Omega-3 fatty acids supplements for dry eye - Are they effective or ineffective?

Purpose: To evaluate effectiveness of omega-3 fatty acid supplements in relieving dry eye symptoms and signs in symptomatic visual display terminal users (VDT). Methods: A randomized controlled study was done; eyes of 470 VDT users were randomized to receive four capsules twice daily for 6 months (O3FAgroup), each containing 180 mg of eicosapentaenoic acid and 120 mg docosahexaenoic acid. The O3FA group was compared with another group (n = 480) who received four capsules of a placebo (olive oil) twice daily. Patients were evaluated at baseline, 1, 3, and 6 months, respectively. The primary outcome was improvement in omega-3 index (a measure of EPA and DHA ratio in RBC membrane). Secondary outcomes were improvement dry eye symptoms, Nelson grade on conjunctival impression cytology, Schirmer test values, tear film breakup time (TBUT), and tear film osmolarity. Means of groups (pre-treatment, 1, 3, and 6-months) were compared with repeated measure analysis of variance. Results: At baseline, 81% patients had low omega-3 index. In the O3FA group, a significant increase in omega-3 index, improvement in symptoms, reduction in tear film osmolarity, and increase in Schirmer, TBUT, and goblet cell density was observed. These changes were not significant in the placebo group. Improvement in test parameters was significantly (P < 0.001) better in patients with low omega3 index (<4%) subgroup. Conclusion: Dietary omega-3 fatty acids are effective for dry eye in VDT users; omega-3 index appears to be the predictor to identify potential dry eye patients who are likely to benefit from oral omega-3 dietary intervention.

Long Chain N3-PUFA Decreases ACE2 Protein Levels and Prevents SARS-CoV-2 Cell Entry.

Angiotensin-converting enzyme 2 (ACE2) is a target of interest for both COVID-19 and cardiovascular disease management. Even though lower ACE2 levels may be beneficial in SARS-CoV-2 infectivity, maintaining the ACE1/ACE2 balance is also crucial for cardiovascular health. So far, reports describing conditions capable of altering ACE2 protein levels, especially via dietary components, are limited. In this study, the effects of omega-3 polyunsaturated fatty acids (n3-PUFA) on the protein levels of ACE1 and ACE2 in rodent tissues, human endothelial and kidney cell lines, and human plasma were examined. The ability of n3-PUFA to affect the entry of the SARS-CoV-2 pseudovirus into cells was also tested. Docosahexaenoic acid (DHA), and in some cases eicosapentaenoic acid (EPA), but not α-linoleic acid (ALA), reduced both ACE1 and ACE2 (non-glycosylated p100 and glycosylated p130 forms) in the heart, aorta, and kidneys of obese rats, as well as in human EA.hy926 endothelial and HEK293 kidney cells. Dietary supplementation with either DHA or ALA had no effect on plasma soluble ACE2 levels in humans. However, treatment of HEK293 cells with 80 and 125 µM DHA for 16 h inhibited the entry of the SARS-CoV-2 pseudovirus. These results strongly suggest that DHA treatment may reduce the ability of SARS-CoV-2 to infect cells via a mechanism involving a decrease in the absolute level of ACE2 protein as well as its glycosylation. Our findings warrant further evaluation of long-chain n3-PUFA supplements as a novel option for restricting SARS-CoV-2 infectivity in the general population.

Omega-3 Polyunsaturated Fatty Acids Protect against High-Fat Diet-Induced Morphological and Functional Impairments of Brown Fat in Transgenic Fat-1 Mice.

