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BACKGROUND: The development of delirium is closely linked to inflammatory processes. Omega-3 fatty acids can modulate the immune response and may contribute to reducing the incidence of sepsis-associated delirium (SAD). AIMS: To investigate the effects of omega-3 fatty acids on delirium in patients with sepsis. MATERIALS AND METHODS: In a single-center clinical trial, 220 intensive care patients diagnosed with sepsis were randomly assigned to receive daily intravenous infusions of either an omega-3 fish oil emulsion or a placebo. Delirium was assessed twice daily using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method (CAM). The primary outcome was the duration of delirium during the first 10 days of admission. Secondary outcomes included the duration of mechanical ventilation, length of intensive care unit (ICU) stay, and mortality. RESULTS: Compared to the control group, the omega-3 group exhibited significantly fewer days with delirium episodes (p = 0.010), shorter ICU stays (p = 0.008), and fewer mechanical ventilation days (p = 0.001). However, there was no statistically significant difference in mortality between the two groups. CONCLUSION: Omega-3 fatty acids may effectively reduce the risk of delirium in sepsis patients, highlighting their potential as a therapeutic intervention in this population.

OBJECTIVE: β-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological complications, including cell death, tissue injury, organ dysfunction, and thyroid dysfunction. The present study examined the effectiveness of omega-3 and Manuka honey combination or Manuka honey alone to the conventional therapy (deferasirox, blood transfusion, and L-carnitine) used for preventing and managing oxidative stress or iron overload-induced oxidative stress conditions in pediatric β-thalassemic patients (type major). PATIENTS AND METHODS: 165 patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 1,000 mg omega-3 fish oil [350 mg eicosapentaenoic acid (EPA) and 250 mg docosahexaenoic acid (DHA)] combined with Manuka honey lozenge (344 mg) daily or Manuka honey alone plus the conventional therapy for ten months. Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), Lactate dehydrogenase (LDH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), CRP (C-reactive protein), ferritin level, and serum iron were determined at baseline and month 10. RESULTS: Omega-3 and Manuka honey combination were a significant add-on to conventional therapy of β-thalassemia in reducing the oxidative stress condition. The combination of Omega-3 and Manuka honey reduced the level of F2-isoprostane(8-iso-PGF2α) significantly compared to the Manuka alone and the control groups. Additionally, they showed an antihemolytic action measured by reduced LDH level. The combination restored the patient's lipid profile (LDL-C and HDL-C) significantly compared to the control group. Manuka honey enhanced the action of omega-3 in reducing oxidative stress by reducing serum iron significantly compared to the control group. CONCLUSIONS: Results showed that omega-3 + Manuka honey was more effective than Manuka alone or the conventional treatment alone in managing oxidative stress of β-thalassemic patients.

BACKGROUND: Fish oil is routinely concentrated into unmodified triglycerides, or trans-esterified into an ethyl ester form. Re-esterification of the ethyl ester form yields re-esterified triglycerides (rTG), which are reportedly more bioavailable than ethyl ester forms. However, the fidelity of the re-esterification process may yield variable triglyceride forms, with only 55-60% being rTG. OBJECTIVE: To determine whether the blood lipidomic response to supplementation with two rTG supplements, varying by degree of re-esterification, would differ between treatments. DESIGN: This was a double-blind, parallel-design, single-center, 128-day study with sixty young, healthy subjects randomized into two groups. One group received a >95% rTG (Ultimate Omega®), as 1,000 mg capsules containing 325 mg eicosapentaenoic acid (EPA) and 225 mg docosahexaenoic acid (DHA), and the other received a <70% rTG (MEG-3) as 1,000 mg capsules containing 300 mg EPA and 200 mg DHA. Total intake was 2,750 and 2,500 mg EPA+DHA for the Ultimate Omega® and MEG-3 groups, respectively, with blood drawn at 4, 16 and 24 weeks and analyzed for serum and erythrocyte phospholipid fatty acid (PLFA) content. RESULTS: For erythrocyte PLFA profiles, EPA, docosapentaenoic acid (DPA) and DHA percentage of total erythrocyte PLFA were significantly greater for the Ultimate Omega® group than for the MEG-3 group, at week 16 (P < 0.05), as were the EPA:arachidonic acid (AA) ratio, DHA:AA ratio and EPA+DHA:AA ratio. For serum PLFA profiles, increases in EPA:AA ratio and EPA+DHA:AA ratio were significantly greater at week 4 in the Ultimate Omega® group compared to the MEG-3 group (P < 0.05). CONCLUSIONS: These data suggest that the percentage of rTG in rTG fish oil preparations may evolve as a new chemoprofile/quality control marker that can influence its lipidomic pharmacodynamics. Additional investigations to assess the physiologic/vascular and metabolic/inflammasome responses to concentrated fish oil preparations differing in the percentage of rTG are warranted. Copyright: © 2023 Minton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permit

BACKGROUND: Omega-3 fatty acids, especially docosahexaenoic acid (DHA), are found in different cell membranes, but more concentrated in the brain, playing an important role in child's behavior and development. AIMS: To evaluate the effect of antenatal omega-3 supplementation on child development and behavior during the first six months of life. STUDY DESIGN: Randomized double-blind placebo-controlled trial. SUBJECTS: Low-risk pregnant women with gestational age between 22 and 24 weeks were randomized in placebo (olive oil; n = 30) or omega-3 (fish oil; 1440 mg/day of DHA; n = 30) groups and supplemented until childbirth. OUTCOME MEASURES: Child development was assessed using the Survey of Well-being of Young Children in the first, fourth and sixth month of life. RESULTS: The comparison between groups showed no differences in the Developmental Milestones score at any time, but when compared to the first month, the omega-3 group showed an increase at the fourth and sixth month. Such increase was not observed in the placebo group. No differences were found between groups for Irritability and Inflexibility scores, however, higher scores for Difficulty with Routine were observed in the placebo group when compared to omega-3 at first, fourth and sixth month. CONCLUSION: There were no differences between groups for child development, but the omega-3 group showed an increase in this score over time. The placebo group had greater difficulty with routine than the omega-3 group, indicating a beneficial effect of antenatal supplementation on child behavior. TRIAL REGISTRATION: ReBec U1111-1215-7952 (June 16th 2018).

