REVIEW | doi:10.20944/preprints202104.0665.v3
Subject: Keywords: Arachidonic acid, 20:4n-6; Brain; Docosahexaenoic acid, 22:6n-3; Fetus; Maternal diet; Cognitive; Infants; Neurodevelopment; Neurogenesis
Online: 14 June 2021 (14:54:08 CEST)
During the last trimester of gestation and for the first 18 months after birth, both docosahexaenoic acid,22:6n-3 (DHA) and arachidonic acid,20:4n-6 (ARA) are preferentially deposited within the cerebral cortex at a rapid rate. Although, the structural and functional roles of DHA in brain development are well investigated, similar roles of ARA are not well documented. The mode of action of these two fatty acids and their derivatives at different structural-functional roles and their levels in the gene expression and signaling pathways of the brain have been continuously emanating. In addition to DHA, importance of ARA has been much discussed in recent years for fetal and postnatal brain development and the maternal supply of ARA and DHA. These fatty acids are also involved in various brain developmental processes; however, their mechanistic cross talks are not clearly known yet. This review describes the importance of ARA, in addition to DHA to support the optimal brain development and growth and functional roles in the brain.
ARTICLE | doi:10.20944/preprints202201.0307.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Docosahexaenoic acid; Chemoprevention; Bcl-2 family; Experimental Study; Hamster Buccal Pouch Carcinogenesis.
Online: 20 January 2022 (13:41:39 CET)
The purpose of the current study was directed to investigate the effectiveness of docosahexaenoic acid (DHA) as a chemopreventive agent on experimentally induced hamster buccal pouch (HBP) carcinogenesis; Material and methods: 40 Syrian male hamsters, five weeks old, were divided into 4 groups of 10 animals in each as follows, GI: Topical application of liquid paraffin alone (thrice a week for 14 weeks), GII: Topical application of 7, 12 dimethyl benz[a]anthracene (DMBA) alone (0.5 % in liquid paraffin, thrice a week for 14 weeks), GIII: Topical application of DMBA (0.5 % in liquid paraffin, thrice a week for 14 weeks) + Oral administration of DHA (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks on alternative days of DMBA application), GIV : Oral administration of DHA alone (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks); Results: Gross observations and histopathological findings revealed a-GI: normal stratified squamous epithelium b- GII: well and moderately differentiated squamous cell carcinoma (SCC) c-: GIII: showed variable results ranges from hyperkeratosis, hyperkeratosis and focal hyperplasia, mild dysplasia, and well differentiated SCC with superficial invasion of tumor cells not extended to deeper areas d: GIV: normal similar to GI. Immunohistochemical results revealed that oral DHA treatment to DMBA treated hamsters restored the normal expression of bcl-2; Conclusion: DHA has the potential to be a dietary chemopreventive agent due to its capacity to improve carcinogen detoxification and to block/suppress the initiation and promotion stages of experimentally produced HBP carcinogenesis.
ARTICLE | doi:10.20944/preprints201710.0157.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: docosahexaenoic acid; apoptosis; SIRT6; Hedgehog signaling; non-small cell lung cancer cells
Online: 24 October 2017 (05:43:16 CEST)
Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was associated with downregulation of Hh signaling, and knockdown of SIRT6 resulted in augmentation of Hh signaling. Pretreatment of NSCLC cells with a Smoothened agonist prevented DHA-induced decreases in the levels of Hh signaling proteins and increases in cleaved PARP levels. Moreover, endogenous production of ω3-PUFAs in PC9 cells via fat-1 expression resulted in elevated SIRT6 levels and reduced levels of Hh signaling molecules, including Gli, following DHA treatment. Overall, these results implicate that ω3-PUFAs induce apoptosis by downregulating Hh signaling via SIRT6 activation in human EGFR mutant NSCLC cells. These findings suggest that ω3-PUFAs potentially represent an effective therapy for the chemoprevention and treatment of NSCLC.
