Efficacy and Optimal Dose of Coenzyme Q10 Supplementation on Inflammation-Related Biomarkers: A GRADE-Assessed Systematic Review and Updated Meta-Analysis of Randomized Controlled Trials.

SCOPE: Coenzyme Q10 (CoQ10) has become a popular nutritional supplement due to its wide range of beneficial biological effects. Previous meta-analyses show that the attenuation of CoQ10 on inflammatory biomarkers remains controversial. This meta-analysis aims to assess the efficacy and optimal dose of CoQ10 supplementation on inflammatory indicators in the general population. METHODS AND RESULTS: Databases are searched up to December 2022 resulting in 6713 articles, of which 31 are retrieved for full-text assessment and included 1517 subjects. Double-blind randomized controlled trials (RCTs) of CoQ10 supplementation are eligible if they contain C reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). CoQ10 supplementation can significantly reduce the levels of circulating CRP (SMD: -0.40, 95% CI: [-0.67 to -0.13], p = 0.003), IL-6 (SMD: -0.67, 95% CI: [-1.01 to -0.33], p < 0.001), and TNF-α (SMD: -1.06, 95% CI: [-1.59 to -0.52], p < 0.001) and increase the concentration of circulating CoQ10. CONCLUSION: This meta-analysis provides evidence for CoQ10 supplementation to reduce the level of inflammatory mediators in the general population and proposes that daily supplementation of 300-400 mg CoQ10 show superior inhibition of inflammatory factors.

J-Shaped Association of Tomato Intake with New-Onset Hypertension in General Adults: A Nationwide Prospective Cohort Study.

We aim to examine the prospective association between the intake of dietary tomatoes and the risk of new-onset hypertension and its modifiable factors in general adults. A total of 11,460 adults without hypertension from the China Health and Nutrition Survey (CHNS) were enrolled, with follow-up beginning in 1997 and ending in 2015. Dietary tomato intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or diagnosed by physicians or under anti-hypertensive treatment during the follow-up. Finally, 4015 subjects developed new-onset hypertension during 92,335.5 person-years of follow-up. After multivariate adjustment for dietary and non-dietary risk factors, hazard ratios for increased consumption of dietary tomatoes were 0.42 (95% confidence interval, 0.37−0.47), 0.51 (0.46−0.57), and 0.82 (0.74−0.92) compared with non-consumers. Overall, cubic spline regression suggested a novel J-shaped association between dietary tomato intake and new-onset hypertension, with the lowest risk observed at approximately 10 to 13 g/day (p < 0.001 for curvature). Moreover, the association between dietary tomato intake and risk of new-onset hypertension was stronger in females or individuals who refrained from smoking or drinking (p = 0.024, p = 0.043, and p = 0.044 for interaction, respectively).

Water-Soluble Tomato Concentrate, a Potential Antioxidant Supplement, Can Attenuate Platelet Apoptosis and Oxidative Stress in Healthy Middle-Aged and Elderly Adults: A Randomized, Double-Blinded, Crossover Clinical Trial.

Increased oxidative stress and platelet apoptotic in middle-aged and elderly adults are important risk factors for atherosclerotic cardiovascular disease (ASCVD). Therefore, it is of great significance to control the oxidative stress and platelet apoptosis in middle-aged and elderly adults. Previous acute clinical trials have shown that water-soluble tomato concentrate (WSTC) from fresh tomatoes could exert antiplatelet benefits after 3 h or 7 h, but its effects on platelet apoptosis and oxidative stress are still unknown, especially in healthy middle-aged and elderly adults. This current study aimed to examine the efficacies of WSTC on platelet apoptosis and oxidative stress in healthy middle-aged and elderly adults via a randomized double-blinded placebo-controlled crossover clinical trial (10 weeks in total). A total of 52 healthy middle-aged and elderly adults completed this trial. The results showed that WSTC could increase the serum total antioxidant capacity levels (p < 0.05) and decrease the serum malondialdehyde levels (p < 0.05) after a 4-week WSTC supplementation in healthy middle-aged and elderly adults. Platelet endogenous reactive oxygen species generation (p < 0.05), mitochondrial membrane potential dissipation (p < 0.05) and phosphatidylserine exposure (p < 0.05) were attenuated. In addition, our present study also found that WSTC could inhibit platelet aggregation and activation induced by collagen or ADP after intervention (p < 0.05), while having no effects on adverse events (p > 0.05). The results suggest that WSTC can inhibit oxidative stress and its related platelet apoptosis, which may provide a basis for the primary prevention of WSTC in ASCVD.

