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Author(s): Zhongliang Xu [sup.1] [sup.2] , Jiewen Xie [sup.1] [sup.2] , Hanyue Zhang [sup.1] [sup.2] , Juan Pang [sup.1] [sup.2] , Qing Li [sup.1] [sup.2] , Xu Wang [sup.1] [sup.2] [...], Background/objectives Numerous clinical trials have confirmed that supplementation with purified anthocyanins has favorable effects on metabolic diseases, but the dose-response of dyslipidemia to anthocyanin supplementation remains unclear. This study aimed to investigate the effect of anthocyanin supplementation in different doses on lipid profile. Subjects/methods We randomly assigned 176 dyslipidemic subjects aged 35-70 to three purified anthocyanin groups (40 mg/day, n = 45; 80 mg/day, n = 42; 320 mg/day, n = 43) and a placebo group (n = 46). Anthropometric parameters, serum lipid profiles, and cholesterol efflux capacity (CEC) were measured at baseline, and at the end of 6 and 12 weeks. Results After 12 weeks of supplementation, significant differences in CEC (P = 0.033), high-density lipoprotein cholesterol (HDL-C) (P = 0.043), and apolipoprotein A-I (ApoA-I) (P = 0.022) were observed between four groups. Compared with placebo, 320 mg/day anthocyanin significantly increased CEC (35.8%, 95% CI: 11.5-60.2%; P = 0.004), HDL-C (0.07 mmol/L, 95% CI: 0.01-0.14; P = 0.003), and ApoA-I (0.07 g/L, 95% CI: 0.01-0.12; P = 0.008). Linear trend analysis showed that anthocyanin supplementation has a strong dose-response relationship with CEC (P = 0.002), HDL-C (P = 0.038), and ApoA-I (P = 0.023). Moreover, the enhancement of CEC showed positive correlations with the increase in HDL-C (r = 0.215, P < 0.01) and APOA-I (r = 0.327, P < 0.01). Conclusions Anthocyanin supplementation at 0-320 mg/day for 12 weeks enhances CEC in a dose-response manner in dyslipidemic subjects. Anthocyanin supplementation doses of 80-320 mg/day can improve serum HDL-C levels and HDL-induced CEC.

Introduction Pancreatic cancer consists of fatal digestive tumours with characteristics such as rapid progression and lack of a definitive diagnosis in the early tumour stage (Strangfeld et al. 2011; Siegel [...], Apolipoprotein E2 (ApoE2) is reportedly critical for cell proliferation and survival, and has been identified as a potential tumour-associated marker in many kinds of cancer. However, studies of the function and mechanisms of ApoE2 in pancreatic cancer proliferation and development are rare. In this study, we performed an analysis to determine the modulatory effects of ApoE2--LRP8 (lipoprotein receptor-related protein 8) pathway on cell cycle and cell proliferation, and explored its mechanisms in pancreatic cancer. High expression levels of ApoE2--LRP8/c-Myc were detected in tumour tissues and cell lines by immunohistochemistry and Western blotting. It was also shown that ApoE2--LRP8 induced phosphorylationofERK1/2toactivate c-Myc and contribute to cell-cycle-related protein expression. ApoE2 conditions induced c-Myc binding to target gene sequences in the [p21.sup.Waf1] promoter, resulting in decreased transcription. ERK/c-Myc contributes to the promotion of the expression levels of cyclin D1, cdc2, and cyclin B1, and reduces [p21.sup.Waf1] activity, thereby promoting cell cycle distribution. We demonstrated the function of ApoE2--LRP8 in the activation of the ERK-c-Myc-[p21.sup.Waf1] signalling cascade and the modulation of G1/S and G2/M transition, indicating ApoE2--LRP8's important role in the cancer cell proliferation. ApoE2 could serve as a diagnostic marker and chemotherapeutic target in pancreatic cancer. Key words: apolipoprotein E2, c-Myc-[p21.sup.Waf1] signalling, cell cycle transition, pancreatic cancer. On rapporte que l'apolipoprotéine E2 (ApoE2) est importante pour la prolifération et la survie des cellules et elle a été identifiée comme un marqueur potentiel associé aux tumeurs dans plusieurs types de cancer. Cependant, les études du fonctionnement etdumécanismede l'ApoE2 dansla proliférationet ledéveloppement ducancer pancréatique sont rares. Dans cette étude, les auteurs ont réalisé une analyse afin de déterminer les effets modulateurs du tandem ApoE2-LRP8 (lipoprotein receptor related protein 8) sur le cycle cellulaire et la prolifération. Ils ont aussi exploré ses mécanismes d'action dans le cancer pancréatique. De hauts niveaux d'expression d'ApoE2-LRP8/c-Myc ont été détectés dans les tissus tumoraux et les lignées cellulaires par immunohistochimie et buvardage western. Il appert aussi que le tandem ApoE2--LRP8 induisait la phosphorylation de ERK1/2 pour activer c-Myc et contribuer à l'expression de protéines reliées au cycle cellulaire. L'apoE2 induisait la liaison de c-Myc aux séquences du promoteur de son gène cible [p21.sup.Waf1], donnant lieu à une diminution de sa transcription. L'axe ERK--c-Myc contribue à la hausse des niveaux d'expression de la cycline D1, de cdc2 et de la cycline B1 et réduit l'activité de [p21.sup.Waf1], favorisant ainsi la progression du cycle cellulaire. Les auteurs ont démontré la fonction du tandem ApoE2--LRP8 dans l'activation de la cascade de signalisation ERK-c-Myc-[p21.sup.Waf1] et la modulation de la transition G1/S et G2/M, indiquant que ApoE2--LRP8 joue un rôle important dans la prolifération des cellules cancéreuses. L'ApoE2 pourrait agir comme marqueur diagnostic et comme cible chimiothérapeutique dans le cancer pancréatique. [Traduit par la Rédaction] Mots-clés : apolipoprotéine E2, signalisation c-Myc-[p21.sup.Waf1], transition du cycle cellulaire, cancer pancréatique.

