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The inappropriate activation of eosinophils is a well-recognized driver of various human inflammatory diseases including asthma, chronic rhinitis, and various gastrointestinal diseases, including eosinophilic esophagitis. Steroids, both topical and systemic, remain a cornerstone of treatment and can be highly effective. However, some individuals suffer side effects, unresolved symptoms, or both. OmeGo, an enzymatically liberated fish oil, has demonstrated anti-inflammatory and antioxidant properties as well the reduction of the activation, migration, and survival of eosinophils. Two animal models of eosinophilic inflammation were used to further assess OmeGo's profile. A house dust mite model of induced asthma showed a significant reduction in eosinophilic lung inflammation compared to the negative control, linoleic acid. The CRTH2 antagonist fevipiprant showed a similar eosinophilic inhibitory profile to OmeGo. In contrast, cod liver oil had no impact on any measure of inflammation. A guinea pig model of mild intraperitoneal eosinophilia showed a significant reduction in eosinophil activity by OmeGo, assessed by chemotaxis and chemokinesis. Apolipoprotein A-IV, an endogenous human protein with anti-inflammatory actions, showed a similar but numerically lower effect. OmeGo therefore combines a consistent antieosinophilic action with the known anti-inflammatory effects of polyunsaturated fatty acids. Proof-of-concept studies in asthma are warranted. publishedVersion

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.

Background: The consumption of oily fish in early childhood diets has been correlated to a reduction in the progression of asthma during adolescence and young adulthood. Extending these results to studies on supplementation with omega-3 fish oils has led to equivocal results, with no clear results. One subset of asthma patients is classified as steroid-treatment resistant, which may be attributable to eosinophil dysfunction. This in-vitro study investigated the prophylactic effect of enzymatically extracted salmon oil, as a proxy for eating fresh whole oily fish, on eosinophil function using allergic human peripheral blood eosinophils. Methods: We measured three eosinophil effector functions in allergic human peripheral blood eosinophils after prophylactic treatment with enzymatically extracted salmonid oil. We measured changes in: i) eosinophil shape change in normal PMNL ii) integrin upregulation in normal PMNL and iii) eosinophil apoptosis. We further measured changes in these functions after prophylactic treatment with omega-3 fish oil, krill oil, and fractions of the salmon oil subjected to several commercial fish oil processing conditions. Results: Prophylactic treatment of allergic human peripheral blood eosinophil with 100 ug/ml of enzymatically extracted salmonid oil showed modulation of eosinophil effect functions and apoptosis comparable to APOA-IV at 3ug/ml. Vigorous processing conditions applied to the salmon oil degraded the observed eosinophil modulation. Krill oil and standard fish oil showed no to low eosinophil modulation. Conclusions: Enzymatically extracted salmonid oil demonstrates potential therapeutic promise for the treatment of eosinophil effector malfunction-based allergic and inflammatory conditions, particularly certain types of asthma and COPD. Treatment of the oil with commercial marine oil processing conditions significantly reduces or eliminates this eosinophil effector function modulation. Keywords: Eosinophils, asthma, salmon oil, APOA-IV, apoptosis

Calcium is an essential mineral that supports bone and joint health. It is used as a supplement, most typically as calcium carbonate, to assist in preserving bone density especially when dietary calcium intake is inadequate. In the present study we examined the effect of five varied calcium sources, three natural and two synthetic, on stimulation, proliferation and mineralization of cultured human osteoblast cells. A MTT assay using cultured human fetal osteoblast cells (hFOB 1.19) was used to determine the effective proliferative dose for salmon collagen bone calcium (0.25 mg/ml). Elemental calcium equivalence was used to select the appropriate doses for algae calcium (0.14 mg/ml), eggshell powder (0.16 mg/ml), calcium citrate (0.22 mg/ml) and calcium carbonate (0.13). Alkaline phosphatase activity, DNA synthesis rates and calcium ion deposition were evaluated after incubation under different conditions and harvesting the cells. Alkaline phosphatase activity, DNA synthesis rates and calcium ion deposition rates were all highest for the natural salmon bone collagen calcium, followed by algae calcium. The eggshell powder, calcium citrate and calcium carbonate did not exhibit significant changes from control in most of these assays. The results of these assays suggest that natural marine collagen calcium such as salmon bone collagen calcium acts as the most effective intervention on osteoblast performance and actual calcium deposition. It should be recommended as a superior supplement for improved bone and joint health function.