Ginsenosides Rb2 and Rd2 isolated from Panax notoginseng flowers attenuate platelet function through P2Y12-mediated cAMP/PKA and PI3K/Akt/Erk1/2 signaling.

Saponins derived from Panax notoginseng root are widely used as herbal medicines and dietary supplements due to their wide range of health benefits. However, the effects of those from Panax notoginseng flowers (PNF) on platelet function and thrombus formation remain largely unknown. Using a series of platelet function assays, we found that G-Rb2 and G-Rd2, among the ten PNF saponin monomers, significantly inhibited human platelet aggregation and activation induced by adenosine diphosphate (ADP) in vitro. The 50% inhibitory concentration (IC50) of G-Rb2 and G-Rd2 against ADP-induced platelet aggregation was 85.5 ± 4.5 µg mL-1 and 51.4 ± 4.6 µg mL-1, respectively. Mechanistically, G-Rb2 and G-Rd2 could effectively modulate platelet P2Y12-mediated signaling by up-regulating cAMP/PKA signaling and down-regulating PI3K/Akt/Erk1/2 signaling pathways. Co-incubation of the P2Y12 antagonist cangrelor with either G-Rb2 or G-Rd2 did not show significant additive inhibitory effects. G-Rb2 and G-Rd2 also substantially suppressed thrombus growth in a FeCl3-induced murine arteriole thrombosis model in vivo. Interestingly, G-Rd2 generally exhibited more potent inhibitory effects on platelet function and thrombus formation than G-Rb2. Thus, our data suggest that PNF-derived G-Rb2 and G-Rd2 effectively attenuate platelet hyperactivity through modulating signaling pathways downstream of P2Y12, which indicates G-Rb2 and G-Rd2 may play important preventive roles in thrombotic diseases.

Protocatechuic Acid Protects Platelets from Apoptosis via Inhibiting Oxidative Stress-Mediated PI3K/Akt/GSK3ß Signaling.

Oxidative stress plays crucial roles in initiating platelet apoptosis that facilitates the progression of cardiovascular diseases (CVDs). Protocatechuic acid (PCA), a major metabolite of anthocyanin cyanidin-3-O-ß-glucoside (Cy-3-g), exerts cardioprotective effects. However, underlying mechanisms responsible for such effects remain unclear. Here, we investigate the effect of PCA on platelet apoptosis and the underlying mechanisms in vitro. Isolated human platelets were treated with hydrogen peroxide (H2O2) to induce apoptosis with or without pretreatment with PCA. We found that PCA dose-dependently inhibited H2O2-induced platelet apoptosis by decreasing the dissipation of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and decreasing phosphatidylserine exposure. Additionally, the distributions of Bax, Bcl-xL, and cytochrome c mediated by H2O2 in the mitochondria and the cytosol were also modulated by PCA treatment. Moreover, the inhibitory effects of PCA on platelet caspase-3 cleavage and phosphatidylserine exposure were mainly mediated by downregulating PI3K/Akt/GSK3ß signaling. Furthermore, PCA dose-dependently decreased reactive oxygen species (ROS) generation and the intracellular Ca2+ concentration in platelets in response to H2O2. N-Acetyl cysteine (NAC), a ROS scavenger, markedly abolished H2O2-stimulated PI3K/Akt/GSK3ß signaling, caspase-3 activation, and phosphatidylserine exposure. The combination of NAC and PCA did not show significant additive inhibitory effects on PI3K/Akt/GSK3ß signaling and platelet apoptosis. Thus, our results suggest that PCA protects platelets from oxidative stress-induced apoptosis through downregulating ROS-mediated PI3K/Akt/GSK3ß signaling, which may be responsible for cardioprotective roles of PCA in CVDs.