OBJECTIVE: Sickle Cell Anemia (SCA), also called the Sickle Cell Disease (SCD), is an inherited hematological disorder characterized by a syndrome of acute anemia and a painful crisis. The sickling hemoglobin, Hgb-S causes viscosity and inflammation of blood vessels. Eventually, the red blood cells get eliminated from the circulation process, which leads to hemolytic anemia. This study examined the comparative effectiveness of supplementation of Omega-3 or vitamin-D to standard therapy (hydroxyurea + Ibuprofen) used for prevention and treatment of pain crises in pediatric patients living with SCD. PATIENTS AND METHODS: 165 patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design trial. The patients were randomly divided into three groups, receiving three capsules of either 1,000 mg Omega-3 fish oil (400 mg EPA and 300 mg DHA) or 1.5 mL vitamin-D (2,800 IU/7 ml) daily for 10 months plus the standard therapy. Lactate dehydrogenase, high-density lipoprotein (HDL), low-density lipoprotein (LDL), hematocrit, reticulocyte count, and white-blood-cell count were determined at baseline (month zero) and end of the 10th month. The pain severity was measured using the visual analog scale method (VAS). Therefore, a 10-cm ruler with a VAS design was used to determine the patient pain intensity. The baseline time point was defined as the time spot before starting to deliver the experimental medication to the patients (month zero). At that time, the biodata of the patient on the frequency of pain episodes and the rest of the variables were collected, and the baseline data were one-year retrospective data. RESULTS: Of 165 patients enrolled in the trial, 150 were included in the final analysis. At the end of the study, there was a significant increase in serum LDL and HDL in the Omega-3 group as compared with the control group (mean of 82 mg/dL vs. 57 mg/dL; p < 0.01 and mean of 47 mg/dL vs. 43 mg/dL; p < 0.028, respectively). Other laboratory parameters were significantly influenced. The number of painful crises and pain levels was significantly decreased in the Omega-3 group compared with the control group (mean of one-episode vs. mea

OBJECTIVE: Randomized double-blind placebo-controlled trial was conducted with sixty pregnant women to evaluate the effect of antenatal omega-3 supplementation on maternal depressive symptoms from pregnancy to 6 months postpartum. METHODS: Participants with gestational age between 22 and 24 weeks were randomized in placebo (olive oil; n = 30) or omega-3 (fish oil; n = 30) groups and supplemented until childbirth. Fish oil capsules provided 1440 mg/day of docosahexaenoic acid. Depressive symptoms were evaluated during the gestational period: (G1) 22-24 weeks; (G2) 26-28 weeks; (G3) 30-32 weeks; (G4) 34-36 weeks; and postpartum: (P1) second week; (P2) first month; (P3) fourth month; and (P4) sixth month, using the Edinburgh Postnatal Depression Scale (EPDS). Intention-to-treat and per-protocol analyses were performed using Generalized Estimating Equations (GEE). RESULTS: Comparison between groups showed no differences in the EPDS score at any time during pregnancy or postpartum, in both intention-to-treat and per-protocol analysis (p > 0.05). Both groups presented a reduction in the EPDS score over time. According to intention-to-treat analysis, when comparing to the baseline, the placebo group showed a reduction in the EPDS score at P1 and P4, while the omega-3 group showed a reduction at all times from G4 to P4. In per-protocol analysis, the placebo group showed a reduction in the EPDS score at P3, while the omega-3 group showed a reduction at all times from G2 to P4. CONCLUSIONS: The supplementation with omega-3 did not promote significant differences between groups. However, an earlier reduction in the EPDS score was observed in the omega-3 group, which may indicate a benefit of antenatal omega-3 supplementation.

OBJECTIVE: To evaluate the relationship between diurnal salivary cortisol patterns and distress from heart palpitations in midlife women. METHODS: We analyzed baseline data from 293 women who were eligible for a 3 × 2 factorial trial of exercise or yoga versus routine activity, and omega-3 fish oil versus placebo for vasomotor symptoms. Women self-collected salivary cortisol using swabs at four time points over 2 consecutive days and reported distress from heart racing or pounding during the past 2 weeks using a single item. Sample description and covariate data included demographics, clinical data, vasomotor symptom frequency from daily diaries, medication use, and validated questionnaires on depression, stress, and insomnia (Patient Health Questionnaire-8, Perceived Stress Scale, and Insomnia Severity index). Data were analyzed using descriptive statistics, chi-square and t tests, and repeated measure linear regression models. RESULTS: Participants were on average 54.6 (SD = 3.6) years old, most were White (67%) postmenopausal (84%), and 26% reported distress related to palpitations. In adjusted models, the morning (wake plus 30-min) geometric mean daily salivary cortisol concentrations were significantly more blunted in those with distress from palpitations compared with those without distress (P ≤ 0.03). When all covariates were controlled, distress from palpitations was the sole significant predictor of wake plus 30-minute cortisol (-0.25 [-0.45 to -0.04], P = 0.02). CONCLUSIONS: Palpitations among midlife women may be associated with blunted morning cortisol, and this relationship is not explained by demographics, clinical variables, vasomotor symptoms, medications, depression, stress, or insomnia.

BACKGROUND: Omega-3 is a nutritional strategie that have been used to recover muscles from exercise-induced muscle damage in a preventive perspective. AIM: To verify whether omega-3 (ω-3) supplementation after a session of resistance exercise facilitates muscle recovery in women undergoing a balanced diet. METHODS: This clinical trial was registered under the number NCT02839525. Thirty healthy women (22.2 ± 3.3 years) participated in this double-blinded, placebo-controlled trial. They were randomly distributed into ω-3 (n=15) and placebo (n=15) groups. They ingested ω-3 fish oil (3200 mg/day) or placebo (olive oil) at the dinner after the exercise bout (10 sets of 10 unilateral eccentric contractions in a knee extension chair), as well as at lunch for the three subsequent days. In addition, both groups followed a balanced diet along the four days. Muscle soreness and maximal isometric and isokinetic voluntary contractions were assessed immediately before, and 24, 48, and 72 hours after the resistance exercise. MAIN FINDINGS: There was no significant group-time interaction for any outcome. Participants presented increased levels of muscle soreness and reduced muscle strength capacity along the three days after exercise. There was no difference between placebo and ω-3 groups. CONCLUSION: Supplementation of ω-3 fish oil for three days after resistance exercise provided no additional benefits compared to placebo supplementation on recovery of healthy young women following a balanced diet.

In the last decades, foods rich in omega-3 (ω-3) fatty acids (FA) have been replaced by omega-6 (ω-6) and trans FA, which are found in processed foods. The influence of ω-6 (soybean oil--SO), trans (hydrogenated vegetable fat--HVF) and ω-3 (fish oil--FO) fatty acids on locomotor and oxidative stress (OS) parameters were studied in an animal model of mania. Rats orally fed with SO, HVF and FO for 8 weeks received daily injections of amphetamine (AMPH--4 mg/kg/mL-ip) for the last week of oral supplementation. HVF induced hyperactivity, increased the protein carbonyl levels in the cortex and decreased the mitochondrial viability in cortex and striatum. AMPH-treatment increased the locomotion and decreased the mitochondrial viability in all groups, but its neurotoxicity was higher in the HVF group. Similarly, AMPH administration increased the protein carbonyl levels in striatum and cortex of HVF-supplemented rats. AMPH reduced the vitamin-C plasmatic levels of SO and HVF-fed rats, whereas no change was observed in the FO group. Our findings suggest that trans fatty acids increased the oxidative damage per se and exacerbated the AMPH-induced effects. The impact of trans fatty acids consumption on neuronal diseases and its consequences in brain functions must be further evaluated.