Author(s): Welma Stonehouse [sup.1], Bianca Benassi-Evans [sup.1], Genevieve James-Martin [sup.1], Mahinda Abeywardena [sup.1] Author Affiliations: (1) Commonwealth Scientific Industrial Research Organisation, Health and Biosecurity, Adelaide, Australia Introduction Cardiovascular disease (CVD) [...], Background/Objectives Hypercholesterolaemic effects of saturated fatty acids (SFA) may be influenced not only by the chain length, but also by their specific location within the triacylglycerol (TAG) molecule. We examined the hypothesis that dietary fats rich in SFA, but containing mostly unsaturated fatty acids in the sn-2 position with most SFA in sn-1 and -3 (palm olein [PO] and cocoa butter [CB]) will have similar serum lipid outcomes to unsaturated olive oil (OO). Subjects/Methods Thirty-eight participants (20-40 yr, 18.5- [less than or equal to] 27.5 kg/m.sup.2) completed a 4-week randomised 3 × 3 crossover feeding intervention, preceded by 2-week run-in and separated by 2-week washout periods. Background diet contained 35 percentage of total energy (%E) fat, 18%E protein, 48%E carbohydrates, differing in test fats only (palm olein (PO), CB, OO; 20%E). Total cholesterol (TC)/high density lipoprotein cholesterol (HDL-C) ratio and related variables; TC, HDL-C, low density lipoprotein cholesterol (LDL-C), TAG, apoA1, ApoB, ApoA1 (apolipoprotein A1)/ApoB (apolipoprotein B), lipoprotein (a) (Lp(a)), NEFA, LDL sub-fractions, were assessed pre- and post-intervention. Data were analysed using mixed effects longitudinal models with a P-value < 0.05 considered significant. Results Changes in plasma fatty acids (P < 0.05) confirmed compliance; C18:1 increased with OO compared to PO and CB; C16:0 decreased with OO and C18:0 increased following CB. No differences were seen for TC/HDL-C (mean [95%CI] change for PO, 0.08[0.00, 0.15] mmol/L; CB, 0.06 [-0.05, 0.16] mmol/L; and OO, -0.01 [-0.15, 0.13] mmol/L; P = 0.53] or any other parameter including LDL sub-fractions. OO decreased IDL-A compared to PO (-2.2 [-4.31, -0.21] mg/dL, P = 0.03). Conclusion In healthy young participants, plasma lipid responses to PO and CB, enriched in SFA but having primarily unsaturated fatty acid in the sn-2 position of TAG, did not differ from OO.

Introduction Inflammatory bowel disease (IBD), inclusive of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. IBD consists of a dysregulated [...], Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn&apos;s-like intestinal inflammation when fed cholate-containing high-fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2-KO but not WT mice. Cox2MKO increased proinflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2-MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, whereas administration of an LXA4 analog rescued disease in Cox2-MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2-MKO/CCHF and piroxicam-accelerated [Il10.sup.-/-] models of inflammatory bowel disease (IBD) and reduced elevated levels of proinflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2-MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides (a) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine-dependent (oxPAPC-dependent) proinflammatory responses in human macrophages and intestinal epithelium, and (b) directly cleared proinflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for proinflammatory and inflammation-resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.

Author(s): Arrigo F. G. Cicero 1,*, Federica Fogacci 1, Adrian V. Hernandez 2,3, Maciej Banach 4,5,6,*, on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the [...], Background Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%; p < 0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%; p < 0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%; p < 0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%; p < 0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%; p < 0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%; p = 0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.