Intermittent hypoxia reduces infarct size in rats with acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: To determine whether intermittent hypoxia (IH) can reduce the infarct size (IS) after acute myocardial infarction (AMI) in rats. METHODS: Articles were identified in PubMed, EMBASE and the Web of Science and were included if they evaluated the effect of IH on the changes in the infarcted area after AMI in rats. RESULTS: A preliminary search identified 3633 articles and 29 data sets from 23 articles (12 in vivo, 16 in vitro). The IS decreased after AMI in IH rats both in vitro (SMD -1.46, 95% CI [- 2.37, - 0.55]; I2 = 85.6%, P = 0.000) and in vivo (SMD -1.43, 95% CI [- 2.05, - 0.82], I2 = 73.6%, P = 0.000). Sensitivity analysis indicated that IH had a strong protective effect against myocardial infarction, and the hypoxia concentration was significantly correlated with the change in IS after AMI. CONCLUSION: IH can reduce IS after AMI in rats. This effect of IH may be related to the dose of hypoxia, and the oxygen concentration may be one of the most important influencing factors.

6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction.

The prevalence of NAFLD increases with age. As the main active ingredient of ginger, 6-gingerol significantly improves lipid metabolism abnormalities in adult rodents. However, few studies have reported its effect on age-related NAFLD. This study was to investigate the effects of 6-gingerol on age-related hepatic steatosis and its potential targets. As expected, 6-gingerol dramatically normalized the hepatic triglyceride content, plasma insulin and HOMA-IR index of ageing rats. Mechanistically, 6-gingerol affected lipid metabolism by increasing ß-oxidation and decreasing lipogenesis through activation of PPARα and CPT1α and inhibition of DGAT-2. Furthermore, 6-gingerol reversed the decreases in citrate, Cs and ATP, lessened the damage caused by ROS, and upregulated mitochondrial marker enzymes NOX, SDH, and SIRT3 in the ageing liver, indicating its ability to strengthen mitochondrial function. Our results showed 6-gingerol exerted a positive effect on insulin sensitivity by regulating Akt. In conclusion, the hepatic anti-steatotic effect of 6-gingerol is associated with inhibition of de novo lipogenesis, upregulation of fatty acid oxidation, reduction in oxidative stress and synergistic enhancement of mitochondrial function.

Response of genes involved in lipid metabolism in rat epididymal white adipose tissue to different fasting conditions after long-term fructose consumption.

There has been much concern regarding the dietary fructose contributes to the development of metabolic syndrome. High-fructose diet changes the expression of genes involved in lipid metabolism. Levels of a number of hepatic lipogenic enzymes are increased by a high-carbohydrate diet in fasted-refed model rats/mice. Both the white adipose tissue (WAT) and the liver play a key role in the maintenance of nutrient homeostasis. Here, the aim of this study was to analyze the expression of key genes related to lipid metabolism in epididymal WAT (eWAT) in response to different fasting condition after long-term chronic fructose consumption. Rats were fed standard chow supplemented with 10% w/v fructose solution for 5 weeks, and killed after chow-fasting and fructose withdrawal (fasting) or chow-fasting and continued fructose (fructose alone) for 14 h. Blood parameters and the expression of genes involved in fatty acid synthesis (ChREBP, SREBP-1c, FAS, SCD1), triglyceride biosynthesis (DGAT-1, DGAT-2) and lipid mobilization (ATGL, HSL) in eWAT were analyzed. In addition, mRNA levels of PPAR-γ, CD36 and LPL were also detected. As expected, fructose alone increased the mRNA expression of FAS, SCD1, and correspondingly decreased ATGL and HSL mRNA levels. However, ChREBP, DGAT-2, ATGL and HSL mRNA levels restored near to normal while FAS and SCD1 tend to basic level under fasting condition. The mRNA expression of SREBP-1c, PPAR-γ and LPL did not changed at any situations but CD36 mRNA decreased remarkably in fructose alone group. In conclusion, these findings demonstrate that genes involved in lipid metabolism in rat eWAT are varied in response to different fasting conditions after long-term fructose consumption.

Long-term fructose consumption prolongs hepatic stearoyl-CoA desaturase 1 activity independent of upstream regulation in rats.