BACKGROUND: Malnutrition is a common problem for patients waiting for orthotopic liver transplantation and a risk factor for post-transplant morbidity. The decision to initiate enteral or parenteral nutrition, to which patients and at which time, is still debated. The effects of nutritional supplements given before or after liver transplantation, or both, still remains unclear. OBJECTIVES: The aim of this review was to assess the beneficial and harmful effects of enteral and parenteral nutrition as well as oral nutritional supplements administered to patients before and after liver transplantation. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (March 2012), the Cochrane Central Register of Controlled Trials (Issue 2 of 12, 2012) in The Cochrane Library, MEDLINE (January 1946 to March 2012), EMBASE (January 1974 to March 2012), Science Citation Index Expanded (January 1900 to March 2012), Social Science Citation Index (January 1961 to October 2010), and reference lists of articles. Manufacturers and experts in the field have also been contacted and relevant journals and conference proceedings were handsearched (from 1997 to October 2010). SELECTION CRITERIA: Randomised clinical trials of parallel or cross-over design evaluating the beneficial or harmful effects of enteral or parenteral nutrition or oral nutritional supplements for patients before and after liver transplantation were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of the trials and extracted data. Dichotomous data were reported as odds ratios (OR) and continuous data as mean differences (MD) along with their corresponding 95% confidence intervals (CI). Meta-analysis was not possible due to clinical heterogeneity of included interventions. MAIN RESULTS: Thirteen trials met the inclusion criteria. Four publications did not report outcomes pre-defined in the review protocol, or other clinically relevant outcomes and additional data could not be obtained. Nine trials could provide data for the review. Most of the 13 included trials were small and at high risk of bias. Meta-analyses were not possible du

INTRODUCTION: Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.

INTRODUCTION: Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child's Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.

INTRODUCTION: Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.

In recent years, opioid abuse has become a major public health crisis affecting millions of individuals throughout the world. This widespread abuse of prescription opioids and dramatic increase in their availability have created the opioid epidemic. Further, oxycodone (oxy), which is prescribed for multiple types of pain, is gaining momentum as a pain reliever in pregnant women. Whilst successful in inducing analgesia, oxy freely passes through the placenta and can impact the overall development of the fetus in major ways. Currently, mechanisms that lead to impairment in the exposed offspring, including identification of biomarkers, are not well described. To fill this gap, our study utilizes a preclinical rodent model to test the therapeutic efficacy of omega-3 fatty acids (O3FA) in attenuating neurodevelopmental deficits in offspring exposed to chronic stress (CS) and oxy in utero which mirrors real-world cases of opioid use during pregnancy co-occurring with chronic psychosocial stress. Our results show that O3FA supplementation partially rescues phenotypic, biochemical, molecular, and behavioral endpoints. Notably, our proteomic study identified distinct key synaptic signatures, including functional pathways impacted in different treatment groups. Furthermore, RT-qPCR results identified key inflammatory markers whose expression was ameliorated by O3FA supplementation. Together, this study bridges an important knowledge gap pertinent to maternal-fetal health that reflects a combined exposure of oxy and CS that is clinically relevant and enumerates the therapeutic efficacy of O3FA in mitigating neurodevelopmental deficits in offspring exposed to in utero oxy and CS. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

BACKGROUND/OBJECTIVES: Omega-3 polyunsaturated fatty acids (PUFAs) influence lipid-mediated inflammatory pathways implicated in migraine, yet randomized trial data evaluating biologic effects of omega-3 supplementation in youth with migraine remain limited. This pilot quasi-randomized clinical trial aimed to determine whether 12 weeks of omega-3 PUFA supplementation produces measurable changes in whole-blood EPA and DHA levels in children and adolescents with migraine, and to characterize changes in patient-reported measures of pain, migraine-related disability, and psychological distress. METHODS: We conducted a parallel-group, quasi-randomized, double-blind, placebo-controlled trial in children and adolescents (ages 10-17) with migraine diagnosed per International Classification of Headache Disorders, 3rd edition criteria, recruited from pediatric neurology clinics at two academic medical centers. Of 57 participants allocated 1:1 to daily omega-3 PUFA supplementation (340 mg EPA + 510 mg DHA) or coconut oil placebo for 12 weeks, 44 completed the study and were analyzed. The primary outcome was change in whole-blood omega-3 PUFA index. Secondary outcomes included patient-reported measures of pain intensity, pain interference, migraine-related disability, and psychological distress. Exploratory outcomes included changes in omega-6/omega-3 and arachidonic acid/eicosapentaenoic acid (AA/EPA) ratios. Between-group differences were evaluated using ANCOVA adjusting for baseline values. RESULTS: Omega-3 supplementation significantly altered lipid biomarker profiles. Compared with placebo, the intervention group demonstrated greater increases in omega-3 PUFA index (adjusted mean difference 1.64; 95% CI 0.94-2.35; p < 0.001) and greater reductions in omega-6/omega-3 ratio (-2.57; 95% CI -4.25 to -0.90; p = 0.003) and AA/EPA ratio (-13.52; 95% CI -21.55 to -5.49; p = 0.002), consistent with the increase in whole-blood omega-3 levels. No significant between-group differences were observed in patient-reported outcomes. CONCLUSIONS: Omega-3 PUFA supplementation significantly altered lipid biomarker profiles in youth with migraine over 12 weeks, supporting a measurable whole

Dietary guidelines shape food policy, education, and food systems worldwide. Recent controversies in dietary guideline development, together with rising burdens of diet-related chronic disease and increasing environmental pressures, highlight the need for globally relevant dietary guidance aligned with both human and planetary health. We developed an evidence-informed International Food Guide Pyramid emphasizing optimal carbohydrate-containing staple foods. The International Carbohydrate Quality Consortium developed the proposed framework using a 4-step evidence-review process involving comparison of major national and regional dietary guideline systems, integration of evidence syntheses and selected primary studies, and expert consensus. Quantitative intake ranges from the EAT-Lancet Commission reference diet informed the relative visual proportions of food groups, whereas the guiding principles were derived from convergence across dietary guideline systems and complementary evidence syntheses. The resulting pyramid depicts a plant-forward omnivorous dietary pattern supported by epidemiological and clinical evidence indicating benefits for cardiometabolic health and chronic disease prevention. Vegetables, fruits, whole grains, and legumes constitute foundational components of the pyramid. Nuts, seeds, and unsaturated plant oils are emphasized as primary fat sources, whereas foods high in saturated fat are generally limited. Animal-source foods are included in modest amounts, with plant protein sources emphasized, poultry and fish preferred over red meat, and dairy incorporated in modest amounts, consistent with dietary patterns associated with lower environmental impacts. Carbohydrate quality is emphasized through the prioritization of whole-grain foods alongside traditional low-glycemic index grain staples, favoring carbohydrate sources rich in dietary fiber, intact plant cells, and micronutrients while limiting sugars consumed in low-nutrient forms, particularly sugar-sweetened beverages. The framework also accommodates vegan and other primarily plant-based dietary patterns. This evidence-informed International Food Guide Pyramid integrates quantitative model

