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Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and treatment of COVID-19. This proposal is supported by the observation that (i) macrophages and T cells (including NK cells, cytotoxic killer cells and other immunocytes) release AA and other BALs especially in the lungs to inactivate various microbes; (ii) pro-inflammatory metabolites prostaglandin E2 (PGE2) and leukotrienes (LTs) and anti-inflammatory lipoxin A4 (LXA4) derived from AA (similarly, resolvins, protectins and maresins derived from eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) facilitate the generation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages respectively; (iii) AA, PGE2, LXA4 and other BALs inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) synthesis; (iv) mesenchymal stem cells (MSCs) that are of benefit in COVID-19 elaborate LXA4 to bring about their beneficial actions and (v) subjects with insulin resistance, obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and the elderly have significantly low plasma concentrations of AA and LXA4 that may render them more susceptible to SARS-CoV-2 infection and cytokine storm that is associated with increased mortality seen in COVID-19. Statins, colchicine, and corticosteroids that appear to be of benefit in COVID-19 can influence BALs metabolism. AA, and other BALs influence cell membrane fluidity and thus, regulate ACE-2 (angiotensin converting enzyme-2) receptors (the ligand through which SARS-CoV2 enters the cell) receptors. These observations lend support to the contention that administration of BALs especially, AA could be of significant benefit in prevention and management of COVI-19 and other enveloped viruses., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Objective: To study whether resolvin D1 (RvD1), a metabolite of docosahexaenoic acid (DHA), prevents NA-STZ-induced type 2 diabetes mellitus (type 2 DM) in vivo and if so, what could be the mechanism of this action., Material and Methods: Single intra-peritoneal (i.p) injection of NA-STZ (175 mg/kg body weight of NA and 65 mg/kg of STZ) was injected simultaneously with RvD1 (60 ng/animal) (injected for 5 consecutive days) to Wistar rats. The effect of RvD1 on plasma glucose levels and apoptotic (Bcl2/Bax) and inflammatory (NF-κB/iNOS) protein expression, plasma lipoxin A4 and BDNF (brain-derived neurotrophic factor) were studied. Protein expressions of PI3k-Akt-mTOR pathway along with histopathological studies of brain were also evaluated., Results: NA-STZ-induced type 2 DM rats showed hyperglycemia, enhanced plasma IL-6/TNF-α (p ≤0.01), reduced plasma BDNF (p ≤0.01) and LXA4 (p ≤0.01) levels and low BDNF in pancreatic, hepatic and brain tissues (p <0.001), which were restored to near normal (p ≤0.01) in RvD1 treated group. RvD1 increased insulin sensitivity by suppressing inflammation (NF-κB/iNOS) (p ≤0.01) and decreasing apoptosis (Bcl2/Bax) and restoring BDNF and LXA4 levels to near normal. RvD1 treatment increased phosphorylation of Akt (Ser473), and subsequent activation (phosphorylation) of downstream signaling molecules of PI3K and mTOR indicating that RvD1 acts through PI3K/Akt/mTOR axis., Discussion: RvD1 is effective in preventing NA-STZ-induced type 2 DM in vivo by suppressing oxidative damage, enhancing the production of anti-inflammatory LXA4 and enhancing neuronal cell survival by augmenting the production of BDNF. Thus, RvD1 may be of benefit not only in preventing diabetes mellitus but also diabetes associated Alzheimer's disease and memory loss., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2, SARS and MERS are all enveloped viruses that can cause acute respiratory syndrome. Arachidonic acid (AA) and other unsaturated fatty acids (especially eicosapentaenoic acd, EPA and docosahexaenoic acid DHA) are known to inactivate enveloped viruses and inhibit proliferation of various microbial organisms. The pro-inflammatory metabolites of AA and EPA such as prostaglandins, leukotrienes and thromboxanes induce inflammation whereas lipoxins, resolvins, protectins and maresins derived from AA, EPA and DHA not only suppress inflammation but also enhance would healing and augment phagocytosis of macrophages and other immunocytes and decrease microbial load. In view of these actions, it is suggested that AA and other unsaturated fatty acids and their metabolites may serve as endogenous anti-viral compounds and their deficiency may render humans susceptible to SARS-CoV-2, SARS and MERS and other similar viruses' infections. Hence, oral or intravenous administration of AA and other unsaturated fatty acids may aid in enhancing resistance and recovery from SARS-CoV-2, SARS and MERS infections., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Resveratrol modulates the transcription factor