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.

Relationship between family function, self-perceived burden and loneliness in patients with type 2 diabetes mellitus: a cross-lagged analysis.

AIMS: To explore the inter-predictive role and causal relationship between family functioning, self-perceived burden and loneliness in people with type 2 diabetes. METHODS: In this study, patients with type 2 diabetes admitted to two tertiary care hospitals in China were selected for an 8-month follow-up, and the patients' scores on the Family Functioning, Self-perceived Burden, and Loneliness scales were measured repeatedly at three time periods: during hospitalisation (T1), 1 month after discharge (T2), and 3 months after discharge (T3). RESULTS: The results showed that family function at the T1 time point had a negative predictive effect on self-perceived burden at the T2 time point, ß = - 0.43, P = 0.005. Loneliness at the T1 time point had a positive predictive effect on self-perceived burden at the T2 time point, ß = 0.08, P = 0.021. Unlike the pathway at time point T1, family functioning at time point T2 negatively predicted loneliness at time point T3, ß = - 0.32, P = 0.013. Loneliness at time point T2 positively predicted family functioning at time point T3, ß = 0.025, P = 0.013. Loneliness at time point T2 negatively predicted self-perceived burden at time point T3 (P = 0.011). CONCLUSIONS: The results of the cross-lagged analysis show that there is a mutually predictive and moderating relationship between family functioning and loneliness in patients with type 2 diabetes. Loneliness can predict the level of self-perceived burden at the next time point.

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.

Associations of Macronutrients Intake With MRI-determined Hepatic Fat Content, Hepatic Fibroinflammation, and NAFLD.

CONTEXT: A healthy lifestyle is the cornerstone of management in nonalcoholic fatty liver disease (NAFLD). However, the associations between dietary macronutrient composition and different aspects of NAFLD pathology are unclear and dietary recommendations for NAFLD are lacking. OBJECTIVE: This work aimed to evaluate the associations of dietary macronutrient composition with hepatic steatosis, hepatic fibroinflammation, and NAFLD. METHODS: In this cross-sectional study, a total of 12 620 UK Biobank participants who completed both the dietary questionnaire and magnetic resonance imaging (MRI) examination were included in this study. Dietary consumption of macronutrient was self-reported and calculated. MRI-determined hepatic fat content, fibroinflammation, and NAFLD were estimated. RESULTS: First, we found that saturated fatty acid (SFA) intake was associated with higher hepatic steatosis, fibroinflammation, and NAFLD prevalence. In contrast, higher fiber or protein intake was reversely correlated with hepatic steatosis and fibroinflammation. Interestingly, starch or sugar intake was significantly associated with hepatic fibroinflammation, whereas monounsaturated fatty acid (MUFA) intake was negatively correlated with hepatic fibroinflammation. Isocaloric analysis revealed that replacing SFA with sugar, fiber, or protein was significantly associated with a reduction in hepatic steatosis, while replacing starch, sugar, or SFA with protein or MUFA was significantly correlated with a decrease in hepatic fibroinflammation. CONCLUSION: Overall, our results demonstrate that specific macronutrients are associated with different aspects of NAFLD, and specific dietary compositions should be recommended for distinct NAFLD-risk populations.

Identification of factors associated with fear of hypoglycemia using the capability, opportunity, motivation and behavior model in people with type 2 diabetes mellitus: a cross-sectional study.

