Dynamic Changes in Gut Microbiota-Derived Metabolite Trimethylamine-N-Oxide and Risk of Type 2 Diabetes Mellitus: Potential for Dietary Changes in Diabetes Prevention.

BACKGROUND: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. METHODS: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. RESULTS: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). CONCLUSION: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.

Non-linear associations of serum spermidine with type 2 diabetes mellitus and fasting plasma glucose: a cross-sectional study.

Background: Previous animal experiments have demonstrated the potential of spermidine to mitigate glucose intolerance, insulin resistance, and hyperinsulinemia. However, there remains a scarcity of epidemiological evidence supporting these findings. Therefore, we aimed to elucidate the associations of serum spermidine with T2DM and FPG. Materials and methods: The cross-sectional study was conducted from June to August 2019 in the rural areas of Fuxin County, Liaoning Province, China. A total of 4,437 participants were included in the study. The serum spermidine was detected using high-performance liquid chromatography with a fluorescence detector. FPG was measured using the hexokinase method. T2DM was defined as participants with a FPG level of 7.0 mmol/L or greater, or self-reported diagnosis of diabetes by a doctor. Restricted cubic spline model and piecewise linear regression model were used to explore the associations of serum spermidine with T2DM and FPG, respectively. Results: The mean (SD) age of the participants was 59.3 (10.0) years, with 622 out of 4,437 participants being defined as T2DM. The serum spermidine in participants stratified by age and BMI categories was significantly different, with p values of 0.006 and 0.001, respectively. Among all the participants, the association of serum spermidine with T2DM was J-shaped. The log (spermidine) was negatively associated with T2DM (OR = 0.68, 95% CI: 0.52 to 0.92, p = 0.01) below the inflection point, while log (spermidine) was not significantly associated with T2DM (OR = 1.97, 95% CI: 0.93 to 4.15, p = 0.07) above the inflection point. Among the participants without T2DM, the association of serum spermidine with FPG was inverted J-shaped. The log (spermidine) was positively associated with FPG (ß = 0.13, 95% CI: 0.05 to 0.21, p = 0.001) below the inflection point, while log (spermidine) was negatively associated with FPG (ß = -0.29, 95% CI: -0.42 to -0.16, p < 0.001) above the inflection point. Conclusion: In conclusion, non-linear associations of serum spermidine with T2DM and FPG were found in the cross-sectional study in Chinese rural adults. This provided insights into the use of spermidine for the prevention of T2DM, highlighting the potential role in public health prevention strategies of spermidine.

Dapagliflozin promotes browning of white adipose tissue through the FGFR1-LKB1-AMPK signaling pathway.

BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.

Degradation and fermentation of hyaluronic acid by Bacteroides spp. from the human gut microbiota.

Bacteroides spp. are prominent members of the human gut microbiota that play critical roles in the metabolism of complex carbohydrates from the daily diet. Hyaluronic acid (HA) is a multifunctional polysaccharide which has been extensively used in the food and biomedical industry. However, how HA is degraded and fermented by Bacteroides spp. has not been fully characterized. Here, we comprehensively investigated the detailed degradation profiles and fermentation characteristics of four different HAs with discrete molecular weight (Mw) by fourteen distinctive Bacteroides spp. from the human gut microbiota. Our results indicated that high-Mw HAs were more degradable and fermentable than low-Mw HAs. Interestingly, B. salyersiae showed the best degrading capability for both high-Mw and low-Mw HAs, making it a keystone species for HA degradation among Bacteroides spp.. Specifically, HA degradation by B. salyersiae produced significant amounts of unsaturated tetrasaccharide (udp4). Co-culture experiments indicated that the produced udp4 could be further fermented and utilized by non-proficient HA-degraders, suggesting a possible cross-feeding interaction in the utilization of HA within the Bacteroides spp.. Altogether, our study provides novel insights into the metabolism of HA by the human gut microbiota, which has considerable implications for the development of new HA-based nutraceuticals and medicines.

Bacteroides salyersiae is a potent chondroitin sulfate-degrading species in the human gut microbiota.