Dietary fructose is considered a risk factor for metabolic disorders, such as fatty liver disease. However, the mechanism underlying the effects of fructose is not well characterized. We investigated the hepatic expression of key regulatory genes related to lipid metabolism following fructose feeding under well-defined conditions. Rats were fed standard chow supplemented with 10% w/v fructose solution for 5 weeks, and killed after chow-fasting and fructose withdrawal (fasting) or chow-fasting and continued fructose (fructose alone) for 14 h. Hepatic deposition of triglycerides was found in rats from both groups. As expected, fructose alone increased mRNA levels of lipogenesis-related genes and correspondingly decreased mRNA levels of lipid oxidative genes in the liver. Interesting, hepatic levels of stearoyl-CoA desaturase (SCD)1 mRNA remained elevated under fructose withdrawn conditions, although expression levels of other genes, including two key transcription factors (carbohydrate response element binding protein (ChREBP) and sterol regulatory element-binding protein (SREBP)-1c) fell to normal levels, indicating that long-term fructose intake increased SCD1 activity, independent of upstream regulatory genes, such as ChREBP and SREBP-1c. In conclusion, SCD1 overexpression in fatty liver disease is not affected by fasting after long-term fructose consumption in rats. Regulation of SCD1 plays an important role in fructose-induced hepatic steatosis.

Treatment with Rhodiola crenulata root extract ameliorates insulin resistance in fructose-fed rats by modulating sarcolemmal and intracellular fatty acid translocase/CD36 redistribution in skeletal muscle.

BACKGROUND: Rhodiola species have been used for asthenia, depression, fatigue, poor work performance and cardiovascular diseases, all of which may be associated with insulin resistance. To disclose the underlying mechanisms of action, the effect of Rhodiola crenulata root (RCR) on insulin resistance was investigated. METHODS: Male Sprague-Dawley rats were treated with liquid fructose in their drinking water over 18 weeks. The extract of RCR was co-administered (once daily by oral gavage) during the last 5 weeks. The indexes of lipid and glucose homeostasis were determined enzymatically and/or by ELISA. Gene expression was analyzed by Real-time PCR, Western blot and/or confocal immunofluorescence. RESULTS: RCR extract (50 mg/kg) suppressed fructose-induced hyperinsulinemia and the increases in the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. Additionally, this treatment had a trend to restore the ratios of glucose to insulin and non-esterified fatty acids (NEFA) to insulin. Mechanistically, RCR suppressed fructose-induced acceleration of the clearance of plasma NEFA during oral glucose tolerance test (OGTT), and decreased triglyceride content and Oil Red O staining area in the gastrocnemius. Furthermore, RCR restored fructose-induced sarcolemmal overexpression and intracellular less distribution of fatty acid translocase/CD36 that contributes to etiology of insulin resistance by facilitating fatty acid uptake. CONCLUSION: These results suggest that RCR ameliorates insulin resistance in fructose-fed rats by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle. Our findings may provide a better understanding of the traditional use of Rhodila species.

Emodin protects against diabetic cardiomyopathy by regulating the AKT/GSK-3ß signaling pathway in the rat model.

Diabetes mellitus (DM) has been recognized as a major health problem. Emodin (Emo) has been reported to exhibit protective effects against diabetic nephropathy. However, little has been known about the effect of Emo on diabetic cardiomyopathy (DCM). A type 2 DM model was induced in rats by low dose streptozotocin (STZ) combined with high energy intake. We found that Emo-treated groups displayed significantly higher body weight (BW) and lower heart weight (HW)/BW. Furthermore, Emo could significantly decrease blood glucose, total cholesterol (TG) levels, and triglyceride (TC) levels in diabetic rats. Moreover, the Emo-treated group showed a marked increase in heart rate (HR) and showed lower left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular posterior wall thickness (LWPWT), and interventricular septal diastolic wall thickness (IVSD). Emo induced a significant increase in phosphorylation of Akt and GSK-3ß in myocardium. These results suggest that Emo may have great therapeutic potential in the treatment of DCM by Akt/GSK-3ß signaling pathway.

[Effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction].