AIMS: To examined the relationship between fear of hypoglycemia and certain variables in people with type 2 diabetes mellitus (T2DM) based on the Capability, Opportunity, Motivation, and Behavior model, combined with the context unique to people with diabetes to provide a basis for developing targeted nursing interventions. METHODS: In this cross-sectional study, 212 people with T2DM were recruited from February 2021 to July 2021. Data were collected using the Hypoglycaemia Fear Survey, Gold score, Patient Assessment of Chronic Illness Care (PACIC) scale and Diabetic Self-Management Attitudes Scale. Multiple linear regression analysis was performed to determine the predictors of fear of hypoglycemia using SPSS 26.0. RESULTS: The mean fear of hypoglycemia score was 74.88 ± 18.28 (range: 37.00-132.00). In people with T2DM, the frequency of blood glucose monitoring, the frequency of hypoglycemia in the past half-year, degree of understanding of hypoglycemia, impaired awareness of hypoglycemia, PACIC, and self-management attitude of diabetes were the influencing factors of fear of hypoglycemia (adjusted R2 = 0.560, F[21,190] = 13.800, P < 0.001). These variables explained 56.0% of the variance in the fear of hypoglycemia. CONCLUSIONS: The level of fear of hypoglycemia in people with T2DM was relatively high. In addition to paying attention to the disease characteristics of people with T2DM, medical staff should also pay attention to patients' own perception and handling ability of disease and hypoglycemia, attitude toward self-management behavior and external environment support, all of which have a positive effect on improving the fear of hypoglycemia in people with T2DM, optimizing the self-management level and improving quality of life.

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.

Prevalence and contributing factors of impaired awareness of hypoglycemia in patients with type 2 diabetes: a meta-analysis.

AIMS: To conduct a systematic review to summarize the definition, measurement tools, prevalence, and contributing factors of impaired awareness of hypoglycemia (IAH) in type 2 diabetes mellitus (T2DM). METHODS: A reproducible search strategy was used to identify factors affecting IAH in T2DM in PubMed, MEDLINE, EMBASE, Cochrane, PsycINFO, and CINAHL from inception until 2022. Literature screening, quality evaluation, and information extraction were performed independently by 2 investigators. A meta-analysis of prevalence was performed using Stata 17.0. RESULTS: The pooled prevalence of IAH in patients with T2DM was 22% (95%CI:14-29%). Measurement tools included the Gold score, Clarke's questionnaire, and the Pedersen-Bjergaard scale. IAH in T2DM was associated with sociodemographic factors (age, BMI, ethnicity, marital status, education level, and type of pharmacy patients visited), clinical disease factors (disease duration, HbAlc, complications, insulin therapy regimen, sulfonylureas use, and the frequency and severity of hypoglycemia), and behavior and lifestyle (smoking and medication adherence). CONCLUSION: The study found a high prevalence of IAH in T2DM, with an increased risk of severe hypoglycemia, suggesting that medical workers should take targeted measures to address sociodemographic factors, clinical disease, and behavior and lifestyle to reduce IAH in T2DM and thus reduce hypoglycemia in patients.

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).

Association of MAFLD with end-stage kidney disease: a prospective study of 337,783 UK Biobank participants.

INTRODUCTION: Metabolic dysfunction-associated fatty liver (MAFLD) has been found to be associated with the prevalence of chronic kidney disease (CKD). However, it is unknown whether MAFLD is associated with CKD development and the incidence of end-stage kidney disease (ESKD). We aimed to clarify the association between MAFLD and incident ESKD in the prospective UK Biobank cohort. METHODS: We analyzed the data of 337,783 UK Biobank participants and relative risks for the ESKD were calculated by using the Cox regression analysis. RESULTS: Among 337,783 participants over a median duration of 12.8 years follow-up, a total of 618 ESKD cases were diagnosed. Participants with MAFLD were twice likely to develop ESKD (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.68-2.46, p < 0.001). The association of MAFLD with ESKD risk remained significant in both non-CKD and CKD participants. Our results also showed that there were graded associations between liver fibrosis scores and the risk of ESKD in MAFLD cases. Compared to non-MAFLD individuals, the adjusted HRs for incident ESKD in MAFLD patients with increasing levels of NAFLD fibrosis score were 1.23 (95% CI 0.96-1.58), 2.45 (1.98-3.03) and 7.67 (5.48-10.73), respectively. Furthermore, the risking alleles of PNPLA3 rs738409, TM6SF2 rs58542926, GCKR rs1260326 and MBOAT7 rs641738 amplified the MAFLD effect on ESKD risk. In conclusion, MAFLD is associated with incident ESKD. CONCLUSION: MAFLD may help identify the subjects at high risk of ESKD development and MAFLD interventions should be encouraged to slow down CKD progression.