Chondroitin sulfate (CS) has widely been used as a symptomatic slow-acting drug or a dietary supplement for the treatment and prevention of osteoarthritis. However, CS could not be absorbed after oral intake due to its polyanionic nature and large molecular weight. Gut microbiota has recently been proposed to play a pivotal role in the metabolism of drugs and nutrients. Nonetheless, how CS is degraded by the human gut microbiota has not been fully characterized. In the present study, we demonstrated that each human gut microbiota was characterized with a unique capability for CS degradation. Degradation and fermentation of CS by the human gut microbiota produced significant amounts of unsaturated CS oligosaccharides (CSOSs) and short-chain fatty acids. To uncover which microbes were responsible for CS degradation, we isolated a total of 586 bacterial strains with a potential CS-degrading capability from 23 human fecal samples. Bacteroides salyersiae was a potent species for CS degradation in the human gut microbiota and produced the highest amount of CSOSs as compared to other well-recognized CS-degraders, including Bacteroides finegoldii, Bacteroides thetaiotaomicron, Bacteroides xylanisolvens, and Bacteroides ovatus. Genomic analysis suggested that B. salyersiae was armed with multiple carbohydrate-active enzymes that could potentially degrade CS into CSOSs. By using a spent medium assay, we further demonstrated that the unsaturated tetrasaccharide (udp4) produced by the primary degrader B. salyersiae could serve as a "public goods" molecule for the growth of Bacteroides stercoris, a secondary CS-degrader that was proficient at fermenting CSOSs but not CS. Taken together, our study provides insights into the metabolism of CS by the human gut microbiota, which has promising implications for the development of medical and nutritional therapies for osteoarthritis. Video Abstract.

Polyguluronate alleviates ulcerative colitis by targeting the gut commensal Lactobacillus murinus and its anti-inflammatory metabolites.

Polyguluronate (PG) is a fermentable polysaccharide from edible algae. The present study was designed to investigate the therapeutic effect of PG on ulcerative colitis (UC) and its underlying mechanisms. Our results suggest that oral intake of PG attenuates UC and improves gut microbiota dysbiosis by promoting the growth of Lactobacillus spp. in dextran sulfate sodium-fed mice. Five different species of Lactobacillus were isolated from the feces of PG-treated mice and L. murinus was identified to have the best anti-colitis effect, suggesting a critical role for L. murinus in mediating the therapeutic effect of PG. Furthermore, PG was degraded potentially by the beta-glucuronidase from L. murinus and adding PG to the culture medium of L. murinus remarkably increased its production of anti-inflammatory metabolites, including itaconic acid, cis-11,14-eicosadienoic acid, and 3-amino-3-(2-chlorophenyl)-propionic acid. Additionally, L. salivarius, a human intestine-derived PG-utilizing species that is closely related to L. murinus, was also demonstrated to have potent anti-colitis effects, suggesting that it is a candidate target of PG in the human gut. Altogether, our study illustrates an unprecedented application of PG in the treatment of UC and establishes the basis for understanding its therapeutic effect from the perspective of L. murinus and its metabolites.

Sex-modified association between grip strength and mild cognitive impairment: a cross-sectional and follow-up study in rural China.

BACKGROUND: The sex difference in the association between grip strength and mild cognitive impairment (MCI) remains controversial and unclear. METHODS: This is a part of a chronic disease cohort study conducted in rural areas, Fuxin, Liaoning Province, China. At the baseline survey, a total of 2633 participants aged 35- 85 were included in the cross-sectional study. Handgrip strength (HGS, kg) was measured by a dynamometer (Jamar +). MCI were assessed using the Chinese version of the Montreal Cognitive Assessment-Basic (MOCA-BC). Then, a total of 1667 cognitively normal individuals (NCs) were planed to follow up and to assess the incident MCI after two years. We used logistic regression to examine the association between HGS (as a continuous variable and quintiles) and MCI and analyzed the interaction between sex and HGS on MCI. Models stratified by sex were adjusted for demographic information (age, ethnicity, education, marital status, income, physical labor level), modifiable risk factors (body mass index, smoking, drinking) and disease history (hypertension, diabetes, dyslipidemia and coronary heart disease). Baseline MOCA-BC scores were additionally adjusted in the longitudinal study. RESULTS: In the cross-sectional study, participants were on average 56.6 ± 9.8 years, and 1713 (65.1%) were females. In the cohort study, 743 individuals were followed up with an average age of 55.9 ± 9.6 years, which included 530 (71.3%) females. The cumulative incidence of MCI over a two-year period was 17.1%. In the cross-sectional study, compared to the highest quintile of HGS, the lowest HGS was associated with higher risk of MCI in males (odds ratio [OR]: 2.66; 95% confidence interval [CI]: 1.54, 4.64) and females (OR: 1.70; 95% CI: 1.17, 2.49) with adjustment of potential confounding factors. In the cohort study, compared to the highest quintile of HGS, the lowest HGS was associated with an increased risk of incident MCI in females (OR: 3.93; 95% CI: 1.39, 13.01) but not in males (OR: 0.56; 95% CI: 0.11, 2.94, P for interaction = 0.015). CONCLUSIONS: Lower grip strength is a risk factor for mild cognitive impairment and predicts a higher risk of MCI in females.

