The potential role and mechanism of circRNAs in Ferroptosis: A comprehensive review.

Cell death encompasses various mechanisms, including necrosis and apoptosis. Ferroptosis, a unique form of regulated cell death, emerged as a non-apoptotic process reliant on iron and reactive oxygen species (ROS). Distinguishing itself from other forms of cell death, ferroptosis exhibits distinct morphological, biochemical, and genetic features. Circular RNAs (circRNAs), a novel class of RNA molecules, play crucial regulatory roles in ferroptosis-mediated pathways and cellular processes. With their circular structure and stability, circRNAs function as microRNA sponges and participate in protein regulation, offering diverse mechanisms for cellular control. Accumulating evidence indicates that circRNAs are key players in diseases associated with ferroptosis, presenting opportunities for diagnostic and therapeutic applications. This study explores the regulatory roles of circRNAs in ferroptosis and their potential in diseases such as cancer, neurological disorders, and cardiovascular diseases. By investigating the relationship between circRNAs and ferroptosis, this research provides new insights into the diagnosis, treatment, and prognosis of ferroptosis-related diseases. Furthermore, the therapeutic implications of targeting circRNAs in cancer treatment and the modulation of ferroptosis pathways demonstrate the potential of circRNAs as diagnostic markers and therapeutic targets. Overall, understanding the involvement of circRNAs in regulating ferroptosis opens up new avenues for advancements in disease management.

Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate.

Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL), primarily, from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results in adults. In this work, we use naturally occurring carbon isotope ratios (13C/12C; δ13C) to uncover the origin of brain PAM at postnatal days 0, 10, 21 and 35, and RNA sequencing to identify the pathways involved in maintaining brain PAM, at day 35, in mice fed diets with low, medium, and high PAM from birth. Here we show that DNL from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM. Importantly, the upregulation of hepatic DNL genes, in response to low PAM at day 35, demonstrates the presence of a compensatory mechanism to maintain total brain PAM pools compared to the liver; suggesting the importance of brain PAM regulation.

Analysis of omega-3 and omega-6 polyunsaturated fatty acid metabolism by compound-specific isotope analysis in humans.

Natural variations in the 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δ13C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m2) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ13C were determined. The H6 intervention exhibited increases in plasma LNA δ13C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ13C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ13C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ13C.

Exosomes as Rheumatoid Arthritis Diagnostic Biomarkers and Therapeutic Agents.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder that causes systemic inflammation, autoimmunity, and joint abnormalities that result in permanent disability. Exosomes are nanosized extracellular particles found in mammals (40-100 nm). They are a transporter of lipids, proteins, and genetic material involved in mammalian cell-cell signaling, biological processes, and cell signaling. Exosomes have been identified as playing a role in rheumatoid arthritis-related joint inflammation (RA). Uniquely functioning extracellular vesicles (EVs) are responsible for the transport of autoantigens and mediators between distant cells. In addition, paracrine factors, such as exosomes, modulate the immunomodulatory function of mesenchymal stem cells (MSCs). In addition to transporting genetic information, exosomes convey miRNAs between cells and have been studied as drug delivery vehicles. In animal models, it has been observed that MSCs secrete EVs with immunomodulatory properties, and promising results have been observed in this area. By understanding the diversity of exosomal contents and their corresponding targets, it may be possible to diagnose autoimmune diseases. Exosomes can be employed as diagnostic biomarkers for immunological disorders. We here discuss the most recent findings regarding the diagnostic, prognostic, and therapeutic potential of these nanoparticles in rheumatoid arthritis and provide an overview of the evidence pertaining to the biology of exosomes in RA.

Increases in plasma n-3 tetracosapentaenoic acid and tetracosahexaenoic acid following 12 weeks of EPA, but not DHA, supplementation in women and men.

