Complete Omega-3

SCIENTIFIC RESEARCH ON THE FOLLOWING INGREDIENTS:

NRF2:

Protein-Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction

Abstract

Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1/Nrf2 protein–protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2-mimetic protein-like polymer (PLP) to inhibit the Keap1-Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1-inhibiting PLPs (Keap1i-PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations in primary cardiomyocytes. Single-digit mg kg−1, single-dose, intravenous PLP administration significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular protein–protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress-driven diseases and conditions.

Source: J. M. Mesfin, K. P. Carrow, A. Chen, M. P. Hopps, J. J. Holm, Q. P. Lyons, M. B. Nguyen, J. D. Hunter, A. Magassa, E. G. Wong, K. Reimold, S. N. Paleti, E. Gardner, M. P. Thompson, C. G. Luo, X. Zhang, K. L. Christman, N. C. Gianneschi, Protein-Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction. Adv. Mater. 2025, 2417885.

Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice

Abstract

Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.

Source: Shimizu, R., Hirano, I., Hasegawa, A. et al. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice. Commun Biol 6, 875 (2023).

Omega 3s:

Analysis of Omega-3 Fatty Acid Content in Fish Oil Products

Abstract

Background: Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosehexaenoic acid (DHA), often found in fish oil supplements, have been linked to cardiovascular benefits in proper doses.

Objectives: Quantify serving sizes and EPA and DHA content of fish oil products and determine which products contain appropriate amounts of EPA and DHA per serving to lower cholesterol.

Methods: Products were identified through the National Institutes of Health’s Dietary Supplement Label Database using the search term “fish oil.” Product labels were reviewed for EPA and DHA content. The number of units, such as capsules, gummies, or milliliters, necessary to obtain a total of at least 2,000 mg of EPA and DHA was also evaluated. Descriptive statistics were used to report findings.

Results: Of 493 products identified, 231 products were analyzed. Two (0.9%) products, both of which were liquid formulations, contained at least 2,000 mg of EPA and DHA in the standard serving size listed on the labeling. The total amount of EPA and DHA per serving ranged from 60.2 mg to 2684 mg with an average of 697 mg. The number of servings necessary to achieve 2,000 mg of EPA and DHA ranged from 1 to 34 servings with an average of 5 servings.

Conclusions: Serving sizes of fish oil products rarely result in adequate EPA and DHA intake to provide cholesterol-lowering benefit. Instruction by a trained healthcare professional, such as a pharmacist, is important to ensure patients are taking an appropriate serving of fish oil to obtain cardiovascular benefit.

Source: Ward ED, Thomasson K, Fischer KR. Analysis of Omega-3 Fatty Acid Content in Fish Oil Products. Journal of Pharmacy Practice. 2021;35(6):870-873. doi:10.1177/08830738211015051

Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials

Abstract

Objectives: To quantify the effect of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on cardiovascular disease (CVD) prevention and the effect of dosage.

Methods: This study is designed as a random effects meta-analysis and meta-regression of randomized control trials with EPA/DHA supplementation. This is an update and expanded analysis of a previously published meta-analysis which covers all randomized control trials with EPA/DHA interventions and cardiovascular outcomes published before August 2019. The outcomes included are myocardial infarction (MI), coronary heart disease (CHD) events, CVD events (a composite of MI, angina, stroke, heart failure, peripheral arterial disease, sudden death, and non-scheduled cardiovascular surgical interventions), CHD mortality and fatal MI. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.

Results: A total of 40 studies with a combined 135,267 participants were included. Supplementation was associated with reduced risk of MI (relative risk [RR], 0.87; 95% CI, 0.80 to 0.96), high certainty number needed to treat (NNT) of 272; CHD events (RR, 0.90; 95% CI, 0.84 to 0.97), high certainty NNT of 192; fatal MI (RR, 0.65; 95% CI, 0.46 to 0.91]), moderate certainty NNT = 128; and CHD mortality (RR, 0.91; 95% CI, 0.85 to 0.98), low certainty NNT = 431, but not CVD events (RR, 0.95; 95% CI, 0.90 to 1.00). The effect is dose dependent for CVD events and MI.

