Exploration of chemical components and metabolite synthesis pathways in eight Ephedra species based on HS-GC-MS and UPLC-Q-TOF-MS.

Objective: Ephedra, widely used in clinical practice as a medicinal herb, belongs to the genus Ephedra in the family Ephedraceae. However, the presence of numerous Ephedra varieties and variants requires differentiation for accurate identification. Methods: In this study, we employed headspace gas chromatography mass spectrometry (HS-GC-MS), ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), and global natural products social molecular networking (GNPS) for chemical component identification. Chemometric analysis was used to analyze the differential components. Metabolic analysis and Kyoto encyclopedia of genes and genomes (KEGG) enrichment were utilized to explore the synthesis pathways of different components. Result: A total of 83 volatile and 79 non-volatile components were identified in Ephedra species. Differential analysis revealed that among the eight Ephedra stems, 18 volatile and 19 non-volatile differential compounds were discovered, whereas Ephedra roots exhibited 21 volatile and 17 non-volatile markers. Volatile compounds were enriched in four synthetic pathways, while non-volatile components were enriched in five pathways among the differentiated components. Conclusion: This study is the first to conduct a comparative analysis of chemical components in different Ephedra species and parts. It provides a foundational reference for authenticating Ephedra herbs, evaluating medicinal resources, and comparing quality in future studies.

Two new flavanones from Polytrichum commune Hedw.

Seven flavanones, including two new compounds coupled with styryl units, communins C (1) and D (2), as well as five known compounds, were isolated from Polytrichum commune Hedw. The planar structures of all compounds were determined using extensive spectroscopic analysis. The absolute configurations of two new compounds were assigned by comparing experimental ECD with calculated ECD. The cytotoxicity of all isolates against HCT-116, BGC803, MCF7 and PANC-1 cell lines was evaluated. Communin D exhibited significant cytotoxic activity on BGC803 cells with an IC50 value of 9.3 µM.

The Relation Between Red Blood Cell Distribution Width and Coronary Atherosclerotic Plaque Vulnerability Detected by Intracoronary Optical Coherence Tomography.

BACKGROUND: A higher red blood cell distribution width (RDW) predicts major adverse cardiac events in patients with coronary artery disease (CAD). However, there are only a few studies regarding the relationship between RDW and vulnerable plaques. Thus, the purpose of the present study is to retrospectively explore the predictive value of the association between RDW and plaque vulnerability assessed by optical coherence tomography (OCT) in patients with cardiovascular (CV) diseases. METHODS: This study included 35 patients with stable angina pectoris (SAP) and 70 patients with the acute coronary syndrome (ACS). We documented clinical features as well as peripheral RDW. Plaque vulnerability was determined by OCT. We defined thin-cap fibroatheroma (TCFA) as a lipid-rich plaque (fibrous cap <65 µm thick). RESULTS: Plaque rupture was detected more frequently in patients with ACS compared with patients with SAP (62.9 vs. 2.9%, p<0.001, and the corresponding TCFA were 50.69±15.68 vs. 80.03±21.60 µm, p<0.001, respectively). A higher RDW was found in patients with ACS than in patients with SAP (p<0.001). A cut-off value of RDW >13.85% could detect ruptured plaque with a sensitivity of 72.3% and a specificity of 62%. CONCLUSION: TCFA and plaque rupture were detected more frequently in patients with ACS compared with SAP. Elevated RDW was positively the predictive value of the association between plaque vulnerability.

Effects of different doses of canagliflozin on blood pressure and lipids in patients with type 2 diabetes: a meta-analysis.

