Resveratrol Improves Hyperuricemia and Ameliorates Renal Injury by Modulating the Gut Microbiota.

Resveratrol (RES) has been reported to prevent hyperuricemia (HUA); however, its effect on intestinal uric acid metabolism remains unclear. This study evaluated the impact of RES on intestinal uric acid metabolism in mice with HUA induced by a high-fat diet (HFD). Moreover, we revealed the underlying mechanism through metagenomics, fecal microbiota transplantation (FMT), and 16S ribosomal RNA analysis. We demonstrated that RES reduced the serum uric acid, creatinine, urea nitrogen, and urinary protein levels, and improved the glomerular atrophy, unclear renal tubule structure, fibrosis, and renal inflammation. The results also showed that RES increased intestinal uric acid degradation. RES significantly changed the intestinal flora composition of HFD-fed mice by enriching the beneficial bacteria that degrade uric acid, reducing harmful bacteria that promote inflammation, and improving microbial function via the upregulation of purine metabolism. The FMT results further showed that the intestinal microbiota is essential for the effect of RES on HUA, and that Lactobacillus may play a key role in this process. The present study demonstrated that RES alleviates HFD-induced HUA and renal injury by regulating the gut microbiota composition and the metabolism of uric acid.

Cohort Profile: Guangzhou Nutrition and Health Study (GNHS): A Population-Based Multi-Omics Study.

BACKGROUND: The Guangzhou Nutrition and Health Study (GNHS) aims to assess the determinants of metabolic disease in nutritional aspects, as well as other environmental and genetic factors, and explore possible biomarkers and mechanisms with multi-omics integration. METHODS: The population-based sample of adults in Guangzhou, China (baseline: 40-83 years old; n = 5118) was followed up about every 3 years. All will be tracked via on-site follow-up and health information systems. We assessed detailed information on lifestyle factors, physical activities, dietary assessments, psychological health, cognitive function, body measurements, and muscle function. Instrument tests included dual-energy X-ray absorptiometry scanning, carotid artery and liver ultrasonography evaluations, vascular endothelial function evaluation, upper-abdomen and brain magnetic resonance imaging, and 14-d real-time continuous glucose monitoring tests. We also measured multi-omics, including host genome-wide genotyping, serum metabolome and proteome, gut microbiome (16S rRNA sequencing, metagenome, and internal transcribed spacer 2 sequencing), and fecal metabolome and proteome. RESULTS: The baseline surveys were conducted from 2008 to 2015. Now, we have completed 3 waves. The 3rd and 4th follow-ups have started but have yet to end. A total of 5118 participants aged 40-83 took part in the study. The median age at baseline was approximately 59.0 years and the proportion of female participants was about 69.4%. Among all the participants, 3628 (71%) completed at least one on-site follow-up with a median duration of 9.48 years. CONCLUSION: The cohort will provide data that have been influential in establishing the role of nutrition in metabolic diseases with multi-omics.

Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux.