Conclusions: Cardiovascular disease remains the leading cause of death worldwide. Supplementation with EPA and DHA is an effective lifestyle strategy for CVD prevention, and the protective effect probably increases with dosage.

Source: Bernasconi, Aldo A et al. “Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials.” Mayo Clinic proceedings vol. 96,2 (2021): 304-313. doi:10.1016/j.mayocp.2020.08.034

Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis

Abstract

Background: The effects of omega-3 fatty acids (FAs), such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, on cardiovascular outcomes are uncertain. We aimed to determine the effectiveness of omega-3 FAs on fatal and non-fatal cardiovascular outcomes and examine the potential variability in EPA vs. EPA+DHA treatment effects.

Methods: We searched EMBASE, PubMed, ClinicalTrials.gov, and Cochrane library databases through June 7, 2021. We performed a meta-analysis of 38 randomized controlled trials of omega-3 FAs, stratified by EPA monotherapy and EPA+DHA therapy. We estimated random-effects rate ratios (RRs) with (95% confidence intervals) and rated the certainty of evidence using GRADE. The key outcomes of interest were cardiovascular mortality, non-fatal cardiovascular outcomes, bleeding, and atrial fibrillation (AF). The protocol was registered in PROSPERO (CRD42021227580).

Findings: In 149,051 participants, omega-3 FA was associated with reducing cardiovascular mortality (RR, 0.93 [0.88-0.98]; p = 0.01), non-fatal myocardial infarction (MI) (RR, 0.87 [0.81–0.93]; p = 0.0001), coronary heart disease events (CHD) (RR, 0.91 [0.87–0.96]; p = 0.0002), major adverse cardiovascular events (MACE) (RR, 0.95 [0.92–0.98]; p = 0.002), and revascularization (RR, 0.91 [0.87–0.95]; p = 0.0001). The meta-analysis showed higher RR reductions with EPA monotherapy (0.82 [0.68–0.99]) than with EPA + DHA (0.94 [0.89–0.99]) for cardiovascular mortality, non-fatal MI (EPA: 0.72 [0.62–0.84]; EPA+DHA: 0.92 [0.85–1.00]), CHD events (EPA: 0.73 [0.62–0.85]; EPA+DHA: 0.94 [0.89–0.99]), as well for MACE and revascularization. Omega-3 FA increased incident AF (RR, 1.26 [1.08–1.48]). EPA monotherapy vs. control was associated with a higher risk of total bleeding (RR: 1.49 [1.20–1.84]) and AF (RR, 1.35 [1.10–1.66]).

Interpretation: Omega-3 FAs reduced cardiovascular mortality and improved cardiovascular outcomes. The cardiovascular risk reduction was more prominent with EPA monotherapy than with EPA+DHA.

Source: Khan, Safi U et al. “Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis.” EClinicalMedicine vol. 38 100997. 8 Jul. 2021, doi:10.1016/j.eclinm.2021.100997

Targeting NRF2-KEAP1 axis by Omega-3 fatty acids and their derivatives: Emerging opportunities against aging and diseases

Abstract

The transcription factor NRF2 and its endogenous inhibitor KEAP1 play a crucial role in the maintenance of cellular redox homeostasis by regulating the gene expression of diverse networks of antioxidant, anti-inflammatory, and detoxification enzymes. Therefore, activation of NRF2 provides cytoprotection against numerous pathologies, including age-related diseases. An age-associated loss of NRF2 function may be a key driving force behind the aging phenotype. Recently, numerous NRF2 inducers have been identified and some of them are promising candidates to restore NRF2 transcriptional activity during aging. Emerging evidence indicates that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their electrophilic derivatives may trigger a protective response via NRF2 activation, rescuing or maintaining cellular redox homeostasis. In this review, we provide an overview of the NRF2-KEAP1 system and its dysregulation in aging cells. We also summarize current studies on the modulatory role of n-3 PUFAs as potential agents to prevent multiple chronic diseases and restore the age-related impairment of NRF2 function.

Source: Davinelli, Sergio et al. “Targeting NRF2-KEAP1 axis by Omega-3 fatty acids and their derivatives: Emerging opportunities against aging and diseases.” Free radical biology & medicine vol. 193,Pt 2 (2022): 736-750. doi:10.1016/j.freeradbiomed.2022.11.017

 

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