In Vitro Fermentation of Polysaccharide from Edible Alga Enteromorpha clathrata by the Gut Microbiota of Patients with Ulcerative Colitis.

Dietary intake of the sulfated polysaccharide from edible alga E. clathrata (ECP) has recently been illustrated to attenuate ulcerative colitis (UC) by targeting gut dysbiosis in mice. However, ECP is not easily absorbed in the gut and, as a potential candidate for next-generation prebiotics development, how it is fermented by human gut microbiota has not been characterized. Here, using in vitro anaerobic fermentation and 16S high-throughput sequencing, we illustrate for the first time the detailed fermentation characteristics of ECP by the gut microbiota of nine UC patients. Our results indicated that, compared to that of glucose, fermentation of ECP by human gut microbiota produced a higher amount of anti-inflammatory acetate and a lower amount of pro-inflammatory lactate. Additionally, ECP fermentation helped to shape a more balanced microbiota composition with increased species richness and diversity. Moreover, ECP significantly stimulated the growth of anti-colitis bacteria in the human gut, including Bacteroides thetaiotaomicron, Bacteroides ovatus, Blautia spp., Bacteroides uniformis, and Parabacteroides spp. Altogether, our study provides the first evidence for the prebiotic effect of ECP on human gut microbiota and sheds new light on the development of ECP as a novel prebiotic candidate for the prevention and potential treatment of UC.

Association between handgrip strength asymmetry and cognitive function across ethnicity in rural China: a cross-sectional study.

Background: Recently, the association between handgrip strength (HGS) asymmetry and cognition has been revealed, but evidences are still scarce. Particularly, the association between asymmetric HGS and cognitive performance in various cognitive domains is unclear and whether this association is stable across ethnic groups is unknown. Method: The population was from a longitudinal study in rural areas of Fuxin, Liaoning, China. The Chinese version of Montreal Cognitive Assessment-Basic (MOCA-BC) was used to evaluate the cognitive function. The HGS ratio was calculated as maximal non-dominant HGS divided by maximal dominant HGS. HGS ratio <0.9 or >1.1 was classified as asymmetric dominant/non-dominant HGS, respectively. Generalized linear models were used to analyze the relationship between asymmetric HGS and cognitive function adjusted for HGS, handedness, wave, age, sex, education, ethnicity, smoking, drinking, physical labor level, BMI, hypertension, diabetes and dyslipidemia. Result: A total of 2,969 participants ≥50 years were included in this study. Adjusted for HGS and other confunding variables, there was an inverted U-shaped association between HGS ratio and MoCA-BC scores (P non-linear = 0.004). The association between HGS ratio and MoCA-BC scores was inconsistent among ethnic groups (P interaction = 0.048). In Han, only asymmetric non-dominant HGS was associated with lower cognitive scores [ß = -0.67, 95% confidence interval (CI): -1.26 ∼-0.08, P = 0.027]; in Mongolians, asymmetric dominant HGS(ß = -0.60, 95% CI: -1.35 ∼ 0.15, P = 0.115) and asymmetric non-dominant HGS (ß = -0.56, 95% CI: -1.42 ∼ 0.31, P = 0.206) were all associated with lower cognitive scores, although no statistical significance was found. Asymmetric non-dominant HGS and lower HGS, but not asymmetric dominant HGS were all independently associated with impairment of Delayed Recall (OR = 1.35, 95% CI: 1.05 ∼ 1.74; OR per 5 kg decrease = 1.10, 95% CI: 1.01 ∼ 1.21) and Fluency (OR = 1.43, 95% CI: 1.15 ∼ 1.78; OR per 5 kg decrease = 1.10, 95% CI: 1.02 ∼ 1.19). Both asymmetric dominant HGS (OR = 1.34, 95% CI: 1.07 ∼ 1.67) and lower HGS (OR per 5 kg decrease = 1.21, 95% CI: 1.10 ∼ 1.32) were associated with impairment of visuoperception. Conclusion: HGS and HGS asymmetry were all independently related to lower global cognitive performance. The association between HGS asymmetry and cognitive function varies among ethnic groups.