BACKGROUND: Canagliflozin is a sodium glucose-cotransporter-2 receptor inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). However, it is less prescribed due to increased LDL cholesterol (LDL-C), high incidence of urinary tract infection (UTI), high cost. Data on the effect of canagliflozin on blood pressure (BP) are also limited. We conducted a meta-analysis of randomized controlled trials (RCTs) to review dosedependent effects of canagliflozin on BP and lipids in patients with T2DM. METHODS: A meta-analysis of RCTs in patients with T2DM was conducted. MEDLINE, the Cochrane Library of Trials and Clinicaltrials.gov were searched for relevant studies from January 2008 to May 2021. RESULTS: Compared with placebo, canagliflozin 100 mg reduced SBP by 3.43 mmHg and DBP by 1.05 mmHg. Canagliflozin 100 mg increased LDL-C by 0.10mmol/l and HDL cholesterol (HDL-C) by 0.05 mmol/l. Compared with placebo, canagliflozin 300 mg reduced SBP by 4.75 mmHg and DBP by 1.69 mmHg. Canagliflozin 300 mg increased LDL-C by 0.16 mmol/l and HDL-C by 0.06 mmol/l. Compared with canagliflozin 100 mg, canagliflozin 300 mg further reduced SBP by 1.21 mmHg and DBP by 0.64 mmHg, and further increased LDL-C by 0.06 mmol/l and HDL-C by 0.02 mmol/l. Compared with placebo and canagliflozin 100 mg, canagliflozin 300 mg increased the risk of UTI. CONCLUSION: The current meta-analysis provides new evidence on different doses of canagliflozin as an antihypertensive agent in T2DM complicated by hypertension; however, LDL-C and the risk of UTI should be monitored.

Excimer laser coronary atherectomy for a severe calcified coronary ostium lesion: A case report.

BACKGROUND: Percutaneous coronary intervention can be challenging for ostial coronary artery lesions due to calcium burden and elastic fiber content. Excimer laser coronary atherectomy (ELCA) is a less common treatment for severe calcified coronary ostium lesions. CASE SUMMARY: An 81-year-old male presented to the Cardiology Department of Qingdao Municipal Hospital with a 1-year history of chest pain. Coronary angiography showed severe calcific stenosis (approximately 90%) in the right coronary artery ostium. The right coronary artery ostium was unable to be advanced using a 2.5 mm × 12.0 mm balloon (NC Sprinter, Medtronic, United States) or dilated using a 2.0 mm × 12.0 mm balloon (Sprinter, Medtronic, United States). The patient underwent successful ELCA and balloon dilation of the calcified coronary ostium lesion. CONCLUSION: ELCA appears to be a safe and effective treatment for the management of severe calcified coronary ostium lesions.

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement: A Meta-Analysis.

We determined the incidence, clinical characteristics, and risk factors of post-transcatheter aortic valve replacement (TAVR)-associated infective endocarditis (IE). We compared the incidence of IE after TAVR versus after surgical aortic valve replacement (SAVR). The incidence rate of IE 1-year post-TAVR was 0.9% (95% confidence interval [CI]: 0.8-1.0). Transcatheter aortic valve replacement was associated with significantly reduced IE incidence (incidence rate ratio: 0.69, 95% CI: 0.52-0.92, P = .011) compared with SAVR. In patients with TAVR IE, the pooled in-hospital mortality was 37.8% (95% CI: 32.4-43.3, I2 = 54.9%). Pooled adjusted hazard ratio (HR) revealed that peri-procedural peripheral artery disease (HR: 4.02, 95% CI: 2.28-7.10, P < .0001), moderate or severe residual aortic regurgitation (HR: 2.34, 95% CI: 1.53-3.59, P < .0001), orotracheal intubation (HR: 2.13, 95% CI: 1.19-3.82, P = .011), and male gender (HR: 1.70, 95% CI: 1.47-1.97, P < .0001) were risk factors for post-TAVR IE. Post-TAVR IE is a life-threatening complication often resulting in in-hospital mortality. The current evidence-based meta-analysis to identify risk factors may lead to the development of effective preventive and therapeutic strategies for post-TAVR IE to ultimately improve patient outcomes.