ARTICLE | doi:10.20944/preprints202112.0267.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: docosahexaenoic acid (DHA) deficiency; mitochondrial function; polyunsaturated fatty acids; membrane permeabilization; oxidative damage markers; adenine nucleotide translocase
Online: 16 December 2021 (10:57:36 CET)
The fatty acid elongase ELOngation of Very-Long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, do-cosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn6) in-vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondial-dehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with high voltage-dependent anion channel (VDAC) and adenine nucleotide trans-locase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission elec-tron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.
ARTICLE | doi:10.20944/preprints202101.0186.v1
Subject: Life Sciences, Biochemistry Keywords: Docosahexaenoic acid (DHA); long chain omega-3 fatty acids; maternal supplementation; pregnancy outcomes; anthropometry; birth weight; birth length; head circumference
Online: 11 January 2021 (11:38:57 CET)
Long-chain omega-3 fatty acid status during pregnancy may influence newborn anthropometry and duration of gestation. Evidence from high-quality trials from LMICs is limited. We conducted a double-blind, randomized, placebo-controlled trial among 957 pregnant women (singleton gestation, 14-20 weeks’ gestation at enrollment) in India to test the effectiveness of 400 mg/d algal docosahexaenoic acid (DHA) compared to placebo provided from enrollment through delivery. Among 3379 women who were screened, 1171 were found eligible; 957 enrolled and were randomized. The intervention was two microencapsulated algal DHA (200 X 2= 400 mg/d) or two microencapsulated soy and corn oil placebo tablets to be consumed daily from enrollment (20 weeks) through delivery. The primary outcome was newborn anthropometry (birth weight, length, head circumference). Secondary outcomes were gestational age and 1 and 5 min Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score. The groups (DHA; n=478 and placebo; n=479) were well balanced at baseline. There were 902 live births. Compliance with the intervention was similar across groups (DHA: 88.5%; placebo: 87.1%). There were no significant differences between DHA and placebo group for birth weight (2750.6 ± 421.5 vs. 2768.2 ± 436.6 g, p=0.54), length (47.3 ± 2.0 vs. 47.5 ±2.0 cm, p=0.13) or head circumference (33.7 ± 1.4 vs 33.8 ± 1.4 cm, p=0.15). The mean gestational age at delivery was similar between groups (DHA: 38.8 ± 1.7 placebo: 38.8 ± 1.7 wk, p= 0.54) as were APGAR scores at 1 and 5 min. Supplementing mothers through pregnancy with 400mg/d DHA did not impact the offspring birthweight, length or head circumference.
ARTICLE | doi:10.20944/preprints202107.0526.v1
Subject: Life Sciences, Biochemistry Keywords: maternal pre-gestational obesity; placenta; lipid metabolism; fatty acid transporter proteins; isoprostanoids; neuroprostanes; isoprostanes; docosahexaenoic acid; arachidonic acid
Online: 23 July 2021 (08:04:47 CEST)
The rise in prevalence of obesity in women of reproductive age in both developed and developing countries might propagate intergenerational cycles of detrimental effects on metabolic health, contributing to substantial economic burden on society. Placental lipid metabolism might be disrupted by maternal obesity, which possibly affects the life-long health of the offspring. Here, we investigated placental lipid metabolism and handling from women with pre-gestational obesity as a sole pregnancy complication and compared to placental responses of lean women. Open profile and targeted lipidomics were used to assess placental lipids and oxidized products of docosahexahenoic acid (DHA), neuroprostanes, and arachidonic acid (AA), isoprostanes. Placental fatty acid transporters FABP1, FABP3 and endothelial lipase protein were measured. Despite no signs of overall alterations in lipid content, increased contents of DHA, AA, DHA-derived neuroprostanes and AA-derived isoprostanes and decreased content of FABP1 protein were found in placentas from obese women. Multivariate analyses suggested that these oxidised fatty acids are associated with maternal and placental inflammation and also with birth weight. These results might shed light on the molecular mechanisms associated with altered fatty acid metabolism and lipid handling in maternal pre-gestational obesity, placing these oxidized fatty acids as novel mediators of placental function.