Isolation of Alginate-Degrading Bacteria from the Human Gut Microbiota and Discovery of Bacteroides xylanisolvens AY11-1 as a Novel Anti-Colitis Probiotic Bacterium.

Alginate has been documented to prevent the development and progression of ulcerative colitis by modulating the gut microbiota. However, the bacterium that may mediate the anti-colitis effect of alginate has not been fully characterized. We hypothesized that alginate-degrading bacteria might play a role here since these bacteria could utilize alginate as a carbon source. To test this hypothesis, we isolated 296 strains of alginate-degrading bacteria from the human gut. Bacteroides xylanisolvens AY11-1 was observed to have the best capability for alginate degradation. The degradation and fermentation of alginate by B. xylanisolvens AY11-1 produced significant amounts of oligosaccharides and short-chain fatty acids. Further studies indicated that B. xylanisolvens AY11-1 could alleviate body weight loss and contraction of colon length, reduce the incidences of bleeding and attenuate mucosal damage in dextran sulfate sodium (DSS)-fed mice. Mechanistically, B. xylanisolvens AY11-1 improved gut dysbiosis and promoted the growth of probiotic bacteria, including Blautia spp. And Prevotellaceae UCG-001, in diseased mice. Additionally, B. xylanisolvens AY11-1 showed no oral toxicity and was well-tolerated in male and female mice. Altogether, we illustrate for the first time an anti-colitis effect of the alginate-degrading bacterium B. xylanisolvens AY11-1. Our study paves the way for the development of B. xylanisolvens AY11-1 as a next-generation probiotic bacterium.

Polysaccharide from Edible Alga Enteromorpha clathrata Improves Ulcerative Colitis in Association with Increased Abundance of Parabacteroides spp. in the Gut Microbiota of Dextran Sulfate Sodium-Fed Mice.

Polysaccharide from the edible alga Enteromorpha clathrata has been demonstrated to exert beneficial effects on human health. However, what effect it has on inflammatory bowel diseases has not been investigated. Here, using a mouse model of dextran sulfate sodium (DSS)-induced ulcerative colitis, we illustrate that Enteromorpha clathrata polysaccharide (ECP) could alleviate body weight loss, reduce incidences of colonic bleeding, improve stool consistency and ameliorate mucosal damage in diseased mice. 16S rRNA high-throughput sequencing and bioinformatic analysis indicated that ECP significantly changed the structure of the gut microbiota and increased the abundance of Parabacteroides spp. in DSS-fed mice. In vitro fermentation studies further confirmed that ECP could promote the growth of Parabacteroides distasonis F1-28, a next-generation probiotic bacterium isolated from the human gut, and increase its production of short-chain fatty acids. Additionally, Parabacteroides distasonis F1-28 was also found to have anti-ulcerative colitis effects in DSS-fed mice. Altogether, our study demonstrates for the first time a beneficial effect of ECP on ulcerative colitis and provides a possible basis for understanding its therapeutic mechanisms from the perspective of symbiotic gut bacteria Parabacteroides distasonis.

Association between pulmonary ventilatory function and mild cognitive impairment: A population-based study in rural China.

