3D-PHARMACOPHORE MODELLING OF OMEGA-3 DERIVATIVES WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA AS AN ANTI-OBESITY AGENT

Objective: The aim of this work was to study the pharmacophore model of omega-3 derivatives with the PPAR-γ receptor using LigandScout 4.4.3 to investigate the important chemical interactions of complex structure. Methods: The methods consisted of structure preparation of nine chemical compounds derived from omega-3 fatty acids, database preparation, creating 3D Pharmacophore modelling, validation pharmacophore, and screening test compounds. Results: The result of the research showed that the omega-3 derivatives docosahexaenoic acid (DHA), when eicosapentaenoic acid (HPA), and docosapentaenoic acid (DPA) have the best pharmacophore fit values of 36.59; 36.56; and 36.56, respectively. According to the results of the pharmacophore study, the carbonyl and hydroxyl of the carboxylate functional groups become the active functional groups that exhibit hydrogen bonding interactions. While the alkyl chain (Ethyl and methyl groups) was the portion that can be modified to increase its activity. Conclusion: Omega-3 derivatives could be used as a lead drug for the powerful PPAR-γ receptor in the prevention and treatment of obesity.

Docosahexaenoic acid-rich algae oil supplementation on breast milk fatty acid profile of mothers who delivered prematurely: a randomized clinical trial

Preterm infants are deficient in long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), a fatty acid (FA) associated with an increase in bronchopulmonary dysplasia (BPD). In two previous randomized control trials, DHA supplementation did not reduce the risk of BPD. We examined the breast milk FA profile, collected 14 days after birth, of mothers who delivered before 29 weeks of gestation and who were supplemented with DHA-rich algae oil or a placebo within 72 h after birth as part of the MOBYDIck trial. Milk FA were analyzed by gas chromatography. The total amount of FA (mg/mL) was similar in both groups but the supplementation increased DHA (expressed as % of total FA, mean ± SD, treatment vs placebo, 0.95 ± 0.44% vs 0.34 ± 0.20%; P < 0.0001), n-6 docosapentaenoic acid (DPA) (0.275 ± 0.14% vs 0.04 ± 0.04%; P < 0.0001) and eicosapentaenoic acid (0.08 ± 0.08% vs 0.07 ± 0.07%; P < 0.0001) while decreasing n-3 DPA (0.16 ± 0.05% vs 0.17 ± 0.06%; P < 0.05). Supplementation changed the ratio of DHA to arachidonic acid (1.76 ± 1.55% vs 0.60 ± 0.31%; P < 0.0001) and n-6 to n-3 FA (0.21 ± 0.06% vs 0.17 ± 0.04%; P < 0.0001). DHA-rich algae supplementation successfully increased the DHA content of breast milk but also included secondary changes that are closely involved with inflammation and may contribute to changing clinical outcomes.

Growth and Lipidomic Analyses of Penaeus monodon Larvae Supplemented With Aurantiochytrium limacinum BCC52274

Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for growth and health of larval marine animals. Marine animals have a limited capability for LC-PUFA synthesis, and the larvae must obtain LC-PUFAs from diet. The protist Aurantiochytrium limacinum (AL) is abundant in 22:6 n-3 (docosahexaenoic acid, DHA), 22:5 n-3 (docosapentaenoic acid, DPA) and 16:0 fatty acids, which qualifies it as an LC-PUFA source for feed application. Therefore, in this study, a common feed containing lower amounts of total LC-PUFAs, Thalasiosira weissflogii, was replaced with AL at graded proportions and supplied to Penaeus monodon larvae from mysis (M) 1 to post-larval (PL) 2 stages to supplement LC-PUFAs in the diet. After that, all shrimp from PL2 to PL12 were continuously reared and subjected to the same diet regime, which was a combination of Artemia and commercial dried feed. The AL-supplemented PL2 shrimp demonstrated marked accumulation of the key fatty acids present in AL—16:0, DPA and DHA. The supplemented larvae showed no difference in growth during the supplementation period from M1 to PL2; however, average body weight and biomass were increased in PL12 shrimp that were fed earlier with AL. Lipidomic analysis revealed that profiles of fatty acids but not lipid classes/subclasses in PL shrimp reflected the supplied diet. The main saturated fatty acid (SFA, 16:0) predominantly accumulated in acylglycerols, which are energy-reserve lipids, in PL2 shrimp. Both LC-PUFAs (DHA and DPA) were preferentially deposited in phospholipids or structural lipids. Furthermore, while the amounts of both LC-PUFAs increased along with the amount of supplied AL, that of the SFA did not. This suggests that LC-PUFAs were prioritized to be stored over SFA when both types of fatty acids were present in high amounts. This analysis substantiates the importance of LC-PUFAs and provides an insight into how different types of the dietary fatty acids were differentially accumulated in lipid classes and subclasses for their biological functions.