Anthocyanins, Anthocyanin-Rich Berries, and Cardiovascular Risks: Systematic Review and Meta-Analysis of 44 Randomized Controlled Trials and 15 Prospective Cohort Studies.

Objective: The associations between intake of anthocyanins and anthocyanin-rich berries and cardiovascular risks remained to be established. We aimed to quantitatively summarize the effects of purified anthocyanins and anthocyanin-rich berries on major surrogate markers of cardiovascular diseases (CVDs) and the longitudinal associations between dietary anthocyanins and CVD events. Methods: Meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies. Results: We included 44 eligible RCTs and 15 prospective cohort studies in this study. Pooled analysis of RCTs showed that purified anthocyanin supplementation could significantly reduce blood LDL cholesterol (weighted mean difference (WMD): -5.43 mg/dL, 95% CI: -8.96, -1.90 mg/dL; p = 0.003) and triglyceride (WMD: -6.18 mg/dL, 95% CI: -11.67, -0.69 mg/dL; p = 0.027) while increase HDL cholesterol (WMD: 11.49 mg/dL, 95% CI: 7.43, 15.55 mg/dL; p < 0.001) concentrations. Purified anthocyanins also markedly decreased circulating tumor necrosis factor alpha (WMD: -1.62 pg/mL, 95% CI: -2.76, -0.48 pg/mL; p = 0.005) and C-reactive protein (WMD: -0.028 mg/dL, 95% CI: -0.050, -0.005 mg/dL; p = 0.014). Besides, administration of anthocyanin-rich berries could significantly lower blood total cholesterol (WMD: -4.48 mg/dL, 95% CI: -8.94, -0.02 mg/dL; p = 0.049) and C-reactive protein (WMD: -0.046 mg/dL, 95% CI: -0.070, -0.022 mg/dL; p < 0.001). Neither purified anthocyanins nor anthocyanin-rich berries could cause any substantial improvements in BMI, blood pressure, or flow-mediated dilation. In addition, meta-analysis of prospective cohort studies suggested that high dietary anthocyanins were related to lower risk of coronary heart disease (CHD) (relative risk (RR): 0.83, 95% CI: 0.72, 0.95; p = 0.009), total CVD incidence (RR: 0.73, 95% CI: 0.55, 0.97; p = 0.030), and total CVD deaths (RR: 0.91, 95% CI: 0.87, 0.96; p < 0.001). Conclusion: Habitual intake of anthocyanins and anthocyanin-rich berries could protect against CVDs possibly via improving blood lipid profiles and decreasing circulating proinflammatory cytokines. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42020208782.

Coenzyme Q10 attenuates platelet integrin αIIbß3 signaling and platelet hyper-reactivity in ApoE-deficient mice.

Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits. However, its effects on platelets and integrin αIIbß3 signaling during atherosclerosis have not been previously explored. Here, apolipoprotein E-deficient (ApoE-/-) mice were fed a standard diet, high-fat diet (HFD) or CoQ10-supplemented HFD for 12 weeks. We found that CoQ10 supplementation in ApoE-/- mice significantly alleviated formation of HFD-induced atherosclerotic lesions, and attenuated platelet hyper-aggregation and granule secretion, including CD62P, CD63 and CD40 ligand (CD40L) expression and platelet factor-4, ß-thromboglobulin and activation normal T cell expressed and secreted (CCL5) release. CoQ10 supplementation decreased soluble fibrinogen and JON/A binding to αIIbß3 on activated platelets, indicating that αIIbß3-mediated inside-out signaling was attenuated. Additionally, CoQ10 down-regulated platelet αIIbß3 outside-in signaling including decreasing phosphorylation of the ß3 intracellular tail, cellular and sarcoma tyrosine-protein kinase (c-Src), and myosin light chain (MLC), and consistently attenuating platelet spreading and clot retraction. Importantly, platelet-monocyte aggregation that was primarily mediated by αIIbß3 and can be blocked using an αIIbß3-specific antagonist tirofiban was also markedly diminished by CoQ10. Thus, CoQ10 supplementation attenuates platelet hyper-reactivity via down-regulating both αIIbß3 inside-out and outside-in signaling, which may play important preventive roles in atherothrombosis.

