All-Cause Mortality and Cardiovascular Death between Statins and Omega-3 Supplementation: A Meta-Analysis and Network Meta-Analysis from 55 Randomized Controlled Trials.

Statins and omega-3 supplementation have shown potential benefits in preventing cardiovascular disease (CVD), but their comparative effects on mortality outcomes, in addition to primary and secondary prevention and mixed population, have not been investigated. This study aimed to examine the effect of statins and omega-3 supplementation and indirectly compare the effects of statin use and omega-3 fatty acids on all-cause mortality and CVD death. We included randomized controlled trials (RCTs) from meta-analyses published until December 2019. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated to indirectly compare the effect of statin use versus omega-3 supplementation in a frequentist network meta-analysis. In total, 55 RCTs were included in the final analysis. Compared with placebo, statins were significantly associated with a decreased the risk of all-cause mortality (RR = 0.90, 95% CI = 0.86-0.94) and CVD death (RR = 0.86, 95% CI = 0.80-0.92), while omega-3 supplementation showed a borderline effect on all-cause mortality (RR = 0.97, 95% CI = 0.94-1.01) but were significantly associated with a reduced risk of CVD death (RR = 0.92, 95% CI = 0.87-0.98) in the meta-analysis. The network meta-analysis found that all-cause mortality was significantly different between statin use and omega-3 supplementation for overall population (RR = 0.91, 95% CI = 0.85-0.98), but borderline for primary prevention and mixed population and nonsignificant for secondary prevention. Furthermore, there were borderline differences between statin use and omega-3 supplementation in CVD death in the total population (RR = 0.92, 95% CI = 0.82-1.04) and primary prevention (RR = 0.85, 95% CI = 0.68-1.05), but nonsignificant differences in secondary prevention (RR = 0.97, 95% CI = 0.66-1.43) and mixed population (RR = 0.92, 95% CI = 0.75-1.14). To summarize, statin use might be associated with a lower risk of all-cause mortality than omega-3 supplementation. Future direct comparisons between statin use and omega-3 supplementation are required to confirm the findings.

Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status.

PURPOSE: Folate-related nutrient-nutrient and nutrient-gene interactions modify disease risk; we therefore examined synergistic relationships between dietary folic acid, vitamin C and variant folate genes with respect to red cell folate status. METHODS: Two hundred and twelve subjects were examined using chemiluminescent immunoassay, PCR and food frequency questionnaire to determine red cell and serum folate, 14 folate gene polymorphisms, dietary folate (natural and synthetic) and vitamin C. RESULTS: When examined independently, synthetic PteGlu correlates best with red cell folate at higher levels of intake (p = 0.0102), while natural 5CH(3)-H(4)-PteGlu(n) correlates best with red cell folate at lower levels of intake (p = 0.0035). However, dietary vitamin C and 5CH(3)-H(4)-PteGlu(n) interact synergistically to correlate with red cell folate at higher levels of intake (p = 0.0005). No interaction between dietary vitamin C and PteGlu was observed. This 'natural' nutrient-nutrient interaction may provide an alternative to synthetic PteGlu supplementation that is now linked to adverse phenomena/health outcomes. On its own, vitamin C also correlates with red cell folate (p = 0.0150) and is strongly influenced by genetic variation in TS, MTHFR and MSR, genes critical for DNA and methionine biosynthesis that underpin erythropoiesis. Similarly, dietary vitamin C and 5CH(3)-H(4)-PteGlu(n) act synergistically to modify red cell folate status according to variation in folate genes: of note, heterozygosity for 2R3R-TS (p = 0.0181), SHMT (p = 0.0046) and all three MTHFR SNPs (p = 0.0023, 0.0015 and 0.0239 for G1793A, C677T and A1298C variants, respectively) promote a significant association with red cell folate. Again, all these genes are critical for nucleic acid biosynthesis. Folate variants with the strongest independent effect on folate status were C677T-MTHFR (p = 0.0004) and G1793A-MTHFR (p = 0.0173). CONCLUSIONS: 5CH(3)-H(4)-PteGlu(n) assimilation and variant folate gene expression products may be critically dependent on dietary vitamin C.

Antioxidant and antithrombus activities of enzyme-treated Salicornia herbacea extracts.

This study was attempted to investigate antioxidant and antithrombus activities of water and methanol extracts of enzyme-treated Salicornia herbacea (SH)by in vitro assays observing the inhibitory activity of a rat liver microsomal lipid peroxidation, DPPH radical scavenging activity, activated partial thromboplastin times (APTT) and thromboplastin times (TT). The water and methanol extracts from enzyme-treated SH inhibited the lipid peroxidation in a dose-dependent manner over a concentration range of 0.1-1.0 mg/ml. The activity of enzyme-treated water and methanol extracts was stronger than that of non-enzyme-treated water and methanol extracts. The inhibitory activity of the water extract was higher at a concentration of 1.0 mg/ml than that of the methanol extract. The activity was the highest in the enzyme-treated water extract, and was approximately 1.08 times higher than alpha-tocopherol, a natural antioxidant. The DPPH radical scavenging activities of the SH extracts were similar to their lipid peroxidation inhibitory activity. The APTT of the water and methanol extracts was delayed at a concentration range of 0.25-2.0 mg/ml in a dose-dependent manner. The APTT of the methanol extract was longer at a concentration of 1.0 mg/ml than that of the water extracts. The enzyme-treated methanol extract exhibited the longest APTT even at a concentration of 0.50 mg/ml. The TT activities of the SH extracts were also similar to their APTT activities. These results suggest that water and methanol extracts of the enzyme-treated SH may be useful as potential antioxidant and antithrombus sources, respectively.