Effects of LCZ696 (Sacubitril/Valsartan) on Blood Pressure in Patients with Hypertension: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: LCZ696 (sacubitril/valsartan), a first-in-class angiotensin receptor-neprilysin inhibitor, can significantly reduce blood pressure in patients with heart failure. We performed this meta-analysis to determine the antihypertensive effect of LCZ696 in patients with hypertension. METHODS: Randomized controlled trials were searched in MEDLINE, the Cochrane Library, and Clinicaltrials.gov. Twelve studies with a total of 6,064 participants were included. RESULTS: Compared with angiotensin receptor blockers (ARBs), LCZ696 100 mg caused a significant reduction in systolic blood pressure (SBP) (mean difference [MD] -1.58 mm Hg, 95% confidence interval [CI] -2.09 to -1.07, p < 0.05) and diastolic blood pressure (DBP) (MD -0.66 mm Hg, 95% CI -0.98 to -0.33, p < 0.05). LCZ696 200 mg caused a significant reduction in SBP (MD -4.94 mm Hg, 95% CI -6.54 to -3.35, p < 0.05), DBP (MD -2.24 mm Hg, 95% CI -2.74 to -1.75, p < 0.05), 24-h ambulatory SBP (24 h ASBP; MD -3.69 mm Hg, 95% CI -4.80 to -2.58, p < 0.05), and 24-h ADBP (MD -1.71 mm Hg, 95% CI -2.13 to -1.28, p < 0.05). LCZ696 400 mg caused a significant reduction in SBP (MD -6.25 mm Hg, 95% CI -7.90 to -4.61, p < 0.05), DBP (MD -2.30 mm Hg, 95% CI -2.80 to -1.80, p < 0.05), 24-h ASBP (MD -4.31 mm Hg, 95% CI -6.56 to -2.07, p < 0.05), and 24 h ADBP (MD -1.69 mm Hg, 95% CI -2.59 to -0.79, p < 0.05). Compared with LCZ696 200 mg, LCZ696 400 mg caused a significant reduction in SBP (MD 1.71 mm Hg, 95% CI 1.15 to 2.27, p < 0.05), DBP (MD 0.90 mm Hg, 95% CI 0.65 to 1.16, p < 0.05), 24-h ASBP (MD 1.50 mm Hg, 95% CI 0.84 to 2.17, p < 0.05), and 24-h ADBP (MD 0.76 mm Hg, 95% CI 0.47 to 1.06, p < 0.05). CONCLUSIONS: The blood pressure-lowering effect of LCZ696 is dose-related. This meta-analysis confirms the antihypertensive effects of LCZ696.

Mangiferin activates Nrf2 to attenuate cardiac fibrosis via redistributing glutaminolysis-derived glutamate.

Cardiac injury is followed by fibrosis, characterized by myofibroblast activation. Excessive deposition of extracellular matrix (ECM) impairs the plasticity of myocardium and results in myocardial systolic and diastolic dysfunction. Mangiferin is a xanthonoid derivative rich in plants mangoes and iris unguicularis, exhibiting the ability to ameliorate metabolic disorders. This study aims to investigate whether mangiferin attenuates cardiac fibrosis via redox regulation. The transverse aortic constriction (TAC) in mice induced cardiac fibrosis with impaired heart function. Oral administration of mangiferin (50 mg/kg, 4 weeks) inhibited myofibroblast activation with reduced formation of ECM. The impaired left ventricular contractive function was also improved by mangiferin. TGF-ß1 stimulation increased glutaminolysis to fuel intracellular glutamate pool for the increased demands of nutrients to support cardiac myofibroblast activation. Mangiferin degraded Keap1 to promote Nrf2 protein accumulation by improving its stability, leading to Nrf2 activation. Nrf2 transcriptionally promotes the synthesis of antioxidant proteins. By activating Nrf2, mangiferin promoted the synthesis of glutathione (GSH) in cardiac fibroblasts, likely due to the consumption of glutaminolysis-derived glutamate as a source. Meanwhile, mangiferin promoted the exchange of intracellular glutamate for the import of extracellular cystine to support GSH generation. As a result of redistribution, the reduced glutamate availability failed to support myofibroblast activation. In support of this, the addition of extracellular glutamate or α-ketoglutarate diminished the inhibitory effects of mangiferin on cardiac myofibroblast proliferation and activation. Moreover, cardiac knockdown of Nrf2 attenuated the cardioprotective effects of mangiferin in mice subjected to TAC. In conclusion, we demonstrated that activated myofibroblasts were sensitive to glutamate availability. Mangiferin activated Nrf2 and redistributed intracellular glutamate for the synthesis of GSH, consequently impairing cardiac myofibroblast activation due to decreased glutamate availability. These results address that pharmacological activation of Nrf2 could restrain cardiac fibrosis via metabolic regulation.

Characteristics of culprit lesions in young patients with metabolic syndrome and classic cardiovascular risk factors.

The association between cardiovascular risk factors (CVRFs) and characteristics of coronary plaque in young patients has remained to be fully elucidated. Therefore, the present study sought to determine the association between CVRFs and phenotypes of culprit coronary plaques revealed by optical coherence tomography (OCT) in young patients with stable coronary heart disease (CHD) and acute coronary syndrome (ACS). OCT imaging pullback was performed at corresponding sites on 123 lesions in 123 young patients (age, 36±7 years), including those with stable CHD and ACS. Patients with analyzable OCT images were classified as having thin-cap fibroatheromas (TCFAs), plaque rupture, macrophage accumulation, calcified nodule, vasa vasorum, cholesterol crystal and erosion. TCFAs were more prevalent in patients with metabolic syndrome (MetS) than in those without MetS (P=0.020). Plaque rupture was more common in smokers than in non-smokers (P=0.002). Multivariate analysis indicated that MetS was independently associated with TCFAs (P=0.041) and smoking was independently associated with plaque rupture (P=0.006). Young patients with MetS were demonstrated to have more extensive TCFAs and young smokers had a higher prevalence of culprit plaque rupture.