NF-κB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the effects of arachidonic acid (AA)-rich ARASCO oil on high-fat diet (HFD) + streptozotocin (STZ)-induced diabetes mellitus in male Wistar rats and its possible mechanisms of action., Methods: Male Wistar rats with HFD + STZ-induced diabetes were employed in the present study. ARASCO oil was administered orally for the first 7 d consecutively, followed by once weekly throughout the study (14 wk). At various time points, blood glucose and body weight and oral glucose tolerance tests were measured. At the end of the study, animals were sacrificed to collect plasma and various organs and stored at -80°C. Plasma insulin, tumor necrosis factor-α, interleukin-6, and lipoxin A4 were measured. Expression of the following genes was determined: nuclear factor-κΒ (NF-κB), cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) in pancreas and lipocalin 2 (LPCLN2) in adipose tissue. Various antioxidants were measured in the plasma and other tissues. Area under the curve and insulin sensitivity index were assessed by computing homeostatic model of assessment for insulin resistance, quantitative insulin check index, Matsuda, and Belfiore indices., Results: ARASCO oil treatment decreased hyperglycemia, restored insulin sensitivity, suppressed inflammation, enhanced plasma lipoxin A4 levels, and reversed altered antioxidant status to near normal in animals with HFD + STZ-induced diabetes., Conclusion: These results suggest that ARASCO, a rich source of AA, can prevent HFD + STZ-induced diabetes in Wistar rats owing to its anti-inflammatory action. It remains to be seen whether ARASCO oil is useful in preventing or postponing the development of type 2 diabetes mellitus in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is desired to selectively kill tumor cells with little or no action on normal cells. Current treatment options are associated with significant side effects including therapy with immune check point inhibitors (ICI). ICI therapy induced side effects are due to excess production of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). At the same time, production of appropriate amounts of IL-6 and TNF-α are needed to eliminate tumor cells. Hence, methods are needed that can selectively eliminate tumor cells and tone down the side effects of cytokine storm. Studies showed that IL-6 and TNF-α activate phospholipases to induce the release of polyunsaturated fatty acids (PUFAs) from the cell membrane phospholipid pool. PUFAs form precursors to pro- and anti-inflammatory eicosanoids and are capable of suppressing IL-6 and TNF-α excess production. PUFAs are endowed with capacity to selectively kill tumor cells by augmenting free radical generation and accumulation of toxic lipid peroxides in tumor but not normal cells. NK cells, TILs (tumor infiltrating cells) and γδ T cells release toxic granules (also called as cytolytic granules) that contain unsaturated fatty acids localized between the granule delimiting membrane and the granule core. Thus, lipids are a universal component of cytolytic granules and play an important role in their cytotoxic actions. Based on this evidence, it is suggested that a combination of ICI/TILs and PUFAs may form a novel method of eliminating cancer with few side effects., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

It is suggested that supplementation of vitamin C reduces hyperglycemia and lowers blood pressure in hypertensives by enhacing the formation of prostaglandin E1 (PGE1), PGI2 (prostacyclin), endothelial nitric oxide (eNO), and restore essential fatty acid (EFA) metabolism to normal and enhance the formation of lipoxin A4 (LXA4), a potent anti-inflammatory, vasodilator and antioxidant. These actions are in addition to the ability of vitamin C to function as an antioxidant. In vitro and in vivo studies revealed that PGE1, PGI2 and NO have cytoprotective and genoprotective actions and thus, protect pancreatic β and vascular endotheilial cells from the cytotoxic actions of endogenous and exogenous toxins. AA, the precursor of LXA4 and LXA4 have potent anti-diabetic actions and their plasma tissue concentrations are decreased in those with diabetes mellitus and hypertension. Thus, vitamin C by augmenting the formation of PGE1, PGI2, eNO, LXA4 and restoring AA content to normal may function as a cytoprotective, anti-mutagenic, vasodilator and platelet anti-agregator actions that explains its benefical action in type 2 diabetes mellitus and hypertension., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to observe whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5 F) cells against streptozotocin (STZ)-induced apoptosis in vitro and type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) in vivo and if so, what would be the mechanism of this action., Methods: RIN5 F cells were used for the in vitro