Effects of green tea catechin on polymorphonuclear leukocyte 5'-lipoxygenase activity, leukotriene B4 synthesis, and renal damage in diabetic rats.

The purpose of this study was to investigate the effects of green tea catechin on polymorphonuclear leukocyte 5'-lipoxygenase activity, leukotriene B4 synthesis, and renal damage in diabetic rats. Male Sprague-Dawley rats weighing 100 +/- 10 g were randomly assigned to 1 normal group and 3 diabetic groups given a catechin-free diet (DM-0C group), 0.25% catechin diet (DM-0.25C group), or 0.5% catechin diet (DM-0.5C group), respectively. 5'-Lipoxygenase activity in the polymorphonuclear leukocytes significantly increased by 54% in the DM-0C group compared to the normal group, while the level in the DM-0.5C group remained the same as in the normal group. The leukotriene B4 content in the polymorphonuclear leukocytes increased 55% in the DM-0C group compared to the normal group, whereas the DM-0.25C and DM-0.5C groups exhibited the same level as the normal group. The superoxide radical content in the kidney microsomes increased 116% in the DM-0C group when compared to the normal group, yet decreased 29% in the DM-0.25C group and 50% in the DM-0.5C group compared to DM-0C group. The lipofuscin content was 197 and 136% higher in the DM-0C and DM-025C groups, respectively, than in the normal group, whereas the DM-0.5C group exhibited the same content as in the normal group. The carbonyl value increased 118% in the DM-0C group compared to the normal group, and the DM-0.25C and DM-0.5C groups were not significantly different from the DM-0C group. Accordingly, these results indicate that dietary catechin inhibited the generation of superoxide radicals, oxidized protein, and lipid peroxide in the kidney of streptozotocin-induced diabetic rats. Furthermore, green tea catechin supplementation in diabetic rats also appeared to inhibit the production of leukotriene B4 based on regulating the activity of 5'-lipoxygenase, thereby potentially reducing renal oxidative damage and inflammatory reactions.

Effects of vitamin E on renal dysfunction in chronic cadmium-poisoned rats.

Cadmium is a highly toxic metal that can be ingested or inhaled from a variety of industrial and dietary sources. The purpose of this study was to investigate the effects of vitamin E on renal dysfunction and blood pressure changes in chronic cadmium-poisoned rats. Sprague-Dawley rats weighing 100 +/- 10 g were randomly assigned to one control group and three cadmium-poisoned groups. Cadmium groups were assigned to dietary groups according to levels of vitamin E supplementation: vitamin E-free diet (Cd-0E group), 40 mg of vitamin E/kg of diet (Cd-40E group), and 400 mg of vitamin E/kg of diet (Cd-400E group). The animals were raised for 20 weeks, and cadmium was supplied in the drinking water at 50 ppm Cd(2+). The morphological changes observed by both light and electron microscopy revealed mitochondria and tubule epithelial cell edema in the Cd-0E group, yet this was alleviated with the highest level of vitamin E supplementation (Cd-400E group). The urinary beta(2)-microglobulin levels indicated that glomerular injury was higher in the Cd-poisoned groups than in the control group, but were lowered by vitamin E supplementation. Although the glomerular filtration rate (GFR) of the Cd-0E group was significantly lower than that of the control group, the vitamin E-supplemented groups exhibited a similar GFR to the control group, suggesting that vitamin E protected the kidney from functional damage. Angiotensin converting enzyme activity, and blood pressure, and heart rate were all significantly higher in the Cd-poisoned group, but each remained nearly normal with vitamin E supplementation. Accordingly, these results indicate that vitamin E supplementation in chronic cadmium-poisoned rats normalized renal dysfunction and blood pressure regulation.

Action of green tea catechin on bone metabolic disorder in chronic cadmium-poisoned rats.

