Diagnostic Utility of Triglyceride-Glucose Index in Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study on Lean Population.

Background: Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD. Methods: 99 patients with lean NAFLD and 1891 healthy controls were included in the health examination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD. Results: Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P<0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886). Conclusion: The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

Alleviation effects of dexmedetomidine on myocardial ischemia/reperfusion injury through fatty acid metabolism pathway via Elovl6.

Dexmedetomidine (Dex) is widely used in the sedation in intensive care units and as an anesthetic adjunct. Considering the anti-inflammatory and antioxidant properties of Dex, we applied in vivo rat model as well as in vitro cardiomyocyte models (embryonic rat cardiomyocytes H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial ischemia reperfusion (I/R) injury. Transcriptomic sequencing for gene expression in heart tissues from control rats and Dex-treated rats identified that genes related to fatty acid metabolism were significantly regulated by Dex. Among these genes, the elongation of long-chain fatty acids (ELOVL) family member 6 (Elovl6) was most increased upon Dex-treatment. By comparing the effects of Dex on both wild type and Elovl6-knockdown H9c2 cells and NRCMs under oxygen-glucose deprivation/reoxygenation (OGD/R) challenge, we found that Elovl6 knockdown attenuated the protection efficiency of Dex, which was supported by the cytotoxicity endpoints (cell viability and lactate dehydrogenase release) and apoptosis as well as key gene expressions. These results indicate that Dex exhibited the protective function against myocardial I/R injury via fatty acid metabolism pathways and Elovl6 plays a key role in the process, which was further confirmed using palmitate exposure in both cells, as well as in an in vivo rat model. Overall, this study systematically evaluates the protective effects of Dex on the myocardial I/R injury and provides better understanding on the fatty acid metabolism underlying the beneficial effects of Dex.

The association between lymphocyte-to-monocyte ratio and all-cause mortality in obese hypertensive patients with diabetes and without diabetes: results from the cohort study of NHANES 2001-2018.

Objective: Obesity, hypertension and diabetes are high prevalent that are often associated with poor outcomes. They have become major global health concern. Little research has been done on the impact of lymphocyte-to-monocyte ratio (LMR) on outcomes in these patients. Thus, we aimed to explore the association between LMR and all-cause mortality in obese hypertensive patients with diabetes and without diabetes. Methods: The researchers analyzed data from the National Health and Nutrition Examination Survey (2001-2018), which included 4,706 participants. Kaplan-Meier analysis was employed to compare survival rate between different groups. Multivariate Cox proportional hazards regression models with trend tests and restricted cubic splines (RCS) analysis and were used to investigate the relationship between the LMR and all-cause mortality. Subgroup analysis was performed to assess whether there was an interaction between the variables. Results: The study included a total of 4706 participants with obese hypertension (48.78% male), of whom 960 cases (20.40%) died during follow-up (median follow-up of 90 months). Kaplan-Meier curves suggested a remarkable decrease in all-cause mortality with increasing LMR value in patients with diabetes and non-diabetes (P for log-rank test < 0.001). Moreover, multivariable Cox models demonstrated that the risk of mortality was considerably higher in the lowest quartile of the LMR and no linear trend was observed (P > 0.05). Furthermore, the RCS analysis indicated a non-linear decline in the risk of death as LMR values increased (P for nonlinearity < 0.001). Conclusions: Increased LMR is independently related with reduced all-cause mortality in patients with obese hypertension, regardless of whether they have combined diabetes.

Adrenomedullin, transcriptionally regulated by vitamin D receptors, alleviates atherosclerosis in mice through suppressing AMPK-mediated endothelial ferroptosis.

PURPOSE: Vitamin D receptors (VDR) play important roles in cardiovascular, immune, metabolic and other functions. Activation of VDR may help improve endothelial dysfunction, atherosclerosis, vascular calcification, and cardiac hypertrophy. However, the specific target genes and mechanisms of VDR in improving Human Umbilical Vein Endothelial Cell (HUVEC) functions remain unclear. This study aims to investigate the function and mechanism of VDR in HUVECs. METHODS: Endothelial dysfunction cell model was constructed by oxidized low-density lipoprotein (ox-LDL). An animal model of atherosclerosis was established in male homozygous Apoe-/- mice (6 weeks) on a high fat diet for 6 weeks. The relationship between VDR and adrenomedullin (ADM) was studied by bioinformatics analysis, ChIP, and luciferase reporter gene analysis. Endothelial cell function was evaluated by Transwell migration and Tube Formation tests. Ferroptosis was detected by measuring intracellular iron content, levels of oxidative stress markers, and ferroptosis related proteins. RESULTS: Overexpression of VDR in HUVECs inhibits ox-LDL-induced endothelial dysfunction and ferroptosis. VDR binds to the ADM promoter sequence and regulates the transcription of ADM. Inhibition of ADM promotes ox-LDL-induced endothelial dysfunction and ferroptosis. ADM regulates ox-LDL-induced endothelial dysfunction and ferroptosis through the AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice inhibited lipid deposition and plaque area in atherosclerotic mice. CONCLUSION: VDR inhibits ox-LDL-induced endothelial dysfunction and ferroptosis by regulating ADM transcription and acting on AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice reduced lipid deposition and plaque area in the thoracic aorta of atherosclerotic mice.