Background: Mild cognitive impairment (MCI), a reversible intermediate state, plays an important role in the development and prevention of dementia. The relationship between pulmonary function and MCI risk has not yet been well-elucidated. Methods: We included 2,947 rural Chinese residents aged ≥35 years who were free from a history of stroke, dementia, or other brain diseases and measured pulmonary ventilatory function using calibrated spirometry according to the recommended method. MCI was assessed with the Montreal Cognitive Assessment-Basic for Chinese scale. Logistic regression models and restricted cubic splines with covariate adjustment were performed to explore the association between pulmonary function and MCI risk. Results: The prevalence of MCI increased with decreasing pulmonary function, from the lowest quartile to the highest quartile of pulmonary function: 63.9, 50.5, 43.8, and 43.6%, respectively. After adjustment for confounding factors, participants in the first quartile had a significantly increased risk of MCI (ORs, 1.691, 95% CI, 1.267-2.258), with the highest quartile as the reference. In the subgroup analysis, a significant association of pulmonary function and MCI was found in females and those with low physical activity. Meanwhile, we observed an L-shaped relationship between pulmonary function and MCI (P non-linear = 0.032). Conclusions: Poor pulmonary function was associated with an increased risk of MCI among rural Chinese adults, and presented a non-linear relationship. These findings remind us of the need for early cognitive assessment in local populations with lower pulmonary function.

Decreased secretion of tumor necrosis factor-α attenuates macrophages-induced insulin resistance in skeletal muscle.

AIMS: Macrophages, as an important member of immune system, engulf and digest pathogens in innate immunity and help initiate adaptive immunity. However, macrophages also involve in occurrence and development of many diseases, such as obesity and type 2 diabetes. Here, we aimed to reveal how activated macrophages cause insulin resistance in skeletal muscle in vitro through simulating body environment. MAIN METHODS: We established RAW264.7 macrophages and C2C12 myotubes co-incubation model in vitro using Transwell filter to simulate body environment and investigated effects of RAW264.7 cells on insulin-regulated glucose metabolism in C2C12 myotubes. Immunofluorescence, Immunoblot and glucose uptake tests were used to assess metabolic changes in C2C12 myotubes. ELISA test detected secretions of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from RAW264.7 cells. In addition, RNA interference and inhibitor treatment were used. KEY FINDINGS: Activated RAW264.7 cells attenuated insulin response in C2C12 myotubes. Activated RAW264.7 cells secreted a lot of TNF-α and IL-6. We found that TNFα, but not IL-6, caused insulin resistance of skeletal muscle in a dose-dependent manner. The results further indicated that activation of TNF-α downstream proteins, inhibitor of nuclear factor κ-B kinase (IKK) and the jun-N-terminal kinase 1 (JNK1) led to phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser residues and insulin resistance in C2C12 myotubes. SIGNIFICANCE: Our research provided further and direct demonstration on activated macrophage-induced insulin resistance in skeletal muscle, suggesting TNF-α might become a therapeutic target to ameliorate and treat type 2 diabetes.

Ginsenoside Re enhances the survival of H9c2 cardiac muscle cells through regulation of autophagy.

We examined the effect of ginsenoside Re (G-Re) on autophagy in H9c2 cardiomyocytes cultured in glucose deprivation (GD). Levels of the membrane-bound autophagy-related microtubule-associated protein 1A/1B-light chain 3 (LC3) B-2 were measured via immunoblotting and immunofluorescence was conducted to assess autophagosome formation. GD H9c2 cells were treated with 100 µmol/l G-Re. Cell viability was determined in culture medium. Phosphorylated 5' AMP-activated protein kinase (AMPK)-α and mammalian target of rapamycin (mTOR) levels were measured to explore the mechanisms underlying the effects of G-Re on autophagy in GD cells. G-Re treatment inhibited autophagosome formation and may be beneficial to GD cardiomyocytes.

Elevated blood pressure level based on 2017 ACC/AHA guideline in relation to stroke risk in rural areas of Liaoning province.