Thraustochytrids of Mangrove Habitats from Andaman Islands: Species Diversity, PUFA Profiles and Biotechnological Potential

Thraustochytrids are the most promising microbial source for the commercial production of docosahexaenoic acid (DHA) for its application in the human health, aquaculture, and nutraceutical sectors. The present study isolated 127 thraustochytrid strains from mangrove habitats of the south Andaman Islands, India to study their diversity, polyunsaturated fatty acids (PUFAs), and biotechnological potential. The predominant strains were identified as belonging to two major genera (Thraustochytrium, Aurantiochytrium) based on morphological and molecular characteristics. The strain ANVKK-06 produced the maximum biomass of 5.42 g·L−1, while ANNK-03 exhibited the maximum total lipid (71.03%). Omega-3 PUFAs such as eicosapentaenoic acid (EPA) accumulated up to 11.03% in ANVKK-04, docosapentaenoic acid (DPA) up to 8.65% in ANVKK-07, and DHA up to 47.19% in ANVKK-06. ANVKK-6 showed the maximum scavenging activity (84.79 ± 2.30%) while ANVKK-03 and ANVKK-10 displayed the highest antibacterial activity against human and fish pathogens, S. aureus (18.69 ± 1.2 mm) and V. parahaemolyticus (18.31 ± 1.0 mm), respectively. All strains were non-toxic as evident by negative blood agar hemolysis, thus, the thraustochytrids are suggested to be a potential source of DHA for application in the health care of human and fish.

The association of N ε-Carboxymethyllysine with polyunsaturated and saturated fatty acids in healthy individuals

Red blood cell (RBC) fatty acids status is used as a biomarker of dietary intake of fats however, there is still a paucity of evidence regarding individual fatty acids and modulation of endogenous advanced glycation end-product (AGE) levels. Due to membrane PUFA being a well-known target for peroxidation, we hypothesized that cellular PUFAs are positively associated with circulatory N ε-carboxymethyllysine (CML) that is also influenced by glyoxal (GO) levels in healthy cohorts. To test this, we investigated the association between RBC fatty acids and circulatory AGEs biomarkers in healthy individuals. The results showed a negative association between saturated fatty acids (SFA) and CML and stepwise multivariate regression analysis indicated stearic acid was negatively associated with CML levels (β = -0.200, p=0.008) after adjusting for age, BMI, and gender. In addition, stearic acid: palmitic acid ratio was also negatively correlated with plasma concentrations of CML (rp= -0.191, p = 0.012) and glucose (rp= -0.288, p = 0.0001). Polyunsaturated fatty acids (PUFA) showed a positive association with CML levels particularly, docosapentaenoic acid, γ-Linolenic acid, arachidonic acid, and docosadienoic acid. However, these associations were not evident after the multiple regression analysis adjusted for age, BMI, and gender. A strong negative correlation (rp= -0.98, p&lt; 0.0001) between total PUFA and total SFA was observed. Furthermore, the SFA:PUFA ratio was inversely correlated with CML (rp= -0.227, p&lt; 0.003). Overall, this study indicates that different fats and their combinations may influence the formation of AGEs and that carefully controlled interventions are required to further test this hypothesis.

Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice

Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).

Lipid Mediator n-3 Docosapentaenoic Acid-Derived Protectin D1­(PD1n-3DPA) Enhances Synaptic Inhibition of Hippocampal Principal Neurons by Interaction with a G-Protein Coupled Receptor

Epilepsy is a severe neurological disease manifested by spontaneous recurrent seizures due to abnormal hyper-synchronisation of neuronal activity. Epilepsy affects about 1% of the population and up to 40% of patients experience seizures that are resistant to currently available drugs, thus highlighting an urgent need for novel treatments. In this regard, anti-inflammatory drugs emerged as potential therapeutic candidates. In particular, specific molecules apt to resolve the neuroinflammatory response occurring in acquired epilepsies have been proven to counteract seizures in experimental models, and in humans. One candidate investigational molecule has been recently identified as the lipid mediator n-3 docosapentaenoic acid-derived protectin D1(PD1 n-3DPA ) which significantly reduced seizures, cell loss and cognitive deficit in a mouse model of acquired epilepsy. However, the mechanisms that mediate PD1 n-3DPA effect remain elusive. We here addressed whether PD1 n-3DPA has direct effects on neuronal activity independent on its anti-inflammatory action. We incubated therefore hippocampal slices with PD1 n-3DPA and investigated its effect on excitatory and inhibitory synaptic inputs to the CA1 pyramidal neurons. We demonstrate that inhibitory drive onto the perisomatic region of the pyramidal neurons is increased by PD1 n-3DPA , and this effect is mediated by pertussis toxin-sensitive G-protein coupled receptors. Our data indicate that PD1 n-3DPA acts directly on inhibitory transmission, most likely at presynaptic site of inhibitory synapses as also supported by oocyte and immunohistochemical experiments. Thus, in addition to its anti-inflammatory effects, PD1 n-3DPA anti-seizure and neuroprotective effects may be mediated by its direct action on neuronal excitability by modulating their synaptic inputs.

Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher).

7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway

Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the current study, we first confirmed the anti-inflammatory effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), a novel DHA dihydroxy derivative synthesized in our previous work. We found that diHEP-DPA significantly reduced lipopolysaccharide (LPS)-induced inflammatory cytokines secretion of THP1 macrophages, IL-6, and TNF-α. As expected, diHEP-DPA also modulated TAM polarization, as evidenced by decreased gene and protein expression of the TAM markers, CD206, CD163, VEGF, and TGF-β1. During the polarization process, diHEP-DPA treatment decreased the concentration of TGF-β1, IL-1β, IL-6, and TNF-α in culture supernatants via inhibiting the NF-κB pathway. Moreover, diHEP-DPA blocked immunosuppression by reducing the expression of SIRPα in TAMs and CD47 in colorectal cancer cells. Knowing that an inflammatory TME largely serves to support epithelial-mesenchymal transition (EMT) and cancer stemness, we tested whether diHEP-DPA acted through polarization of TAMs to regulate these processes. The intraperitoneally injected diHEP-DPA inhibited tumor growth when administered alone or in combination with 5-fluorouracil (5-FU) chemotherapy in vivo. We further found that diHEP-DPA effectively reversed TAM-conditioned medium (TCCM)-induced EMT and enhanced colorectal cancer stemness, as evidenced by its inhibition of colorectal cancer cell migration, invasion and expression of EMT markers, as well as cancer cell tumorspheres formation, without damaging colorectal cancer cells. DiHEP-DPA reduced the population of aldehyde dehydrogenase (ALDH)-positive cells and expression of colorectal stemness marker proteins (CD133, CD44, and Sox2) by modulating TAM polarization. Additionally, diHEP-DPA directly inhibited cancer stemness by inducing the production of reactive oxygen species (ROS), which, in turn, reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). These data collectively suggest that diHEP-DPA has the potential for development as an anticancer agent against colorectal cancer.