Associations between healthy food groups and platelet-activating factor, lipoprotein-associated phospholipase A2 and C-reactive protein: a cross-sectional study.

PURPOSE: To investigate the association between pro-inflammatory markers platelet-activating factor (PAF), lipoprotein-associated phospholipase A2 (Lp-PLA2), hsCRP, and intake of core food groups including fruit, cruciferous and other vegetables, grains, meat and poultry, fish and seafood, nuts and legumes, and dairy. METHODS: A cross-sectional study was conducted. 100 adults (49 ± 13 years, 31% male) with variable cardiovascular disease risk were recruited. Data were collected in 2021 and 2022. Fasting PAF, Lp-PLA2 activity, hsCRP and usual dietary intake (via a validated food frequency questionnaire) were measured. Intake of foods were converted into serves and classified into food groups. Correlations and multiple regressions were performed with adjustment for confounders. RESULTS: A one-serve increase in cruciferous vegetables per day was associated with 20-24% lower PAF levels. An increase of one serve per day of nuts and legumes was associated with 40% lower hsCRP levels. There were small correlations with PAF and Lp-PLA2 and cheese, however, these were not significant at the Bonferroni-adjusted P < 0.005 level. CONCLUSION: The lack of associations between PAF and Lp-PLA2 and other healthy foods may be due to confounding by COVID-19 infection and vaccination programs which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and food groups. Future research should aim to examine the relationship with these novel markers and healthy food groups in a non-pandemic setting.

The association between dietary quality scores with C-reactive protein and novel biomarkers of inflammation platelet-activating factor and lipoprotein-associated phospholipase A2: a cross-sectional study.

Healthy dietary patterns are associated with lower inflammation and cardiovascular disease (CVD) risk and adherence can be measured using diet quality scores. Inflammation is traditionally measured with C-reactive protein (hsCRP), however there is interest in novel pro-inflammatory markers platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2) that are specifically involved in endothelial dysfunction and inflammation. This cross-sectional study investigated the association between PAF, Lp-PLA2, hsCRP, and six diet scores. One hundred adults (49 ± 13 years, 31% male) with variable CVD risk were recruited. Fasting PAF, Lp-PLA2 and hsCRP and usual dietary intake were measured. Adherence to Dietary Approaches to Stop Hypertension (DASH), Dairy-adjusted DASH, Vegetarian Lifestyle Index, Healthy Eating Index for Australians (HEIFA), Mediterranean Diet Adherence Screener (MEDAS) and PREDIMED-Plus (erMedDiet) scores were calculated. Correlations and multiple regressions were performed. hsCRP, but not PAF, independently correlated with several diet scores. Lp-PLA2 independently correlated with Vegetarian Lifestyle Index only in unadjusted models. A one-point increase in adherence to the DASH Index, the Dairy-adjusted DASH Index and the Vegetarian Lifestyle Index was associated with a 30%, 30%, and 33% reduction in hsCRP levels, respectively. Smaller effects were seen with the other diet scores with a one-point increase in adherence resulting in a 19%, 22% and 16% reduction in hsCRP with HEIFA, MEDAS, erMedDiet scores, respectively. The lack of stronger associations between the novel markers of inflammation and diet scores may be due to confounding by COVID-19 infection and vaccination programs, which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and healthy dietary patterns. Future research should aim to examine the relationship with these novel markers and healthy dietary patterns in a non-pandemic setting.

Interrelationships among platelet-activating factor and lipoprotein-associated phospholipase A2 activity and traditional cardiovascular risk factors.