BACKGROUND: The new ACC/AHA hypertension guideline lower the definition of hypertension from 140/90 mmHg to 130/80 mmHg and eliminate the category of prehypertension thus increasing the prevalence of hypertension. A purpose of this study is to explore the applicability of the new guidelines in rural China. METHODS: In total, 3229 participants aged ≥35 years and free of stroke at baseline were followed for up to 4.8 years during 2012 to 2017 in a rural community-based prospective cohort study of Xifeng County. The hazard ratio (HR) and 95% Confidence interval (CI) of different blood pressure (BP) levels for risk of incident stroke were analyzed by multivariable Cox proportional hazard models. RESULTS: During the follow-up, 81 new strokes occurred among the 3229 participants. Compared with normal BP (Systolic BP (SBP)<120 mmHg and Diastolic BP (DBP)<80 mmHg), stage 2 hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) had approximately 2.1 greater risks for stroke (HR: 2.10, 95% CI: 1.13 to 3.91, P = 0.020). However, there was no significant association between elevated (SBP:120-129 mmHg and DBP<80 mmHg), stage1 hypertension (SBP:130-139 mmHg or DBP:80-89 mmHg) and stroke incidence (HR: 0.93, 95% CI: 0.33 to 2.61, P = 0.888; HR: 0.96, 95% CI: 0.46 to 2.02, P = 0.920, respectively). An increase of the SBP by 1-SD increases the risk for stroke by 56% (HR: 1.56, 95%CI: 1.29 to 1.88, P < 0.001). An increase of the SBP by 20 mmHg increases the risk for stroke by 51% (HR: 1.51, 95%CI: 1.27 to 1.80, P < 0.001). CONCLUSIONS: Compared with normal BP, the stage 2 hypertension based on 2017 ACC/AHA guideline significantly increases the risk of stroke incidence, but this association was not observed between elevated, stage1 hypertension and stroke incidence in Chinese rural adults.

Effect of loading dose of atorvastatin therapy prior to percutaneous coronary intervention in patients with acute coronary syndrome: a meta-analysis of six randomized controlled trials.

PURPOSE: The study sought to summarize the evidence of pre-procedural atorvastatin therapy to improve the prognosis of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). PATIENTS AND METHODS: We searched PubMed and Embase from inception to July 2018 for randomized controlled trials that compared loading dose atorvastatin pretreatment with no or low dose for the prevention of cardiovascular events. The primary end points were all-cause mortality and myocardial infarction (MI) at 30 days. The secondary end point was 30-day major adverse cardiovascular events (MACE), a composite of all-cause mortality, MI, and revascularization. RESULTS: Six trials with 4,991 individuals were included in our meta-analysis. High-dose atorvastatin preloading before PCI was associated with a 27% relative reduction in MI (OR: 0.73, 95% CI, 0.56-0.94, P=0.015). All-cause mortality was nonsignificantly reduced by early treatment with high-potency atorvastatin (OR: 0.94, 95% CI, 0.69-1.30, P=0.725). There was a 20% reduction in MACE in the group of patients treated with statin loading prior to PCI (OR: 0.80, 95% CI, 0.66-0.97, P=0.026). When stratified according to the diagnosis of ACS, the results of MACE were only significant for those ST-elevation myocardial infarction patients undergoing PCI (OR: 0.67, 95% CI, 0.48-0.94, P=0.022) and were not noted in the group of non-ST elevation ACS patients (OR: 0.65, 95% CI, 0.35-1.22, P=0.179). CONCLUSION: High-dose atorvastatin pretreatment leads to a significant reduction in MI and MACE at 30 days in ACS patients undergoing PCI, especially in ST-segment elevation MI.

Bidirectional modulation of insulin action by reactive oxygen species in 3T3­L1 adipocytes.

Reactive oxygen species (ROS) serve an important role in glucose­lipid metabolic regulation. In the present study, the results demonstrated that there was bidirectional regulation of insulin action in 3T3­L1 adipocytes treated with ROS. Transient and acute ROS exposure improved insulin­induced metabolic effects in 3T3­L1 adipocytes. Hydrogen peroxide (H2O2), as a stable and diffusible ROS, diffused into adipocytes and altered intracellular redox homeostasis, resulting in oxidation and inactivation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Inactivation of PTEN enhanced the activation of insulin­induced protein kinase B (AKT), leading to increased glucose transporter 4 (GLUT4) redistribution and glucose uptake in 3T3­L1 adipocytes. However, chronic ROS treatment induced insulin resistance in 3T3­L1 adipocytes. It was also revealed that insulin­induced AKT activation, GLUT4 translocation to cell membrane and glucose uptake were significantly inhibited in chronic ROS­treated 3T3­L1 adipocytes. Taken together, the present study provided further demonstration that transient ROS treatment improved insulin sensitivity; however, chronic ROS exposure induced insulin resistance in 3T3­L1 adipocytes.