Protective effects of induced cardiosphere on myocardial ischemia-reperfusion injury through secreting interleukin 10.

BACKGROUNDS: Myocardial ischemia-reperfusion injury (MI-RI) has many adverse complications with high mortality rate. It has been demonstrated that the induced cardiospheres (iCS), generated from adult skin fibroblasts via somatic reprogramming, represents a novel source for cell therapy in myocardial infarction. However, whether the iCS could also be applied to treat MI-RI remains unclear. Thus, we investigated the therapeutic application of iCS in the mice model MI-RI. METHODS: The mice model of MI-RI was established and the iCS cells were transplanted to the mice via tail-vein injection. Left ventricular (LV) dimensions and LV pressure-volume measurements were assessed by parasternal long-axis echocardiography. The infarct size was determined by histology analysis. And the inflammatory responses were analyzed by using enzyme-linked immunosorbent assay (ELISA). RESULTS: The LV function was significantly improved after the iCS transplantation when compared to the vehicle control group, including the end-systolic pressure and dP/dtMax. Furthermore, the infarct size was significantly decreased after the iCS transplantation. The protein levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), were down-regulated by the iCS transplantation while the IL-10 was up-regulated. The anti-inflammatory factor IL-10 was found to be expressed and secreted by the iCS cells and knocking down the IL-10 in iCS would significantly impair the therapeutic effects of iCS in the mice model of MI-RI. CONCLUSION: The present study indicated that the iCS had therapeutic effects on the mice model of MI-RI through secreting the IL-10.

[Discussion on medicinal value of Saposhnikoviae Radix based on difference of ketone content in cortex and wood of Saposhnikoviae Radix].

In order to confirm the tradition that bolting Saposhnikoviae Radix could not be used as medicine,the content of four chromone components in the cortex and wood of Saposhnikoviae Radix was analyzed by high performance liquid chromatography( HPLC),and the chemical fingerprints were established,12 common peaks were calibrated. The similarity analysis found that the similarity between batches was 0. 115-0. 995,it indicates that the cortex and wood of Saposhnikoviae Radix have certain differences. On this basis,systematic clustering analysis,principal component analysis and orthogonal partial least squares discriminant analysis were carried out with the content of four chromone components and whether they met the pharmacopoeia criteria as the original variables. The results showed that the content of the four components in the cortex of Saposhnikoviae Radix was much higher than that in the wood,and the four components detected were able to distinguish the cortex and the wood of Saposhnikoviae Radix. The results of the study reveal the tradition that bolting Saposhnikoviae Radix should not be used as medicine dut to decreased quality.

Chelidonine enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.

BACKGROUND: Lenvatinib is a newly approved molecular targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the high cost associated with this treatment poses a huge financial burden on patients and the entire public health system. Therefore, there is an urgent need to develop novel strategies that enhance the antitumor effect of lenvatinib. METHODS: The antitumor effects of chelidonine or/and lenvatinib on HCC cell lines MHCC97-H and LM-3 were examined using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2- H-tetrazolium bromide (MTT) assay. For the in-vivo investigation, the effect on subcutaneous or intrahepatic tumor growth in nude mice was also determined. The mRNA levels of epithelial mesenchymal transition (EMT)-related factors were examined through quantitative polymerase chain reaction or Western blot. RESULTS: In the present study, we found that treatment with chelidonine enhanced the apoptotic effect of lenvatinib on HCC cells and the in-vivo growth of HCC tumors in nude mice. Mechanistically, treatment with chelidonine increased the expression of epithelial indicator E-cadherin, whereas it decreased the expression of mesenchymal indicators N-cadherin and Vimentin. These findings suggest that chelidonine restricted the EMT in HCC cells. CONCLUSION: Chelidonine inhibits the process of EMT and enhances the antitumor effect of lenvatinib on HCC cells.

