs. 5.24±1.56). Eleven (log10 CFU/g: 5.14±1.13 vs. 4.16±0.82) and 17 days after inoculatioin (log10 CFU/g: 3.77±2.02 vs. 1.72±1.87) it was the reverse situation. At dissection, the carriage of C. jejuni in caecal content was higher in younger than in older birds (log10 CFU/g: 8.57±0.46 vs. 6.66±1.43). An effect of genetic breed on C. jejuni prevalence was seen at dissection, this being lowest in Lohmann Dual chickens (91% vs. 98.9% in other breeds). At d 17 after challenge, C. jejuni counts in the excreta of young Lohmann Brown-Classic were lower in comparison to Ross 308 and Hubbard JA 757 (log10 CFU/g: 3.77±2.02 vs. 5.21±0.85 and 5.62±0.90). Lohmann Dual chickens showed an intermediary excretion, this being only significant lower compared to Hubbard JA 757 (log10 CFU/g: 4.31±0.89). In summary, the effect of lauric acid is limited to the initial phase after experimental inoculation. A higher age at infection seems to lead to a more rapid limitation of the infection. The excretion of C. jejuni appears to decrease more rapidly in layer breeds than in broiler lines after experimental inoculation.

In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers.

This study reports a new strategy for in situ fabrication of plasmonic hollow silver-gold nanoshell (with resonance tuned to NIR region) encased in the hollow mesoporous silica as an efficient platform to efficiently and precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy. The mesopores were capped with thermosensitive phase-change material lauric acid, which allowed for remote, precise, and spatiotemporal control of drug release via external heating or photothermal heating of plasmonic silver-gold nanoshell via NIR laser irradiation. The system was nanometric, monodispersed, and showed negative surface charge. The nanocarrier showed better pH stability and thermodynamic stability compared to dense silica-coated gold nanoshells. The drug release could be triggered remotely by applying low powered continuous wave NIR laser (λ = 808 nm). The nanocarrier showed improved internalization by cancer cells, which was further enhanced by laser irradiation. High powered laser directly killed the cancer cells via photothermal effect in the region irradiated. Thus, this system fabricated by novel synthetic strategy provided efficient chemo- and phototherapy.

Acute Treatment with Lauric Acid Reduces Blood Pressure and Oxidative Stress in Spontaneously Hypertensive Rats.

The effects of acute administration of lauric acid (LA), the most abundant medium-chain fatty acid of coconut oil, on blood pressure, heart rate and oxidative stress were investigated in spontaneously hypertensive rats (SHR). Intravenous doses of LA reduced blood pressure in a dose-dependent fashion (1, 3, 4, 8 and 10 mg/kg) in both SHR and Wistar Kyoto rats. LA (10-8 to 3 × 10-3 M) induced vasorelaxation in isolated superior mesenteric artery rings of SHR in the presence (n = 7) or absence (n = 8) of functional endothelium [maximum effect (ME) = 104 ± 3 versus 103 ± 4%]. After exposure to KCl (60 mM), LA also induced concentration-dependent vasorelaxation (n = 7) compared to that under Phe-induced contraction (ME = 113.5 + 5.1 versus 104.5 + 4.0%). Furthermore, LA-induced vasorelaxation in vessels contracted with S(-)-BayK8644 (200 nM), a L-type Ca2+ channel agonist (ME = 91.4 + 4.3 versus 104.5 + 4.0%, n = 7). Lastly, LA (10-3 M) reduced NADPH-dependent superoxide accumulation in the heart (18 ± 1 versus 25 ± 1 MLU/min/µg protein, n = 4, p < 0.05) and kidney (82 ± 3 versus 99 ± 4 MLU/min/µg protein, n = 4, p < 0.05). Our data show that LA reduces blood pressure in normotensive and hypertensive rats. In SHR, this effect might involve Ca+2 channels in the resistance vessels and by its capability of reducing oxidative stress in heart and kidneys.

A Fatty Acids Mixture Reduces Anxiety-Like Behaviors in Infant Rats Mediated by GABAA Receptors.

Fatty acids (C6-C18) found in human amniotic fluid, colostrum, and maternal milk reduce behavioral indicators of experimental anxiety in adult Wistar rats. Unknown, however, is whether the anxiolytic-like effects of fatty acids provide a natural mechanism against anxiety in young offspring. The present study assessed the anxiolytic-like effect of a mixture of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, and linoleic acid in Wistar rats on postnatal day 28. Infant rats were subjected to the elevated plus maze, defensive burying test, and locomotor activity test. Diazepam was used as a reference anxiolytic drug. A group that was pretreated with picrotoxin was used to explore the participation of γ-aminobutyric acid-A (GABAA) receptors in the anxiolytic-like effects. Similar to diazepam, the fatty acid mixture significantly increased the frequency of entries into and time spent on the open arms of the elevated plus maze and decreased burying behavior in the defensive burying test, without producing significant changes in spontaneous locomotor activity. These anxiolytic-like effects were blocked by picrotoxin. Results suggest that these fatty acids that are contained in maternal fluid may reduce anxiety-like behavior by modulating GABAergic neurotransmission in infant 28-day-old rats.

Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation.