BACKGROUND: Clinical observations have suggested an association between a high-fat diet (HFD) and neuropathic pain (NP). Studies also revealed that maresin 1 (MaR1) can regulate macrophage phagocytosis, modulate tissue repair and inflammatory resolution, and influence the progression of NP. However, the specific regulatory mechanisms of MaR1 in HFD-induced NP remain unclear. OBJECTIVE: The aim of this study is to explore the effect of MaR1 on neuroinflammation in mice with NP induced by an HFD. METHODS: A tibial nerve crush model with a HFD was used to establish HFD-induced chronic pain. The paw withdrawal threshold (PWT), which reflects mechanical allodynia, was measured to evaluate changes in pain-related behavior. Immunofluorescence was used to detect the relative number of macrophages and microglia, and the expression of growth-associated protein 43 (GAP43), while qPCR was used to measure the levels of proinflammatory cytokines. RESULTS: HFD consumption exacerbates nerve injury-induced NP formation and upregulates GAP43 expression. Macrophage infiltration and proinflammatory cytokine expression were increased in the DRGs of HFD-induced nerve injury mice. Intrathecal injection of the specialized proresolving mediator MaR1 alleviated nerve injury-induced chronic pain and decreased GAP43 expression in HFD-fed mice. Furthermore, MaR1 decreased proinflammatory macrophage migration in the damaged tibial nerves and DRGs of HFD-induced nerve injury model mice. CONCLUSIONS: The specialized proresolving mediator MaR1 can reduce neuroinflammation and GAP43 expression in the DRG and injured nerve fibers and alleviate NP in HFD-fed mice.

Background/Objectives: Prospective studies of omega-3 supplementation during breast cancer chemotherapy differ in intervention composition, co-supplementation, dose, treatment setting, and outcomes. We summarized and critically appraised interventions comprising DHA alone, EPA + DHA, EPA + DHA + GLA, or EPA + DHA with or without vitamin D, stratified by intervention composition and outcome domain. Methods: PubMed/MEDLINE, the Cochrane Library/CENTRAL, ClinicalTrials.gov, Scopus, Web of Science Core Collection, and Embase were last searched on 8 July 2026, supplemented by citation searching. Eligible studies prospectively administered EPA and/or DHA during chemotherapy and reported inflammatory/biological, nutritional/functional, quality-of-life, treatment-related, anticancer-response, or safety outcomes. Active co-supplementation was analyzed separately. Owing to clinical and methodological heterogeneity, findings were synthesized narratively; risk of bias and outcome-specific certainty were assessed using RoB 2-informed and GRADE approaches. Results: Fourteen reports representing ten prospective interventional trials were included. No eligible EPA-only trial was found. Interventions comprised EPA + DHA/fish oil without another active nutrient, DHA alone, EPA + DHA plus gamma-linolenic acid, and a factorial trial of EPA + DHA with or without vitamin D. One trial reported lower paclitaxel-induced neuropathy, whereas another found no benefit for paclitaxel-associated acute pain or neuropathic symptoms. Biomarker, nutritional, functional, and quality-of-life findings were inconsistent and often derived from small trials, exploratory or compliance-restricted analyses, companion reports, or co-supplementation designs. No consistent improvement in treatment response or survival was demonstrated. Serious supplementation-related adverse events were not reported, although adverse-event reporting varied. Certainty was low for safety and very low for efficacy-related domains. Conclusions: Current evidence is preliminary. The evaluated interventions appeared generally tolerated, but independent clinical efficacy of DHA alone, EPA + DHA without another active nutrient, EPA +

Streptococcus pneumoniae remains a leading cause of lower respiratory tract infections and pneumonia-related mortality worldwide. Although neutrophil recruitment is essential for pneumococcal containment, excessive and dysregulated neutrophilic inflammation can drive severe lung injury and acute respiratory distress syndrome. Specialized pro-resolving mediators, such as Resolvin D5 (7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid; RvD5), are produced in the lungs and have the potential to promote pathogen clearance and limit inflammatory injury. Using a mouse model of severe pneumococcal pneumonia, we investigated the actions of RvD5 on disease progression. Exogenous RvD5 was administered either at the time of infection or post-infection together with the antibiotic ceftriaxone. Outcomes measured included lung neutrophil accumulation, bacterial burden, neutrophil activation markers, and indices of alveolar barrier integrity. Complementary in vitro assays were performed to assess the effects of RvD5 on human neutrophil phagocytosis and activation by LTB4. When administered at the time of infection, RvD5 reduced neutrophil accumulation in bronchoalveolar lavage (BAL) and lung tissue and enhanced clearance of S. pneumoniae. RvD5 decreased neutrophil activation marker expression and lowered total protein levels in BAL fluid, consistent with reduced inflammatory lung injury. When administered post-infection together with ceftriaxone, RvD5 significantly reduced lung neutrophil numbers and barrier disruption compared with antibiotic treatment alone. In vitro, RvD5 enhanced phagocytic uptake and intracellular killing of bacteria by human neutrophils, and blunted secondary calcium mobilization responses to LTB4. In summary, these findings indicate that RvD5 can initiate pro-resolving mechanisms adjunctive to antibiotics to enhance bacterial clearance and limit inflammation-driven lung injury in severe pneumococcal pneumonia. © 2026 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Elevated saturated fatty acids, such as palmitic acid (PA), induce lipotoxicity in peripheral nerve cells, a pathological feature of metabolic disorders such as type 2 diabetes and obesity that are frequently associated with neuropathic pain (NP). PA overload elicits a maladaptive stress response characterized by endoplasmic reticulum (ER) stress, disrupted intracellular calcium homeostasis, and impaired autophagic flux, ultimately promoting cell death. Although omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) protect against PA-induced lipotoxicity (PA-LTx), the mechanisms linking lipid handling, ER stress, and autophagy in Schwann cells remain poorly defined. Here, we investigated how PA and DHA regulate autophagic flux, ER stress signaling, and fatty acid-binding protein 5 (FABP5)-dependent lipid trafficking in immortalized Schwann cells (ISCs). PA exposure (300 µM PA:150 µM BSA, 24-48 h) significantly reduced cell viability, impaired autophagic flux as indicated by LC3-II and p62 accumulation, disrupted autophagosome-autolysosome balance, and increased susceptibility to autophagic inhibition by chloroquine. DHA co-treatment (50 µM) preserved cell viability, restored autophagic flux, and normalized autophagosome-autolysosome fusion. Mechanistically, PA induced ER stress marked by increased CHOP, ATF4, and Xbp1 expression, along with progressive ER calcium depletion, whereas DHA suppressed these responses and stabilized calcium homeostasis. Building on prior evidence that FABP5 protects neuron-like cells from PA-LTx, we identified a regulatory role for FABP5 in Schwann cells. PA robustly induced FABP5 expression, which was normalized by DHA and modulated by pharmacological manipulation of autophagy. FABP5 silencing exacerbated PA-induced ER stress, triggered a dysfunctional compensatory autophagy response, and impaired DHA-induced lipid droplet formation. Collectively, these findings demonstrate that functional autophagy and FABP5-dependent lipid buffering are critical adaptive responses to lipotoxic stress in Schwann cells, highlighting these pathways as potential therapeutic targets for NP-associated metabolic neuropathies. © 2026. The