study, whereas the in vivo study was performed in Wistar rats. STZ was used to induce apoptosis of RIN5 F cells in vitro and T1- and T2DM in vivo. The effect of PUFAs: γ-linolenic acid (GLA), arachidonic acid (AA) of ω-6 series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of ω-3 series; cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors and antiinflammatory metabolite of AA and DHA, lipoxin A4 (LXA4), and resolvin D2 and protectin, respectively against STZ-induced cytotoxicity to RIN5 F cells in vitro and LXA4 against T1- and T2DM in vivo was studied. Changes in the antioxidant content, lipid peroxides, nitric oxide, and expression of PDX1, P65, nuclear factor-κb (NF-κb), and IKB genes in STZ-treated RIN5 F cells in vitro and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue of T1- and T2DM and LPCLN2 (lipocalin 2), NF-κb, IKB I in adipose tissue of T2DM after LXA4 treatment were studied. Plasma glucose, insulin, and tumor necrosis factor (TNF)-α levels also were measured in STZ-induced T1- and T2DM Wistar rats., Results: Among all PUFAs tested, AA and EPA are the most effective against STZ-induced cytotoxicity to RIN5 F cells in vitro. Neither COX nor LOX inhibitors blocked the cytoprotective action of AA in vitro and T1- and T2DM by STZ. LXA4 production by RIN5 F cells in vitro and plasma LXA4 levels in STZ-induced T1- and T2DM animals were decreased by STZ that reverted to normal after AA treatment. AA prevented both T1- and T2DM induced by STZ. Antiinflammatory metabolite of AA and LXA4 prevented both T1- and T2DM induced by STZ. The expression of Pdx1, NF-κb, IKB genes in the pancreas and plasma TNF-α levels in T1- and T2DM; Nrf2, Glut2, COX2, and iNOS proteins in pancreatic tissue of T1DM and LPCLN2, NF-κb, IKB I in adipose tissue of T2DM reverted to normal in LXA4-treated animals., Conclusion: Both AA and LXA4 prevented STZ-induced cytotoxicity to RIN5 F cells in vitro and T1- and T2DM in vivo, suggesting that these two bioactive lipids may function as antidiabetic molecules. AA is beneficial against STZ-induced cytotoxicity and T1- and T2DM by enhancing the production of LXA4., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Evidence suggests that quantity and quality of dietary polyunsaturated fatty acids (PUFAs) play a role in the development of cancer. However, the mechanisms involved in this interaction(s) are not clear. Endocannabinoids are lipid metabolites known to have growth modulatory actions. We studied the effect of supplementation with PUFAs ω-6 and ω-3 (essential fatty acids, EFAs), saturated and monounsaturated fatty acids (non-EFAs) on the growth of tumor cells and modifications in their endocannabinoid content., Methods: Cell cultures of human glioblastoma (T98G) and breast cancer (MCF7) were supplemented with 50 or 100 mmol EFAs and non-EFAs for 72 h. Cell proliferation was then determined by MTT, anandamide (AEA) levels by HPLC, total fatty acids profiles by GLC, CB1 receptor expression by WB and FAAH activity by spectrophotometric method., Results: Fatty acids profile reflected the incorporation of the lipids supplemented in each assay. Arachidonic acid (EFA ω-6) supplementation increased AEA levels and inhibited the growth of T98G, whereas palmitic acid (non-EFA) enhanced their proliferation. In breast cancer (MCF7) cells, eicosapentaenoic acid (EFA ω-3) reduced and oleic acid (non-EFA) enhanced their proliferation. CB1 expression was higher in T98G and no differences were observed in FAAH activity., Conclusions: The growth of tumor cells can be differentially modulated by fatty acids and, at least in part, can be attributed to their ability to act on the components of the endocannabinoid system., (Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.)

Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs))}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Flavonoid resveratrol modulates the transcription factor NF-κB; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms-like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor-α; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma phospholipid concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), the precursors of lipoxins (from AA), resolvins (from EPA and DHA), and protectins (from DHA) and prostaglandin E1 (PGE1 from DGLA: dihomo-γ-linolenic acid) and prostacyclin (PGI2 derived from AA). Based on these evidences, it is proposed that preeclampsia may occur due to deficiency of PUFAs and their anti-inflammatory products: lipoxins, resolvins, protectins, and maresins., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma., Methods: BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry., Results: TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05)., Conclusions: This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model., (Published by Elsevier Inc.)