ARTICLE | doi:10.20944/preprints201701.0093.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: 22:6 docosahexaenoic acid; ω-3 fatty acids; offspring of obese mothers; offspring of lean mothers; insulin-dependent skeletal muscle glucose uptake
Online: 20 January 2017 (04:59:25 CET)
Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. Circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women and who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: 37 elderly women were separated into an elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using 1H-NMR and also insulin-dependent tissue specific glucose uptake in skeletal muscle were assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the 22:6 docosahexaenoic acid percentage of the total long chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (P = 0.015). DHA/FA associated significantly to skeletal muscle GU (P = 0.031) and M-value in the OLM group only (P = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and that this association is significantly weakened in the offspring of obese mothers.
ARTICLE | doi:10.20944/preprints201807.0065.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: hypothalamus; insulin resistance; inflammation; docosahexaenoic acid; PI3K inhibitor; AKT
Online: 4 July 2018 (09:58:03 CEST)
Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin resistance, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect seems involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented palmitate-induced insulin resistance. Similarly to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented palmitate-induced insulin resistance after 12 h. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier time points.
Subject: Life Sciences, Biotechnology Keywords: single cell oil; biomass; PUFA; docosahexaenoic acid (DHA); fish byproducts; biodiesel
Online: 5 August 2019 (04:13:54 CEST)
The following study reports on the first thraustochytrid isolates identified from Iceland. They were collected from three different locations off the northern coast of the country (Location A, Skagaströnd; Location B, Hveravík; and Location C, Eyjafjörður). Using 18S rDNA sequence analysis, isolates from Locations A and B were identified within the Thraustochytrium kinnei species while other isolates within the Sicyoidochytrium minutum species when compared to other known strains. Cells isolated from Locations A (2.10 ± 0.70 g/L) and B (1.54 ± 0.17 g/L) produced more biomass than the ones isolated from Location C (0.43 ± 0.02 g/L). This study offers the first-time examination of the utility of byproducts from fisheries as a nitrogen source in media formulation for thraustochytrids. Experiments showed that isolates produced more biomass (per unit of substrate) when cultured on nitrogen of marine (2.55 ± 0.74 g/L) as compared to of commercial origin (1.06 ± 0.57 g/L). Glycerol (2.43 ± 0.56 g/L) was a better carbon source than glucose (1.84 ± 0.57 g/L) in growth studies. Fatty acid (FA) profiles showed that the isolates from Location C (S. minutum) had low ratios of monounsaturated (4.21 ± 2.96%) and omega-6 (0.68 ± 0.59%) FAs. However, the isolates also had high ratios of docosahexaenoic acid (DHA; 35.65 ± 1.73%) and total omega-3 FAs (40.39 ± 2.39%), indicating that they could serve as a source of marine oils for human consumption and in aquaculture feeds. The T. kinnei isolates from Location A could be used in biodiesel production due to their high ratios of monounsaturated (18.38 ± 6.27%) long chain (57.43 ± 8.27%) FAs.
ARTICLE | doi:10.20944/preprints202112.0228.v1
Subject: Life Sciences, Biophysics Keywords: lipofuscin; retina; retinal pigment epithelium; docosahexaenoate; docosahexaenoic acid; fluorescence; photodegradation; photobleaching; cell viability; endocytic activity
Online: 14 December 2021 (11:41:14 CET)
Retinal lipofuscin accumulates with age in the retinal pigment epithelium (RPE) where its fluorescence properties are used to assess the retinal health. It was observed that there is a decrease in lipofuscin fluorescence above the age of 75 years and in early stages of age-related macular degeneration (AMD). The purpose of this study was to investigate the response of lipofuscin isolated from human RPE, and lipofuscin-laden-cells to visible light, and determine whether an abundant component of lipofuscin, docosahexaenoate (DHA) can contribute to lipofuscin fluorescence upon oxidation. Exposure of lipofuscin to visible leads to a decrease of its long-wavelength fluorescence at about 610 nm with concomitant growth of the short-wavelength fluorescence. The emission spectrum of photodegraded lipofuscin exhibits similarity with that of oxidized DHA. Exposure to light of lipofuscin-laden cells leads to loss of lipofuscin granules from cells, while retaining cell viability. The spectral changes of fluorescence in lipofuscin-laden cells resemble those seen during photodegradation of isolated lipofuscin. Our results demonstrate that fluorescence emission spectra together with quantitation of intensity of long-wavelength fluorescence can serve as a marker useful for lipofuscin quantification and for monitoring its oxidation, thereby useful for screening the retina for increased oxidative damage and early AMD-related changes.