Spatio-temporal evolution patterns of influenza incidence and its nonlinear spatial correlation with environmental pollutants in China.

BACKGROUND: Currently, the influenza epidemic in China is at a high level and mixed with other respiratory diseases. Current studies focus on regional influenza and the impact of environmental pollutants on time series, and lack of overall studies on the national influenza epidemic and the nonlinear correlation between environmental pollutants and influenza. The unclear spatial and temporal evolution patterns of influenza as well as the unclear correlation effect between environmental pollutants and influenza epidemic have greatly hindered the prevention and treatment of influenza epidemic by relevant departments, resulting in unnecessary economic and human losses. METHOD: This study used Chinese influenza incidence data for 2007-2017 released by the China CDC and air pollutant site monitoring data. Seasonal as well as inter monthly differences in influenza incidence across 31 provinces of China have been clarified through time series. Space-Time Cube model (STC) was used to investigate the spatio-temporal evolution of influenza incidence in 315 Chinese cities during 2007-2017. Then, based on the spatial heterogeneity of influenza incidence in China, Generalized additive model (GAM) was used to identify the correlation effect of environmental pollutants (PM2.5, PM10, CO, SO2, NO2, O3) and influenza incidence. RESULT: The influenza incidence in China had obvious seasonal changes, with frequent outbreaks in winter and spring. The influenza incidence decreased significantly after March, with only sporadic outbreaks occurring in some areas. In the past 11 years, the influenza epidemic had gradually worsened, and the clustering of influenza had gradually expanded, which had become a serious public health problem. The correlation between environmental pollutants and influenza incidence was nonlinear. Generally, PM2.5, CO and NO2 were positively correlated at high concentrations, while PM10 and SO2 were negatively correlated. O3 was not strongly correlated with the influenza incidence. CONCLUSION: The study found that the influenza epidemic in China was in a rapidly rising stage, and several regions had a multi-year outbreak trend and the hot spots continue to expand outward. The association between environmental pollutants and influenza incidence was nonlinear and spatially heterogeneous. Relevant departments should improve the monitoring of influenza epidemic, optimize the allocation of resources, reduce environmental pollution, and strengthen vaccination to effectively prevent the aggravation and spread of influenza epidemic in the high incidence season and areas.

The spatial distribution of interleukin-4 (IL-4) reference values in China based on a back propagation (BP) neural network.

This study aimed to investigate the geospatial distribution of normal reference values of Interleukin 4 (IL-4) in healthy Chinese adults and to provide a basis for the development of standard references. IL-4 values of 5,221 healthy adults from 64 cities in China were collected and analyzed for a potential correlation with 24 topographical, climatic and soil factors. Seven of these factors were extracted and used to build a back propagation (BP) neural network model that was used to predict IL-4 reference values in healthy individuals from 2,317 observation sites nationwide. The predicted values were tested for normality and geographic distribution by analytic Kriging interpolation to map the geographic distribution of IL-4 reference values in healthy Chinese subjects. The results showed that IL-4 values generally decreased and then increased from the South to the North. We concluded that the BP neural network model applies to this approach, where certain geographical factors determine levels of various biochemical and immunological standards in healthy adults in regions with different topography, climate and soil indices.

Spatial distribution of anti-mullerian hormone in females of childbearing age in China under the influence of geographical environmental factors.