Dietary feeding and stable isotope studies in rodents support that the 24-carbon omega-3 polyunsaturated fatty acids, tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA), are immediate precursors to docosahexaenoic acid (DHA, 22:6n-3). In this study, we assessed for the first time, changes in TPAn-3 or THA levels following omega-3 PUFA supplementation in humans, providing insight into human omega-3 PUFA metabolism. In this secondary analysis of a double-blind randomized control trial, women and men (19 - 30 years, n = 10 - 14 per sex, per diet) were supplemented with 3 g/day EPA, DHA, or olive oil control for 12 weeks. Plasma TPAn-3 and THA concentrations were determined by gas chromatography-mass spectrometry to determine changes following supplementation in a sex-specific manner (sex x time). EPA supplementation significantly increased (p < 0.0001) plasma TPAn-3 by 215% (1.3 ± 0.1 - 4.1 ± 0.7, nmol/mL ± SEM) and THA by 112% (1.7 ± 0.2 - 3.6 ± 0.5, nmol/mL ± SEM). Furthermore, women had 111% and 99% higher plasma TPAn-3 and THA in the EPA supplemented group compared to men (p < 0.0001). There were no significant effects of time on plasma TPAn-3 or THA concentrations in the DHA supplemented or olive oil supplemented groups. In conclusion, EPA, but not DHA, supplementation in humans increased plasma TPAn-3 and THA levels, suggesting that THA accumulates prior to conversion to DHA in the n-3 PUFA synthesis pathway. Furthermore, women generally exhibit higher plasma TPAn-3 and THA concentrations compared with men, suggesting that women have a greater ability to accumulate 24-carbon n-3 PUFA in plasma via EPA and DPAn-3 elongation, which may explain the known higher DHA levels in women. Summary: In this secondary analysis of a double-blind randomized control trial, we assessed changes in omega-3 (n-3) tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA) plasma levels in women and men (19 - 30 years, n = 10 - 14 per sex, per diet) following 12-weeks of n-3 PUFA supplementation (3 g/day EPA, DHA or olive oil). Women had higher plasma TPAn-3 in all supplementation groups and higher THA levels in the EPA and olive oil groups (p < 0.0001) compared to men. EPA supplementation increased (p < 0.0001) plasma TPAn-3 by 215% (1.3 ± 0.1 - 4.1 ± 0.7, nmol/mL ± SEM) and THA by 112% (1.7 ± 0.2 - 3.6 ± 0.5, nmol/mL ± SEM), but DHA supplementation had no effect. For the first time in humans, we show that plasma TPAn-3 and THA levels are higher in women and increased with EPA, but not DHA supplementation, suggesting an accumulation of THA prior to conversion to DHA in the n-3 PUFA synthesis pathway.

Plasma unesterified eicosapentaenoic acid is converted to docosahexaenoic acid (DHA) in the liver and supplies the brain with DHA in the presence or absence of dietary DHA.

Recent meta-analyses suggest that high eicosapentaenoic acid (EPA, 20:5n-3) supplements may be beneficial in managing the symptoms of major depression. However, brain EPA levels are hundreds-fold lower than docosahexaenoic acid (DHA, 22:6n-3), making the potential mechanisms of action of EPA in the brain less clear. Using a kinetic model the goal of this study was to determine how EPA impacts brain DHA levels. Following 8 weeks feeding of a 2% alpha-linolenic acid (ALA, 18:3n-3) or DHA diet (2% ALA + 2% DHA), 11-week-old Long Evans rats were infused with unesterified 13C-EPA at steady-state for 3 h with plasma collected at 30 min intervals and livers and brains collected after 3 h for determining DHA synthesis-accretion kinetics in multiple lipid fractions. Most of the newly synthesized liver 13C-DHA was in phosphatidylethanolamine (PE, 37%-56%), however, 75-80% of plasma 13C-DHA was found in triacylglycerols (TAG) at 14 ± 5 and 46 ± 12 nmol/g/day (p < 0.05) in the ALA and DHA group, respectively. In the brain, PE and phosphatidylserine (PS) accreted the most 13C-DHA, and DHA compared to ALA feeding shortened DHA half-lives in most lipid fractions, resulting in total brain DHA half-lives of 32 ± 6 and 96 ± 24 (days/g ± SEM), respectively (p < 0.05). EPA was predominantly converted and stored as PE-DHA in the liver, secreted to plasma as TAG-DHA and accumulated in brain as PE and PS-DHA. In conclusion, EPA is a substantial source for brain DHA turnover and suggests an important role for EPA in maintaining brain DHA levels.