Background: Endometriosis is a chronic, estrogen-dependent inflammatory disorder associated with pain and immune dysregulation. Omega-3 (n-3) fatty acids and fish-derived bioactive lipids may modulate inflammation and metabolism. This study investigated whether adding fish-derived lipids (FDLs) to a Healthy Eating Plate diet improves inflammatory markers, gut inflammation, pain, and quality of life in women with endometriosis. Methods: In this 12-week randomized controlled trial, 46 women with confirmed endometriosis were assigned to either a Healthy Eating Plate diet alone (control group, CG) or the same diet plus FDLs (intervention group, IG). Primary outcomes included serum cytokine concentrations (interleukin [IL]-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha [TNF-α]) and fecal calprotectin (CAL). Secondary outcomes included pain intensity measured using the visual analog scale (VAS) and health-related quality of life assessed with the Endometriosis Health Profile-30 (EHP-30). Results: IL-10 levels (pg/mL) increased in the IG (32.5 ± 51.5 to 265 ± 508; p = 0.024) with a significant adjusted effect (ANCOVA: 5.07 [95% CI: 1.32-19.48], p = 0.019). Other cytokines showed heterogeneous responses, and CAL levels remained unchanged. EHP-30 Pain scores improved within both groups (CG p = 0.016; IG p = 0.002) without significant between-group change or adjusted effects (all p > 0.05). VAS scores decreased within the IG (5.0 ± 2.1 to 4.3 ± 2.1; p = 0.011), although there were no between-group differences in change and ANCOVA (all p > 0.05). However, ≥1-point responder rates were higher in the IG vs. CG (73.9% vs. 34.8%): adjusted RR = 2.11 (95% CI: 1.16; 3.89; p = 0.014). Conclusions: Overall, FDL supplementation was associated with a selected regulatory immune signal, reflected mainly by the IL-10 response, while most inflammatory, pain-related, and quality-of-life outcomes did not show consistent significant between-group effects. The observed greater likelihood of pain reduction in the FDL-supplemented group of women with endometriosis, along with the IL-10 response, should be interpreted with caution and confirmed in larger studies with longer follow-up/i

False-positive annotations in untargeted lipidomics limit biological interpretation. A modified equivalent carbon number (mECN) rule was developed with independently fitted parameters to overcome the fixed coefficient limitation of the classical ECN model, enabling quantifiable false-positive filtering. Validated with a fish oil of known composition and five independent data sets, this workflow improved precision by 8.4% over traditional methods, with 0.5% recall loss and 3.4% F1 gain. Multilevel verification integrating structural (subclass, lipid species, fatty acid) and analytical (metabolite, pathway, network) dimensions was established to strengthen biological interpretation. Applied to a neuropathic pain model, six lipids (CE 20:5, LPC 20:5, LPE 20:5, PG 22:6_22:6, PE 16:1_22:6, and LPI 22:6) were associated with pain modulation, implicating fatty acid elongation/desaturation and phospholipase A2-mediated acyl chain remodeling. This study provides a robust analytical framework for untargeted lipidomics and mechanistic insight into ω-3 nutritional intervention for pain management.

This retrospective study investigated whether eicosapentaenoic acid (EPA) reduces paclitaxel-associated chemotherapy-induced peripheral neuropathy (CIPN) and acute neuropathic pain in dyslipidemic cancer patients. The medical records of cancer patients treated with paclitaxel or nab-paclitaxel at Okayama University Hospital between January 2018 and December 2022 were reviewed. Patients receiving concomitant therapy for dyslipidemia were categorized as EPA users or non-EPA users. Numbness and pain severity were extracted from medical records. The primary endpoint was the change from baseline in Common Terminology Criteria for Adverse Events (CTCAE) grade for peripheral neuropathy and pain; groups were analyzed using the Mann-Whitney U test. Of 184 eligible patients, 18 received EPA. Bleeding events were more frequent in the EPA group; however, changes in numbness and pain did not differ significantly between groups at any time point. Overall, EPA did not show a preventive effect on paclitaxel-associated CIPN or acute neuropathic pain. Future studies should evaluate EPA in combination with other neuroprotective agents to better define its potential role in CIPN prevention.

Breast cancer is one of the leading causes of death among women worldwide, and its occurrence is shaped by both nonmodifiable factors (such as age and genetics) and modifiable factors, among which diet plays a central role. This review addresses the role of polyunsaturated fatty acids (PUFAs) in the prevention, development, and treatment of breast cancer, highlighting their capacity to modulate inflammatory processes and impact mammographic density. Evidence indicates a negative association between n-3 PUFAs intake and breast cancer risk, whereas the role of n-6 PUFAs in disease development remains poorly elucidated. N-3 PUFAs supplementation has been shown to improve patient's quality of life by alleviating treatment-related side effects, such as aromatase inhibitors-induced musculoskeletal pain, and by reducing systemic inflammation. However, responses vary among individuals, emphasizing the need to personalize dietary strategies by considering factors such as body mass index and nutritional status. Although current evidence reinforces the importance of incorporating n-3 PUFAs and regulating n-6 PUFAs intake, further research is needed to optimize dosage and supplementation duration and to assess their long-term impact on breast cancer prevention and treatment.

BACKGROUND: Osteoarthritis (OA) is a leading cause of chronic pain and functional impairment, associated with persistent inflammation, potentially due to impaired resolution. Specialized pro-resolving lipid mediators (SPMs) regulate inflammation resolution and restore homeostasis. The GAUDI study previously demonstrated that SPM supplementation reduces pain and improves quality of life (QoL) in patients with knee OA. This analysis assesses the impact of SPM supplementation on inflammatory biomarkers (IB) and SPM levels and their relationship with clinical outcomes. METHODS: This is a secondary analysis of the GAUDI trial, a randomized, multicenter, double-blind, placebo-controlled study conducted in Spain in adults with symptomatic knee OA who received daily supplementation with SPMs or placebo for 12 weeks. Endpoints included changes in plasma IB and SPM levels and their correlation with clinical outcomes. RESULTS: Changes in IL-1 (15.9 vs. -1.1 pg/ml, p-value: 0.051) and IL-18 (10.3 vs. -1.4 pg/ml, p-value: 0.29) showed a tendency toward reduction in the SPM group compared to the placebo group. Changes in IL-1 and IL-8 positively correlated (r = 0.707, p-value: 0.005 and r = 0.551, p-value: 0.04; respectively) with changes in WOMAC score and negatively correlated (r = -0.797, p-value <0.001 and r = -0.804, p-value <0.001; respectively) with changes in EuroQoL-5 VAS score. Changes in IL-1 (r = 0.554, p-value: 0.048) and IL-6 (r = 0.631, p-value: 0.014 and r = 0.572, p-value: 0.031) correlated with changes in OMERACT-OARSI pain score. No significant differences in IB levels were observed between groups during the intervention. Minor changes in SPM levels point to metabolic pathways at work with SPM supplementation. In patients with a BMI ≥25 kg/m², most IB tended to decrease following SPM consumption. CONCLUSIONS: This analysis suggests a potential association between SPM supplementation, decreased inflammation, and improved pain and QoL in patients with knee OA. Subtle changes in blood plasma SPM levels were detected that indicate, through bioinformatics analysis, a pathway-specific metabolome activation induced by SPM supplementation. TRIAL REGISTRATION: NCT05