BACKGROUND & AIMS: While it is recognized that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD), how NAFLD affects the development and progression of CVD remains unclear and debatable. Hence, we aimed to determine the role of steatotic hepatocyte-derived small extracellular vesicles (sEVs) in foam cell formation and atherosclerosis progression. METHODS: sEVs from steatotic hepatocytes were isolated and characterized. MicroRNA (miRNA) deep sequencing was utilized to identify functional miRNA in sEVs. Lastly, we conducted a cross-sectional study on patients with NAFLD to validate these findings. RESULTS: Treatment of sEVs from steatotic hepatocytes promoted macrophage-derived foam cell formation and atherosclerosis progression via inhibition of ABCA1-mediated cholesterol efflux. Macrophage-specific deletion of Abca1 in ApoE-/- mice abolished the role of steatotic hepatocyte-derived sEVs in atherosclerosis progression. In addition, hepatocyte-specific deletion of Rab27a, which is the key GTPase regulating sEV release, significantly ameliorated high-fat, high-cholesterol diet-induced atherosclerosis progression in ApoE-/- mice. The miRNA deep sequencing results showed that miR-30a-3p was enriched in sEVs from steatotic hepatocytes. miR-30a-3p directly targeted the 3' untranslated region of ABCA1 to inhibit ABCA1 expression and cholesterol efflux. Treatment with antagomiR-30a-3p significantly attenuated atherosclerosis progression in high-fat, high-cholesterol diet-fed ApoE-/- mice. Moreover, serum sEVs from patients with NAFLD and sEV-miR-30a-3p expression were associated with decreased cholesterol efflux levels in foam cells. CONCLUSION: Steatotic hepatocyte-derived sEVs promote foam cell formation and facilitate atherogenesis via the miR-30a-3p/ABCA1 axis. Reducing sEV secretion by steatotic hepatocytes or targeting miR-30a-3p may be potential therapeutic approaches to slow the progression of NAFLD-driven atherosclerosis. IMPACT AND IMPLICATIONS: The presence of hepatic steatosis is strongly correlated with the risk of cardiovascular disease and cardiovascular events, yet the molecular mechanisms linking steatosis to progression of atherosclerosis are unclear. Herein, we identified small extracellular vesicles from steatotic hepatocytes as a trigger that accelerated the progression of atherosclerosis. Steatotic hepatocyte-derived small extracellular vesicles promoted foam cell formation via the miR-30a-3p/ABCA1 axis. Our findings not only provide mechanistic insight into non-alcoholic fatty liver disease-driven atherosclerosis but also provide potential therapeutic targets for patients with atherosclerosis.

Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis.

AIMS: Vascular senescence, which is closely related to epigenetic regulation, is an early pathological condition in cardiovascular diseases including atherosclerosis. Inhibition of S-adenosylhomocysteine hydrolase (SAHH) and the consequent increase of S-adenosylhomocysteine (SAH), a potent inhibitor of DNA methyltransferase, has been associated with an elevated risk of cardiovascular diseases. This study aimed to investigate whether the inhibition of SAHH accelerates vascular senescence and the development of atherosclerosis. METHODS AND RESULTS: The case-control study related to vascular aging showed that increased levels of plasma SAH were positively associated with the risk of vascular aging, with an odds ratio (OR) of 3.90 (95% CI, 1.17-13.02). Elevated pulse wave velocity, impaired endothelium-dependent relaxation response, and increased senescence-associated ß-galactosidase staining were observed in the artery of SAHH+/- mice at 32 weeks of age. Additionally, elevated expression of p16, p21, and p53, fission morphology of mitochondria, and over-upregulated expression of Drp1 were observed in vascular endothelial cells with SAHH inhibition in vitro and in vivo. Further downregulation of Drp1 using siRNA or its specific inhibitor, mdivi-1, restored the abnormal mitochondrial morphology and rescued the phenotypes of vascular senescence. Furthermore, inhibition of SAHH in APOE-/- mice promoted vascular senescence and atherosclerosis progression, which was attenuated by mdivi-1 treatment. Mechanistically, hypomethylation over the promoter region of DRP1 and downregulation of DNMT1 were demonstrated with SAHH inhibition in HUVECs. CONCLUSIONS: SAHH inhibition epigenetically upregulates Drp1 expression through repressing DNA methylation in endothelial cells, leading to vascular senescence and atherosclerosis. These results identify SAHH or SAH as a potential therapeutic target for vascular senescence and cardiovascular diseases.

Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.

Protocatechuic acid boosts continual efferocytosis in macrophages by derepressing KLF4 to transcriptionally activate MerTK.