The Anti-mullerian hormone (AMH) reference value is an important indicator of ovarian function. The main targets of this were to screen the geographical environmental factors that may influence the distribution of AMH reference values in Chinese females of childbearing age, and to further explore the geographical distribution differences of AMH reference values. We gathered the AMH data of 28,402 healthy Chinese females from 62 cities in China for this study in order to conduct a spearman regression analysis to determine the relationship between the AMH and 30 geography factors. The AMH reference value in different regions was forecasted by using a ridge regression model. The magnitude of influence from the geographical factor on different regions was analysed by geographically weighted regression. Ultimately, We were able to figure out the geographic distribution risk prediction of AMH reference values by utilizing the disjunctive Kriging method. The AMH reference value was significantly correlated with the 16 secondary indexes. The geographical distribution of AMH showed a trend of being higher in Qinghai-Tibet and Southern regions, and lower in the Northwest and Northern regions. This study lays the foundation for future investigations into the mechanism of different influencing factors on the reference value of AMH. It is suggested that such regional variations in AMH reference values be taken into account while diagnosing and treating individuals with reproductive medicine.

Development and validation of a model to predict the risk of hypertension using anthropometric indicators in the Chinese population: a retrospective cohort study.

BACKGROUND: The prevalence of hypertension and obesity in China has sharply increased in recent decades. We aimed to develop and validate a novel model for predicting the risk of hypertension based on anthropometric indicators relating to obesity in the general population of China. METHODS: In this retrospective study, 6196 participants from the China Health and Nutrition Survey (CHNS) during the 2009-2015 waves were included. Risk factors for hypertension were assessed by LASSO regression combined with multivariate logistic regression analysis. A nomogram was developed as a predictive model based on the screening prediction factors. The discrimination and calibration of the model were evaluated by receiver operating curve (ROC) and calibration plots, respectively. Decision curve analysis (DCA) was used to evaluate the clinical application value of the model. RESULTS: A total of 6196 participants were divided into two sets at a ratio of 7:3, using computer-generated random numbers: 4337 individuals were assigned to the training set and 1859 to the validation set. The training set was divided into a hypertension group (n = 1016) and a non-hypertension group (n = 3321) based on the follow-up outcomes for hypertension. Predictive factors of hypertension included age, drinking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and arm-to-height ratio (AHtR) at baseline as predictors. The area under the ROC curve (AUC) for the training and validation sets was 0.906 (95% CI: 0.897-0.915) and 0.905 (95% CI: 0.887-0.922), respectively. In bootstrap validation, the C-index was 0.905 (95% CI: 0.888-0.921). The model also had good predictive accuracy according to the calibration plot. DCA demonstrated that people would benefit more when the threshold probability was between 5% and 80%. CONCLUSION: A nomogram model was successfully established to effectively predict the risk of hypertension based on anthropometric indicators. The model could be a feasible tool for hypertension screening in the general population of China.

Associations of environmental factors with total cholesterol level of middle-aged and elderly people in China.

BACKGROUND: Dyslipidemia is a key factor causing cardio cerebrovascular diseases, and the total cholesterol (TC) is an important lipid indicator among them. Studies have shown that environmental factors have a strong association with TC levels. Previous studies only focused on the seasonal variation of TC level and the short-term effects of some environmental factors on TC level over time, and few studies explored the geographical distribution of TC level and quantified the impact of environmental factors in space. METHODS: Based on blood test data which was from China Health and Retirement Longitudinal Study (Charls) database, this study selected the TC level test data of middle-aged and elderly people in China in 2011 and 2015, and collected data from 665 meteorological stations and 1496 air pollutant monitoring stations in China. After pretreatment, the spatial distribution map of TC level was prepared and the regional statistics were made. GeoDetector and geographically weighted regression (GWR) were used to measure the relationship between environmental factors and TC level. RESULTS: The TC level of middle-aged and elderly in China was higher in females than in males, and higher in urban areas than in rural areas, showing a clustered distribution. The high values were mainly in South China, Southwest China and North China. Temperature, humidity, PM10 and PM2.5 were significant environmental factors affecting TC level of middle-aged and elderly people. The impact of pollutants was more severe in northern China, and TC level in southern China was mainly affected by meteorological factors. CONCLUSIONS: There were gender and urban-rural differences in TC levels among the middle-aged and elderly population in China, showing aggregation in geographical distribution. Meteorological factors and air pollutants may be very important control factors, and their influencing mechanism needs further study.

Palmitic acid inhibits vascular smooth muscle cell switch to synthetic phenotype via upregulation of miR-22 expression.