Aortic Arch Calcification Is a Strong Predictor of the Severity of Coronary Artery Disease in Patients with Acute Coronary Syndrome.

BACKGROUND: The purpose of this study was to investigate the correlation of the extent of aortic arch calcification (AAC) detectable on chest X-rays with the severity of coronary artery disease (CAD) as evaluated by the SYNTAX score (SS) in patients with acute coronary syndrome (ACS). METHODS: A total of 1,418 patients (344 women; 59 ± 10 years) who underwent coronary angiography for ACS and were treated with coronary revascularization were included in the present study; chest X-rays were performed on admission. The AAC extent was divided into four grades (0-3). SS was calculated based on each patient's coronary angiographic findings. The relationship between the AAC extent and SS was assessed. RESULTS: The AAC extent was positively correlated with SS (ρ = 0.639, P < 0.001). In the multivariate analysis, compared with grade 0, odds ratios (ORs) of AAC grades 1, 2, and 3 in predicting SS >22 were 12.95 (95% CI, 7.85-21.36), 191.76 (95% CI, 103.17-356.43), and 527.81 (95% CI, 198.24-1405.28), respectively. Receiver operating characteristic curve analysis yielded a strong predictive ability of the AAC extent for SS >22 (area under curve = 0.840, P < 0.001). Absence of AAC had a sensitivity, specificity, positive prognostic value, negative prognostic value, and accuracy of 46.7%, 95.9%, 94.1%, 56.4%, and 67.3%, respectively, for SS ≤22. AAC grades ≥2 had a sensitivity of 66.3%, specificity of 89.2%, positive prognostic value of 81.5%, negative prognostic value of 78.6%, and accuracy of 79.6% for the correct identification of SS >22. CONCLUSIONS: The extent of AAC detectable on chest X-rays might provide valuable information in predicting CAD severity in ACS patients.

Self-healing hydrogel with cross-linking induced thermo-response regulated light emission property.

With increasing attention paid to smart materials, self-healing hydrogels with thermo-responses have been greatly developed in the past several years. At the same time, fluorescent or light emitting polymers have been studied for use as bioimaging tools and drug delivery vehicles. In this research, thermo-responsive self-healing hydrogels with aggregation-induced emission (AIE) property were prepared from tetraphenylethylene (TPE) containing TPE-poly(N,N-dimethylacrylamide-stat-Diacetone acrylamide) [TPE-P(DMA-stat-DAA)] cross-linked by diacylhydrazide. In addition to self-healing based on reversible acylhydrazone bond, the copolymer and hydrogels showed thermo-responses. The lower critical solution temperature (LCST) of the hydrogels was regulated to body temperature. Based on the AIE property of the TPE unit, the hydrogels showed an enhanced light emitting property above the LCST, which was regulated by temperature change. The in vitro cytotoxicity experiment showed that the hydrogels are not toxic, and the DOX release rate can be enhanced by low pH values, which endowed this kind of thermo-responsive light emitting hydrogel with great potential for applications in bio-diagnosis, drug delivery, artificial organs with light sensitive detection, etc.

Culprit Lesion Characteristics in Young Patients with Hyperhomocysteinemia.

BACKGROUND The relationships between culprit coronary plaque characteristics and hyperhomocysteinemia (HHcy) are not fully understood in young patients. In this study we investigated the relationship between culprit atherosclerotic plaque phenotype assessed by optical coherence tomography (OCT) and hyperhomocysteinemia (HHcy) in young patients. MATERIAL AND METHODS We investigated the OCT imaging and HHcy of 123 lesions in 123 young patients (≤45 years of age). According to OCT images, culprit lesions were classified as thin-cap fiber atheroma (TCFA), thrombus, and other. The 123 patients were grouped as: HHcy group (53 cases, HHcy ≥15.5 µmol/l) and control group (70 cases, HHcy <15.5 µmol/l). RESULTS Compared with the control group, the HHcy group had a higher proportion of OCT-TCFA (p=0.03), OCT-vasa vasorum (p=0.013), and OCT-thrombus (p=0.012), and a larger lipid arc (p=0.002). HHcy (P=0.037) and metabolic syndrome (MetS) (P=0.016) remained independent predictors of TCFAs. HHcy (P=0.026) and smoking (P=0.005) remained independent determinants of thrombus. CONCLUSIONS HHcy and MetS are associated with TCFAs, and HHcy and smoking are associated with thrombus in young patients with coronary artery disease.