PURPOSE: This study investigated the effects of docosahexaenoic acid (DHA) supplementation on delayed onset muscle soreness (DOMS), physical function, and inflammation following eccentric exercise-induced muscle damage in physically trained male and female adults (training ≥ 5d/wk). METHODS: Thirty-eight participants (12 Control, 26 DHA) completed a 12-week double-blind, placebo-controlled matched-pair trial. The Control group received high-oleic acid tablets. The DHA group received 715 mg/d of microencapsulated DHA tablets. Participants performed eccentric cycling at weeks 0 and 12, with assessments conducted pre-exercise, 0-h, 24-h, and 48-h post-exercise. The primary outcomes were DOMS (visual analogue scale) and the Omega-3 Index (O3I) (estimated by finger-stick dry blood spot). Secondary outcomes included neuromuscular function and inflammatory cytokines. RESULTS: O3I was not different between groups at week 0 but was elevated in the DHA group (∆2.43%, [95% CI; 2.10, 2.77], P < 0.001) and between Control at week 12 (P < 0.001). DOMS was lower at 24-h and 48-h post-exercise in the DHA group and between Control at week 12 (P < 0.01). At week 12, jump height and peak vertical force improved at 48-h post-exercise in the DHA group (P < 0.05), resulting in moderate (d = 0.60) and small (d = 0.32) effect sizes for 48-h post-exercise area under the curve (AUC) between groups, respectively. There were interaction effects for 48-h post-exercise AUC of IL-6 (P = 0.049), TNF-α (P = 0.010), and IL-10 (P = 0.026). CONCLUSION: A dietary achievable dose of DHA elevated the O3I and reduced DOMS in physically trained adults. These outcomes support protracted intake of DHA to attenuate the physiological impact of eccentric exercise and promote recovery. © 2026. The Author(s).

Mobility limitations due to chronic musculoskeletal pain are a major contributor to disability in older adults, yet current pharmacological treatments often have limited efficacy and increase the risk of polypharmacy. Omega (ω)-3 PUFA, particularly EPA and DHA, have demonstrated anti-inflammatory and analgesic properties, but are under-consumed among older USA adults. Krill oil, a marine-derived source of EPA and DHA with enhanced bioavailability compared with typical fish oils and additional bioactive compounds such as astaxanthin and choline, may offer a promising nutritional intervention. This pilot study will assess the feasibility and acceptability of a 3-month randomised, double-blind, placebo-controlled trial of krill oil supplementation (4 g/d: 1288 mg EPA + DHA, 0·45 mg astaxanthin, 320 mg choline) v. placebo (mixed vegetable oils) in forty community-dwelling adults aged ≥ 60 years with chronic musculoskeletal pain. Primary outcomes include feasibility (recruitment, retention and adherence) and acceptability (participant satisfaction). Secondary outcomes include changes in the omega-3 index, ω-6/ω-3 ratio and inflammation (high-sensitivity C-reactive protein), as well as exploratory changes in pain intensity and functional interference, and physical function (Short Physical Performance Battery, 6-Minute Walk Test). Findings will inform the design of future fully powered trials that may ultimately contribute to the evidence for omega-3 supplementation as a non-pharmacological strategy to support healthy aging and functional independence in older adults.

Background: Supplementation with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may mitigate exercise-induced muscle damage (EIMD) and enhance post-exercise recovery. However, the systematic reviews/meta-analyses evaluating these effects across populations and exercise models are limited and do not provide dosing recommendations. Objective: This systematic review and meta-analysis aimed to evaluate the effects of LC n-3 PUFA supplementation on key post-exercise recovery outcomes, including muscle soreness, muscle function, and muscle damage biomarkers in healthy adults. Methods: Following the PRISMA guidelines, a comprehensive search of PubMed, Scopus, and clinical trial registry databases was conducted (to January 2025). All studies that met the inclusion criteria underwent appropriate methodological quality assessments using established tools. The data were extracted for inputting into random-effects models, with effect sizes reported as Hedges' g and 95% confidence intervals (CIs). Heterogeneity was assessed using the I2 statistic. Results: Among the 2539 records, 43 studies met the inclusion criteria for the systematic review, and nine met the inclusion criteria for the meta-analysis. The effect of LC n-3 PUFA supplementation on recovery outcomes was equivocal, with significant methodological limitations noted across the literature. However, the meta-analysis of nine placebo-controlled, eccentric exercise trials demonstrated that LC n-3 PUFA supplementation significantly reduced delayed onset muscle soreness (DOMS) (Hedges' g = -0.75; 95% CI: -1.14 to -0.36), creatine kinase (CK) (Hedges' g = -0.40; 95% CI: -0.70 to -0.10), and muscle swelling (Hedges' g = -0.45; 95% CI: -0.83 to -0.07), and significantly improved muscle strength (Hedges' g = 0.45; 95% CI: 0.07 to 0.83) and range of motion (ROM) (Hedges' g = 0.93; 95% CI: 0.33 to 1.53) at peak impairment compared with placebo. Conclusions: LC n-3 PUFA supplementation may support recovery from EIMD. However, due to the methodological limitations across the literature base it was not possible to assess effective dosing str

