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The omega-3 polyunsaturated fatty acids (PUFAs) Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) exert multiple cardioprotective effects, influencing inflammation, platelet activation, endothelial function and lipid metabolism, besides their well-established triglyceride lowering properties. It is not uncommon for omega-3 PUFAs to be prescribed for hypertriglyceridemia, alongside antiplatelet therapy in cardiovascular disease (CVD) patients. In this regard, we studied the effect of EPA and DHA, in combination with antiplatelet drugs, in platelet aggregation and P-selectin and αIIbβ3 membrane expression. The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y12; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6. Both DHA and EPA displayed a dose-dependent inhibitory effect on platelet aggregation induced by AA, ADP and TRAP-6. In platelet aggregation induced by AA, DHA significantly improved acetylsalicylic acid (ASA) and triflusal’s inhibitory activity, while EPA enhanced the inhibitory effect of ASA. In combination with EPA, ASA and ticagrelor expressed an increased inhibitory effect towards ADP-induced platelet activation. Both fatty acids could not improve the inhibitory effect of vorapaxar on AA- and ADP-induced platelet aggregation. In the presence of EPA, all antiplatelet drugs displayed a stronger inhibitory effect towards TRAP-6-induced platelet activation. Both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though they had no effect on P-selectin expression induced by ADP or TRAP-6. The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αIIbβ3 membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component.

The simultaneous administration of three antiplatelet agents has been proposed as an efficient strategy for the secondary prevention of atherothrombotic events and is included in the European guidelines. However, this strategy presented an increased risk of bleeding; therefore, the identification of new antiplatelet agents, with improved efficacy and diminished side effects, is of great importance. In silico studies, UPLC/MS Q-TOF plasma stability, in vitro platelet aggregation experiments, and pharmacokinetic studies were exploited. In the present study, it has been predicted that the flavonoid apigenin could target different platelet activation pathways, including P2Y12, protease-activated receptor-1 (PAR-1), and cyclooxygenase 1 (COX-1). To enhance apigenin’s potency, hybridization with docosahexaenoic acid (DHA) was performed, as fatty acids have illustrated potent efficacy against cardiovascular diseases (CVDs). The new molecular hybrid, termed 4′-DHA-apigenin, demonstrated enhanced inhibitory activity against platelet aggregation induced by thrombin receptor activator peptide-6 (TRAP-6), adenosine diphosphate (ADP), and arachidonic acid (AA), with respect to the parent apigenin. The 4′-DHA-apigenin hybrid illustrated an almost 2-fold enhanced inhibitory activity, with respect to apigenin, and an almost 3-fold enhanced inhibitory activity, with respect to DHA, for the ADP-induced platelet aggregation. Additionally, the hybrid presented a more than 12-fold enhanced inhibitory activity with respect to DHA for the TRAP-6 induced platelet aggregation. Furthermore, a 2-fold enhanced inhibitory activity was recorded for the 4′-DHA-apigenin hybrid for the AA-induced platelet aggregation with respect to apigenin. To surmount the reduced LC-MS based plasma stability, a novel dosage form in olive oil has been developed. The 4′-DHA-apigenin olive oil-based formulation presented an enhanced antiplatelet inhibitory effect in three activation pathways. To further explore the pharmacokinetic profile of 4′-DHA-apigenin in olive oil formulations, a UPLC/MS Q-TOF protocol has been established to quantify the serum levels of apigenin after oral administration to C57BL/6J wild type mice. The olive oil-based formulation of 4′-DHA-apigenin demonstrated an increase in apigenin bioavailability of 262 %. This study may offer a new therapeutic strategy tailored to improve the treatment of CVDs.