ARTICLE | doi:10.20944/preprints201806.0119.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: preterm infant; enteral nutrition; lipids; omega-3 fatty acids; omega-6 fatty acids; Docosahexaenoic acid; Arachidonic acid; long-chain polyunsaturated fatty acids.
Online: 7 June 2018 (11:34:53 CEST)
Human milk fat is a concentrated source of energy and provides essential and long chain polyunsaturated fatty acids. According to previous experiments, human milk fat is partially lost during continuous enteral nutrition. However, these experiments were done over relatively short infusion times, and a complete profile of the lost fatty acids was never measured. Whether this lost happens considering longer infusion times or if some fatty acids are lost more than others remain unknown. Pooled breast milk was infused through a feeding tube by a peristaltic pump over a period of 30 minutes and 4, 12 and 24 hours at 2 ml/hour. Adsorbed fat was extracted from the tubes, and the fatty acid composition was analyzed by Gas chromatography-mass spectrometry. Total fat loss (average fatty acid loss) after 24 hours was 0.6 ± 0.1%. Short-medium chain (0.7%, p=0.15), long chain (0.6%, p=0.56) saturated (0.7%, p=0.4), monounsaturated (0.5%, p=0.15), polyunsaturated fatty (0.7%, p=0.15), linoleic (0.7%, p=0.25), and docosahexaenoic acids (0.6%, p=0.56) were not selectively adsorbed to the tube. However, very long chain fatty (0.9%, p=0.04), alpha-linolenic (1.6%, p=0.02) and arachidonic acids (1%, p=0.02) were selectively adsorbed and therefore lost in a greater proportion than other fatty acids. In all cases, the magnitude of the loss was clinically low.
REVIEW | doi:10.20944/preprints201710.0006.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: essential fatty acids; ascorbic acid; glutathione; aging; parkinson’s disease; alzheimer’s disease; senescence; nervous system; growth factors; neuroprotection; docosahexaenoic acid; α-linolenic acid.
Online: 2 October 2017 (08:59:13 CEST)
Polyunsaturated fatty acids (PUFAs) and antioxidants are important mediators in the central nervous system (CNS). Lipid derivatives may be used to generate endocannabinoids or prostanoids derived from arachidonic acid, which attenuates excitotoxicity in quadripartite synapses with a focus in astrocytes and microglia; on the other hand, antioxidants, such as glutathione (GSH) and ascorbate, have been shown to signal through transmitter receptors and protect against acute and chronic oxidative stress, modulating the activity of different signaling pathways. Several authors have investigated the role of these nutrients in young and senescent brain, as well as in degenerative conditions such as Alzheimer’s and Parkinson's diseases. Through literature review, we aimed to highlight recent data on the role of fatty acids, antioxidants and physical activity in physiology and in molecular mechanisms of brain senescence. Data indicate the complexity and essentiality of endogenous/dietary antioxidants for maintenance of the redox status and control of neuroglial signaling under stress. Recent studies also indicate that omega-3 and -6 fatty acids act in a competitive manner to generate mediators for energy metabolism, feeding behavior, plasticity and memory mechanisms throughout aging. Finding pharmacological or dietary resources that mitigate or prevent neurodegenerative affections continues to be a great challenge and require additional efforts from researchers, clinicians and nutritionists in the field.