Warfarin therapy in Chinese patients with atrial fibrillation treated with percutaneous coronary intervention: a 5 year follow-up retrospective cohort study.

Objective: To evaluate warfarin use in Chinese patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) by investigating the stroke and major adverse cardiac and cerebral events (MACCEs) and bleeding events. Methods: Retrospective cohort study of the 5 year follow-up of 1134 patients with AF who underwent PCI. The patients were grouped according to whether they received warfarin or not. Baseline characteristics and the occurrence of MACCEs and bleeding events were compared between the two groups using the CHA2DS2-VASc and HAS-BLED scoring. Cox regression analysis was used to identify factors related to the occurrence of MACCEs and bleeding. Results: Overall MACCE (p = .008) and mortality (p = .004) rates were significantly lower in the warfarin group compared with the non-warfarin group. Major bleeding, minor bleeding and overall bleeding were comparable in the two groups. Recurrent myocardial infarction (HR = 10.129, 95% CI = 4.737-21.655; p < .001) and a baseline CHA2DS2-VASc score >4 (HR = 2.035, 95% CI = 1.121-3.692; p = .019) were independent predictors of MACCEs in the warfarin group. A baseline HAS-BLED score ≥3 (HR = 5.498, 95% CI = 3.773-8.013; p < .001) and previous bleeding (HR = 3.058, 95% CI = 1.319-7.088; p = .009) were independent predictors of bleeding. Conclusions: Warfarin reduces the incidence of MACCEs but does not increase bleeding events in Chinese patients with AF who underwent PCI. For patients taking warfarin, recurrent myocardial infarction and a baseline CHA2DS2-VASc score >4 were related to MACCE occurrence.

Correction to: Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium.

In the original publication of the article error has occurred in Fig. 1b.

Association Between TG-to-HDL-C Ratio and In-Stent Stenosis Under Optical Coherence Tomography Guidance.

We determined the relevance between the TG-to-HDL-C ratio and stent restenosis. Ninety-nine patients with in-stent stenosis (ISR) who were admitted to An Zhen Hospital in Beijing between April 2014 and June 2017 were selected. At the same time, 122 patients with coronary stenosis <50% were selected. All patients were tested for TG, HDL-C, and TG/HDL-C ratio. Optical coherence tomography (OCT) can assess microscopic status in all ISR patients. The proportion of male and Diabetic patients were significantly higher for ISR. There were differences in the prevalence of cigarette smokers among the different tissue types, among which the layered tissue type accounted for the highest proportion. In logistic regression analysis the study showed that male, diabetes mellitus, and the TG/HDL-C ratio are risk factors for ISR. The ISR ROC was 0.725 based on the TG/HDL-C ratio diagnosis. It is related to the degree of coronary stenosis and effective in diagnosing in-stent stenosis in ISR.

Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium.

PURPOSE: Mangiferin is a naturally occurring glucosylxanthone with beneficial effects on glucose and lipid homeostasis. This study investigates the potential therapeutic effect of Mangiferin in perivascular adipose tissue (PVAT) and whether it contributes to regulating insulin action in the endothelium. METHODS: Palmitate challenge evoked ROS-associated endoplasmic reticulum stress (ER stress) and NLRP3 inflammasome activation in PVAT. The conditioned medium from PA-stimulated PVAT was prepared to induce endothelial insulin resistance, and improved endothelium-dependent vasodilation in response to insulin was detected in vitro and in vivo. RESULTS: Mangiferin treatment enhanced LKB1-dependent AMPK activity and suppressed ER stress with downregulation of TXNIP induction, leading to the inhibition of NLRP3 inflammasome activation evidenced by attenuated NLRP3 and cleaved caspase-1 expression as well as reduced IL-1ß secretion. Moreover, Mangiferin restored insulin-mediated Akt and eNOS phosphorylations with increased NO production, immunohistochemistry examination of adipocytes, and endothelial tissue in high-fat diet-fed mice also showed that oral administration of Mangiferin inhibited ER stress and NLRP3 induction in PVAT, and then effectively prevented insulin resistance in the vessel endothelium. CONCLUSIONS: Taken together, these results revealed that Mangiferin suppressed ER stress-associated NLRP3 inflammasome activation in PVAT through regulation of AMPK activity, which prevented endothelial insulin resistance. These findings suggested that the amelioration of PVAT dysfunction may be a therapeutic strategy for the prevention of endothelial insulin resistance.