Naturally occurring antibodies (NAbs), which are major components of innate immunity, exist in circulation under healthy conditions without prior antigenic stimulation and are able to recognize both self- and non-self-constituents. The present study aimed at identifying potential immunological differences between commercial fast- and slow-growth broilers (n = 555) raised in conventional and free-range systems, respectively, through the use of the specificity, isotypes and levels of circulating NAbs. The possible beneficial effect of oregano-based dietary supplementation was also evaluated. To this end, serum IgM and IgY NAbs against self- (actin and DNA) and non-self- antigens (trinitrophenol and lipopolysaccharide) were measured by ELISA and further correlated with genotype, season and performance. Significantly higher levels of IgM NAbs against all antigens were found in slow-growth compared to fast-growth broilers. IgM NAb levels were also significantly increased in dietarily supplemented slow-growth broilers versus those consuming standard feed. Moreover, significantly elevated levels of anti-DNA IgY NAbs were found in fast-growth compared to slow-growth broilers, whereas the opposite was observed for anti-LPS IgY NAbs. Multivariate linear regression analysis confirmed multiple interactions between NAb levels, genotype, season and performance. Overall, serum NAbs have proven to be valuable innovative immunotools in the poultry industry, efficiently differentiating fast-growing versus slow-growing broilers, and dietary supplementation of plant extracts can enhance natural immunity.

This study investigated the influence of dietary supplementation with oregano oil premix on the antioxidant status, performance, and meat quality of slow-growth genotype chickens raised under a commercial production system. The study included two groups, with nine replicates: Group A) 54.000 broilers raised in free-range farms and fed the basal diet, and Group B) 27.000 broilers raised in free-range farms and fed the basal diet supplemented with oregano oil premix. Oregano oil was blended with a standard premix (120 g/ton), which was then mixed with the feed (amount adjusted on the growth stage). The results showed that serum total antioxidant capacity (TAC) was significantly higher (p ≤ 0.05) in the non-supplemented group compared to the dietary-supplemented group with oregano oil premix. In contrast, thigh muscle total antioxidant capacity was significantly increased in the supplemented group compared to the non-supplemented group (p ≤ 0.05). There were no differences in serum and thigh muscle Thiobarbituric Acid Reactive Substances (TBARS) and performance parameters between the two groups. Chickens fed with the oregano oil premix exhibited increased protein and ash content, pH value, and higher smell, taste, and colour scores compared to the non-supplemented group. Summarising, our large-scale in field study showed that incorporating oregano oil premix in slow-growth and free-range chickens’ diet improves the thigh muscle total antioxidant capacity and meat quality. The results indicate that the oregano oil premix positively impacts the nutritional value of the final product. However, more research is needed under in field conditions to draw a safer conclusion.

Background: The mechanisms underlying the impact of estradiol (E2) on low-density lipoprotein cholesterol (LDL-C) levels are not completely understood, although a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed. We aimed to investigate the association between levels of E2, PCSK9, and lipid parameters in premenopausal women undergoing in vitro fertilization (IVF). Methods: Healthy women undergoing IVF in the Department of Obstetrics and Gynecology of the University General Hospital of Ioannina were recruited. Their levels of E2, PCSK9, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides (TGs) were measured 10 days after ovarian depression (E2min) and 7 days after ovarian stimulation (E2max). Results: We included 34 consecutive women of median age 38 (interquartile range 26–46) years who underwent a full IVF cycle. As expected, E2 levels increased by 329.6% from E2min to E2max (108 [47–346] to 464 [241–2471] pg/mL, p < 0.05). During the same time, serum PCSK9 levels decreased by 30.8% (245 ± 80 to 170 ± 64 ng/mL, p < 0.05). TC, LDL-C, and TGs decreased by 0.4%, 3.8%, and 2.2%, respectively, while HDL-C levels increased by 5.3% (all p = NS). Conclusions: The rise in endogenous E2 during an IVF cycle was related with a significant decline in serum PCSK9 levels, but no significant change in plasma lipids during a 7-day period.