The transition from acute inflammation to chronic pain represents a significant clinical challenge, often driven by a failure of endogenous resolution programs. Specialized pro-resolving mediators (SPMs), derived from polyunsaturated fatty acids, are crucial for actively terminating inflammation and restoring tissue homeostasis. Maresin 1 (MaR1), a prototypical SPM biosynthesized from docosahexaenoic acid (DHA), has emerged as a powerful modulator of pain. This review comprehensively synthesizes the current preclinical evidence, primarily derived from preclinical animal models, detailing the analgesic effects of MaR1 across a spectrum of pain models, including inflammatory, neuropathic, postoperative, osteoarthritis-related pain, etc. We dissect the multifaceted mechanisms underlying its efficacy, which extend beyond simple anti-inflammation. MaR1 exerts its effects by: (1) attenuating neuroinflammation including the suppression of glial (microglia and astrocyte) activation and reprogramming macrophage phenotypes; (2) directly modulating neuronal function by inhibiting nociceptive ion channels (e.g. TRPV1) and reversing central synaptic plasticity; and (3) promoting robust tissue repair, including peripheral nerve regeneration. These actions are mediated through potential specific receptors, notably G-protein-coupled receptor 37-like 1 (GPR37L1) on glial cells and retinoic acid-related orphan receptor α (RORA) on neurons. While MaR1 demonstrates significant therapeutic potential, challenges related to its pharmacokinetic instability and observed sex-dependent analgesic effects must be addressed for successful clinical translation. This review provides a comprehensive mechanistic framework supporting MaR1 as a next-generation therapeutic candidate for pain management, and outlines the core research directions to overcome key translational barriers for MaR1-based therapies. © 2026 Wang et al.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem neurologic disease characterized by profound fatigue and decreased functional capacity, postexertional malaise, and unrefreshing sleep, along with cognitive impairment and/or orthostatic intolerance. Its prevalence has risen exponentially with the COVID-19 pandemic. Pharmacologic therapies have been used successfully by ME/CFS specialists but may be underused by the general medical field. METHODS: To assess this potential practice gap, we retrospectively analyzed the records of 571 patients with an ME/CFS diagnosis referred to our ME/CFS specialty clinic in Minnesota during 2018-2022. We ascertained medications that had already been tried at the time of consultation and also ascertained supplement use. RESULTS: With the exception of medications primarily used for pain and anxiety, use of pharmacotherapy for ME/CFS symptom management as proposed by specialists was limited. Overall, 68.3% of patients had had at least 1 medication potentially prescribed for ME/CFS; the most common were serotonin-norepinephrine reuptake inhibitors, gabapentin, and tricyclic antidepressants. A slightly larger share of patients, 72.2%, reported having taken at least 1 dietary supplement; the most common were vitamin D, vitamin B12 and B complex, and fish oil. CONCLUSIONS: Our findings suggest that potentially helpful medications for ME/CFS are being underprescribed in the general medical field and that patients may resort to supplements to manage symptoms. Better education of clinicians about available treatment options and treatment guides may improve management of this debilitating disease. © 2026 Annals of Family Medicine, Inc.

BACKGROUND: In dentistry, gingival hyperpigmentation is a common aesthetic issue caused mainly by excessive melanin deposits. Traditional surgical methods for depigmentation, like surgical techniques, can be effective, but they often associated with pain after the procedure and longer healing times. Because of their anti-inflammatory and antioxidant qualities, omega-3 polyunsaturated fatty acids (PUFAs) have demonstrated potential benefits in tissue regeneration and dermatological depigmentation. OBJECTIVE: To investigate the effectiveness of locally and systemically administered Omega-3 (PUFAs) in reducing gingival pigmentation, thereby contributing to advancements in aesthetic periodontal care. METHODOLOGY: Two groups were randomly selected from thirty patients who presented with mild to moderate gingival pigmentation grade (1,2 or 3) in the maxillary esthetic area. Group I was given a daily oral dose of 2 g of Omega-3 PUFAs before and after one weekly intragingival injections of 1–2 g of omega-3. Group II was depigmented using a traditional surgical technique. At one, three, and six months, the primary outcome Dummett Oral Pigmentation Index (DOPI). Secondary outcomes Hedin index measured at 1,3,6 months, Visual Analogue Scale (VAS) and wound healing were measured at one and seven days following the procedure. Hemorrhage during the surgery were also noted. RESULTS: Both groups displayed a significant decrease (P ≤ 0.05) in the DOPI and Hedin index at various time points. However, after six months, there was no significant difference between the groups (P ≥ 0.05). When compared to Group II at various time

BACKGROUND: A parental high-fat diet (HFD) enriched in inflammatory omega-6 polyunsaturated fatty acids (n-6 PUFAs) increases the severity of post-traumatic osteoarthritis (PTOA) in adult offspring, a risk factor which lacks therapeutic interventions. This study investigated whether rebalancing the maternal omega-6 to omega-3 fatty acid (n-6/n-3 FA) ratio during pregnancy and lactation could mitigate PTOA severity in adult offspring. METHODS: Wildtype (WT) and fat-1 female mice, which endogenously convert n-6 to n-3 PUFAs, were fed either a control or n-6-enriched HFD and mated to control-fed males. WT offspring were evaluated developmentally at embryonic day E17.5 and in adulthood for metabolic and musculoskeletal outcomes 12-weeks following destabilization of the medial meniscus (DMM) surgery. RESULTS: WT fetal offspring from fat-1 dams had increased circulating levels of the anti-inflammatory cytokine IL-4 and decreased levels of the inflammatory cytokine TNFα, indicating a less inflammatory systemic environment than offspring from WT dams. Fetal offspring of fat-1 dams also had increased bone volume and bone mineral density. When raised to adulthood, offspring displayed sexually dimorphic metabolic and musculoskeletal responses. Male offspring: Neither maternal diet nor genotype influenced whole body metabolism or cartilage damage following DMM in male offspring. Maternal HFD increased osteophyte severity and increased subchondral bone remodeling in the lateral tibial plateau. Maternal fat-1 genotype mitigated DMM-induced synovitis, but this change did not protect offspring from displaying pain-related behaviors. Female offspring: Maternal HFD increased body fat, cartilage damage, and synovitis following DMM surgery in offspring of WT dams. Maternal HFD also impaired trabecular bone properties at the tibial metaphysis in offspring of both WT and fat-1 dams. Maternal fat-1 genotype did not protect against structural changes in the knee joints following injury. However, female offspring of fat-1 dams were remarkably protected from displaying pain-related behaviors. Furthermore, decreasing the maternal n-6/n-3 FA ratio decoupled the correlation between synoviti

Background: Visceral pain is the primary symptom of functional gastrointestinal disorders, yet its spinal molecular mechanisms remain poorly defined. Methods: Using a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced chronic inflammatory visceral pain model, the role of the spinal CXCL10/CXCR3/ERK signaling axis and the analgesic effect of docosahexaenoic acid (DHA) were investigated. Results: TNBS significantly upregulated CXCL10 and CXCR3 in spinal dorsal horn neurons and increased ERK phosphorylation. Intrathecal CXCL10-neutralizing antibody or CXCR3 antagonist NBI-74330 reduced visceral hypersensitivity and suppressed spinal ERK activation in TNBS mice. Exogenous CXCL10 induced CXCR3-dependent hyperalgesia and ERK phosphorylation in the spinal cord. Intrathecal DHA attenuated TNBS-induced visceral pain, downregulated spinal CXCL10/CXCR3 expression, and inhibited ERK signaling. In Neuro-2a cells, DHA also blocked LPS-induced activation of the same pathway. Conclusions: This study suggests that the analgesic effect of DHA may involve the inhibition of the spinal CXCL10/CXCR3/ERK signaling pathway.