The role of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the regulation of energy homeostasis remains poorly understood. In this study, we used a transgenic fat-1 mouse model, which can produce n-3 PUFAs endogenously, to investigate how n-3 PUFAs regulate the morphology and function of brown adipose tissue (BAT). We found that high-fat diet (HFD) induced a remarkable morphological change in BAT, characterized by "whitening" due to large lipid droplet accumulation within BAT cells, associated with obesity in wild-type (WT) mice, whereas the changes in body fat mass and BAT morphology were significantly alleviated in fat-1 mice. The expression of thermogenic markers and lypolytic enzymes was significantly higher in fat-1 mice than that in WT mice fed with HFD. In addition, fat-1 mice had significantly lower levels of inflammatory markers in BAT and lipopolysaccharide (LPS) in plasma compared with WT mice. Furthermore, fat-1 mice were resistant to LPS-induced suppression of UCP1 and PGC-1 expression and lipid deposits in BAT. Our data has demonstrated that high-fat diet-induced obesity is associated with impairments of BAT morphology (whitening) and function, which can be ameliorated by elevated tissue status of n-3 PUFAs, possibly through suppressing the effects of LPS on inflammation and thermogenesis.

Effect of Omega-3 fatty acids supplementation on serum level of C-reactive protein in patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Omega-3 may alleviate the severity of coronavirus disease 2019 (COVID-19) by reducing the C-reactive protein (CRP) level, a marker for systemic inflammation. Because the scientific evidence indicating such a role is inconsistent, we aimed to evaluate the effect of Omega-3 on CRP change and CRP level in patients with COVID-19. METHODS: We conducted a comprehensive search on four databases (PubMed, Web of Science, EMBASE, and Scopus). We included all RCTs comparing Omega-3 with a control group regarding their effect on the CRP levels in patients with COVID-19. We used version two of the Cochrane risk of bias assessment tool to appraise the included studies. We extracted data to an online data extraction sheet. The primary outcomes were CRP change from baseline and CRP serum levels. RESULTS: We included four randomized controlled trials (RCTs) with 274 patients in this study. The overall effect estimate favored Omega-3 over the control group in terms of CRP change from baseline (mean difference (MD) =- 2.53, 95% confidence interval (CI): - 4.40, - 0.66) and CRP serum levels at the end of the study (MD =- 6.24, 95% CI: - 11.93, - 0.54). CONCLUSION: Omega-3 showed promising effects on systemic inflammation by reducing CRP levels in COVID-19 patients. Based on this finding, we recommend Omega-3 for COVID-19 patients for its anti-inflammatory actions.

N-3 polyunsaturated fatty acids block the trimethylamine-N-oxide- ACE2- TMPRSS2 cascade to inhibit the infection of human endothelial progenitor cells by SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is a novel coronavirus that infects many types of cells and causes cytokine storms, excessive inflammation, acute respiratory distress to induce failure of respiratory system and other critical organs. In this study, our results showed that trimethylamine-N-oxide (TMAO), a metabolite generated by gut microbiota, acts as a regulatory mediator to enhance the inerleukin-6 (IL-6) cytokine production and the infection of human endothelial progenitor cells (hEPCs) by SARS-CoV-2. Treatment of N-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) could effectively block the entry of SARS-CoV-2 in hEPCs. The anti-infection effects of N-3 PUFAs were associated with the inactivation of NF-κB signaling pathway, a decreased expression of the entry receptor angiotensin-converting enzyme 2 (ACE2) and downstream transmembrane serine protease 2 in hEPCs upon the stimulation of TMAO. Treatment of DHA and EPA further effectively inhibited TMAO-mediated expression of IL-6 protein, probably through an inactivation of MAPK/p38/JNK signaling cascades and a downregulation of microRNA (miR)-221 in hEPCs. In conclusion, N-3 PUFAs such as DHA and EPA could effectively act as preventive agents to block the infection of SARS-CoV-2 and IL-6 cytokine production in hEPCs upon the stimulation of TMAO.

A biological rationale for the disparate effects of omega-3 fatty acids on cardiovascular disease outcomes.