Aim/Objective We correlated serum levels of oxidized low-density lipoprotein β2-glycoprotein I complex (oxLDL/β2GPI) with normal and dyslipidemic subjects with described familial CVD histories. Material and methods A total of 188 subjects were enrolled [dyslipidemic (n−103) and normal (n−88)]. Clinical assessment, lipid profile and serum ELISA analysis of oxLDL/β2GPI were measured. Results A statistically significant difference (P Conclusion The oxidative marker oxLDL/β2GPI was significantly elevated in dyslipidemic subjects and correlated with family history of CVD increasing its potential as an additional independent marker for predicting cardiovascular disease in India.

Background: Under physiological conditions, molecular oxygen generates reactive oxygen species (ROS) as metabolic by-products. In the absence of an adequate defense mechanism, the accumulation of ROS leads to cell membrane and DNA damage, in addition to tissue degeneration. The up/down regulation of one or more oxidative stress-related genes is one mechanism which confers cytoprotection to tissues exposed to oxidative injury.Methods: We measured up/down regulation of 84 oxidative protective genes in primary human gingival epithelial pooled cells and human intestinal epithelial cells after pretreatment with 25, 50, and 100 μM/ml of salmon protein hydrolysate solution. A human RT2 Profiler PCR array was used to evaluate the relative change in the expression of these common oxidative protective genes. The salmon protein hydrolysate contains a mixture of bioactive peptides, resulting from enzyme hydrolysis of salmon head and backbones.Results: Treatment with salmon protein hydrolysate peptides demonstrated up-regulation for 16 human oxidative protective genes and down-regulation for 9 human oxidative stress-related genes. Three genes (ferritin heavy polypeptide-1 (FTH1), heme oxygenase-1 (HMOX1), and arachidonate 12-lipoxygenase (ALOX12)) showed regulation changes at physiologically applicable levels.Conclusions The improved oxidation protection observed after SPH treatment conferred by HMOX1 / ALOX12 regulation to HGEPp and HIEC-6 cells may find ultimate utility for these bioactive peptides in the modulation of gastrointestinal stress in irritable bowel syndrome and enterocolitis.

In the article, we show that a daily dietary intake of 16 g of salmon protein hydrolysate powder for 42 days statistically significantly reduced Body Mass Index by 5.6% in overweight subjects, in comparison with a placebo-control of whey protein isolate. Four metabolism-relevant serum biomarkers - bile acid, interleukin-6, Preheparin lipoprotein lipase mass and adiponectin - were also positively impacted using one-tailed, paired student t-test analysis, leading to the proposed metabolism-elevating mode-of-action. Exercise levels were maintained for each subject as per their normal levels. Further research will seek to identify the active individual peptide components from the salmon protein hydrolysate with specific biological activity for obesity control. Salmon protein hydrolysate powder in supplemental doses may be a useful tool in the long-term management of obesity.

Osteoporosis is a multifactorial skeletal disease that is characterized by compromised bone strength predisposing a person to an increased risk of fracture. This ovariectomized (OVX) Sprague-Dawley rat model study measured the changes in serum calcium, as well as femur dimensions and mineral density, when consuming calcium carbonate, calcium gluconate and salmon bone calcium. Our results show that salmon bone calcium and to a lesser extent calcium gluconate showed a statistically significant increase in femur dimension and mineral density while calcium carbonate showed no impact on either bone parameter. Our results also show that none of the three calcium sources affected serum calcium levels after 8 weeks of treatment.

Circulating levels of oxidized low density lipoprotein β2-glycoprotein I complex (oxLDL-GP) have been previously correlated with adverse cardio-vascular events. This study measured the effect of consuming various dietary oil capsules on oxLDL-GP serum concentrations in healthy human subjects. The dietary oil capsules tested were: enzymatically liberated salmon oil, as a proxy for the entire lipid soluble fraction of whole salmon, high DHA algae oil and standard 18/12 fish oil. Our results showed that only the enzymatically liberated salmon oil had a significant lowering of circulating serum concentration ofoxLDL-GP, after 3 weeks of treatment. This result lends support to the developing theory, that eating whole functional foods for their nutritive and health benefiting effects may not be reproduced by highly-refined supplements derived from these foods.