OBJECTIVE: To investigate the effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction (MI). METHODS: Adult male SD rats were divided into six groups (n = 20 each group): control, diabetes mellitus (DM), MI, DM+MI, DM+MI+ghrelin, DM+MI+ghrelin+D-Lys3-GHRP-6 (GHSR1a inhibitor). DM was induced by streptozotocin (STZ, 60 mg/kg), 3 months later, MI was induced by left anterior descending artery ligation in DM rats. DM+MI+ghrelin group received ghrelin 200 µg×kg(-1)×d(-1) and DM+MI+ghrelin+D-Lys3-GHRP-6 group received ghrelin 200 µg×kg(-1)×d(-1) and D-Lys3-GHRP-6 50 mg×kg(-1)×d(-1) for 4 weeks. Then, cardiac function was measured by echocardiography, microvascular density (MVD) was measured by CD34 immunohistochemistry, myocardial infarct size was determined by Masson staining, the mRNA and protein expressions of vascular endothelial growth factor (VEGF) and receptors Flk-1, Flt-1 were detected by real-time PCR and Western-blot, respectively. RESULTS: Compared with MI group, MVD (15.3 ± 1.0 vs.20.7 ± 1.6, P < 0.05), left ventricular ejection fraction (LVEF) ((64.2 ± 3.4)% vs. (81.3 ± 3.8)%, P < 0.01), left ventricular fractional shortening (LVFS) ((31.7 ± 1.1)% vs. (48.8 ± 3.3)%, P < 0.01) and the mRNA and protein expression of VEGF, Flk-1 and Flt-1 (P < 0.01) were reduced, while myocardial infarct size ((55.8 ± 3.1)% vs. (35.7 ± 2.5)%, P < 0.01) was increased in DM+MI group. These effects were partly reversed in DM+MI+ghrelin group and the beneficial effects of ghrelin were partly abolished by D-Lys3-GHRP-6 (all P < 0.05). CONCLUSIONS: Our results demonstrate that ghrelin could improve microvascular density, cardiac function, and reduce myocardial infarct size of diabetic rats with myocardial infarction via modulating GHSR1a-mediated expressions of VEGF, Flk-1 and Flt-1.

Evaluation of the correlation between fetuin-B levels and essential hypertension: a cross-sectional study.

Background: Fetuin-B, a cytokine that regulates lipid metabolism, has recently been linked to cardiovascular diseases such as coronary heart disease. In this study, we discussed the relationship between fetuin-B and essential hypertension. Method: A bioinformatics analysis of fetuin-B was performed. A total of 206 with essential hypertension and 180 age- and-sex-matched healthy subjects were enrolled. Plasma fetuin-B, endothelin 1 (ET-1), nitric oxide (NO), and adiponectin (ADI) levels were measured using ELISA kits. Results: Bioinformatics analysis has revealed that fetuin-B plays an important role in pathways such as lipid metabolism. Compared with healthy subjects, serum fetuin-B levels in patients with essential hypertension were significantly increased. Correlation analysis showed that the serum fetuin-B level was positively correlated with systolic blood pressure (SBP), diastolic blood pressure, body mass index, fat percentage in vivo, waist-hip ratio, intima-media thickness, low-density lipoprotein cholesterol (LDL-C), glutamyltranspeptidase, alanine transaminase, albumin, fasting blood glucose (FBG), glycated hemoglobin, and ET-1 in the overall study subjects (all P < 0.05) and negatively correlated with HDL-C, ADI, and NO (all P < 0.05). Multivariate linear regression analysis showed that SBP, FBG, LDL-C, ADI, and ET-1 were independent factors affecting serum fetuin-B. A binary logistic regression analysis showed that fetuin-B was an independent risk factor for primary hypertension (odds ratio: 1.060, 95% CI: 1.034-1.086, P < 0.001). Receiver operating characteristic curve analysis was used to evaluate the predictive value of fetuin-B for primary hypertension, and the optimal cutoff point was 83.14 µg/mL (sensitivity 77.4%, specificity 63.3%) (area under the curve) = 0.7738, 95% CI 0.7276-0.8200, P < 0.001). Conclusion: Elevated fetuin-B levels are associated with an increased risk of essential hypertension.

Rhubarb charcoal-crosslinked chitosan/silk fibroin sponge scaffold with efficient hemostasis, inflammation, and angiogenesis for promoting diabetic wound healing.