Macrophages clear apoptotic cells through a process called continual efferocytosis. We found that protocatechuic acid (PCA), a polyphenolic compound abundant in fruits and vegetables, increased the continual efferocytic capacity of macrophages and inhibited the progression of advanced atherosclerosis. PCA reduced the intracellular amounts of microRNA-10b (miR-10b) by promoting its secretion in extracellular vesicles, which led to an increase in the abundance of the miR-10b target Krüppel-like factor 4 (KLF4). In turn, KLF4 transcriptionally induced the gene encoding Mer proto-oncogene tyrosine kinase (MerTK), an efferocytic receptor for the recognition of apoptotic cells, resulting in increased continual efferocytic capacity. However, in naive macrophages, the PCA-induced secretion of miR-10b did not affect KLF4 and MerTK protein abundance or efferocytic capacity. In mice, oral administration of PCA increased continual efferocytosis in macrophages residing in the peritoneal cavities, thymi, and advanced atherosclerotic plaques through the miR-10b-KLF4-MerTK pathway. In addition, pharmacological inhibition of miR-10b with antagomiR-10b also increased the efferocytic capacity of efferocytic but not naive macrophages in vitro and in vivo. Together, these data describe a pathway that promotes continual efferocytosis in macrophages through miR-10b secretion and a KLF4-dependent increase in MerTK abundance, which can be activated by dietary PCA and which has implications for understanding the regulation of continual efferocytosis in macrophages.

Re-Visiting Antioxidant Therapy in Murine Advanced Atherosclerosis with Brussels Chicory, a Typical Vegetable in Mediterranean Diets.

Brussels chicory, a typical vegetable in Mediterranean diets, has been recently reported to stabilize advanced atherosclerotic plaques in the brachiocephalic artery of apoE-deficient (Apoe-/-) mice. Herein, we investigated whether Brussels chicory can stabilize advanced plaques in the aorta via improving oxidative stress. Thirty week old Apoe-/- mice were fed the AIN-93G diet or supplemented with 0.5% freeze-dried Brussels chicory for twenty weeks. Aortic plaque size and stability, aortic relaxation, monocyte adhesion to aortic endothelium, free radicals, and enzymatic and non-enzymatic factors involved in free radical production and elimination in aorta and serum were measured. Brussels chicory consumption did not alter aortic plaque size, however, it stabilized aortic plaques, promoted aortic relaxation, and also inhibited monocyte adhesion to aortic endothelium. Moreover, this administration reduced oxidized LDL (ox-LDL) and 4-hydroxynonenal (4-HNE) content in aortic plaques, associated with inhibited aortic NADPH oxidase (NOX) and uncoupled endothelial nitric oxide synthase (eNOS)-mediated free radical production. However, Brussels chicory consumption did not appreciably alter aortic and serum superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, aortic glutathione (GSH), as well as serum non-enzymatic antioxidants, such as bilirubin, uric acid, and GSH. Collectively, improved oxidative stress might contribute to the atheroprotective effect of Brussels chicory, supporting the prospect of the antioxidant therapy in advanced atherosclerosis progression.

A Randomized Trial on Resveratrol Supplement Affecting Lipid Profile and Other Metabolic Markers in Subjects with Dyslipidemia.

Resveratrol is a polyphenol with a well-established beneficial effect on dyslipidemia and hyperuricemia in preclinical experiments. Nonetheless, its efficacy and dose-response relationship in clinical trials remains unclear. This study examined whether resveratrol supplement improves the serum lipid profile and other metabolic markers in a dose-response manner in individuals with dyslipidemia. A total of 168 subjects were randomly assigned to placebo (n = 43) and resveratrol treatment groups of 100 mg/d (n = 41), 300 mg/d (n = 43), and 600 mg/d (n = 41). Anthropometric and biochemical parameters were analyzed at baseline and 4 and 8 weeks. Resveratrol supplementation for 8 weeks did not significantly change the lipid profile compared with the placebo. However, a significant decrease of serum uric acid was observed at 8 weeks in 300 mg/d (-23.60 ± 61.53 µmol/L, p < 0.05) and 600 mg/d resveratrol groups (-24.37 ± 64.24 µmol/L, p < 0.01) compared to placebo (8.19 ± 44.60 µmol/L). Furthermore, xanthine oxidase (XO) activity decreased significantly in the 600 mg/d resveratrol group (-0.09 ± 0.29 U/mL, p < 0.05) compared with placebo (0.03 ± 0.20 U/mL) after 8 weeks. The reduction of uric acid and XO activity exhibited a dose-response relationship (p for trend, <0.05). Furthermore, a marked correlation was found between the changes in uric acid and XO activity in the resveratrol groups (r = 0.254, p < 0.01). Resveratrol (10 µmol/L) treatment to HepG2 cells significantly reduced the uric acid levels and intracellular XO activity. Nevertheless, we failed to detect significant differences in glucose, insulin, or oxidative stress biomarkers between the resveratrol groups and placebo. In conclusion, resveratrol supplementation for 8 weeks had no significant effect on lipid profile but decreased uric acid in a dose-response manner, possibly due to XO inhibition in subjects with dyslipidemia. The trial was registered on ClinicalTrials.gov (NCT04886297).