The omega-3 fatty acids (n3-FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) rapidly incorporate into cell membranes where they modulate signal transduction pathways, lipid raft formation, and cholesterol distribution. Membrane n3-FAs also form specialized pro-resolving mediators and other intracellular oxylipins that modulate inflammatory pathways, including T-cell differentiation and gene expression. Cardiovascular (CV) trials have shown that EPA, administered as icosapent ethyl (IPE), reduces composite CV events, along with plaque volume, in statin-treated, high-risk patients. Mixed EPA/DHA regimens have not shown these benefits, perhaps as the result of differences in formulation, dosage, or potential counter-regulatory actions of DHA. Indeed, EPA and DHA have distinct, tissue-specific effects on membrane structural organization and cell function. This review summarizes: (1) results of clinical outcome and imaging trials using n3-FA formulations; (2) membrane interactions of n3-FAs; (3) effects of n3-FAs on membrane oxidative stress and cholesterol crystalline domain formation during hyperglycemia; (4) n3-FA effects on endothelial function; (5) role of n3-FA-generated metabolites in inflammation; and (6) ongoing and future clinical investigations exploring treatment targets for n3-FAs, including COVID-19.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients?

In around 10% of SARS-CoV-2 infected patients, coronavirus disease-2019 (Covid-19) symptoms are complicated with a severe lung damage called Acute Respiratory Distress Syndrome (ARDS), which is often lethal. ARDS is mainly associated with an uncontrolled overproduction of immune cells and cytokines, called "cytokine storm syndrome"; it appears 7-15 days following the onset of symptoms, leading to systemic inflammation and multiple organ failure. Because they are well-known metabolic precursors of specialized pro-resolving lipid mediators (SPMs), omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs) could help improve the resolution of the inflammatory balance, limiting therefore the level and duration of the critical inflammatory period. Omega-3 LC-PUFAs may also interact at different stages of the viral infection, notably on the virus entry and replication. In the absence of demonstrated treatment and while waiting for vaccine possibility, the use of omega-3 LC-PUFAs deserve therefore to be considered, based on previous clinical studies suggesting that omega-3 supplementation could improve clinical outcomes of critically ill patients at the acute phase of ARDS. In this context, it is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remains largely below the current recommendations, considering both the omega-3 precursor α-linolenic acid (ALA) and long chain derivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). An optimized omega-3 PUFAs status could be helpful to prevent infectious diseases, including Covid-19.

Maternal nutrients and effects of gestational COVID-19 infection on fetal brain development.

BACKGROUND & AIMS: Maternal gestational infection is a well-characterized risk factor for offsprings' development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses. METHOD: Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed. RESULTS: Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect. CONCLUSIONS: Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2.

The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial.

BACKGROUND: Omega-3 polyunsaturated fatty acids (n3-PUFAs) may exert beneficial effects on the immune system of patients with viral infections. This paper aimed to examine the effect of n3-PUFA supplementation on inflammatory and biochemical markers in critically ill patients with COVID-19. METHODS: A double-blind, randomized clinical trial study was conducted on 128 critically ill patients infected with COVID-19 who were randomly assigned to the intervention (fortified formula with n3-PUFA) (n = 42) and control (n = 86) groups. Data on 1 month survival rate, blood glucose, sodium (Na), potassium (K), blood urea nitrogen (BUN), creatinine (Cr), albumin, hematocrit (HCT), calcium (Ca), phosphorus (P), mean arterial pressure (MAP), O2 saturation (O2sat), arterial pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), bicarbonate (HCO3), base excess (Be), white blood cells (WBCs), Glasgow Coma Scale (GCS), hemoglobin (Hb), platelet (Plt), and the partial thromboplastin time (PTT) were collected at baseline and after 14 days of the intervention. RESULTS: The intervention group had significantly higher 1-month survival rate and higher levels of arterial pH, HCO3, and Be and lower levels of BUN, Cr, and K compared with the control group after intervention (all P < 0.05). There were no significant differences between blood glucose, Na, HCT, Ca, P, MAP, O2sat, PO2, PCO2, WBCs, GCS, Hb, Plt, PTT, and albumin between two groups. CONCLUSION: Omega-3 supplementation improved the levels of several parameters of respiratory and renal function in critically ill patients with COVID-19. Further clinical studies are warranted. Trial registry Name of the registry: This study was registered in the Iranian Registry of Clinical Trials (IRCT); Trial registration number: IRCT20151226025699N3; Date of registration: 2020.5.20; URL of trial registry record: https://en.irct.ir/trial/48213.

Strengthening the immunity of the Swiss population with micronutrients: A narrative review and call for action.

