Administration Of Linoleic Acid Research Articles

Linoleic Acid Alleviates Lipopolysaccharide Induced Acute Liver Injury via Activation of Nrf2.

Linoleic acid (LA) not only functions as an essential nutrient, but also profoundly modulates oxidative stress and inflammatory response. However, the potential mechanisms have not been adequately researched. Hence, this study examined the potential pharmacological roles of LA and the underlying mechanisms in mice with lipopolysaccharide (LPS)-associated acute liver injury (ALI). The results indicated that treatment with LA alleviated the histopathological abnormalities in the hepatic and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione-S-transferase (GST) in mice with LPS exposure. In addition, LA inhibited the LPS-associated generation of proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and downregulated the hepatic myeloperoxidase (MPO) level. In addition, the administration of LA resulted in a reduction in hepatic malondialdehyde (MDA) levels and an elevation in liver superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Further investigations revealed that LA promoted the expression of nuclear factor E2-related factor (Nrf2) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.

Mitigation and mechanism of low dose linoleic acid on depression caused by disorder of gut microbiome

ABSTRACT Objectives Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated. Methods Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin–eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively. Results The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain. Discussion LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.

Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth

Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.

Oral administration of linoleic acid immediately before glucose load ameliorates postprandial hyperglycemia.

Introduction: Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats. Methods: Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Blood glucose levels were measured before, then 15, 30, 60 and 120min after glucose load. CACO-2 cells were used to measure the uptake of [14C] α-MDG for 30min with or without LA. Gastric content from rats administered LA was collected 15 and 30min after glucose load, and blood samples were collected for measurement of glucagon-like peptide 1 (GLP-1) and cholecystokinin concentrations. Results: The elevation of postprandial blood glucose levels was slowed by LA but not by trilinolein in rats without promotion of insulin secretion, and this effect was also observed in rats with type 1 diabetes. The uptake of α-MDG, an SGLT-specific substrate, was, however, not inhibited by LA. Gastric emptying was slowed by LA 15min after glucose load, and GLP-1, but not cholecystokinin, level was elevated by LA 15min after glucose load. TUG-891, a GPR120 agonist, ameliorated postprandial hyperglycemia but TAK-875, a GPR40 agonist, did not. Pretreatment with AH7614, a GPR120 antagonist, partially canceled the improvement of postprandial hyperglycemia induced by LA. α-LA, which has high affinity with GPR120 as well as LA, slowed the elevation of postprandial blood glucose levels, but oleic acid, which has lower affinity with GPR120 than LA, did not. Conclusion: Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway.

Oral administration of linoleic acid immediately before glucose load slowed the elevation of postprandial glucose levels via GPR120 pathway

Oral administration of linoleic acid immediately before glucose load slowed the elevation of postprandial glucose levels via GPR120 pathway

Identification of linoleic acid as an antithrombotic component of Wenxin Keli via selective inhibition of p-selectin-mediated platelet activation

Atrial fibrillation significantly increases the risk of thromboembolism and stroke. Wenxin Keli (WXKL) is a widely used Chinese patent medicine against arrhythmia but if it has antithrombotic activity is unknown. Since platelet activation is a critical factor in thrombosis and the key target for many antithrombotic drugs, this study aims to demonstrate the antithrombotic efficacy of WXKL. In vitro platelet activation experiments showed that WXKL significantly inhibited platelet adhesion and aggregation. The potential active monomers in WXKL were screened by in silico prediction and in vitro platelet aggregation/adhesion assays. From WXKL chemical fractions and more than 40 monomers, linoleic acid (LA) was identified as the strongest antiplatelet compound. Oral administration of WXKL (1.2 g/kg/day) and LA (50 mg/kg/day) for 7 days significantly improved FeCl3-induced carotid thrombus formation in ICR mice without prolonging bleeding time. Flow cytometry showed that both WXKL and LA inhibited the release of p-selectin after platelet activation. ELISA showed that WXKL and LA also inhibited the expression of 6-Keto-PGF1α in plasma of mice with thrombus, but had no obvious effect on the expression of TXB2. WXKL inhibited platelet activation by broadly inhibiting the phosphorylation of protein kinase B (Akt), mitogen-activated protein kinases (MAPKs) and phospholipase C (PLC) β3. In contrast, LA only inhibited the phosphorylation of PLCβ3. In conclusion, WXKL and its active component LA showed good antiplatelet and antithrombotic efficacy in vivo and in vitro. Mechanistically, the multicomponent Chinese medicine WXKL acts on multiple targets in the platelet activation pathway whereas its active monomer linoleic acid acts specifically on phospholipase C β3.

Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents.

Long-chain fatty acids (LCFAs) are not only energy sources but also serve as signaling molecules. GPR120, an LCFA receptor, plays key roles in maintaining metabolic homeostasis. However, whether endogenous ligand-GPR120 circuits exist and how such circuits function in pancreatic islets are unclear. Here, we found that endogenous GPR120 activity in pancreatic δ-cells modulated islet functions. At least two unsaturated LCFAs, oleic acid (OA) and linoleic acid (LA), were identified as GPR120 agonists within pancreatic islets. These two LCFAs promoted insulin secretion by inhibiting somatostatin secretion and showed bias activation of GPR120 in a model system. Compared with OA, LA exerted higher potency in promoting insulin secretion, which is dependent on β-arrestin2 function. Moreover, GPR120 signaling was impaired in the diabetic db/db model, and replenishing OA and LA improved islet function in both the db/db and streptozotocin-treated diabetic models. Consistently, the administration of LA improved glucose metabolism in db/db mice. Collectively, our results reveal that endogenous LCFA-GPR120 circuits exist and modulate homeostasis in pancreatic islets. The contributions of phenotype differences caused by different LCFA-GPR120 circuits within islets highlight the roles of fine-tuned ligand-receptor signaling networks in maintaining islet homeostasis.

Direct effects of linoleic and linolenic acids on bovine uterine function using in vivo and in vitro studies.

The aim of the present study was to evaluate the effects of continuous administration of linoleic acid or linolenic acid into the intra-uterine horn, ipsilateral to the corpus luteum, on the duration of the estrous cycle and plasma progesterone (P4) concentration. The effects of linoleic and linolenic acids on bovine uterine and luteal functions were also studied using a tissue culture system. Intra-uterine administration of linoleic or linolenic acid (5 mg/10 ml of each per day) in cows, between days 12 and 21, resulted in a prolonged estrous cycle compared to the average duration of the last one to three estrous cycles before administration in each group (P < 0.05). Moreover, plasma P4 concentration in cows treated with linoleic or linolenic acid was high between days 19 and 21 (linoleic acid), or on day 20 (linolenic acid), compared to that of the control cows (saline administration; P < 0.05 or lower). Both linoleic (500 µg/ml) and linolenic (5 and 500 µg/ml) acids stimulated prostaglandin (PG) E2 but inhibited PGF2α production by cultured endometrial tissue (P < 0.01), while P4 production by cultured luteal tissue was not affected. These findings suggest that both linoleic and linolenic acids support luteal P4 production by regulating endometrial PG production and, subsequently, prolonging the duration of the estrous cycle in cows.

Metabolomic Profiles in the Intestine of Shrimp Infected by White Spot Syndrome Virus and Antiviral Function of the Metabolite Linoleic Acid in Shrimp

White spot syndrome virus (WSSV) is a threatening pathogenic virus in shrimp culture, and at present, no effective strategy can prevent and control the disease. Intestinal flora and its metabolites are important for the resistance of shrimp to lethal pathogenic viruses. However, the changes of metabolites in the shrimp intestines after WSSV infection remain unclear. We established an artificial oral infection method to infect shrimp with WSSV and analyzed the metabolites in intestinal content of shrimp by HPLC and tandem mass spectrometry. A total of 78 different metabolites and five different metabolic pathways were identified. Among them, we found that the content of linoleic acid, an unsaturated fatty acid, increased significantly after WSSV infection, indicating that linoleic acid might be involved in antiviral immunity in shrimp. Further study showed that, after oral administration of linoleic acid, WSSV proliferation decreased evidently in the shrimp, and survival rate of the shrimp increased significantly. Mechanical analysis showed that linoleic acid directly bound to WSSV virions and inhibited the viral replication. Linoleic acid also promoted the expression of antimicrobial peptides and IFN-like gene Vago5 by activating the ERK-NF-κB signaling pathway. Our results indicated that WSSV infection caused metabolomic transformation of intestinal microbiota and that the metabolite linoleic acid participated in the immune response against WSSV in shrimp.