The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs-Therapeutic potential exploration in lung injury.

Since 2005, GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) have been developed as therapeutic agents for type 2 diabetes (T2D). GLP-1R is not only expressed in pancreatic islets but also other organs, especially the lung. However, controversy on extra-pancreatic GLP-1R expression still needs to be further resolved, utilizing different tools including the use of more reliable GLP-1R antibodies in immune-staining and co-immune-staining. Extra-pancreatic expression of GLP-1R has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs, aiming to repurpose them into therapeutic agents for other disorders. Extensive studies have demonstrated promising anti-inflammatory features of GLP-1RAs. Whether those features are directly mediated by GLP-1R expressed in immune cells also remains controversial. Following a brief review on GLP-1 as an incretin hormone and the development of GLP-1RAs as therapeutic agents for T2D, we have summarized our current understanding of the anti-inflammatory features of GLP-1RAs and commented on the controversy on extra-pancreatic GLP-1R expression. The main part of this review is a literature discussion on GLP-1RA utilization in animal models with chronic airway diseases and acute lung injuries, including studies on the combined use of mesenchymal stem cell (MSC) based therapy. This is followed by a brief summary.

Higher maternal thyroid resistance indices were associated with increased neonatal thyroid-stimulating hormone- analyses based on the Huizhou mother-infant cohort.

Objectives: This study aimed to explore the relationship of maternal thyroid function and thyroid resistance parameters with neonatal thyroid-stimulating hormone (TSH). Methods: This work was a longitudinal study. Singleton pregnant women without a history of thyroid disorders were recruited in their first prenatal visit from October 2018 to June 2020. Maternal thyroid markers including TSH, free triiodothyronine (FT3), free thyroxine (FT4), and neonatal TSH were tested in the clinical laboratory of the hospital by electrochemiluminescence immunoassay. Thyroid resistance indices including Thyroid Feedback Quantile-based Index (TFQI), TSH index (TSHI), and thyrotroph T4 resistance index (TT4RI) were estimated in accordance with maternal FT4 and TSH levels. Multivariable linear and logistic regression was applied to explore the associations of maternal thyroid indices with infantile TSH level. Results: A total of 3,210 mothers and 2,991 newborns with valid TSH data were included for analysis. Multivariable linear regression indicated that maternal thyroid variables were significantly and positively associated with neonatal TSH levels with standardized coefficients of 0.085 for TSH, 0.102 for FT3, 0.100 for FT4, 0.076 for TSHI, 0.087 for TFQI, and 0.089 for TT4RI (all P < 0.001). Compared with the lowest quartile, the highest quartile of TSHI [odds ratio (OR) = 1.590, 95% CI: 0.928-2.724; Ptrend = 0.025], TFQI (OR = 1.746, 95% CI: 1.005-3.034; Ptrend = 0.016), and TT4RI (OR = 1.730, 95% CI: 1.021-2.934; Ptrend = 0.030) were significantly associated with an increased risk of elevated neonatal TSH (>5 mIU/L) in a dose-response manner. Conclusion: The longitudinal data demonstrated that maternal thyroid resistance indices and thyroid hormones in the first half of gestation were positively associated with neonatal TSH levels. The findings offered an additionally practical recommendation to improve the current screening algorithms for congenital hypothyroidism.

Higher S-adenosylhomocysteine and lower ratio of S-adenosylmethionine to S-adenosylhomocysteine were more closely associated with increased risk of subclinical atherosclerosis than homocysteine.