Nutritional factors such as magnesium, folic acid, vitamins B12 and B6, L-arginine, and polyunsaturated fatty acids (PUFAs) appear to be significantly beneficial for patients with coronary artery disease (CAD), and in the prevention and arresting the progression of HF and cardiac arrhythmias. Additionally, ingestion of adequate amounts of protein and maintaining normal concentrations of plasma albumin seem to be essential for these patients. These nutrients closely interact with the metabolism of L-arginine-nitric oxide (NO) system, essential fatty acids, and eicosanoids such that beneficial products such as NO, prostaglandin E1, prostacyclin, prostaglandin I3, lipoxins, resolvins, and protectins are generated and synthesis of proinflammatory cytokines is suppressed that results in platelet anti-aggregation, vasodilation, angiogenesis, and prevention of CAD, cardiac arrhythmias, and stabilization of HF. This implies that individuals at high risk for CAD, cardiac arrhythmias, and HF and those who have these diseases need to be screened for plasma levels of magnesium, folic acid, vitamins B12 and B6, L-arginine, NO, various PUFAs, lipoxin A4, resolvins, protectins, asymmetrical dimethylarginine (an endogenous inhibitor of NO), albumin, and various eicosanoids and cytokines and correct their abnormalities to restore normal physiology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance; inflammation; oxidative stress; vascular damage; and dysfunction of glucose, protein, and lipid metabolisms. However, comparatively less attention has been paid to neurologic alterations seen in elderly individuals with type 2 diabetes. We review clinical, metabolic, and biochemical aspects of diabetic encephalopathy (DE) and propose that quality of dietary lipids is closely linked to DE. This implies that preventive nutritional interventions may be designed to improve DE., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Aims: Many studies show that fish oil with high content of n-3 polyunsaturated fatty acids (PUFAs) plays an important role in human health and disease. But the effects of fish oil with high content of PUFAs on gut microbiota, which are also known play a significant role in several human diseases, is not clear. In the present study we evaluated the effects of fish oil with high content of n-3 PUFAs on gut microbiota., Methods: Changes in gut microbiota in ICR mice after supplementation of fish oil (containing eicosapentaenoic acid and docosahexaenoic acid: ∼40 and 27% respectively) for 15 days was characterized using the hypervariable V3 region of the 16 rRNA gene-based polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) profiling, DNA sequencing, and phylogenetic analysis techniques., Results: Fish oil treatment resulted in a decrease in Helicobacter, Uncultured bacterium clone WD2&#95;aaf07d12 (GenBank: EU511712.1), Clostridiales bacterium, Sphingomonadales bacterium and Pseudomonas species Firmicutes, and several uncultured bacteria., Conclusions: Fish oil with a high content of n-3 PUFAs are capable of producing significant changes in the gut microbiota that may, at least in part, explain the health benefits or injury induced by fish oil use., (Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effect of effect of Yellow Capsicum extract (YCE) that is rich in capsaicin on the proliferation and differentiation of 3T3-L1 preadipocytes in vitro., Methods: 3T3 L1 cells that were exposed to differentiation-inducing medium containing high glucose DMEM (Dulbecco's Modified Eagle's Medium) and subsequently were treated with capsaicin and YCE for their effect on adipocyte differentiation, changes in their triglyceride content, leptin secretion, expression of lipoprotein lipase, PPARγ, and CCAAT/enhancer-binding protein alpha (C/EBPα)., Results: Both YCE and capsaicin inhibited proliferation and differentiation 3T3-L1 preadipocytes and suppressed accumulation of intracellular triglyceride in a dose-dependent manner. In addition, a significant decrease in the expression of lipoprotein lipase (LPL), leptin, PPARγ, and C/EBPα was noted in 3T3-L1 preadipocytes when induced to differentiate by YCE and Capsaicin., Conclusions: The potent inhibitory action of YCE and Capsaicin on the differentiation of 3T3-L1 preadipocyte observed suggests that they (YCE and Capsaicin) have the potential to inhibit obesity that needs to be explored in future studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Aims: Both oxidative stress and inflammation play a significant role in the pathobiology of diabetic retinopathy. Increased consumption of polyunsaturated fatty acids (PUFAs) may prevent or postpone the occurrence of diabetic retinopathy. Hence, the effect of α-linolenic acid (ALA), an essential fatty acid, on oxidative stress, inflammatory indices and production of vascular endothelial growth factor (VEGF) in streptozotocin-induced diabetic retinopathy indices in vivo was studied., Methods: Serum and retina concentrations of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), plasma and retina concentrations of lipid peroxides and antioxidant enzymes were estimated in streptozotocin (STZ)-induced diabetic animals., Results: STZ-induced diabetic rats had significantly higher levels of VEGF in the serum and retina and IL-6 in the serum, whereas BDNF was lower in the serum, all of which reverted to near normal in ALA-treated diabetic animals. STZ treatment decreased serum glutathione peroxidase levels, which was restored to normal by both pre- and post-ALA treatment groups., Conclusions: STZ-induced changes in serum glutathione peroxidase, BDNF, VEGF and IL-6 that reverted to near control by ALA treatment, especially in ALA + STZ group, lending support to the concept that both oxidative stress and inflammation participate in DR and ALA treatment is of benefit in its prevention., (Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.)

Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Diabetic macular edema and retinopathy are low-grade inflammatory conditions. Infusions of antitumor necrosis factor-α (anti-TNF-α) antibody and antivascular endothelial growth factor (anti-VEGF) antibody have been shown to be at least partly effective in the treatment of diabetic macular edema and proliferative diabetic retinopathy. Intravitreal therapy of diabetic macular edema by the anti-TNF-α antibody has been found to produce significant side effects and anti-VEGF therapy to be ineffective. Nevertheless, these studies have indicated that the suppression of TNF-α and other proinflammatory cytokines and VEGF could be of benefit in diabetic macular edema and retinopathy. The retina is rich in polyunsaturated fatty acids, especially in ω-3, and several studies have shown that polyunsaturated fatty acids prevent diabetic retinopathy. Lipoxins, resolvins, and protectins derived from various polyunsaturated fatty acids possess anti-inflammatory actions and suppress the production of interleukin-6, and TNF-α and VEGF have antiangiogenic actions. In view of these evidences, I propose that lipoxins, resolvins, and protectins could be of significant benefit in the prevention and management of diabetic macular edema and retinopathy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The inflammatory process seen in multiple sclerosis is due to an excess production of proinflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-α, interferons, macrophage migration inhibitory factor, HMGB1 (high mobility group B1), and, possibly, a reduction in antiinflammatory cytokines IL-10, IL-4, and transforming growth factor-β that leads to increased secretion of reactive oxygen species, including nitric oxide, resulting in neuronal damage. It is suggested that failure of production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation and reactive oxygen species production, enhance wound healing, and have neuroprotective properties results in inappropriate inflammation and delay in the healing/repair process, and so neuronal damage continues, as seen in multiple sclerosis. Hence, methods designed to enhance the production and/or administration of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of multiple sclerosis and other similar autoimmune diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Proinflammatory cytokines and essential fatty acids (EFAs) and their metabolites are altered in coronary heart disease, stroke, diabetes mellitus, hypertension, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases, indicating that these diseases not only are low-grade systemic inflammatory conditions but also have defects in the metabolism of EFAs. EFAs and their metabolites such as eicosanoids, lipoxins, resolvins, protectins, maresins, and nitrolipids are biologically active molecules that regulate gene expression and enzyme activity, modulate inflammation, the immune response, and gluconeogenesis by direct and indirect pathways, function directly as agonists of a number of G-protein-coupled receptors, and thus regulate several cellular processes. EFAs and their metabolites activate phosphatidylinositol 3-kinase/murine thymoma viral oncogene homolog 1 (Akt) and p44/42 mitogen-activated protein kinases and stimulate gluconeogenesis and cell proliferation by Ca(2+), phospholipase C/protein kinase, events that are also necessary for stem cell proliferation. Stem cells are pluripotent and expected to be of benefit in the management of many clinical conditions. Therefore, I propose that the beneficial actions of EFAs and their metabolites seen in coronary heart disease, stroke, diabetes mellitus, hypertension, atherosclerosis, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases could be ascribed to their ability to enhance the proliferation and differentiation of embryonic stem cells in addition to their capacity to suppress inflammation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obesity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mechanisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that regulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotrophic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion, and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut, liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that management of obesity needs a multifactorial approach., (Copyright 2010 Elsevier Inc. All rights reserved.)