Synthetic phenotype switch of vascular smooth muscle cells (VSMCs) has been shown to play key roles in vascular diseases. Mounting evidence has shown that fatty acid metabolism is highly associated with vascular diseases. However, how fatty acids regulate VSMC phenotype is poorly understood. Hence, the effects of palmitic acid (PA) on VSMC phenotype were determined in this study. The effect of the PA on VSMCs was measured by live/dead and EdU assays, as well as flow cytometry. Migration ability of VSMCs was evaluated using transwell assay. The underlying targets of miR-22 were predicted using bioinformatics online tools, and confirmed by luciferase reporter assay. The RNA and protein expression of certain gene was detected by qRT-PCR or western blot. PA inhibited VSMC switch to synthetic phenotype, as manifested by inhibiting VSMC proliferation, migration, and synthesis. PA upregulated miR-22 in VSMCs, and miR-22 mimics exerted similar effects as PA treatment, inhibiting VSMC switch to synthetic phenotype. Inhibition of miR-22 using miR-22 inhibitor blocked the impacts of PA on VSMC phenotype modulation, suggesting that PA modulated VSMC phenotype through upregulation of miR-22 expression. We found that ecotropic virus integration site 1 protein homolog (EVI1) was the target of miR-22 in regulation of VSMC phenotype. Overexpression of miR-22 or/and PA treatment attenuated the inhibition of EVI1 on switch of VSMCs. These findings suggested that PA inhibits VSMC switch to synthetic phenotype through upregulation of miR-22 thereby inhibiting EVI1, and correcting the dysregulation of miR-22/EVI1 or PA metabolism is a potential treatment to vascular diseases.

Urotensin II activates the ferroptosis pathway through circ0004372/miR-124/SERTAD4 to promote the activation of vascular adventitial fibroblasts.

Both vascular adventitial fibroblasts (VAFs) and urotensin II (UII) play important roles in vascular remodeling diseases, but the mechanism of UII in VAFs is still unclear. UII inhibited miR-124 expression through up-regulating circ0004372 expression, thereby promoting SERTAD4 expression. UII significantly promoted the generation of ROS, MDA and 4-HNE, reduced the activities of SOD, GST and GR, increased Fe2+ concentration and inhibited GPX4 expression through circ0004372/miR-124/SERTAD4. Both UII and ferroptosis inducer Erastin significantly promoted the expression of α-SMA, Collagen I and TGF-ß1 in VAFs, but circ0004372 siRNA, miR-124 mimics, SERTAD4 siRNA or Ferrostatin-1 significantly inhibited the effect of UII and Erastin on cell activation. When co-transfected with circ0004372 siRNA and miR-124 inhibitors or miR-124 mimics and SERTAD4 overexpression vector, UII still significantly increased the expression of α-SMA, Collagen I and TGF-ß1. After transfection with circ0004372 overexpression vector, miR-124 inhibitors or SERTAD4 overexpression vector and then treating with UII and Ferrostatin-1, the expression of α-SMA, Collagen I and TGF-ß1 was still significant; when the circ0004372 overexpression vector and miR-124 mimics or miR-124 inhibitors and SERTAD4 siRNA were co-transfected and then UII and Ferrostatin-1 were added, the expression of α-SMA, Collagen I and TGF-ß1 was not significantly increased. Therefore, these results indicate that UII promotes the activation of VAFs through the circ0004372/miR-124/SERTAD4/ferroptosis pathway.

Lactate promotes vascular smooth muscle cell switch to a synthetic phenotype by inhibiting miR-23b expression.

Recent research indicates that lactate promotes the switching of vascular smooth muscle cells (VSMCs) to a synthetic phenotype, which has been implicated in various vascular diseases. This study aimed to investigate the effects of lactate on the VSMC phenotype switch and the underlying mechanism. The CCK-8 method was used to assess cell viability. The microRNAs and mRNAs levels were evaluated using quantitative PCR. Targets of microRNA were predicted using online tools and confirmed using a luciferase reporter assay. We found that lactate promoted the switch of VSMCs to a synthetic phenotype, as evidenced by an increase in VSMC proliferation, mitochondrial activity, migration, and synthesis but a decrease in VSMC apoptosis. Lactate inhibited miR-23b expression in VSMCs, and miR-23b inhibited VSMC's switch to the synthetic phenotype. Lactate modulated the VSMC phenotype through downregulation of miR-23b expression, suggesting that overexpression of miR-23b using a miR-23b mimic attenuated the effects of lactate on VSMC phenotype modulation. Moreover, we discovered that SMAD family member 3 (SMAD3) was the target of miR-23b in regulating VSMC phenotype. Further findings suggested that lactate promotes VSMC switch to synthetic phenotype by targeting SMAD3 and downregulating miR-23b. These findings suggest that correcting the dysregulation of miR-23b/SMAD3 or lactate metabolism is a potential treatment for vascular diseases.