Aim: To examine the relationship of C1 metabolites of the methionine cycle with the risk of subclinical atherosclerosis (SA) in the Chinese population. Methods: A total of 2,991 participants aged 45-75 years old were included for data analyses based on the baseline data of the Guangzhou Nutrition and Health Cohort. Three core serum methionine metabolites including serum S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and homocysteine (Hcy) were measured by UPLC-MS/MS. SA was determined by B-mode ultrasound measured carotid intima-media thickness (CIMT) at the common artery and bifurcation segments. Multivariable logistic and linear regression models were performed to estimate the associations of C1 metabolites of the methionine cycle with SA risk or CIMT. Results: After controlling for potential cofounders and other C1 metabolites, in comparison with the lowest quartile, participants in the highest quartile had lower risk of SA by 27.6% (OR = 0.724; 95% CI:0.563-0.93, P trend = 0.007) for SAM and 32.2% (OR = 0.678; 95% CI:0.538-0.855, P trend < 0.001) for SAM/SAH, while increased SA risk by 27.9% (OR = 1.279; 95% CI: 1.065-1.535, P trend < 0.001) for SAH. No significant association was observed for Hcy with SA after further adjustment of SAH and SAM. The results of multivariable linear regression showed similar findings. The highest two standardized coefficients were observed for SAH (ß = 0.104 for CCA and 0.121 for BIF, P< 0.001) and SAM/SAH (ß = -0.071 for CCA and -0.084 for BIF, P< 0.001). Subgroup analyses suggested more evident associations of SAH with SA were observed in participants of higher cardiovascular risk profiles. Conclusion: Our cross-sectional data showed higher serum SAH, but lower SAM/SAH were independently associated with increased risk of SA among the Chinese middle-aged and elderly population.

Hepatoprotective effect of curcumin against bisphenol A-induced hepatic steatosis via modulating gut microbiota dysbiosis and related gut-liver axis activation in CD-1 mice.

Chronic exposure to low-dose bisphenol A (BPA) has become a global problem of public health. Our previous work showed that low-dose BPA exposure caused gut microbial dysbiosis and hepatic steatosis. Curcumin, a polyphenol extracted from turmeric, has an inhibitory effect on liver lipid accumulation, whether curcumin can alleviate BPA-induced hepatic steatosis through improving intestinal flora and modulating gut-liver axis remains to be elucidated. Male CD-1 mice were fed with BPA-contaminated diet supplemented with or not with curcumin for 24 weeks. Curcumin supplementation markedly ameliorated liver fat accumulation and hepatic steatosis induced by BPA. Gut microbiota analysis via 16S rRNA sequencing revealed that the relative abundance of Proteobacteria and Firmicutes/Bacteroidetes ratio were increased in BPA-fed mice, and this alteration was reversed by curcumin treatment. Akkermansia, which was recognized as a potential probiotic, was significantly reduced after BPA exposure and was restored to the control level with curcumin addition. Furthermore, curcumin supplementation reversed the down-regulation of intestinal tight junction protein expressions (zona occludens-1 and occludin), improved increased gut permeability, reduced serum lipopolysaccharide level and suppressed the activation of hepatic toll-like receptor 4 / nuclear factor-κB (TLR4/NF-κB) pathway induced by BPA. These results indicated that the protective effect of curcumin against hepatic steatosis induced by BPA and further revealed that its mechanism might be its prebiotic effect on maintaining intestinal flora homeostasis and improving intestinal barrier function, consequently reducing serum lipopolysaccharide-triggered inflammatory response in the liver. Our work provides evidence for curcumin as a potential nutritional therapy for BPA-mediated hepatic steatosis.

Gut Microbially Produced Indole-3-Propionic Acid Inhibits Atherosclerosis by Promoting Reverse Cholesterol Transport and Its Deficiency Is Causally Related to Atherosclerotic Cardiovascular Disease.

BACKGROUND: Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear. METHODS: We performed integrated microbiome-metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action. RESULTS: Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE-/- mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels. CONCLUSIONS: Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD.

Vascular benefits of vitamin C supplementation against fine particulate air pollution in healthy adults: A double-blind randomised crossover trial.

