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.

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.

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.

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.

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.

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.

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.

6-Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC-1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1.

SCOPE: This study investigates the dual actions of 6-gingerol in stimulating both plasma adiponectin and muscular adiponectin receptor signaling in naturally ageing rats. METHODS AND RESULTS: Twenty-two-month-old male SD rats were treated with 6-gingerol (0.2 mg kg-1 , once daily) for 7 weeks. 6-Gingerol can attenuate age-associated high plasma triglyceride, glucose, and insulin concentrations under fasting conditions as well as suppress the increase in the HOMA-IR index and inhibit the decrease of muscular p-Akt/Akt protein in ageing rats, which indicates an improvement of systemic and muscular insulin sensitivity. Accompanying these changes, treatment with 6-gingerol attenuates excessive triglyceride accumulation, enhances mitochondrial function, and promotes a transition from a fast- to slow-fiber type and muscle oxidative metabolism in the red gastrocnemius of ageing rats. More importantly, 6-gingerol not only increases the plasma and adipose tissue adiponectin concentrations, but also elevates muscular AdipoR1 expression and activates downstream AMPK phosphorylation as well as upregulates PGC-1α in vivo and in vitro. CONCLUSION: 6-Gingerol may improve ectopic lipid accumulation, mitochondrial dysfunction, and insulin resistance in skeletal muscle of ageing rats. These effects rely, at least in part, on the elevated plasma adiponectin concentration and muscle AdipoR1 level to dually activate the AMPK/PGC-1α signaling pathway.

Ghrelin inhibits atherosclerotic plaque angiogenesis and promotes plaque stability in a rabbit atherosclerotic model.

Intraplaque angiogenesis associates with the instability of atherosclerotic plaques. In the present study, we investigated the effects of ghrelin on intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis. The rabbits were randomly divided into three groups, namely, the control group, atherosclerotic model group, and ghrelin-treated group, with treatments lasting for 4 weeks. We found that the thickness ratio of the intima to media in rabbits of the ghrelin-treated group was significantly lower than that in rabbits of the atherosclerotic model group. The number of neovessels and the levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) decreased dramatically in rabbits of the ghrelin-treated group compared to those of the atherosclerotic model group. Ghrelin significantly decreased the plaque content of macrophages, matrix metalloproteinase (MMP)-2, and MMP-9, in a rabbit model of atherosclerosis. In addition, the level of the pro-inflammatory factor monocyte chemoattractant protein (MCP)-1 was significantly lower in rabbits of the ghrelin-treated group than in rabbits of the atherosclerotic model group. In summary, ghrelin can inhibit intraplaque angiogenesis and promote plaque stability by down-regulating VEGF and VEGFR2 expression, inhibiting the plaque content of macrophages, and reducing MCP-1 expression at an advanced stage of atherosclerosis in rabbits.

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.

Jiangzhi Capsule improves fructose-induced insulin resistance in rats: Association with repair of the impaired sarcolemmal glucose transporter-4 recycling.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiangzhi Capsule, originated from an experienced formula in traditional Chinese Medicine, has been listed and used for the management of metabolic abnormalities in Australia for a long time. To better understand Jiangzhi Capsule, this study investigated its effect on insulin resistance. MATERIALS AND METHODS: Male rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. RESULTS: Treatment with Jiangzhi Capsule (100mg/kg) attenuated fructose overconsumption-induced increases in basal plasma insulin concentrations, the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. The increased plasma glucose concentrations during oral glucose tolerance test were also inhibited. Furthermore, Jiangzhi Capsule had a trend to attenuate the decreased ratios of glucose and non-esterified fatty acids to plasma insulin concentrations. Mechanistically, this insulin-sensitizing action was accompanied by normalization of the downregulated sarcolemmal glucose transporter (GLUT)-4 protein expression and the decreased phosphorylated Akt to total Akt protein ratio in gastrocnemius. CONCLUSIONS: These results suggest that Jiangzhi Capsule ameliorates fructose-induced insulin resistance with a link to repair of the impaired sarcolemmal GLUT-4 recycling through modulation of the ratio of phosphorylated Akt to total Akt in gastrocnemius. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule for the management of insulin resistance-associated disorders.

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.

Effectiveness of Ivabradine in Treating Stable Angina Pectoris.

Many studies show that ivabradine is effective for stable angina.This meta-analysis was performed to determine the effect of treatment duration and control group type on ivabradine efficacy in stable angina pectoris.Relevant articles in the English language in the PUBMED and EMBASE databases and related websites were identified by using the search terms "ivabradine," "angina," "randomized controlled trials," and "Iva." The final search date was November 2, 2015.Articles were included if they were published randomized controlled trials that related to ivabradine treatment of stable angina pectoris.Patients with stable angina pectoris were included.The patients were classified according to treatment duration (<3 vs ≥3 months) or type of control group (placebo vs beta-receptor blocker). Angina outcomes were heart rate at rest or peak, exercise duration, and time to angina onset.Seven articles were selected. There were 3747 patients: 2100 and 1647 were in the ivabradine and control groups, respectively. The ivabradine group had significantly longer exercise duration when they had been treated for at least 3 months, but not when treatment time was less than 3 months. Ivabradine significantly improved time to angina onset regardless of treatment duration. Control group type did not influence the effect of exercise duration (significant) or time to angina onset (significant).Compared with beta-blocker and placebo, ivabradine improved exercise duration and time to onset of angina in patients with stable angina. However, its ability to improve exercise duration only became significant after at least 3 months of treatment.

Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis.

UNLABELLED: 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) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. 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). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. CONCLUSION: CD47 can enhance the homing rate and repairing efficacy of MSC. 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.

Ghrelin ameliorates impaired angiogenesis of ischemic myocardium through GHSR1a-mediated AMPK/eNOS signal pathway in diabetic rats.

OBJECTIVES: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), has been found to stimulate angiogenesis in vivo and in vitro. However, the effect and the corresponding mechanisms of ghrelin on impaired myocardial angiogenesis in diabetic and myocardial infarction (MI) rat model are still unknown. METHODS: In the present study, adult SD rats were randomly divided into 4 groups: control, DM, DM+ghrelin, DM+ghrelin+[D-Lys3]-GHRP-6 groups. DM was induced by streptozotocin (STZ) 60 mg/kg body weight. 12 weeks post STZ injection all groups were subjected to MI, which was induced by ligation left anterior descending artery (LAD). Ghrelin and [D-Lys3]-GHRP-6 were administered via intraperitoneal injection at the doses 200 µg/kg and 50mg/kg for 4 weeks, respectively. Left ventricular function, microvascular density (MVD), myocardial infarct size, the expression of hypoxia-inducible factor (HIF1α), vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1), AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation were examined. RESULTS: Compared with the DM group, left ventricular ejection fraction (LVEF), fractional shortening (FS), and MVD were increased, whereas myocardial infarct size decreased remarkably in DM+ghrelin group. For the mechanism study, we found that ghrelin promoted the HIF1α, VEGF, Flk-1 and Flt-1 expression, AMPK and eNOS phosphorylation in diabetic rats. However, the above biochemical events in ghrelin treated diabetic rats were completely inhibited by GHSR-1a blocker [D-Lys3]-GHRP-6. CONCLUSIONS: These results suggest that administration of ghrelin ameliorates impaired angiogenesis in diabetic MI rats. And these beneficial effects derive from regulating GHSR1a-mediated AMPK/eNOS signal pathway by upregulating of HIF1α, VEGF and its receptors Flk-1, Flt-1 expressions.