Diabetic patients often experience long-term risks due to chronic inflammation and delayed re-epithelialization during impaired wound healing. Although the severity of this condition is well known, the treatment options for diabetic wounds are limited. Rhubarb charcoal, a well-known traditional Chinese medicine, has been used to treat skin wounds for thousands of years. We produced a chitosan/silk fibroin sponge scaffold loaded with natural carbonized rhubarb and crosslinked it by freeze-drying to create a highly efficient RCS/SF scaffold. Rhubarb carbon and carboxymethyl chitosan exhibit antibacterial activity and promote wound healing. Owing to its 3D porous structure, this scaffold is antibacterial and pro-angiogenic. It also possesses remarkable properties, such as excellent swelling and biocompatibility. The supportive effect of carbonized rhubarb on mouse fibroblast migration is mediated at the cellular/tissue level by increased skin neovascularization and re-epithelization. Compared to the control group, RCS/SF scaffolds promoted faster healing, increased neovascularization, enhanced collagen deposition, and re-epithelialization within two weeks. The scaffold's pro-healing properties and efficient release of carbonized rhubarb, with rapid hemostatic and good sterilization effects, make it an outstanding candidate for treating diabetic wounds and novel therapeutic interventions for diabetic ulcers.

Local tumor destruction and liver resection increase overall survival in intermediate/advanced hepatocellular carcinoma patients: evidence from a population-based study.

Background: Liver resection (LR) and local tumor destruction (LTD) are effective treatments, but not commonly recommended for patients with intermediate/advanced hepatocellular carcinoma (HCC). This study aimed to explore whether LR/LTD could improve overall survival (OS) of these patients, and to identify the patients who will most likely benefit from LR/LTD. Methods: Data of patients with intermediate/advanced HCC between 2001 and 2018 were extracted from Surveillance, Epidemiology, and End Results database. OS was compared between HCC patients who received LR/LTD and those who did not. A nomogram was constructed for predicting OS, and it was then validated. Results: A total of 535 eligible patients were included, among which 128 received LR/LTD while 407 did not. Significantly higher OS in patients who received LR/LTD was observed (P<0.001). Based on independent prognostic factors obtained from univariate and multivariate analyses, a nomogram was constructed. The C-indices of nomogram were higher than those of the TNM staging system (training cohort: 0.74 vs. 0.59; validation cohort: 0.78 vs. 0.61). Similarly, areas under receiver operating characteristic curves and calibration curves indicated good accuracy of the nomogram. Decision curve analysis curves revealed good clinical practicability of the nomogram. Furthermore, low-risk patients (nomogram score: 0-221.9) had higher OS compared with high-risk patients (nomogram score: higher than 221.9) (P<0.001). Conclusion: LR/LTD significantly improves OS in patients with intermediate/advanced HCC. The nomogram developed in the present study shows high predicating value for OS in patients with intermediate/advanced HCC, which might be useful in selecting patients who are most suitable for LR/LTD.

Oleanolic Acid Inhibits SCD1 Gene Expression to Ameliorate Fructose-Induced Hepatosteatosis through SREBP1c-Dependent and -Independent Mechanisms.

SCOPE: The mechanisms of oleanolic acid (OA) regulating hepatic sterol regulatory element-binding protein (SREBP) 1c/stearoyl-CoA desaturase (SCD) 1 pathway to ameliorate fructose-induced hepatosteatosis are investigated. METHODS AND RESULTS: Rats treated with 10% w/v fructose solution are co-administered by OA for 5 weeks, and then sacrifice after fasting for 14 h. OA reverses the fructose-induced increase in hepatic triglyceride (TG) content and downregulates Scd1 mRNA expression. However, two upstream transcription factors, ChREBP and SREBP1c, remain at normal levels with or without fructose and/or OA. In vivo and in vitro studies using SREBP1c-/- mice and HepG2 cell models show that OA also inhibits SCD1 gene overexpression and high hepatic TG levels induced by fructose. On the other hand, in SCD1-/- mice, when the fructose diet is supplemented with high levels of oleic acid (OLA) to compensate for the deficiency of SCD1, OA inhibits hepatic SREBP1c and lipogenic gene expression and reduces hepatic OLA (C18:1) production to improve fructose and/or OLA induced liver lipid deposition. Furthermore, OA promotes PPARα and AMPK to enhance fatty acid oxidation in fructose + OLA-fed SCD1-/- mice. CONCLUSION: OA may inhibit SCD1 gene expression to ameliorate fructose-induced hepatosteatosis through SREBP1c-dependent and -independent mechanisms.