Evidence on the health benefits of vitamin C supplementation in highly polluted areas has not been evaluated. We aimed to evaluate whether dietary vitamin C supplementation can improve vascular health linked to particulate matter (PM) exposure. A randomised double-blind crossover trial involving 58 health young adults was performed in Shijiazhuang, China in 2018. All subjects were randomly assigned to the vitamin C supplementation group (2000 mg/d) or placebo group for a week alternating with a 2 week washout period. Fifteen circulating biomarkers were measured. Linear mixed-effect model was applied to evaluate the effect of vitamin C supplementation on health outcomes. The average concentrations of PM2.5 and PM10 were 164.91 and 327.05 µg/m3, respectively. Vitamin C supplementation was significantly associated with a 19.47% decrease in interleukin-6 (IL-6), 17.30% decrease in tumour necrosis factor-a (TNF-α), 34.01% decrease in C-reactive protein (CRP), 3.37% decrease in systolic blood pressure (SBP) and 6.03% decrease in pulse pressure (PP). Furthermore, glutathione peroxidase (GSH-Px) was significantly increased by 7.15%. Sex-subgroup analysis showed that vitamin C significantly reduced TNF-α by 27.85% in male participants and significantly increased APOB by 6.28% and GSH-Px by 14.47% only in female participants. This study indicated that vitamin C supplementation may protect vascular vessels against PM exposure among healthy young adults in China.

Inhibition of S-adenosylhomocysteine hydrolase induces endothelial senescence via hTERT downregulation.

BACKGROUND AND AIMS: It has been established that endothelial senescence plays a critical role in the development of atherosclerosis. Elevated S-adenosylhomocysteine (SAH) level induced by inhibition of S-adenosylhomocysteine hydrolase (SAHH) is one of the risk factors of atherosclerosis; however, the interplay between endothelial senescence and inhibition of SAHH is largely unknown. METHODS: Human umbilical vein endothelial cells (HUVECs) after serial passage were used. SAHH-specific inhibitor adenosine dialdehyde (ADA) and SAHH siRNA treated HUVECs and SAHH+/-mice were used to investigate the effect of SAHH inhibition on endothelial senescence. RESULTS: HUVECs exhibited distinct senescence morphology as HUVECs were passaged, together with a decrease in intracellular SAHH expression and an increase in intracellular SAH levels. SAHH inhibition by ADA or SAHH siRNA elevated SA ß-gal activity, arrested proliferation, and increased the expression of p16, p21 and p53 in HUVECs and the aortas of mice. In addition, decreased expression of hTERT and reduced occupancy of H3K4me3 over the hTERT promoter region were observed following SAHH inhibition treatment. To further verify the role of hTERT in the endothelial senescence induced by SAHH inhibition, hTERT was overexpressed with a plasmid vector under CMV promoter. hTERT overexpression rescued the senescence phenotypes in endothelial cells induced by SAHH inhibition. CONCLUSIONS: SAHH inhibition induces endothelial senescence via downregulation of hTERT expression, which is associated with attenuated histone methylation over the hTERT promoter region.

Cyanidin-3-O-ß-Glucoside Attenuates Platelet Chemokines and Their Receptors in Atherosclerotic Inflammation of ApoE-/- Mice.

Platelet chemokines play well-established roles in the atherosclerotic inflammation. Cyanidin-3-O-ß-glucoside (Cy-3-g) is one of the main bioactive compounds in anthocyanins, but its effects on chemokines during atherosclerosis have not been determined yet. In the present study, ApoE-/- mice were fed on the chow diet, high-fat diet (HFD), and HFD-supplemented Cy-3-g at 200, 400, and 800 mg/kg diet. After 16 weeks, Cy-3-g significantly alleviated the atherosclerotic lesion and inhibited platelet aggregation and activation. Moreover, Cy-3-g significantly reduced inflammatory chemokines CXCL4, CXCL7, CCL5, CXCL5, CXCL12, and CCL2 in plasma and downregulated CXCR4, CXCR7, and CCR5 on platelets and peripheral blood mononuclear cells. Besides, Cy-3-g decreased the mRNA of TNFα, IFNγ, ICAM-1, VCAM-1, CD68, MMP7, CCL5, CXCR4, and CCR5 in the aorta of mice. Therefore, it suggests that Cy-3-g plays important preventive roles in the process of atherosclerosis via attenuating chemokines and receptors in ApoE-/- mice.