Induction of Beneficial Changes in Glucose Homeostasis, Lipid Profile, Inflammation, Retinopathy, Bile Acids and Gut Microbiota in Streptozotocin-Induced Type 1 Diabetes Mellitus by Essential Fatty Acids

Background: Essential fatty acids (EFAs) n3 alpha-linolenic acid (ALA) and n6 linoleic acid (LA) have been shown to improve lipid metabolism, promote nervous system development, suppress inflammation, and are of benefit in diabetes mellitus and cancer. But the exact mechanism of their action(s) is not clear. In the present study, we evaluated the effects of ALA and LA on glucose homeostasis, circulating lipid profile, inflammatory markers, gut microbiome, and bile acids in streptozotocin (STZ)-induced type 1 diabetes with retinopathy in rats. We also measured vitreal LXA4 levels in patients with diabetic retinopathy since arachidonic acid (AA), the precursor of LXA4, is derived from LA. Methods: The study was performed in male Sprague Dawley rats. Type 1 DM was induced by intraperitoneal injection of STZ. The type 1 DM animals received LA or ALA 100 ug/day via intraperitoneal route on alternate days till the end of the study (21 days after the DM onset). In these animals, glucose homeostasis and lipid profile were evaluated. Plasma and retinal fatty acid profile by gas chromatography (GC), retinal histology by H&E staining, activities of desaturases in the retina and liver tissues and inflammatory markers by qRT-PCR, and composition of the gut microbiota by 16S rDNA sequencing technology of the fecal samples were performed. In addition, short-chain fatty acids (SCFAs) and bile acids (BAs) in the feces and liver of rats were assayed by GC and liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS), respectively. Human vitreal samples obtained from patients with proliferative diabetic retinopathy (PDR) were analyzed for their fatty acids profile and LXA4 levels and compared with those with macular hole (control). Findings: LA and ALA-treated STZ-induced type 1 DM animals showed significant reduction in their plasma glucose levels, pro-inflammatory cytokines (IL-6 and TNF-α), changes in the composition of gut microbiome in the form of an increase in the abundance of Ruminococcaceae (ALA-treated group), Alloprevotella, Prevotellaceae_Ga6A1_group, Ruminococcaceae_UCG_010 and Ruminococcus_1 (in LA-treated group) , an increase in acetic acid and butyric acid, and an increase in the fecal concentrations of CA, CDCA and TUDCA and a decrease in GCA. Concentrations of hepatic CDCA, TCDCA, and TUDCA were significantly increased in ALA treated animals while CDCA were elevated in those with LA treatment. STZ-treated animals showed significant decrease in plasma LA, GLA, and AA and ALA levels with no significant changes in retinal fatty acid composition. All these changes reverted to normal in LA and ALA treated group. The changes in the plasma fatty acid composition were accompanied by significant alterations in the expression of desaturases, COX-2 and 5-LOX and 12-LOX enzymes and pro- and anti-inflammatory cytokines. In addition, retinal LXA4 levels were found to be decreased in patients with PDR. Interpretation: The results of the present study suggest that ALA and LA administration can improve plasma glucose levels, suppress inflammation, and produce significant beneficial alterations in the gut microbiota, plasma lipid profile and EFAs metabolism. Decrease in retinal LXA4 levels in those with PDR agree with the suggestion that EFAs metabolism is altered in T1DM and DR. These results imply a significant role for EFAs and their metabolites in the pathobiology of type 1 DM and diabetic retinopathy. Funding Information: The project was funded by the National Natural Science Foundation of China (No. 82000886), and Natural Science Foundation of Zhejiang Province (No.LQ20H120011). Declaration of Interests: Authors have no conflicts of interest to declare. Ethics Approval Statement: This study was approved by the animal ethics committee of the Second Affiliated Hospital of Zhejiang University school of medicine. All experimental procedures using animals were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. This study was approved by the Clinical Ethical Research Committee of the Second Affiliated Hospital of Zhejiang University school of medicine. The study was performed as per the tenets of Helsinki declaration. Informed consent obtained from all the participating patients.

Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson's disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA-deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria-ER contact site-resident protein C19orf12 in iPLA2-VIA-deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.

Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms.

Group V phospholipase A2 (Pla2g5) is a lipid-generating enzyme necessary for macrophage effector functions in pulmonary inflammation. However, the lipid mediators involved and their cellular targets have not been identified. Mice lacking Pla2g5 showed markedly reduced lung ILC2 activation and eosinophilia following repetitive Alternaria Alternata inhalation. While Pla2g5-null mice had Wt levels of immediate IL-33 release after one Alternaria dose, they failed to upregulate IL-33 in macrophages following repeated Alternaria administration. Unexpectedly, while adoptive transfer of bone marrow-derived (BM)-macrophages restored ILC2 activation and eosinophilia in Alternaria-exposed Pla2g5-null mice, exogenous IL-33 did not. Conversely, transfers of Pla2g5-null BM-macrophages reduced inflammation in Alternaria-exposed Wt mice. Mass spectrometry analysis of free fatty acids (FFAs) demonstrated significantly reduced FFAs (including linoleic acid (LA) and oleic acid (OA)) in lung and BM-macrophages lacking Pla2g5. Exogenous administration of LA or LA+OA to Wt mice sharply potentiated IL-33-induced lung eosinophilia and ILC2 expansion in-vitro and in-vivo. In contrast, OA potentiated IL-33-induced inflammation and ILC2 expansion in Pla2g5-null mice, but LA was inactive both in-vivo and in-vitro. Notably, Pla2g5-null ILC2s showed significantly reduced expression of the FFA-receptor-1 compared to Wt ILC2s. Thus, macrophage-associated Pla2g5 contributes significantly to type-2 immunity through regulation of IL-33 induction and FFA-driven ILC2 activation.

Correction: Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury.

[This corrects the article DOI: 10.1371/journal.pone.0169494.].

Correction: Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats

[This corrects the article DOI: 10.1371/journal.pone.0165115.].

Impact of 8-week linoleic acid intake in soy oil on Lp-PLA2 activity in healthy adults

BackgroundNo intervention follow-up study has examined the association between plasma n-6 polyunsaturated fatty acids (PUFAs) and lipoprotein-associated phospholipase A2 (Lp-PLA2), which is a risk factor for cardiovascular disease (CVD). We aimed to determine whether the administration of linoleic acid (LA, 18:2n-6) in soy oil affected Lp-PLA2 activity in healthy adults.MethodsSelf-reported healthy participants (n = 150) were randomly assigned to three groups: a low LA group, in which 10 mL soy oil was replaced with one apple; a medium LA group, in which the typical food intake was maintained; and a high LA group, in which 1/3 cup of cooked refined rice was replaced with 9.9 g of soy oil capsules daily. Plasma fatty acids and Lp-PLA2 activity were measured along with other CVD risk factors.ResultsAfter 8 weeks of treatment, plasma LA levels decreased in the low LA group and increased in the high LA group. The high LA group showed greater increases in apolipoprotein B (apoB) and oxidized low-density lipoprotein (ox-LDL) than those in the low LA group. Plasma LA levels and Lp-PLA2 activities demonstrated greater increases in the high LA group than those in the medium and low LA groups. Changes in plasma LA positively and independently correlated with changes in Lp-PLA2 activity, which was negatively correlated with changes in collagen-epinephrine closure time (CEPI-CT).ConclusionsAn increase in plasma LA following intake of soy oil was independently associated with Lp-PLA2 activity, which was also related to apoB, ox-LDL and CEPI-CT.Trial registrationClinicalTrail.gov Identifier: NCT02753907, registered 25 April 2016 (retrospectively registered).