Coenzyme Q10 Upregulates Platelet cAMP/PKA Pathway and Attenuates Integrin αIIbß3 Signaling and Thrombus Growth.

SCOPE: Platelet integrin αIIbß3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat-soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbß3 signaling and thrombosis, the major cause of cardiovascular diseases. METHODS AND RESULTS: Using a series of platelet functional assays in vitro, it is demonstrated that CoQ10 reduces human platelet aggregation, granule secretion, platelet spreading, and clot retraction. It is further demonstrated that CoQ10 inhibits platelet integrin αIIbß3 outside-in signaling. These inhibitory effects are mainly mediated by upregulating cAMP/PKA pathway, where CoQ10 stimulates the A2A adenosine receptor and decreases phosphodiesterase 3A phosphorylation. Moreover, CoQ10 attenuates murine thrombus growth and vessel occlusion in a ferric chloride (FeCl3 )-induced thrombosis model in vivo. Importantly, the randomized, double-blind, placebo-controlled clinical trial in dyslipidemic patients demonstrates that 24 weeks of CoQ10 supplementation increases platelet CoQ10 concentrations, enhances the cAMP/PKA pathway, and attenuates αIIbß3 outside-in signaling, leading to decreased platelet aggregation and granule release. CONCLUSION: Through upregulating the platelet cAMP/PKA pathway, and attenuating αIIbß3 signaling and thrombus growth, CoQ10 supplementation may play an important protective role in patients with risks of cardiovascular diseases.

Cyanidin-3-o-ß-Glucoside Induces Megakaryocyte Apoptosis via PI3K/Akt- and MAPKs-Mediated Inhibition of NF-κB Signalling.

Apoptotic-like phase is an essential step in thrombopoiesis from megakaryocytes. Anthocyanins are natural flavonoid pigments that possess a wide range of biological activities, including protection against cardiovascular diseases and induction of tumour cell apoptosis. We investigated the effects and underlying mechanisms of cyanidin-3-o-ß-glucoside (Cy-3-g, the major bioactive compound in anthocyanins) on the apoptosis of human primary megakaryocytes and Meg-01 cell line in vitro. We found that Cy-3-g dose-dependently increased the dissipation of the mitochondrial membrane potential, caspase-9 and caspase-3 activity in megakaryocytes from patients with newly diagnosed acute myeloid leukaemia but not in those from healthy volunteers. In Meg-01 cells, Cy-3-g regulated the distribution of Bak, Bax and Bcl-xL proteins in the mitochondria and cytosol, subsequently increasing cytochrome c release and stimulating caspase-9 and caspase-3 activation and phosphatidylserine exposure. However, Cy-3-g did not exert significant effects on factor-associated suicide (Fas), Fas ligand, caspase-8 or Bid expression. Cy-3-g inhibited nuclear factor kappa B (NF-κB) p65 activation by down-regulating inhibitor of NF-κB kinase (IKK)α and IKKß expression, followed by the inhibition of inhibitor of NF-κB (IκB)α phosphorylation and degradation and subsequent inhibition of the translocation of the p65 sub-unit into the nucleus, and finally stimulating caspase-3 activation and phosphatidylserine exposure. The inhibitory effect of Cy-3-g on NF-κB activation was mediated by the activation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinase (MAPK) and the inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling. U0126 (Erk1/2 inhibitor), SB203580 (p38 MAPK inhibitor) and 740 Y-P (PI3K agonist) significantly reversed Cy-3-g-reduced phosphorylation of p65. Taken together, our data indicate that Cy-3-g induces megakaryocyte apoptosis via the inhibition of NF-κB signalling, which may play important roles in regulating thrombopoiesis.