Identifying blood components influenced by rearing systems that serve as biomarkers to distinguish free-range from conventional broilers can improve animal health, welfare, and productivity. The current study aimed to evaluate specific blood parameters related to immune function and tissue stress, as biomarkers to differentiate free-range, slow-growing Sasso broilers from conventionally raised fast-growing Ross 308 broilers. For this purpose, serum IgM Natural Antibodies (NAbs) targeting actin and lipopolysaccharides (LPS) as key immunological parameters of natural immunity, along with creatine phosphokinase (CPK) and other significant stress and tissue-related biochemical parameters, were measured in a total of 300 broilers (150 per group) raised under industrial scale rearing systems, by standard methodology. Our results showed significantly higher IgM-NAb levels to both antigens and lower CPK and Aspartate Aminotransferase levels in Sasso broilers compared to Ross 308 broilers (p < 0.001). Combination of anti-LPS IgM-NAbs and CPK levels, as the most potent biomarker candidates, achieved 90% sensitivity and 84% specificity in distinguishing Ross 308 from Sasso broilers. In conclusion, the combined evaluation of these blood biomarkers can effectively discriminate conventional from free-range broilers analyzed herein, with potent novel applications in the poultry industry making it a promising, cost effective and easy-to-use, diagnostic tool.

Adipokines released by the adipose tissue are known to play a role in atherogenesis. The hypertrophic mesenteric fat in patients with inflammatory bowel diseases (IBD) also produces adipokines that are considered to play a role in intestinal inflammation. Whether they also contribute to accelerated atherosclerosis in IBD is unknown. The aim of this study was to assess the role of 2 adipokines, resistin and adiponectin, in IBD.MethodsWe previously published data on 3 markers of cardiovascular risk, carotid intima-media thickness, carotid-femoral pulse wave velocity, and lipoprotein-associated phospholipase A2, in 44 patients with IBD and 44 controls matched for established cardiovascular risk factors. In this study, we measured resistin and adiponectin levels, and assessed their correlations with carotid intima-media thickness, pulse wave velocity, and lipoprotein-associated phospholipase A2.ResultsResistin levels were significantly higher in patients with IBD (13.7 versus 10 ng/mL; P = 0.022), but there was no difference in adiponectin levels. Resistin levels were significantly higher in patients with active disease compared with those in remission (18.9 versus 11.3 ng/mL; P = 0.014). Adiponectin levels were significantly lower in Crohn's disease compared with ulcerative colitis (6736.3 ± 3105 versus 10,476.1 ± 5575.7 ng/mL; P = 0.026). Adiponectin correlated inversely with pulse wave velocity (rho = −0.434; P < 0.0005) and carotid intima-media thickness (rho = −0.255; P = 0.021).ConclusionsThis is the first study to suggest that adipokines produced by the hypertrophic mesenteric fat in IBD may play a role not only in intestinal inflammation but also in atherogenesis. Resistin has mainly pro-inflammatory properties, whereas adiponectin likely exerts an angioprotective effect.

Background Surgical interventions activate a cascade of reactions that result in an aseptic inflammatory reaction. This inflammatory response initiates the organism’s innate immunity. Laparoscopic surgery reduces the trauma, and patients benefit from diminished surgical trauma and maintained immune function. Cytokine levels and C-reactive protein (CRP) are related to the magnitude of surgical trauma and surgical stress. Toll-like receptors (TLRs) 2 and 4 are the first sensor-recognition receptors of the invading pathogens for the innate immune response. This study aimed to compare the inflammatory response and then the stress response during laparoscopic and open colectomy for cancer by calculating TLR-2 and TLR-4 as the first sensor-recognition receptors together with interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity CRP (hsCRP). Methods A total 40 patients with colorectal cancer were randomized in two groups: group A (open colectomy, n  = 20) and group B (laparoscopic colectomy, n  = 20). An epidural catheter was placed in all patients 1 h preoperatively. Rupivocaine was administered perioperatively and 48 h postoperatively. Blood samples were taken for calculation of IL-6, TNF-α, hsCRP, TLR-2, and TLR-4 preoperatively and 5 min after deflation of pneumoperitoneum (group B) or 5 min after division of the colon (group A), then 6 and 24 h postoperatively. Results The mean operative time was 115 for group A and 142 min for group B. The mean blood loss was respectively 240 and 105 ml ( P  < 0.001), and the mean hospital stay was respectively 8 and 5 days ( P  < 0.05). The IL-6 level was significant higher in group A than in group B at 6 and 24 h postoperatively ( P  < 0.0001), and the hsCRP level was significant higher in group A than in group B at 24 h postoperatively ( P  < 0.001). The TNF-α values did not differ between the two groups. The TLR-2 level was significantly higher in group A than in group B at 5 min ( P  = 0.013) and 24 h ( P  = 0.007) postoperatively. The TLR-4 level was significant higher in group A than in group B at 5 min postoperatively ( P  = 0.03). Conclusion The inflammatory response and the resultant stress response are significantly less during laparoscopic colectomy than during open colectomy for colorectal cancer. This is an obvious short-term clinical benefit for the patient, providing tinder for further study to investigate the long-term results of laparoscopic colectomy versus open colectomy for colorectal cancer (Registered clinical trial no. NCT00942461; www.clinicaltrials.gov ).