Coenzyme Q10 supplementation improves cholesterol efflux capacity and antiinflammatory properties of high-density lipoprotein in Chinese adults with dyslipidemia.

OBJECTIVES: Coenzyme Q10 (CoQ10) had shown promising effects in improving the lipid and glycemic profile in dyslipidemic individuals in our previous work, but little is known about how it affects high-density lipoprotein (HDL) function in patients with dyslipidemia. The aim of this study was to explore the effects of CoQ10 supplementation on HDL function in people with dyslipidemia. METHODS: A 24-wk, randomized, double-blind, placebo-controlled trial was conducted in 101 people with dyslipidemia. All patients were randomized into the CoQ10 group (120 mg/d, n = 51) or the placebo group (n = 50). High-density lipoprotein-mediated cholesterol efflux capacity (CEC), HDL inflammatory index (HII), and HDL intrinsic oxidation were measured at baseline, 12 wk, and 24 wk. RESULTS: CoQ10 supplementation for 24 wk significantly improved HDL-mediated CEC (mean change, 1.21±2.44 versus -0.12±2.94; P = 0.014) and reduced HII (mean change, -0.32±0.58 versus -0.05±0.49, P = 0.014) compared with placebo. However, there was no significant difference in the effect of CoQ10 on HDL intrinsic oxidation between the two groups after 24 wk (P = 0.290). A positive correlation was found between the changes in CEC and HDL cholesterol in the CoQ10 group (r, 0.30; P = 0.032). Furthermore, we also found that the improved HDL functions were more obvious in elderly, female, or non-obese individuals, which indicated a specific population that benefits most from CoQ10 intervention. CONCLUSIONS: This study suggested that supplementation of CoQ10 for 24 wk can significantly improve HDL-mediated CEC and antiinflammatory function of HDL in patients with dyslipidemia.

Associations between plasma tryptophan and indole-3-propionic acid levels and mortality in patients with coronary artery disease.

BACKGROUND: Indole-3-propionic acid (IPA), a microbiota-produced tryptophan metabolite, has been shown to exhibit cardioprotective effects in animal models. However, the relation of IPA with cardiovascular risk in humans is currently unknown. OBJECTIVES: This prospective study aimed to investigate whether plasma tryptophan and IPA levels are associated with decreased risks of mortality. METHODS: Ultra-HPLC-MS/MS was used to measure plasma tryptophan and IPA levels in 1829 patients with coronary artery disease (CAD). Cox proportional hazards regression models were used to estimate the associations between tryptophan and IPA levels and the risks of cardiovascular and all-cause mortality. RESULTS: During the median 9.2-year follow-up, 424 all-cause deaths occurred, of which 272 were cardiovascular deaths. Plasma tryptophan and IPA levels were significantly associated with reduced risks of cardiovascular and all-cause mortality. Patients with CAD with the highest quartiles of tryptophan and IPA levels had multivariable-adjusted HRs of 0.62 (95% CI, 0.43-0.89) and 0.71 (95% CI, 0.50-0.99), respectively, for cardiovascular mortality and 0.67 (95% CI, 0.50-0.90) and 0.75 (95% CI, 0.57-0.99), respectively, for all-cause mortality compared with those in patients with CAD in the lowest quartile. After multivariable adjustments, 1-SD increases in the continuous plasma tryptophan and IPA levels were associated with 16% and 14% decreases, respectively, in the risks of cardiovascular mortality and with 13% and 14% decreases, respectively, in the risks of all-cause mortality. Restricted cubic splines displayed linear associations between plasma tryptophan and IPA levels and cardiovascular and all-cause mortality among patients with CAD. CONCLUSIONS: Our findings suggest that plasma tryptophan and IPA levels are significantly associated with decreased risks of cardiovascular and all-cause mortality in patients with CAD. Further studies are needed to determine the clinical diagnostic and therapeutic values of tryptophan and IPA levels on the risks of mortality among patients with CAD.