Traditionally cardiovascular disease (CVD) risk has been assessed through blood lipids and inflammatory marker C-reactive protein (hsCRP). Recent clinical interest in novel pro-inflammatory markers platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2 ) recognizes that vascular damage can exist in the absence of traditional risk factors. This cross-sectional study investigated the potential relationship between circulating PAF, Lp-PLA2 , hsCRP, and traditional risk factors for CVD. One hundred adults (49 ± 13 years, 31% male) with variable CVD risk were recruited. Fasting inflammatory markers PAF, Lp-PLA2 and hsCRP and total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, and triglycerides were measured. Blood pressure, body mass index, and waist circumference were measured. Medical and physical activity data were self-reported. Linear and multiple regressions were performed. PAF, Lp-PLA2 , and hsCRP independently correlated with several CVD risk factors. PAF was correlated significantly with risk factors in an unexpected way; there was a medium positive correlation between PAF and HDL cholesterol (r = 0.394, p < 0.001) and medium negative correlations with Total:HDL cholesterol; (r = -0.436, p < 0.001) systolic blood pressure; (r = -0.307, p = 0.001); BMI (r = -0.381, p < 0.001); and waist circumference (r = -0.404, p < 0.001). There were large positive correlations between Lp-PLA2 and LDL (r = 0.525, p < 0.001) and non-HDL cholesterol (r = 0.508, p < 0.001). There were large positive correlations between hsCRP and Total:HDL cholesterol (r = 0.524, p < 0.001); BMI (r = 0.668, p < 0.001); and waist circumference (r = 0.676, p < 0.001). PAF, Lp-PLA2 , and hsCRP are implicated in the pathophysiology of inflammation in CVD; however, the relationships between each marker and traditional risk factors were different suggesting they may be involved in different atherogenic pathways.

Extra virgin olive oil improves HDL lipid fraction but not HDL-mediated cholesterol efflux capacity: a double-blind, randomised, controlled, cross-over study (OLIVAUS).

Olive oil (OO) polyphenols have been shown to improve HDL anti-atherogenic function, thus demonstrating beneficial effects against cardiovascular risk factors. The aim of the present study was to investigate the effect of extra virgin high polyphenol olive oil (HPOO) v. low polyphenol olive oil (LPOO) on the capacity of HDL to promote cholesterol efflux in healthy adults. In a double-blind, randomised cross-over trial, fifty participants (aged 38·5 (sd 13·9) years, 66 % females) were supplemented with a daily dose (60 ml) of HPOO (320 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for 3 weeks. Following a 2-week washout period, participants crossed over to the alternate treatment. Serum HDL-cholesterol efflux capacity, circulating lipids (i.e. total cholesterol, TAG, HDL, LDL) and anthropometrics were measured at baseline and follow-up. No significant between-group differences were observed. Furthermore, no significant changes in HDL-cholesterol efflux were found within either the LPOO and HPOO treatment arms; mean changes were 0·54 % (95 % CI (0·29, 1·37)) and 0·10 % (95 % CI (0·74, 0·94)), respectively. Serum HDL increased significantly after LPOO and HPOO intake by 0·13 mmol/l (95 % CI (0·04, 0·22)) and 0·10 mmol/l (95 % CI (0·02, 0·19)), respectively. A small but significant increase in LDL of 0·14 mmol/l (95 % CI (0·001, 0·28)) was observed following the HPOO intervention. Our results suggest that additional research is warranted to further understand the effect of OO with different phenolic content on mechanisms of cholesterol efflux via different pathways in multi-ethnic populations with diverse diets.

Extra virgin olive oil high in polyphenols improves antioxidant status in adults: a double-blind, randomized, controlled, cross-over study (OLIVAUS).

PURPOSE: Olive oil polyphenols have been associated with cardiovascular health benefits. This study examined the antioxidant and anti-inflammatory effect of extra-virgin high polyphenol olive oil (HPOO) vs. low polyphenol olive oil (LPOO) in healthy Australian adults. METHODS: In a double-blind cross-over trial, 50 participants (aged 38.5 ± 13.9 years, 66% females) were randomized to consume 60 mL/day of HPOO (320 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for three weeks. Following a 2-week wash-out period, participants crossed-over to the alternate treatment. Plasma oxidized low-density lipoprotein (ox-LDL), total antioxidant capacity (TAC), high-sensitivity C-reactive protein (hs-CRP) and anthropometrics were measured at baseline and follow-up. RESULTS: Fourty-three participants completed the study. Although there were no significant differences between treatments in the total sample, plasma ox-LDL decreased by 6.5 mU/mL (95%CI - 12.4 to - 0.5) and TAC increased by 0.03 mM (95% CI 0.006-0.05) only in the HPOO arm. Stratified analyses were also performed by cardiovascular disease risk status defined by abdominal obesity (WC > 94 cm in males, > 80 cm in females) or inflammation (hs-CRP > 1 mg/L). In the subgroup with abdominal obesity, ox-LDL decreased by 13.5 mU/mL (95% CI - 23.5 to - 3.6) and TAC increased by 0.04 mM (95% CI 0.006-0.07) only after HPOO consumption. In the subgroup with inflammation, hs-CRP decreased by 1.9 mg/L (95% CI - 3.7 to -0.1) only in the HPOO arm. CONCLUSIONS: Although there were no significant differences between treatments, the changes observed after HPOO consumption demonstrate the antioxidant and anti-inflammatory effect of this oil, which is more pronounced in adults with high cardiometabolic risk (Clinical Trial Registration: ACTRN12618000706279).