Association between FTO gene polymorphism and cancer risk: evidence from 16,277 cases and 31,153 controls.

A recent genome-wide association study showed that the rs9939609 polymorphism in the fat mass and obesity-associated (FTO) gene was associated with body mass index (BMI)/obesity in Europeans. Subsequently, several studies have investigated the association between FTO polymorphism and cancer risk. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the association between FTO polymorphism and cancer risk. Published literature from PubMed and Embase databases were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed-effects model. A total of 13 studies involving 16,277 cases and 31,153 controls were identified. The results suggested that FTO rs9939609 polymorphism was not significantly associated with the increased risk of cancer (OR = 1.01, 95 %CI 0.98-1.04), with the exception that a statistically significant association was found for pancreatic cancer (OR = 1.10, 95 %CI 1.03-1.19). No publication bias was detected (Begg's test: P = 0.760; Egger's test: P = 0.553). Our meta-analysis indicated that there was no association between FTO rs9939609 polymorphism and the increased risk of cancer, although this polymorphism was marginally associated with pancreatic cancer. However, the conclusion should be made with caution since most included studies did not take BMI/obesity into account.

[Ghrelin stimulates in vitro angiogenic capacity of rat cardiac microvascular endothelial cells].

OBJECTIVE: To clarify whether ghrelin could promote in vitro rat cardiac microvascular endothelial cells (CMECs) angiogenesis and related mechanisms. METHODS: CMECs were isolated from myocardial tissue of adult male SD rats and characterized by the immunocytochemistry staining with Factor VIII and the capacity of in vitro capillary tube-like formation. The mRNAs and protein expressions of ghrelin and its receptor (growth hormone secretagogue receptor, GHS-R) of CMECs were determined by RT-PCR, Immunofluorescence, ELISA and Western blot. Proliferation, migration and in vitro angiogenesis as well as ERK2 phosphorylation of CMECs were tested in the presence of ghrelin (10(-9) - 10(-7) mol/L) with or without pretreatment with specific MAPK/ERK2 inhibitor PD98059. RESULTS: Purity of CMECs characterized by immunocytochemistry staining with Factor VIII was about 95%, and the cells showed a high ability to form the capillary tube-like structures on Matrigel. Ghrelin and GHS-R were constitutively expressed in CMECs. Proliferation, migration and in vitro angiogenesis capacities of CMECs (72.20 ± 5.72 vs. 28.60 ± 5.13, P < 0.001; 71.00 ± 7.78 vs. 28.60 ± 5.13, P < 0.001) as well as ERK2 phosphorylation (0.92 ± 0.13 vs. 0.29 ± 0.04, P < 0.001; 1.15 ± 0.16 vs. 0.29 ± 0.04, P < 0.001) were significantly enhanced by exogenous ghrelin (10(-8) - 10(-7) mol/L). PD98059 abolished ghrelin-induced ERK2 phosphorylation and in vitro angiogenesis. CONCLUSIONS: Ghrelin and its receptor are expressed in CMECs and ghrelin could stimulate CMECs in vitro angiogenesis through activation of MAPK/ERK2 signaling pathway.

Safety and immunogenicity of inactivated COVID-19 vaccine in patients with metabolic syndrome: A cross-sectional observational study.