Repeated morphine administration leads to analgesic tolerance, reducing its pain-relief effectiveness and increasing overdose risks. However, the changes in endogenous levels of specialized pro-resolving mediators and their relationship with the mu-opioid receptor, as well as their role in analgesic tolerance during extended morphine use, have yet to be fully understood. Our study demonstrates that chronic morphine exposure reduces maresin1 levels in mice, correlating with morphine dosage in tolerant patients. Systemic or intrathecal administration of maresin1 alleviates morphine tolerance, but intracerebroventricular administration does not. Additionally, Lgr6 expression decreases in the dorsal root ganglia of morphine-tolerant mice, and reducing Lgr6 expression in dorsal root ganglia via AAV injection negates the protective effects of maresin1. Maresin1 works by preventing β-arrestin2 recruitment and mu-opioid receptor internalization, preserving morphine's pain-relief effects. In conclusion, this study elucidates the functions of maresin1 in the modulation of morphine tolerance, suggesting it as a potential target to improve opioid effectiveness.

BACKGROUND: Chronic musculoskeletal (MSK) pain is highly prevalent in older adults and the leading cause of disability. Long-chain omega-3 (ω-3) polyunsaturated fatty acids have anti-inflammatory and analgesic properties, yet intake and circulating levels are low in older US adults. Krill oil, a phospholipid-bound source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that also contains astaxanthin and choline, may represent a feasible nutrition-based intervention for chronic MSK pain. OBJECTIVES: To evaluate the feasibility and acceptability of krill oil supplementation in older adults with chronic MSK pain and to characterize changes in ω-3 status and exploratory pain outcomes. METHODS: A 12-wk, randomized, double-blind, placebo-controlled pilot trial in 40 community-dwelling adults aged ≥60 y with moderate chronic MSK pain. Participants were stratified by sex and randomly assigned 1:1 to krill oil (4 g/d; 1288 mg EPA+DHA) or placebo. Primary outcomes were feasibility metrics (recruitment, retention, adherence, and acceptability). Secondary outcomes included biomarkers of ω-3 status and inflammation. Exploratory outcomes included pain intensity, pain interference, pain distribution, and global improvement. RESULTS: Recruitment targets were met within 8 mo; retention was 95%, adherence exceeded prespecified thresholds (>70%) in both groups, and overall acceptability was rated 7.7 ± 2.3 of 10. Krill oil supplementation increased the ω-3 index from 4.3% to 7.4%, approaching levels consistent with lower cardiometabolic risk (≥8%), whereas the placebo group showed no meaningful change. Preliminary analyses showed trends favoring krill oil for reduced pain intensity (ΔKO - ΔP = ‒1.05), fewer pain sites (rate ratio: 0.59; 95% confidence interval: 0.41, 0.84), and global improvement (adjusted odds ratio: 4.35; 95% confidence interval: 0.97, 19.55). No serious adverse events occurred. CONCLUSIONS: Krill oil supplementation was feasible and acceptable among older US adults with chronic MSK pain. These findings support a fully powered randomized controlled trial to evaluate krill oil as a nutritional strategy for pain management in aging populations. This t

The acute inflammatory response is a highly coordinated programmed sequence that enables neutrophils to transmigrate from venules into tissues. Ideally self-limited, the active resolution phase produces specialized molecules that stimulate resolution and prevent collateral tissue damage from excessive neutrophil infiltration. The superfamily of pro-resolving molecules is termed specialized pro-resolving mediators including the essential polyunsaturated fatty acid-derived lipoxins, resolvins, protectins, and maresins. Given the intimate interactions between leukocytes and endothelial cells in inflammation resolution, we investigated whether unique bioactive molecules carrying pro-resolution properties are biosynthesized by human neutrophils coincubated with activated vascular endothelial cells. Using metabololipidomics, we found that human coronary aortic valves from transplants contained 13-hydroxy-4Z,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid (13-HDHA) and inflammatory eicosanoids. We report that human endothelial cells convert DHA to 13-HDHA which in turn is transformed by human neutrophils to a previously unknown bioactive product 4,13-dihydroxy-docosahexaenoic acid. This structure was established using physical properties including tandem-mass spectrometry, UV-analysis, and conversion of deuterated substrate. Biosynthesis of this product during neutrophil-endothelial coincubations involved bidirectional crosstalk between neutrophil 5-LOX and endothelial COX-2 as confirmed using isolated recombinant enzymes. The bioactive 4S,13R-dihydroxy-5E,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid, also produced by M2-like macrophages and mononuclear cells, demonstrated potent nanomolar pro-resolving actions including, a) limiting neutrophil infiltration into mouse air pouch, b) reducing human neutrophil adherence to endothelial cells, c) protecting endothelial cell from senescence, and d) stimulating human macrophage efferocytosis of senescent red blood cells. These results provide evidence for a previously unknown pro-resolving pathway and molecule biosynthesized from DHA via cyclooxygenase-2-5-lipoxygenase during leukocyte crosstalk with the vasculature.

Pain is a protective mechanism of the body that is intensified during inflammatory processes through the sensitization of nociceptive neurons. Although current drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and opioids, are effective, their side effects reinforce the search for safer alternatives. In this context, studies investigating the analgesic effects of specialized pro-resolving mediators (SPMs), derived from polyunsaturated fatty acids, stand out. Resolvin D1 (RvD1), derived from the omega-3 fatty acid docosahexaenoic acid, acts in a multimodal manner to modulate pain and inflammation by regulating immunological, neuronal, and glial responses. Thus, RvD1 is a promising molecule for resolving inflammatory and painful processes. Herein, we address the main analgesic mechanisms of RvD1 in different preclinical models.

Cartilage endplate (CEP) degeneration is a primary cause of intervertebral disc degeneration (IVDD) and subsequent low back pain (LBP). While n-3 polyunsaturated fatty acids (PUFAs) have been confirmed to suppress inflammation and delay IVDD, their effects and molecular mechanisms on LBP remain unclear. This study utilized C57BL/6 wild-type (WT) and fatty acid transgenic-1 (fat-1) transgenic (TG) mice to establish aged mouse model and lumbar spine instability (LSI) models. Behavioral tests revealed pronounced LBP symptoms and accelerated CEP degeneration in WT-aged and WT LSI mice. Conversely, TG mice exhibited significantly improved hypersensitivity and attenuated CEP degeneration. The elevation of endogenous n-3 PUFA substantially suppressed the elevated expression of substance P (SP) in degenerative CEPs. In vitro, IL-1β and SP established a positive feedback loop of expression in chondrocytes. n-3 PUFAs inhibited IL-1β/SP expression and release by downregulating key receptors (IL-1R1, NMDAR, and NK1R), thereby disrupting the positive feedback loop associated with IL-1 and SP and improving the CEP inflammatory microenvironment. These findings shed light on the mechanism through which n-3 PUFAs alleviate LBP by modulating neuropeptide expression in chondrocytes.