Background: Circulating serum levels of oxidized low-density lipoprotein, β2-glycoprotein I complex (oxLDL-GP), have been previously correlated with adverse cardiovascular events and have been shown to be reduced by consumption of enzymatically liberated extra virgin salmon oil (EVSO). This mouse study measured the changes in the oxLDL-GP lowering effect when consuming EVSO with varying levels of EPA+DHA (eicosapentenoic acid and docosahexenoic acid) as well as when consuming EVSO that was subjected to various processing treatments commonly carried out during fish oil production.Methods: Sprague Dawley mice were fed a diet containing eight different EVSO’s incorporated into a normal diet at the Human Equivalent Dose (HED) of 1000 mg for 8 weeks. Serum was collected at the start and at the end of the trial and the oxLDL-GP concentrations were measured using an ELISA assay. Statistical analysis of the results was carried out using a 1-tail, paired Student t-Test.Results: In order to lower circulatory oxLDL-GP levels, the mice had to consume a minimum of 80 mg per day HED of EPA+DHA. Heat treatment of the EVSO did not affect this bioactivity but hydrolysis with acid or base and re-esterification to the triglyceride form or significant oxidation (rancidity) rendered the oil inactive on this important cardio-vascular disease (CVD) biomarker.Conclusions: This result shows that harsh processing conditions on fish oils can lead to the destruction of biological efficacy in spite of increasing the concentration of typical fish oil bioactive constituents such as EPA+DHA. It also lends support to the developing nutrition theory that eating highly-refined, processed or concentrated-ingredient supplements derived from functional foods may not be able to reproduce their full nutritive and health-benefiting effects.Keywords: Oxidized-LDL; processing; Salmon; Oil; omega-3; rancidity

Background: The TIM-1 system is a computer-controlled multi-compartmental dynamic model that closely simulates in vivo gastrointestinal tract digestion in humans. During digestion, the compounds released from meal matrix by gastric and intestinal secretions (enzymes) are progressively absorbed through semipermeable membranes depending on their molecular weight. These absorbed (dialysed) compounds are considered as bioaccessible, which means that they can be theoretically absorbed by the small intestine in the body.Methods: Salmon protein hydrolysate (SPH), whey protein hydrolysates extensively (WPH-High) or weakly (WPH-Low) hydrolysed, non-hydrolysed whey protein isolate (WPI) and mixtures of WPI:SPH (90:10, 80:20) were digested in TIM-1 using the conditions for a fast gastrointestinal transit that simulate the digestion of a liquid meal in human adults. During digestion (2 hours), samples were collected in intestinal compartments (duodenum, jejunum, and ileum) and in both jejunal and ileal dialysates to determine their nitrogen content. All the products were compared in terms of kinetics of nitrogen absorption through the semipermeable membranes (bioaccessible nitrogen) and nitrogen distribution throughout the intestinal compartments at the end of the 2 hour digestion.Results: After a 2 h-digestion in TIM-1, SPH was the protein substrate from which the highest amount of nitrogen (67.0%) becomes available for the small intestine absorption. WPH-High had the second highest amount (56.0%) of bioaccessible nitrogen while this amount decreased to 38.5–42.2% for the other protein substrates. The high nitrogen bioaccessibility of SPH is consistent with its richness in low molecular weight peptides (50% < 1000 Da).Conclusions: The results of this study indicate that SPH provides a higher proportion of bioaccessible nitrogen to a healthy adult compared to all forms of whey proteins, including extensively hydrolysed whey protein hydrolysate. The substitution of non-hydrolysed WPI by small amounts of SPH (10–20%) improved slightly its nitrogen bioaccessibility, making the mixture particularly suitable for applications such as medical foods that require rapid protein uptake and where the use of extensively hydrolysed whey protein is unfeasible due to its undesirable organoleptic properties.Keywords: Salmon protein hydrolysate, Whey protein, Nitrogen bioaccessibility, TIM-1