Diabetes mellitus is an independent risk factor for atrial fibrillation in a general Chinese population.

AIMS/INTRODUCTION: To explore the association between atrial fibrillation (AF) and diabetes mellitus in a general Chinese population, and the influence of hypertension. MATERIALS AND METHODS: From January 2013 to August 2013, we carried out a cross-sectional study involving 11,956 permanent residents aged ≥35 years from the general population in the Liaoning province of China (response rate 85.3%). Each participant completed a questionnaire, had a physical examination, and underwent an electrocardiogram and echocardiogram. AF was diagnosed on the basis of the electrocardiogram findings. Logistic regression analyses were carried out to estimate the associations between diabetes mellitus and AF. The associations were also analyzed in hypertensive and normotensive subgroups. RESULTS: There was a higher prevalence of AF in participants with diabetes mellitus than those without diabetes mellitus (1.2 vs 0.5%; P = 0.004). In the hypertensive subgroup, the prevalence of AF in participants with diabetes mellitus was significantly higher than in participants without diabetes mellitus (1.5 vs 0.6%; P = 0.008); however, the prevalences were similar in the normotensive subgroup (0.3 vs 0.4%; P = 1.000). Similar trends were present in both men and women. After adjustment for cardiovascular risk factors, the independent association between diabetes mellitus and AF remained in the total sample (odds ratio 2.33, 95% confidence interval 1.20-4.54) and hypertensive subgroup (odds ratio 3.15, 95% confidence interval 1.52-6.56), but not in the normotensive subgroup (odds ratio 0.64, 95% confidence interval 0.08-5.31). CONCLUSIONS: Diabetes mellitus is an independent risk factor for AF in the general population in China, this association was present in total and hypertensive participants, but not in normotensive participants.

Advanced glycation end products promote proliferation and suppress autophagy via reduction of Cathepsin D in rat vascular smooth muscle cells.

Autophagy is closely involved in vascular smooth muscle cell (VSMC) function, but little is known about the association between advanced glycation end products (AGEs) and autophagy and its role in AGEs-induced proliferation and migration of VSMCs. The current study investigated the effects of AGEs on the phenotypic modulation and autophagy of VSMCs, as well as the potential underlying mechanisms. Primary rat VSMCs were treated with bovine serum albumin or AGEs. Cell proliferation was detected by MTT assay, real-time cell analyzer and EdU incorporation. Cell cycle was analyzed by Hoechst staining and flow cytometry. The migration of VSMCs was detected by wound-healing assay and transwell migration assay. LC3 transition and p62 accumulation were detected using Western blotting. Acidic vacuoles were measured using AO and MDC staining. Cathepsin D (CatD) was transduced to VSMCs via lentiviral vectors. AGEs enhanced proliferation and migration of primary rat VSMC in a time-dependent manner. AGEs significantly increased LC3-II transition and p62 expression, as well as accumulation of acidic vacuole, which was not further increased by bafilomycin A1. AGEs decreased CatD expression in a time-dependent pattern, and overexpression of CatD prohibited autophagy attenuation mediated by AGEs. CatD overexpression suppressed AGEs-induced proliferation of VSMCs. Nevertheless, CatD exhibited no effects on AGEs-induced migration of VSMCs. AGEs promote proliferation of VSMCs and suppress autophagy, at least in part via CatD reduction.

Conjugated Polymer Nanoparticles for Label-Free and Bioconjugate-Recognized DNA Sensing in Serum.

Hybridbio/-synthetic sensory conjugated polymer nanoparticles (CPNs) are developed for selective label-free detection of target ssDNA in serum. Carboxylic acid-functionalized anionic polyfluorene nanoparticles are rationally designed as signal amplifying unit to bioconjugate with amine functionalized single stranded oligonucleotides as a receptor. The covalent DNA coating can significantly improve the photostability of the DNA-bioconjugated CPNs over a wide range of buffer conditions. Better ssDNA discrimination for the DNA-bioconjugated CPNs sensor is achieved owing to increased interchain interactions and more efficient exciton transport in nanoparticles. The distinguishable fluorescent color for DNA-bioconjugated CPNs in the presence of target ssDNA allows naked-eye detection of ssDNA under UV irradiation.