Renal ischemia reperfusion (IR)-injury induces activation of innate immune response which sustains renal injury and contributes to the development of delayed graft function (DGF). Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory evolutionary conserved pattern recognition receptor expressed on a variety of innate immune cells. TREM-1 expression increases following acute and chronic renal injury. However, the function of TREM-1 in renal IR is still unclear. Here, we investigated expression and function of TREM-1 in a murine model of renal IR using different TREM-1 inhibitors: LP17, LR12 and TREM-1 fusion protein. In a human study, we analyzed the association of non-synonymous single nucleotide variants in the TREM1 gene in a cohort comprising 1263 matching donors and recipients with post-transplant outcomes, including DGF. Our findings demonstrated that, following murine IR, renal TREM-1 expression increased due to the influx of Trem1 mRNA expressing cells detected by in situ hybridization. However, TREM-1 interventions by means of LP17, LR12 and TREM-1 fusion protein did not ameliorate IR-induced injury. In the human renal transplant cohort, donor and recipient TREM1 gene variant p.Thr25Ser was not associated with DGF, nor with biopsy-proven rejection or death-censored graft failure. We conclude that TREM-1 does not play a major role during experimental renal IR and after kidney transplantation.

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation.

The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.

Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ(12,14)-prostagandin J2 prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring.

Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) therapy can rescue programmed hypertension in the DEX+HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX+HF, AUDA, and 15dPGJ2. Dexamethasone (0.1mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25mg/L in drinking water during lactation. In the 15dPGJ2 group, male offspring received 15dPGJ2 1.5mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ2. The beneficial effects of AUDA and 15d-PGJ2 therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake.

Different oral sensitivities to and sensations of short-, medium-, and long-chain fatty acids in humans.

Fatty acids that vary in chain length and degree of unsaturation have different effects on metabolism and human health. As evidence for a "taste" of nonesterified fatty acids (NEFA) accumulates, it may be hypothesized that fatty acid structures will also influence oral sensations. The present study examined oral sensitivity to caproic (C6), lauric (C12), and oleic (C18:1) acids over repeated visits. Analyses were also conducted on textural properties of NEFA emulsions and blank solutions. Oral thresholds for caproic acid were lower compared with oleic acid. Lauric acid thresholds were intermediate but not significantly different from either, likely due to lingering irritating sensations that prevented accurate discrimination. From particle size analysis, larger droplets were observed in blank solutions when mineral oil was used, leading to instability of the emulsion, which was not observed when emulsions contained NEFA or when mineral oil was removed from the blank. Rheological data showed no differences in viscosity among samples except for a slightly higher viscosity with oleic acid concentrations above 58 mM. Thus, texture was unlikely to be the property used to distinguish between the samples. Differences in oral detection and sensation of caproic, lauric, and oleic acids may be due to different properties of the fatty acid alkyl chains.

Effects of feeding lauric acid or coconut oil on ruminal protozoa numbers, fermentation pattern, digestion, omasal nutrient flow, and milk production in dairy cows.

The objectives of this study were to evaluate the feeding of coconut oil (CO), in which lauric acid (La) comprises about 50% of the fatty acid composition, as a practical rumen protozoa (RP) suppressing agent, to assess whether the source of La affects ruminal fermentation and animal performance and to test whether suppressing RP improves N utilization, nutrient digestion, nutrient flow at the omasal canal, and milk production. Fifteen multiparous Holstein cows (3 fitted with ruminal cannulas) and 15 primiparous Holstein cows (3 fitted with ruminal cannulas) were used in a replicated 3×3 Latin square experiment with 14d of adaptation and 14d of sample collection. Diets were fed as total mixed ration and contained (dry matter basis) 10% corn silage, 50% alfalfa silage, and 40% concentrate. The control diet contained 3% (dry matter basis) calcium soaps of palm oil fatty acids (Megalac, Church & Dwight Co. Inc., Princeton, NJ) as a ruminally inert fat source and had no added La or CO. Diets with La and CO were formulated to contain equal amounts of La (1.3%, dry matter basis). Dry matter intake was not affected by treatment. Both CO and La reduced RP numbers by about 40%. Lauric acid reduced yield of milk and milk components; however, CO did not affect yield of milk and yields of milk components. Both La and CO caused small reductions in total VFA concentration; CO increased molar proportion of ruminal propionate, reduced ruminal ammonia and branched-chain volatile fatty acids, suggesting reduced protein degradation, and reduced milk urea N and blood urea N concentrations, suggesting improved protein efficiency. Lauric acid reduced total-tract apparent digestibility of neutral detergent fiber and acid detergent fiber as well as ruminal apparent digestibility of neutral detergent fiber and acid detergent fiber as measured at the omasal canal; however, CO did not alter fiber digestion. Microbial protein flow at the omasal canal, as well as the flow of N fractions at the omasal canal, did not differ among treatments. Results from this experiment have confirmed that dietary La is not a practical agent for suppressing RP population in dairy cows, mainly because of its negative effects on fiber digestion and ruminal fermentation. Intake of CO appeared to reduce ruminal and improve protein efficiency, but did not improve milk production, milk composition, or increase microbial outflow from the rumen. Based on the results of this study, a 40% reduction of RP population is not sufficient to improve N utilization in dairy cows.