The laminin tyrosine-isoleucine-glycine-serine-arginine (YIGSR) peptide, corresponding to the 929-933 sequence of beta1 chain, is known to inhibit tumor growth and metastasis. In the present study, we observed that YIGSR not only inhibited the growth and migration of prostate cancer cells in a dose-dependent manner but also decreased mitochondrial membrane potential, inhibited ATP synthesis and increased caspase-9 activity. Investigation into the interaction of YIGSR with 67LR, the receptor for laminin and polyphenol (-) epigallocatechin-3-gallate (EGCG) employing MVD (Molegro Virtual Docker, an integrated platform for predicting protein ligand interactions), revealed that the binding site of YIGSR was the same as that of EGCG that explains as to why YIGSR is able to inhibit the cytotoxicity of EGCG against PC-3 cells.

Objective: In the present study we evaluated the effect of exercise on the plasma levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory molecule uric acid in the Zucker diabetic fatty (ZDF) rats that are more prone to develop type 2 diabetes mellitus., Methods: Sixteen obese ZDF (Gmi fa/fa) rats (8 wk old, 228.40 +/- 4.05 g) were randomly assigned to one of two groups (n = 8 each): an exercise-trained group and a sedentary one. In addition, 16 lean ZDF (Gmi +/+) rats (8 wk old, 199.00 +/- 3.50 g) were subjected to identical sedentary and exercise conditioning (n = 8 each). Initially, rats swam 15 min/d (5 d/wk) in a 36 degrees C bath. The exercise protocol was gradually increased by 15 min/d until a swimming period of 1 h/d (1 wk) was attained. Thereafter, rats swam 1 h/d, 3 d/wk, for an additional period of 11 wk. Rats were sacrificed 48 h after the last training period and the blood and pancreas were collected. Circulating levels of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, insulin, uric acid, IL-6, and TNF-alpha were assessed. The concentrations of proinflammatory cytokines in the pancreas were also evaluated., Results: In the diabetic ZDF (fa/fa) rats, exercise decreased hyperuricemia (-37.3%) and IL-6 and TNF-alpha levels (-16.9% and -12.7% respectively) and maintained the weight of the pancreas at near normal. Immunohistochemistry revealed a marked decrease in the expression of TNF-alpha and IL-6 in the pancreatic islet cells of ZDF (fa/fa) rats., Conclusion: These results indicate that aerobic exercise is anti-inflammatory in nature.

An imbalance between pro- and anti-inflammatory molecules occurs in metabolic syndrome X. High-energy diet, saturated fats and trans-fats during perinatal period could suppress Delta(6) and Delta(5) desaturases both in the maternal and fetal tissues, resulting in a decrease in the concentrations of long-chain polyunsaturated fatty acids (LCPUFAs): arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that have a negative feedback control on inflammation. EPA, DHA and AA augment endothelial nitric oxide synthesis, potentiate insulin action both in the peripheral tissues and brain and alter leptin production. LCPUFAs are essential for brain growth and development and synaptogenesis and modulate the action of several neurotransmitters and hypothalamic peptides. This suggests that metabolic syndrome X could be a disorder of the brain due to suboptimal LCPUFAs during perinatal period that triggers low-grade systemic inflammation, implying that perinatal strategies are needed to prevent its development.

Pyruvic acid is an effective scavenger of reactive oxygen species. Ethyl pyruvate has demonstrated anti-inflammatory actions and improved hyperpermeability and bacterial translocation due to endotoxemia and is of benefit in animal models of sepsis and septic shock. Ethyl pyruvate specifically inhibits tumor necrosis factor-alpha production and decreases circulating levels of high-mobility group box-1 and nuclear factor-kappaB signaling pathways by specifically targeting its p65 subunit in animals with established endotoxemia or sepsis and in macrophage cultures. Ethyl pyruvate also decreases cyclo-oxygenase-2, inducible nitric oxide synthase, and interleukin-6 mRNA expression in the liver, ileal mucosa, and colonic mucosa in animal models with hemorrhagic shock. Similar beneficial actions have been seen in endotoxemia. These and other studies suggest that ethyl pyruvate could be of significant benefit in the treatment of patients who are critically ill and have sepsis/septic shock.