Antioxidants Attenuate Oxidative Stress-Induced Hidden Blood Loss in Rats.

Objective:Hidden blood loss (HBL), commonly seen after total knee or hip arthroplasty, causes postoperative anemia even after reinfusion or blood transfusion based on the visible blood loss volume. Recent studies demonstrated that oxidative stress might be involved in HBL. However, whether the antioxidants proanthocyanidin (PA) or hydrogen water (HW) can ameliorate HBL remains poorly understood. The aim of this study was to evaluate the effects of PA and HW on HBL.Materials and Methods:A rat HBL model was established through administration of linoleic acid with or without treatment with PA or HW. The levels of hemoglobin (Hb), red blood cell (RBC) count, superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-PX) activity, malondialdehyde (MDA), and ferryl Hb were measured.Results:RBC and Hb values as well as the activity of SOD and GSHPX were reduced after administration of linoleic acid, which was ameliorated by treatment with PA or HW. In addition, the quantity of MDA was significantly decreased with the administration of PA or HW.Conclusion:PA and HW could ameliorate HBL in a rat model by reducing oxidative stress, suggesting that they might be used as a novel therapeutic approach in the prophylaxis or treatment of HBL in clinics.

Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury.

Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5–6 month old male Sprague Dawley rats received a focal injury (craniectomy + controlled cortical impact (CCI; n = 17)) or Sham injury (craniectomy alone; n = 12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n = 16) or saline (n = 13) every 48 h for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p = 0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p < 0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypoadrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCI-injured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p > 0.05) animals by post-injury day 29, but rapidly reversed by post-injury day 1 the hypoadrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0 s) compared to saline treated Sham animals (8.8 ± 1.7 s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCI-injured rats treated with saline (30.7 ± 5.5 s, p < 0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCI-induced hypogonadism, but does reverse craniectomy- and craniectomy + CCI-induced hypoadrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight.

Acute Effects of Intravenous Administration of Polyunsaturated Fatty Acids on Blood Pressure and Heart Rate in U46619- and Noradrenaline-infused Rats

Experimental studies and epidemiological surveys have indicated that chronic oral administration of the n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic (DHA) or eicosapentaenoic (EPA) acids reduces blood pressure in hypertensive patients. However, few reports have described the acute blood pressure lowering effects of these PUFAs. In this study, we determined the acute effects of DHA and EPA on blood pressure of rats with increased blood pressure resulting from continuous injection of pressor substances. U46619 (a TXA2 receptor agonist) and noradrenaline (NA) were continuously infused (500 μg/kg/h each) into urethane-anesthetized male Wistar rats and produced sustained elevated mean blood pressure (MBP). In both U46619- and NA-infused rats, bolus administration of DHA (3–30 mg/kg, i.v.) reduced blood pressure in a dose-dependent manner, although the MBP reduction was greater in U46619-infused rats. Similarly, administration of EPA (3–30 mg/kg, i.v.) also induced a greater reduction in MBP of U46619-infused rats. In contrast, bolus administration of linoleic acid (3–30 mg/kg, i.v.), an n-3 type unsaturated fatty acid, failed to reduce blood pressure in all drug-infused rats. Finally, administration of the nitric oxide donor sodium nitroprusside (0.3–100 μg/kg, i.v.) showed a similar blood pressure drop in all drug-infused rats. These findings clearly indicate that both DHA and EPA induce acute blood pressure reduction in anesthetized rats, and suggest that the blood pressure drop is mediated via the TXA2 receptor. These characteristic blood pressure lowering effects of these PUFAs are likely to be useful for prevention and treatment of hypertension.

Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats.

IntroductionImpaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals.ObjectivesWe investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats.MethodsDorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process.ResultsLA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αβ), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2).ConclusionsOral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis.

Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine.

Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-coupled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we examined the effect of FFAR1 activation on GLP-1 secretion using isolated, perfused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 agonists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 μmol/L TAK-875, 10 μmol/L AMG 837, 1 μmol/L and 0.1 μmol/L AM-1638, 1 μmol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P < 0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-molecule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.