BACKGROUND: The enormous health impact of the COVID-19 pandemic has refocused attention on measures to optimize immune function and vaccine response. Dietary deficiencies of micronutrients can weaken adaptive immunity. The aim of this review was to examine links between micronutrients, immune function and COVID-19 infection, with a focus on nutritional risks in subgroups of the Swiss population. METHODS: Scoping review on the associations between selected micronutrients (vitamins D and C, iron, selenium, zinc, and n-3 PUFAs) and immunity, with particular reference to the Swiss population. These nutrients were chosen because previous EFSA reviews have concluded they play a key role in immunity. RESULTS: The review discusses the available knowledge on links between sufficient nutrient status, optimal immune function, and prevention of respiratory tract infections. Because of the rapid spread of the COVID-19 pandemic, controlled intervention studies of micronutrients in the context of COVID-19 infection are now underway, but evidence is not yet available to draw conclusions. The anti-inflammatory properties of n-3 PUFAs are well established. In Switzerland, several subgroups of the population are at clear risk of nutrient deficiencies; e.g., older adults, multiple comorbidities, obesity, pregnancy, and institutionalized. Low intakes of n-3 PUFA are present in a large proportion of the population. CONCLUSION: There are clear and strong relationships between micronutrient and n-3 PUFA status and immune function, and subgroups of the Swiss population are at risk for deficient intakes. Therefore, during the COVID-19 pandemic, as a complement to a healthy and balanced diet, it may be prudent to consider supplementation with a combination of moderate doses of Vitamins C and D, as well as of Se, Zn and n-3 PUFA, in risk groups.

Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry.

The strain SARS-CoV-2, newly emerged in late 2019, has been identified as the cause of COVID-19 and the pandemic declared by WHO in early 2020. Although lipids have been shown to possess antiviral efficacy, little is currently known about lipid compounds with anti-SARS-CoV-2 binding and entry properties. To address this issue, we screened, overall, 17 polyunsaturated fatty acids, monounsaturated fatty acids and saturated fatty acids, as wells as lipid-soluble vitamins. In performing target-based ligand screening utilizing the RBD-SARS-CoV-2 sequence, we observed that polyunsaturated fatty acids most effectively interfere with binding to hACE2, the receptor for SARS-CoV-2. Using a spike protein pseudo-virus, we also found that linolenic acid and eicosapentaenoic acid significantly block the entry of SARS-CoV-2. In addition, eicosapentaenoic acid showed higher efficacy than linolenic acid in reducing activity of TMPRSS2 and cathepsin L proteases, but neither of the fatty acids affected their expression at the protein level. Also, neither reduction of hACE2 activity nor binding to the hACE2 receptor upon treatment with these two fatty acids was observed. Although further in vivo experiments are warranted to validate the current findings, our study provides a new insight into the role of lipids as antiviral compounds against the SARS-CoV-2 strain.

In Silico Study of Polyunsaturated Fatty Acids as Potential SARS-CoV-2 Spike Protein Closed Conformation Stabilizers: Epidemiological and Computational Approaches.

SARS-CoV-2 infects host cells by interacting its spike protein with surface angiotensin-converting enzyme 2 (ACE2) receptors, expressed in lung and other cell types. Although several risk factors could explain why some countries have lower incidence and fatality rates than others, environmental factors such as diet should be considered. It has been described that countries with high polyunsaturated fatty acid (PUFA) intake have a lower number of COVID-19 victims and a higher rate of recovery from the disease. Moreover, it was found that linoleic acid, an omega-6 PUFA, could stabilize the spike protein in a closed conformation, blocking its interaction with ACE2. These facts prompted us to perform in silico simulations to determine if other PUFA could also stabilize the closed conformation of spike protein and potentially lead to a reduction in SARS-CoV-2 infection. We found that: (a) countries whose source of omega-3 is from marine origin have lower fatality rates; and (b) like linoleic acid, omega-3 PUFA could also bind to the closed conformation of spike protein and therefore, could help reduce COVID-19 complications by reducing viral entrance to cells, in addition to their known anti-inflammatory effects.

The Role of Micronutrients in Support of the Immune Response against Viral Infections.

Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).