The impact of spouse health on social participation of older adults in China: Evidence from the CLHLS.

BACKGROUND: China is dealing with a serious aging issue. Social participation is essential for active aging. The health status of spouses is intertwined with the trajectory of the social function of the elderly. OBJECTIVES: This study examined the association between spouse health and social participation among older Chinese adults. The study also explored the mediating role of loneliness and anxiety between spousal health and social participation. METHODS: The analytic sample included 6125 adults aged 60 years and above. Prospective data were obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). First, we described basic socio-demographic information about the sample. Secondly, Spearman's correlation analysis was used to determine whether correlations existed between spousal health, loneliness, anxiety, and social participation. Finally, mediation analysis was run using the SPSS macro PROCESS program. RESULTS: Spousal health, loneliness, anxiety, and social participation were significantly correlated (P < 0.01). Spousal health could not only have a direct positive impact on social participation in older adults (ß = 0.239, 95 % CI: 0.120, 0.359), but also indirectly on social participation through three pathways: an independent mediating effect of loneliness (ß = 0.020, 95 % CI: 0.009, 0.034), an independent mediating effect of anxiety (ß = 0.018, 95%CI: 0.009, 0.032), and a chain mediating effect of loneliness and anxiety (ß = 0.004, 95%CI: 0.002, 0.007). CONCLUSION: This study suggests paying more attention to elderly couples and decreasing the negative consequences of changes in spousal health.

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.

Association between distinct body mass index trajectories according to the group-based trajectory modeling and the risk of incident diabetes: A systematic review.

We aimed to determine the association between distinct body mass index (BMI) trajectories, using group-based trajectory modeling, and the subsequent risk of incident diabetes. Five databases were systematically searched. Fourteen population-based cohort studies that summarized the association between different BMI trajectories and subsequent diabetes, with the four most common BMI trajectories including the "stable," "increasing," "decreasing," and "turning" groups, were included. The rapid increase and stable high-level BMI groups showed the strongest association with the subsequent risk of diabetes compared with the stable normal BMI group. Increased baseline BMI levels resulted in a steeper slope and greater risk of subsequent diabetes. In the decreasing BMI group, one study reported that those aged >50 years showed the highest incidence of subsequent diabetes, whereas the other two studies reported no association between these two variables. In the turning group, an increase followed by a decrease in BMI levels from adolescence to late adulthood could reduce the risk of developing diabetes, although the residual risk remained. By contrast, the incidence of subsequent diabetes remained high in the middle-aged BMI-turning group. This study can provide further insights for identifying populations at high risk of diabetes and for developing targeted prevention strategies.

Identification of Potential Prognostic Biomarkers Associated with Monocyte Infiltration in Lung Squamous Cell Carcinoma.

The five-year survival rate of lung squamous cell carcinoma is significantly lower than that of other cancer types. It is therefore urgent to discover novel prognosis biomarkers and therapeutic targets and understand their correction with infiltrating immune cells to improve the prognosis of patients with lung squamous cell carcinoma. In this study, we employed robust rank aggregation algorithms to overcome the shortcomings of small sizes and potential bias in each Gene Expression Omnibus dataset of lung squamous cell carcinoma and identified 513 robust differentially expressed genes including 220 upregulated and 293 downregulated genes from six microarray datasets. Functional enrichment analysis showed that these robust differentially expressed genes were obviously involved in the extracellular matrix and structure organization, epidermis development, cell adhesion molecule binding, p53 signaling pathway, and interleukin-17 signaling pathway to affect the progress of lung squamous cell carcinoma. We further identified six hub genes from 513 robust differentially expressed genes by protein-protein interaction network and 10 topological analyses. Moreover, the results of immune cell infiltration analysis from six integrated Gene Expression Omnibus datasets and our sequencing transcriptome data demonstrated that the abundance of monocytes was significantly lower in lung squamous cell carcinoma compared to controls. Immune correlation analysis and survival analysis of hub genes suggested that three hub genes, collagen alpha-1(VII) chain, mesothelin, and chordin-like protein 1, significantly correlated with tumor-infiltrating monocytes as well as may be potential prognostic biomarkers and therapy targets in lung squamous cell carcinoma. The investigation of the correlation of hub gene markers and infiltrating monocytes can also improve to well understand the molecular mechanisms of lung squamous cell carcinoma development.