Spatial distribution differences of 25-hydroxyvitamin D in healthy elderly people under the influence of geographical environmental factors.

The main targets of this were to screen the factors that may influence the distribution of 25-hydroxyvitamin D[25(OH)D] reference value in healthy elderly people in China, and further explored the geographical distribution differences of 25(OH)D reference value in China. In this study, we collected the 25(OH)D of 25,470 healthy elderly from 58 cities in China to analyze the correlation between 25(OH)D and 22 geography secondary indexes through spearman regression analysis. Six indexes with significant correlation were extracted, and a ridge regression model was built, and the country's urban healthy elderly'25(OH)D reference value was predicted. By using the disjunctive Kriging method, we obtained the geographical distribution of 25(OH)D reference values for healthy elderly people in China. The reference value of 25(OH)D for healthy elderly in China was significantly correlated with the 6 secondary indexes, namely, latitude (°), annual temperature range (°C), annual sunshine hours (h), annual mean temperature (°C), annual mean relative humidity (%), and annual precipitation (mm). The geographical distribution of 25(OH)D values of healthy elderly in China showed a trend of being higher in South China and lower in North China, and higher in coastal areas and lower in inland areas. This study lays a foundation for further research on the mechanism of different influencing factors on the reference value of 25(OH)D index. A ridge regression model composed of significant influencing factors has been established to provide the basis for formulating reference criteria for the treatment factors of the vitamin D deficiency and prognostic factors of the COVID-19 using 25(OH)D reference value in different regions.

Effects of geographical factors on reference values of the thyroid stimulating hormone in healthy adults in China and its clinical significance.

The thyroid stimulating hormone (TSH) plays an important regulatory role in maintaining normal function of the thyroid gland. The purpose of this study was to explore the geographical, spatial distribution of TSH normal values in healthy Chinese adults to be used for the formulation of a standard reference. TSH values of 9321 healthy adults from 120 cities in China were collected together with 24 topographic, climatic and soil variables and used for the determination of spatial, significant relationships between TSH and these geographical factors by correlation analysis. Eleven significant factors were extracted and subjected to ridge regression and construction of vector machine models. The predicted values were tested for normality, with the disjunctive Kriging interpolation method used for geographical distribution. The values found showed a spatial pattern of higher values in the North and west but lower in the South and east We concluded that ridge regression models are useful for this kind of investigations and that certain geographical factors determine the level of TSH in healthy adults in a large expanse of land where topography, climate and soil indices vary.

Nonlinear associations between environmental factors and lipid levels in middle-aged and elderly population in China: A national cross-sectional study.

BACKGROUND: Blood lipid is an important factor affecting cardiovascular disease in middle-aged and elderly people. At present, the associations between environmental factors and blood lipid level in elderly people has been controversial, and the nonlinear effect of their relationship is lack of research. METHODS: This study used data from a national cross-sectional survey of blood lipid levels in 13,354 subjects and data from environmental monitoring sites. Logistic regression was used to measure the relationship between the basic characteristics of the study population and blood lipid levels. After controlling the confounding factors, the nonlinear associations between environmental factors and blood lipid levels of middle-aged and elderly people in different geographical regions were studied by random forest model. RESULTS: The risk of dyslipidemia is significantly higher in middle-aged women, obese people, elderly people, and urban people. Smoking and alcohol consumption increase the risk. The associations between environmental factors and lipid levels of middle-aged and elderly people are nonlinear, the correlation effect between air pollutants and blood lipid level is mainly shown in northern China, and the correlation between meteorological factors and blood lipid level is more obvious in southern China. CONCLUSIONS: This study shows that the associations between environmental factors and lipid levels in middle-aged and elderly population are nonlinear and have regional differences. Therefore it should be considered in optimizing the allocation of public health resources and preventing and controlling environmental exposure of middle-aged and elderly population.

Correction: A fluorescent biosensor for cardiac biomarker myoglobin detection based on carbon dots and deoxyribonuclease I-aided target recycling signal amplification.

[This corrects the article DOI: 10.1039/C8RA09459D.].

Sodium glucose cotransporter 2 inhibitor dapagliflozin depressed adiposity and ameliorated hepatic steatosis in high-fat diet induced obese mice.