The purpose of this study was to investigate the effects of green tea catechin on bone metabolic disorders and its mechanism in chronic cadmium-poisoned rats. Sprague-Dawley male rats weighing 100+/-10 g were randomly assigned to one control group and three cadmium-poisoned groups. The cadmium groups included a catechin free diet (Cd-0C) group, a 0.25% catechin diet (Cd-0.25C) group and a 0.5% catechin diet (Cd-0.5C) group according to their respective levels of catechin supplement. After 20 weeks, the deoxypyridinoline and crosslink values measured in urine were significantly increased in the Cd-0C group. Cadmium intoxication seemed to lead to an increase in bone resorption. In the catechin supplemented group (Cd-0.5C group), these urinary bone resorption marks, were decreased. The serum osteocalcin content in the cadmium-poisoned group was significantly increased as compared with the control group. In the catechin supplemented group serum osteocalcin content values were lower than the control group. The cadmium-intoxicated group (Cd-0C group), had lower bone mineral density than the control group (total body, vertebra, pelvis, tibia and femur). The catechin supplement increased bone mineral density to about the same as the control group. Bone mineral content showed a similar trend to total bone mineral density. Therefore, the bone mineral content of the Cd-0C group at the 20th week was significantly lower than the control group. The catechin supplemented group (Cd-0.5C group) was about the same as the control group. The cause of decreasing bone mineral density and bone mineral content by cadmium poisoning was due to the fast bone turnover rate, where bone resorption occurred at a higher rate than bone formation. The green tea catechin aided in normalizing bone metabolic disorders in bone mineral density, bone mineral content and bone calcium content caused by chronic cadmium intoxication.

Effect of green tea catechin on arachidonic acid cascade in chronic cadmium-poisoned rats.

The purpose of this study was to investigate the effect of green tea catechin on the cyclooxygenase and lipoxygenase pathways in chronic cadmium-poisoned rats. Sprague-Dawley male rats weighing 100 +/- 10 g were randomly assigned to one normal and three cadmium-poisoned groups. The cadmium groups were classified as catechin-free diet group (Cd-0C), 0.25% catechin diet group (Cd-0.25C) and 0.5% catechin diet group (Cd-0.5C), in accordance with the level of catechin supplement. The phospholipase A2 activity was remarkably increased 117% in the Cd-0C group and 60% in the Cd-0.25C group compared with the normal group, and the level in the Cd-0.5C group was the same as the normal group. Activity of platelet cyclooxygenase increased 284% in the Cd-0C group, 147% in the Cd-0.25C group and 193% in the Cd-0.5C group. The synthesis of platelet thromboxane A2 (TXA2) increased 157% in the Cd-0C group and 105% in the Cd-0.25C group, compared with the normal group. The Cd-0.5C group showed the same level as the normal group. Prostacyclin (PGI2) formation in the aorta decreased 24% in the Cd-0C group and 18% in the Cd-0.25C group. The ratio of PGI2/TXA2, the thrombocyte synthesis index, decreased 70% in the Cd-0C group and 59% in the Cd-0.25C group. The activity of 5'-lipoxygenase in the polymorphonuclear leukocyte was increased 40% in the Cd-0C group as compared with the normal group. Catechin-supplemented Cd-0.25C and Cd-0.5C groups showed the level of the normal group. In this study, the observed content of leukotriene B4, which induces the inflammatory process, increased 54% in the Cd-0C group, and in catechin-supplemented groups, showed the same level as in the normal group. The serum peroxide value increased 60% in the Cd-0C group compared with the normal group; but in the Cd-0.5C group, it showed the level of the normal group. These results indicate that chronic cadmium poisoning in rats accelerates arachidonic acid metabolism. Inhibition of arachidonic acid metabolism due to catechin supplementation, however, decreases platelet aggregation and inflammatory action. In conclusion, it would appear that green tea catechin supplementation in chronic cadmium-poisoned rats inhibits the arachidonic acid cascade by regulating the activity of phospholipase A2.

Green tea catechin improves microsomal phospholipase A2 activity and the arachidonic acid cascade system in the kidney of diabetic rats.

The purpose of this study was to investigate the effects of green tea catechin on the microsomal phospholipase A2 activity and arachidonic acid cascade in the kidneys of streptozotocin-induced diabetic rats. Sprague-Dawley male rats weighing 100 +/- 10 g were assigned randomly to one normal and three streptozotocin-induced diabetic groups. The diabetic groups were the DM-0C group (n = 10), fed a catechin-free diet, the DM-0.25C group (n = 10), fed a 0.25 g catechin per 100 g diet, and the DM-0.5C group (n = 10), fed a 0.5 g catechin per 100 g diet. The kidney microsomal phospholipase A2 activity was higher in the diabetic groups than in the normal group, while it was lower in the DM-0.25C and DM-0.5C groups than in the DM-OC group. The percentage of phosphatidylcholine hydrolysed in the kidney microsomes was not significantly different between any of the four groups. The percentage of phosphatidylethanolamine hydrolysed in the kidney microsomes was progressively higher in the DM-0.5C, DM-0.25C and DM-OC groups, respectively, compared to the normal group. The formation of thromboxane A2 was significantly higher while the formation of prostacyclin was lower in kidney microsomes of the streptozotocin-induced diabetic groups compared with the normal group, but this condition was improved by catechin supplementation. Kidney microsomal vitamin E concentrations were progressively lower in the DM-0.5C, DM-0.25C, and DM-0C groups, respectively, compared to the normal group. The kidney thiobarbituric acid reactive substance (TBARS) contents became higher in the DM-0C and DM-0.25C groups as compared with the normal group, whereas the DM-0.5C group did not differ from the normal group. Kidney function appears to be improved by green tea catechin supplementation due to its antithrombus action, which in turn controls the arachidonic acid cascade system.