Global burden of nonalcoholic steatohepatitis-related liver cancer, 1990-2019: a systematic analysis for the GBD 2019.

With the pandemic of metabolic diseases, nonalcoholic fatty liver disease (NAFLD) prevalence has dramatically elevated. NAFLD encompasses a spectrum of diseases including simple steatosis and nonalcoholic steatohepatitis (NASH), which can further progress to cirrhosis or liver cancer (LC). However, data are lacking on the burden and trend of NASH-related LC. Here, we analyzed the trends and changes of NASH-related LC burden using Global Burden of Disease (GBD) data (1990-2019). In 2019, the global incidence, prevalence, disability-adjusted life years (DALYs) and deaths of NASH related LC were 36.3 thousand (95% UI 29.5-44.9), 46.8 thousand (38.2-57.6), 796 thousand (657-976) and 34.7 thousand (28.4-43.2), respectively. The absolute numbers and rates of NASH-related LC incidence, mortality, and DALY significantly elevated from 1990 to 2019. With the age increased, the incidences, DALYs and deaths of NASH-related LC significantly elevated. The incidence and mortality rate of NASH-related LC significantly increased from 2010 to 2019 in individuals aged from 20 to 54 and older than 55 years old. We also found that a large disparity of NASH-related LC burden in different socio-demographic index (SDI) locations. The crude number and the age-standardized rate of incidences, DALYs and deaths was highest in the middle SDI locations and high SDI locations showed the largest increase of NASH-related LC burden from 1990 to 2019. Moreover, the proportion of LC incidences, deaths and DALYs attributed to NASH were 4.74%, 5.30% and 4.25%, respectively in 1990 which were increased by 43.5%, 35.3% and 49.4%, respectively in 2019. Conclusion: The global burden of NASH-related LC and the proportion LC burden attributed to NASH are significantly increasing.

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.

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.

Liraglutide stimulates the ß-catenin signaling cascade in mouse epididymal fat tissue.

Although canonical Wnt signaling pathway activation was shown to negatively regulate adipogenesis, recent investigations suggest that Wnt pathway effectors TCF7L2 and ß-catenin (ß-cat) in adipose tissues are also involved in energy homeostasis during adulthood. In assessing the metabolic beneficial effect of GLP-1-based diabetes drugs in high-fat diet (HFD)-challenged mice, we observed that liraglutide treatment affected the expression of a battery of adipose tissue-specific genes, including those that encode adiponectin and leptin, mainly in epididymal white adipose tissue (eWAT). Fourteen-week HFD challenge repressed TCF7L2 and ß-cat S675 phosphorylation in eWAT, while such repression was reversed by liraglutide treatment (150 µg/kg body weight daily) during weeks 10-14. In Glp1r-/-mice, liraglutide failed in stimulating TCF7L2 or ß-cat in eWAT. We detected Glp1r expression in mouse eWAT and its level is enriched in its stromal vascular fraction (SVF). Mouse eWAT-SVF showed reduced expression of Tcf7l2 and its Tcf7l2 level could not be stimulated by liraglutide treatment; while following adipogenic differentiation, rat eWAT-SVF showed elevated Tcf7l2 expression. Direct in vitro liraglutide treatment in eWAT-SVF stimulated CREB S133, ß-cat S675 phosphorylation, and cellular cAMP level. Thus, cAMP/ß-cat signaling cascade can be stimulated by liraglutide in eWAT via GLP-1R expressed in eWAT-SVF.

Comparison of Beneficial Metabolic Effects of Liraglutide and Semaglutide in Male C57BL/6J Mice.

OBJECTIVES: Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions. METHODS: Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 µg/kg body weight); or semaglutide (12 µg/kg body weight, low dose [LD]; or 60 µg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized. RESULTS: HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice. CONCLUSIONS: Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.