Ezetimibe effectively reduces low-density lipoprotein cholesterol (LDL-C). In this study, we tested the hypothesis that ezetimibe monotherapy may also decrease markers of oxidative stress in subjects with hypercholesterolemia. Subjects with hypercholesterolemia and no evidence of cardiovascular disease were randomly allocated to open-label ezetimibe monotherapy 10 mg/day (EZT group) or therapeutic lifestyle changes (TLC group). At baseline and 12 weeks post-treatment serum lipoprotein and apolipoprotein levels as well as oxidative stress parameters, including oxidized LDL (ox-LDL), 8-isoprostanes (8-epiPGF2a) and reactive oxygen metabolites (d-ROMs) levels, were blindly determined. A total of 60 patients were included; 30 in each group. Despite a significant decrease in ox-LDL levels (by 20.8%, p  < 0.001 vs. baseline; p  < 0.001 vs. TLC group) in the EZT group no change in the ratio ox-LDL to LDL-C was noticed following ezetimibe treatment. No significant change in 8-epiPGF2a and d-ROMs levels was observed in the EZT group. Of note, a significant decrease in 8-epiPGF2a and d-ROMs levels (by 20.4% and 18.2%, respectively, p  < 0.01 vs. baseline for both), was noted among patients in the EZT group who exhibited ‘high oxidative stress’ at baseline. No change in any of oxidative stress parameters was noted in the TLC group. Ezetimibe may decrease markers of oxidative stress in hypercholesterolemic subjects. This benefit may be more profound among patients who exhibit ‘high oxidative stress’ at baseline.

Background: Toll-like receptors (TLRs) are key players in the innate immune system whose activation leads to an inflammatory response. Inflammation plays an important role in the pathogenesis of chronic kidney disease (CKD) and diabetes mellitus. The aim of our study was to assess the proinflammatory state of nondialysis CKD patients by evaluating the membrane expression of TLR2 and TLR4 and the intracellular IL-1β and IL-6 production in response to the ligand Pam3Cys-Ser-(Lys)4 (Pam3CSK4). Methods: 85 nondialysis CKD patients [mean estimated glomerular filtration rate: 34 (17-90) ml/min/1.73 m2] were divided in 2 groups: 55 nondiabetic CKD patients (CKD group) and 30 patients with diabetic nephropathy (DN group). The two groups were compared with 36 healthy subjects (control group). TLR2 and TLR4 membrane expression in monocytes and Pam3CSK4-induced intracellular production of IL-1β and IL-6 were assessed by flow cytometry. Results: Both patient groups showed increased TLR2 membrane expression compared with the control group, both at baseline (p < 0.05 for both) and after Pam3CSK4 stimulation (p < 0.05 for both). The DN group exhibited significantly higher TLR4 expression at baseline compared to the CKD and control groups (p < 0.04 and p < 0.02, respectively). Intracellular IL-1β and IL-6 levels at baseline were significantly lower in CKD patients compared to the DN and control groups. After Pam3CSK4 stimulation, intracellular IL-1β and IL-6 increased in all groups, but were lower in the CKD group versus the control group or DN group, which exhibited higher levels than the controls. Conclusions: Nondialysis CKD patients showed significant alterations in TLR2 and TLR4 membrane expression, and impaired Pam3CSK4-induced cytokine production in monocytes, a phenomenon that is markedly influenced by the presence of diabetes. © 2015 S. Karger AG, Basel