With the increasing obesity prevalence, the rates of obesity-related diseases, including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases, have increased dramatically. Dapagliflozin, one of the sodium glucose cotransporter inhibitors, not only exerts hypoglycaemic effects through increasing urinary glucose excretion but alsoreprograms the metabolic system, leading to benefits in metabolic and cardiovascular diseases. In this study, pre-established obese mice on a high-fat diet were given dapagliflozin by gavage for fourweeks. It showed that dapagliflozin can enhance fat utilization and browning of adipose tissue and improve local oxidative stress, thus inhibiting fat accumulation and hepatic steatosis without disturbance in body weight or plasma glycolipid level. Overall, our study highlights the potential clinical application of SGLT2 inhibition in the prevention of obesity and related metabolic diseases, such as insulin resistance, NAFLD, and diabetes.

Glutamine switches vascular smooth muscle cells to synthetic phenotype through inhibiting miR-143 expression and upregulating THY1 expression.

AIMS: Vascular smooth muscle cells (VSMCs) are involved in the pathogenesis of many human cardiovascular diseases. They modulate their phenotype from "contractile" to "synthetic" in response to changes in local environmental cues. How glutamine regulates the differentiation of VSMCs and the underlying mechanisms remain largely unknown. MAIN METHODS: Here, we explored the effects of various doses of glutamine (0 mM, 1 mM, 2 mM, and 4 mM) on the proliferation, migration, and phenotypic switch of human VSMCs in vitro. Glutamine dose-dependently enhanced VSMC proliferation, and markedly increased VSMC migration. KEY FINDINGS: Notably, glutamine promoted the phenotypic switch of VSMCs towards a synthetic phenotype, as evidenced by significantly decreased expression of contractile markers myosin heavy chain 11 (MYH11) and calponin while increased expression of synthetic markers collagen I and vimentin. Importantly, these changes upon glutamine treatments were attenuated after additional treatments with glutamine metabolism inhibitor BPTES. Additionally, glutamine downregulated miR-143 expression, and miR-143 inactivation alone resulted in enhanced proliferation, migration, and promoted the synthetic phenotype of VSMCs. Moreover, Thy-1 cell surface antigen (THY1) was validated as a downstream target of miR-143, and THY1 expression was upregulated by glutamine in VSMCs. Furthermore, either miR-143 overexpression or THY1 silencing abolished the effect of glutamine on proliferation, migration, and phenotypic switch of VSMCs, supporting a novel glutamine-miR-143-THY1 pathway in modulating VSMC functions. SIGNIFICANCE: This study demonstrated a novel mechanism of glutamine in modulation of VSMC phenotypic switch by targeting miR-143 and THY1, and provides significant insight on targeted therapy of patients with cardiovascular diseases.

Quercetin improves vascular endothelial function through promotion of autophagy in hypertensive rats.

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.

Tanshinone IIA attenuates high glucose induced human VSMC proliferation and migration through miR-21-5p-mediated tropomyosin 1 downregulation.

The proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the development and progression of diabetes-related vascular complications. Recently, microRNAs (miRNAs) have been suggested to be involved in the pathogenesis of vascular diseases. This study was designed to investigate the influences of tanshinone IIA, an active compound extracted from Chinese herb Salvia miltiorrhiza, on the proliferation and migration of human aortic VSMCs (HASMCs). cultured in a high glucose medium and the underlying mechanisms related miRNAs. Using a miRNA microarray method, we profiled the miRNA expression signature in human aortic VSMCs (HASMCs) exposed to normal glucose, high glucose with and without Tanshinone IIA. Cell proliferation was measured with 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell migration was evaluated using transwell migration assay and wound scratch assay. Western blot was used to examine the expression of tropomyosin 1 (TPM1) and miRNA level was quantified by real-time PCR. The results showed that several miRNAs that were highly expressed in the high glucose group were significantly decreased in the high glucose with Tanshinone IIA group compared with the normal glucose group (P < 0.05). Among these miRNAs, miR-21-5p was significantly upregulated in the high glucose group and downregulated after Tanshinone IIA treatment (P < 0.05). The depletion of miR-21-5p in HASMCs resulted in decreased cell proliferation and migration (P < 0.05). Moreover, we found that Tanshinone IIA inhibited proliferation and migration partly through miR-21-5p-mediated TPM1 downregulation (P < 0.05). In conclusion, the present study demonstrates that Tanshinone IIA is able to protect HASMCs from high glucose-induced proliferation and migration through regulating expression of miRNAs.