It is proposed that metabolic syndrome X is initiated in the perinatal period as a low-grade systemic inflammatory condition. Increased consumption of energy-dense diets by pregnant women and lactating mothers suppresses the activities of Delta-6 and Delta-5 desaturases not only in maternal tissues but also in fetal liver and the placenta, resulting in decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids omega-6 arachidonic acid (AA), omega-3 eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA, DHA, and AA have negative feedback control on tumor necrosis factor-alpha and IL-6 synthesis. Hence, EPA, DHA, and AA deficiencies induced by an energy-dense diet increase generation of tumor necrosis factor-alpha and interleukin-6, markers of inflammation that in turn decrease production of endothelial nitric oxide and adiponectin to induce insulin resistance in maternal and fetal tissues. Increased concentrations of tumor necrosis factor-alpha and interleukin-6 enhance expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 enzyme, which produces abdominal obesity, insulin resistance, hyperlipidemia, hyperphagia, and hyperleptinemia, characteristic features of metabolic syndrome X. Continued consumption of an energy-dense diet in childhood aggravates these molecular events. This implies that supplementation of long-chain polyunsaturated fatty acids (especially AA, EPA, and DHA in appropriate ratios) from the perinatal period through adulthood could prevent, arrest, or postpone development of metabolic syndrome X.

Huntington's disease is an inherited neurodegenerative disorder due to a mutation in exon 1 of the Huntingtin gene that encodes a stretch of polyglutamine (polyQ) residues close to the N-terminus of the huntingtin protein. Aggregated polyQ residues are highly toxic to the neuronal cells when they enter the cell nucleus. The mechanisms by which aggregated polyQ induces neurodegeneration include the binding of abnormal huntingtin to cyclic adenosine monophosphate response element binding protein, which hampers its ability to turn on transcription of other genes; mutant huntingtin binding to the active site on the cyclic adenosine monophosphate response element binding protein, which is essential for its acetyltransferase activity and, hence, the drugs that inhibit histone deacetylase arrest polyQ-dependent neurodegeneration; and/or disrupting the ubiquitin-proteasome system. Transgenic R6/1 mice that incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of the huntingtin gene responsible for Huntington's disease develop late-onset neurologic deficits in a manner similar to the motor abnormalities of Huntington's disease and show increased survival rates and decreased neurologic deficits when supplemented with essential fatty acids throughout life. A randomized, placebo-controlled, double-blind study has shown that highly unsaturated fatty acids are beneficial to patients with Huntington's disease. These results raise the possibility that unsaturated fatty acids may prevent or arrest polyQ aggregation, inhibit histone deacetylase, and/or activate the ubiquitin-proteasome system. In view of the encouraging results with essential fatty acids in Huntington's disease, it is proposed that their possible use in other neurodegenerative conditions need to be explored.

I investigated whether metabolism of essential fatty acids and the concentrations of their long-chain metabolites (long-chain polyunsaturated fatty acids [LCPUFAs]) are altered in fetal or perinatal growth retardation, maternal hypercholesterolemia, low-grade systemic inflammation, insulin resistance, and atherosclerosis, conditions that predispose to the development of coronary heart disease (CHD).I critically reviewed the literature pertaining to the metabolism of essential fatty acids in CHD and conditions that predispose to it.LCPUFAs enhance endothelial nitric oxide synthesis, suppress the production of the proinflammatory cytokines tumor necrosis factor and interleukin-6, attenuate insulin resistance, and have antiatherosclerotic properties. Low-birthweight infants have decreased concentrations of LCPUFAs, especially arachidonic acid. Neonatal arachidonic acid status is related to intrauterine growth, and LCPUFAs improve fetal and postnatal growth. LCPUFAs are useful in the management of hyperlipidemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, and may mediate the beneficial actions of statins. Plasma concentrations of various LCPUFAs are low in diabetes mellitus, hypertension, and CHD and in populations at high risk of CHD. Breast milk is rich in LCPUFAs, and this may explain why and how adequate (6 mo to 1 y) breast feeding protects against the development of obesity, hypertension, insulin resistance, and CHD.LCPUFAs are essential for the growth and development of the fetus and infant. LCPUFAs can prevent various conditions that predispose to the development of CHD. The low incidence of CHD seen in adequately breast-fed infants can be linked to the LCPUFA content of breast milk. Based on this evidence, I suggest that provision of LCPUFAs during critical periods of growth, especially from the second trimester of pregnancy to age 5 y, prevents CHD in adult life.

Objectives: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated., Methods: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed., Results: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels., Conclusions: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.