The association between dietary patterns and the novel inflammatory markers platelet-activating factor and lipoprotein-associated phospholipase A2: a systematic review.

CONTEXT: Atherosclerosis is a disease of chronic inflammation. Recent research has identified 2 novel inflammatory biomarkers: platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Diet has been proposed as a mediator of inflammation, but to date, the focus for these novel biomarkers has been on individual foods and nutrients rather than overall dietary patterns. OBJECTIVE: To systematically review the literature on the association between dietary patterns and PAF and Lp-PLA2. DATA SOURCES: The PubMed, Embase, CINAHL, and Cochrane CENTRAL literature databases were searched. DATA ANALYSIS: Study quality was evaluated using the Quality Criteria Checklist. Sixteen studies (n = 4 observational and n = 12 interventional) were included and assessed for associations between dietary patterns and PAF and Lp-PLA2. CONCLUSION: Study quality varied from neutral (n = 10) to positive (n = 6). Mediterranean, heart healthy, and vegetarian dietary patterns were associated with improved levels of PAF and Lp-PLA2. Conversely, Western dietary patterns were less favorable. A range of well-established, healthier dietary patterns may lower inflammation and the risk of atherosclerosis. More well-designed studies are needed to confirm these findings and identify other dietary patterns that improve inflammation.

A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists.

Elucidating details of the relationship between molecular structure and a particular biological end point is essential for successful, rational drug discovery. Molecular docking is a widely accepted tool for lead identification however, navigating the intricacies of the software can be daunting. Our objective was therefore to provide a step-by-step guide for those interested in incorporating contemporary basic molecular docking and homology modelling into their design strategy. Three molecular docking programs, AutoDock4, SwissDock and Surflex-Dock, were compared in the context of a case study where a set of steroidal and non-steroidal ligands were docked into the human androgen receptor (hAR) using both rigid and flexible target atoms. Metrics for comparison included how well each program predicted the X-ray structure orientation via root mean square deviation (rmsd), predicting known actives via ligand ranking and comparison to biological data where available. Benchmarking metrics were discussed in terms of identifying accurate and reliable results. For cases where no three dimensional structure exists, we provided a practical example for creating a homology model using Swiss-Model. Results showed an rmsd between X-ray ligands from wild-type and mutant receptors and docked poses were 4.15Å and 0.83Å (SwissDock), 2.69Å and 8.80Å (AutoDock4) and 0.39Å and 0.71Å (Surflex-Dock) respectively. Surflex-Dock performed consistently well in pose prediction (less than 2Å) while Auto- Dock4 predicted known active non-steroidal antiandrogens most accurately. Introducing flexibility into target atoms produced the largest degree of change in ligand ranking in Surflex-Dock. We produced a viable homology model of the P2X1 purireceptor for subsequent docking analysis.

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale).

Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale). These compounds have demonstrated in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. These were assessed concurrently with the top-scoring poses of the docked ligands and included key active gingerols, shogaols and dehydroshogaols as well as competitive antagonists (e.g. setron class of pharmacologically active drugs), serotonin and its structural analogues, curcumin and capsaicin, non-competitive antagonists and decoys. Unexpectedly, we found that the ginger compounds and their structural analogs generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues. We have identified new residues important for binding the ginger compounds. Overall, the results suggest that the ginger compounds and their structural analogues possess a high binding affinity to both sites. Notwithstanding the limitations of such theoretical analyses, these results suggest that the ginger compounds could act both competitively or non-competitively as has been shown for palonosetron and other modulators of CYS loop receptors.

Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 µM and 29-151 µM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

Preliminary investigations into triazole derived androgen receptor antagonists.

A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 µM, the most promising three compounds were found to display IC50 values of 40-50 µM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.