Background and aims: The prevalence of metabolic syndrome (MS), wich mainly including hypertension, hyperglycemia, hyperlipidemia, remains high, and the safety and antibody response of inactivated coronavirus disease 2019 (COVID-19) vaccination in patients with metabolic syndrome (MS) is still inconsistency, therefore it is necessary to explore the safety and antibody responses of inactivated COVID-19 vaccination in MS patients in clinical practice. Methods: 157 adults patients who were suffering from MS and 117 health controls (HC) at an interval of at least 21 days after full-course (2nd dose) vaccination were enrolled. The safety of inactivated COVID-19 vaccination was evaluated through collected adverse events (AEs) by questionnaire. The immunogenicity of included participant to inactivated COVID-19 vaccination was represented by serum seropositivity rate of anti-receptor binding domain (RBD) IgG, SARS-CoV-2 neutralizing antibodies (CoV-2 Nab) and titers of anti-RBD IgG, CoV-2 Nab. The B cells, mainly including RBD-specific B cells, RBD-specific memory B cell (MBC), RBD+ resting MBC cells, RBD+ activated MBC cells, RBD+ atypical MBC cells (atyMBCs), and RBD+ intermediate MBC cells, were also analyzed. Results: In terms of safety, all AEs in MS patients were mild and self-limiting, and the incidence was comparable to that of HC participants, with overall AEs within seven days reported in 9.6% (15/157) of 3H and 11.1% (13/117) of HC. Both groups experienced no serious adverse events. As for immunogenicity of MS patients to inactivated COVID-19 vaccination, compared with health controls, the seroprevalence of anti-RBD IgG and CoV-2 Nab was significantly decreased in MS patients (p = 0.000, p = 0.003, respectively), while the titers of anti-RBD IgG (AU/ml) and CoV-2 Nab (µg/ml) were also significant lower in MS patients (p = 0.014, p = 0.002, respectively). As for frequencies of B cells, MS patients had lower frequencies of RBD-specific B cells, RBD+ resting MBCs, and RBD+ intermediate MBCs (p = 0.003, p = 0.000, p = 0.000, respectively), but had a higher frequencies of RBD+ atypical MBCs (p = 0.000) than HC. In comorbidity number subgroups analysis of MS, except frequencies of RBD+ resting MBC cells, RBD+ activated MBC cells and RBD+ intermediate MBC cells had significant difference among three groups (p = 0.035, p = 0.042, p = 0.046, respectively), antibody response had no significant difference among 1H, 2H, and 3H groups (p > 0.05). And took 70 years old as a boundary, also no statistically significant differences (p > 0.05) were found in age subgroups. Lastly, comprehensive analysis in MS patients indicated that interval time after 2nd dose vaccine was the statistical significant factor which impacting antibody response in MS individuals. Conclusions: Inactivated COVID-19 vaccines were well-tolerated, but induced a poorer antibody response against SARS-CoV-2 in MS patients comparing to HC participants. Patients with MS should therefore be more proactive in receiving inactivated COVID-19 vaccine, and a booster vaccination may be considered necessary. Clinical trial registration: https://clinicaltrials.gov/, identifier: NCT05043246.

The association of plasma sortilin with essential hypertension and subclinical carotid atherosclerosis: A cross-sectional study.

Background: Sortilin, a protein that regulates glucose and lipid metabolism, has recently been linked to cardiovascular diseases (CVDs) such as coronary heart disease and carotid artery stenosis. In this study, we measured circulating sortilin concentrations in essential hypertensive (EH) patients, and evaluated the association between sortilin, hypertension, and subclinical carotid atherosclerosis in hypertensive individuals. Methods: This cross-sectional study included 336 individuals, including 186 newly diagnosed EH patients and 150 age-and-sex-matched normotensive healthy subjects (NT). Plasma sortilin and adiponectin (ADI) levels were measured using ELISA kits. In the EH group, high-resolution B-mode ultrasound was used to detect the existence of subclinical carotid atherosclerosis (subAS), which was defined as having a carotid intima-media thickness (cIMT) ≥ 1.0 mm and/or plaque on the carotid artery without any clinical manifestations. Results: Our findings showed that plasma sortilin concentrations ranged from 3.34-11.34 ng/ml for all subjects. Sortilin levels were significantly higher in the EH group than in the NT group (8.10 ± 1.82 ng/ml vs. 6.37 ± 1.52 ng/ml, P < 0.001) and were further upregulated in the EH with subclinical carotid atherosclerosis (EH + subAS) group compared to the EH without subclinical carotid atherosclerosis (EH-subAS) group (8.42 ± 1.75 ng/ml vs. 7.79 ± 1.84 ng/ml, P < 0.05). In correlation analysis, sortilin was positively correlated with systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), white blood cell (WBC), endothelin-1 (ET-1), high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and cIMT (all P < 0.05) and negatively associated with NO and ADI (P < 0.001). Multiple linear regression analysis revealed that SBP, LDL-C, and ET-1 were independently associated with plasma sortilin levels. Increased sortilin levels were independently associated with the risk of EH (OR: 1.86, 95%CI: 1.56-2.20, P < 0.001) and EH + subAS (OR: 1.33, 95%CI: 1.07-1.66, P = 0.011), after adjustment for multiple risk factors. Restricted spline curve showed that elevated sortilin levels increase the odds of having EH. Conclusion: Elevated sortilin levels are associated with an increased risk of essential hypertension and subclinical carotid atherosclerosis in hypertensive patients.

Suppression of NHE1 by small interfering RNA inhibits HIF-1α-induced angiogenesis in vitro via modulation of calpain activity.

Hypoxia-inducible factor-1 (HIF-1) orchestrates angiogenesis under hypoxic conditions mainly due to increased expression of such target genes as vascular endothelial growth factor (VEGF). Na+/H+exchanger-1 (NHE1), a potential HIF target gene product, plays a pivotal role in proliferation, survival, migration, adhesion and so on. However, it is unknown whether NHE1 is involved in HIF-1α-induced angiogenesis. This present study demonstrated that the expression of NHE1 was much higher in human umbilical vein endothelial cells (HUVECs) infected with adenovirus encoding HIF-1α (rAd-HIF) than with vacuum adenovirus (vAd). HIF-1α also increased the expression of VEGF, the expression and activity of calpains, and the intracellular pH. Moreover, small interfering RNA targeting NHE1 (NHE1 siRNA) dramatically decreased the expression of NHE1 and thus lowered the intracellular pH, and it also attenuated the protein expression of calpain-2 but not calpain-1, resulting in the lower calpain activity. Furthermore, HIF-1α enhanced the proliferation, migration and Matrigel tube formation, which were inhibited by NHE1 siRNA. Finally, the inhibitory effect of NHE1 siRNA was reversed by VEGF and the reversibility of the later was abrogated by the calpain inhibitor ALLM. In conclusion, the findings have revealed that NHE1 might participate in HIF-1-induced angiogenesis due, at least in part, to the alteration of the calpain activity, suggesting that NHE1 as well as calpains might represent a potential target of controlling angiogenesis in response to the hypoxic stress under various pathological conditions.

Bone marrow mesenchymal stromal cells with support of bispecific antibody and ultrasound-mediated microbubbles prevent myocardial fibrosis via the signal transducer and activators of transcription signaling pathway.

BACKGROUND AIMS: This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). METHODS: BiAb (anti-CD29 × anti-myosin light chain antibody; AMLCA) was prepared and combined with isolated MSC from male mice and transfused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB (MSC + BiAb + MB). This study included seven groups: MSC + BiAb + MB; MSC; BiAb; MB; MSC + BiAb; untreated; and control. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). Collagen distribution was observed using Sirius Red staining. The protein expression of signal transducer and activators of transcription (STAT)1 and STAT3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the MSC + BiAb + MB group, second highest in the MSC + BiAb group, and lowest in MSC alone. Compared with the untreated group, MSC + BiAb + MB, MSC + BiAb and MSC groups had decreased levels of MMP-9, TIMP-1, STAT1 and collagen deposition, and increased levels of STAT3. Upregulated STAT3 and downregulated TIMP-1 were significantly different in MSC + BiAb + MB compared with MSC alone or MSC + BiAb. CONCLUSIONS: The homing rate and repairing efficacy of MSC improved with treatment utilizing a combination of BiAb and MB. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway.

Sitagliptin on carotid intima-media thickness in type 2 diabetes and hyperuricemia patients: a subgroup analysis of the PROLOGUE study.

BACKGROUND AND AIMS: Studies have shown that dipeptidyl peptidase-4 (DDP-4) inhibitors have anti-atherosclerotic effects. However, in the PROLOGUE study, sitagliptin failed to slow the progression of carotid intima-media thickness (CIMT) relative to conventional therapy. We conducted a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in CIMT in subgroups with or without hyperuricemia. METHODS: The PROLOGUE study was a randomized controlled trial of 442 patients with type 2 diabetes mellitus (T2DM). Patients were randomized to receive sitagliptin added therapy or conventional therapy. Based on the serum uric acid levels of all study populations in the PROLOGUE study, we divided them into hyperuricemia subgroup (n = 104) and non-hyperuricemia subgroup (n = 331). The primary outcome was changed in carotid intima-media thickness (CIMT) parameters compared with baseline during the 24 months treatment period. RESULTS: In the hyperuricemia subgroup, compared with the conventional therapy group, the changes in the mean internal carotid artery (ICA)-IMT and max ICA-IMT at 24 months were significantly lower in the sitagliptin group [-0.233 mm, 95% confidence interval (CI) (-0.419 to 0.046), p = 0.015 and -0.325 mm, 95% CI (-0.583 to -0.068), p = 0.014], although there was no significant difference in the common carotid artery CIMT. CONCLUSION: The results of our analysis indicated that sitagliptin attenuated the progression of CIMT than conventional therapy in T2DM and hyperuricemia patients.

Apple pomace and rosemary extract ameliorates hepatic steatosis in fructose-fed rats: Association with enhancing fatty acid oxidation and suppressing inflammation.

Apple pomace and rosemary (AR) have been reported to contain rich bioactive molecules, which have numerous metabolic effects. Our preliminary work revealed that AR ameliorated fructose-induced insulin resistance in rats by modulating sarcolemmal CD36 and glucose transporter-4. The present study aimed to further examine how AR improves metabolic disorders by investigating the effect of AR on hepatic steatosis induced by fructose overconsumption. The results demonstrated that AR (100 mg/kg daily by gavage for 5 weeks) attenuated chronic liquid fructose consumption-induced increases in liver triglyceride content in rats. Mechanistically, reverse transcription-quantitative PCR and western blot analysis results indicated that AR reversed fructose-induced suppression of hepatic peroxisome proliferator-activated receptor α, carnitine palmitoyl-transferase 1α, sirtuin 1 and peroxisome proliferator-activated receptor-γ coactivator 1α, which were associated with the fatty acid oxidative (FAO) pathway. In addition, AR treatment decreased the expression levels of the pro-inflammatory proteins NF-κB and tumor necrosis factor-α. However, AR had no effect on the genes related to lipogenesis and the very low-density lipoprotein-export pathway in rat liver. Thus, the present results suggested that AR treatment diminished long-term fructose overconsumption-induced fatty liver, which was associated with enhanced FAO and suppressed inflammation.

Rhodiola crenulata root extract ameliorates fructose-induced hepatic steatosis in rats: Association with activating autophagy.

BACKGROUND: Increasing evidence has shown the beneficial effects of Rhodiola species on metabolic disorders, but their mechanisms are not clear. Hepatic steatosis is closely related to metabolic disorders, we aim to investigate the therapeutic effects of Rhodiola crenulata root (RCR) on fructose-induced hepatic steatosis and explore the underlying mechanisms. PURPOSE: To observe the effect of Rhodiola crenulata root extract (RCR) on fructose-induced hepatic steatosis in Sprague-Dawley (SD) rats and explore its possible mechanism. METHODS: Male Sprague-Dawley rats were treated with liquid fructose in their drinking water over 18 weeks. The extract of RCR was co-administered (once daily by oral gavage) during the last 5 weeks. Liver lipid deposition and morphological changes were observed by Oil red O staining. Real-time fluorescence quantitative PCR, Western blot and immunoprecipitation were used to detect gene and protein expression in liver. RESULTS: RCR (50 mg/kg) reversed liquid fructose-induced increase in hepatic triglyceride content in rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in RCR-treated rats. However, RCR treatment did not affect chow intake and body weight of rats. Although some genes of the pathways involved in DNL (ChREBP, SREBP-1c, FAS, ACC1, SCD1, DGAT1, DGAT2 and MGAT2), fatty acid ß-oxidation (PPARα, CPT1a, ACO and FGF21), VLDL-export (MTTP) and decomposition (HSL, ATGL) in the liver of fructose-fed rats were not changed significantly after RCR administration, the decrease in PPARα and PGC-1α proteins was reversed by RCR. Notably, SIRT1 mRNA and protein expression increased significantly with RCR administration. Furthermore, RCR increased expression of ATG4B, Beclin1 and decreased expression of Bcl2-Beclin1 complex dramatically. Meanwhile, RCR decreased the acetylation of beclin1. Moreover, RCR increased expression of autophagosome markers including LC3B and ATG5-ATG12-ATG16L1, and decreased expression of autophagolysosome marker p62 in the livers of fructose-fed rats. CONCLUSIONS: RCR has a certain improvement effect on fructose-induced hepatic steatosis, which is related to the activation of autophagy.