Association between diabetes mellitus and primary restenosis following endovascular treatment: a comprehensive meta-analysis of randomized controlled trials.

IMPORTANCE: Diabetes mellitus (DM) is thought to be closely related to arterial stenotic or occlusive disease caused by atherosclerosis. However, there is still no definitive clinical evidence to confirm that patients with diabetes have a higher risk of restenosis. OBJECTIVE: This meta-analysis was conducted to determine the effect of DM on restenosis among patients undergoing endovascular treatment, such as percutaneous transluminal angioplasty (PTA) or stenting. DATA SOURCES AND STUDY SELECTION: The PubMed/Medline, EMBASE and Cochrane Library electronic databases were searched from 01/1990 to 12/2022, without language restrictions. Trials were included if they satisfied the following eligibility criteria: (1) RCTs of patients with or without DM; (2) lesions confined to the coronary arteries or femoral popliteal artery; (3) endovascular treatment via PTA or stenting; and (4) an outcome of restenosis at the target lesion site. The exclusion criteria included the following: (1) greater than 20% of patients lost to follow-up and (2) a secondary restenosis operation. DATA EXTRACTION AND SYNTHESIS: Two researchers independently screened the titles and abstracts for relevance, obtained full texts of potentially eligible studies, and assessed suitability based on inclusion and exclusion criteria.. Disagreements were resolved through consultation with a third researcher. Treatment effects were measured by relative ratios (RRs) with 95% confidence intervals (CIs) using random effects models. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. MAIN OUTCOMES AND MEASURES: The main observation endpoint was restenosis, including > 50% stenosis at angiography, or TLR of the primary operation lesion during the follow-up period. RESULTS: A total of 31,066 patients from 20 RCTs were included. Patients with DM had a higher risk of primary restenosis after endovascular treatment (RR = 1.43, 95% CI: 1.25-1.62; p = 0.001). CONCLUSIONS AND RELEVANCE: This meta-analysis of all currently available RCTs showed that patients with DM are more prone to primary restenosis after endovascular treatment.

Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1ß-mediated pyroptosis after balloon injury in the rat carotid artery.

Background: Ischemia‒reperfusion (IR) is a pathological process that causes secondary damage to blood vessels. However, whether IR can further worsen neointima formation after balloon injury and the detailed mechanism are unclear. Methods: An in vivo model of balloon injury to the rat carotid artery was established to study the effect of IR following balloon injury on neointima formation. Smooth muscle cells (SMCs) were isolated from rat aortas and exposed to hypoxia-reoxygenation to mimic the IR process in vitro. The in vitro cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an in vivo rat model. Results: IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury (P < 0.001). Compared with that of normal SMCs in the rat carotid artery, the expression of IL-1ß, a key proinflammatory cytokine associated with pyroptosis, was increased more than 3-fold in the IR-induced neointima (P < 0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs (P < 0.0001). This process was alleviated by the antioxidant acetylcysteine (NAC), suggesting its partial dependence on intracellular ROS. In the rat model of IR following balloon injury in the carotid artery, the carotid artery that was locally transfected with AAV carrying sh-IL-1ß or sh-caspase-1, which alleviated neointima formation, as indicated by a reduction in intima-media thickness in the rat carotid artery (P < 0.0001). Conclusion: Our results suggested that IR could promote IL-1ß production in SMCs in the carotid artery after balloon injury and aggravate neointimal hyperplasia, which was alleviated by silencing caspase-1/IL-1ß signaling in SMCs in the carotid artery. These results suggest that IL-1ß may be an effective target to combat IR-related neointima formation.

Molecular Imprinting Technology Enables Proactive Capture of Nitrogen for Boosted Ammonia Synthesis under Ambient Conditions.

Electrochemical nitrogen reduction reaction (NRR) is a burgeoning field for green and sustainable ammonia production, in which numerous potential catalysts emerge endlessly. However, satisfactory performances are still not realized under practical applications due to the limited solubility and sluggish diffusion of nitrogen at the interface. Herein, molecular imprinting technology is adopted to construct an adlayer with abundant nitrogen imprints on the electrocatalyst, which is capable of selectively recognizing and proactively aggregating high-concentrated nitrogen at the interface while hindering the access of overwhelming water simultaneously. With this favorable microenvironment, nitrogen can preferentially occupy the active surface, and the NRR equilibrium can be positively shifted to facilitate the reaction kinetics. Approximately threefold improvements in both ammonia production rate (185.7 µg h-1 mg-1 ) and Faradaic efficiency (72.9%) are achieved by a metal-free catalyst compared with the bare one. It is believed that the molecular imprinting strategy should be a general method to find further applicability in numerous catalysts or even other reactions facing similar challenges.

Eliminating Concentration Polarization with Cationic Covalent Organic Polymer to Promote Effective Overpotential of Nitrogen Fixation.

Electrocatalytic nitrogen reduction reaction offers a sustainable alternative to the conventional Haber-Bosch process. However, it is currently restricted by low effective overpotential due to the concentration polarization, which arises from accumulated products, ammonium, at the reaction interface. Here, a novel covalent organic polymer with ordered periodic cationic sites is proposed to tackle this challenge. The whole network exhibits strong positive charge and effectively repels the positively charged ammonium, enabling an ultra-low interfacial product concentration, and successfully driving the reaction equilibrium to the forward direction. With the given potential unchanged, the suppressed overpotential can be much liberated, ultimately leading to a continuous high-level reaction rate. As expected, when this tailored microenvironment is coupled with a transition metal-based catalyst, a 24-fold improvement is generated in the Faradaic efficiency (73.74 %) as compared with the bare one. The proposed strategy underscores the importance of optimizing dynamic processes as a means of improving overall performance in electrochemical syntheses.

Turning Waste into Wealth: Sustainable Production of High-Value-Added Chemicals from Catalytic Coupling of Carbon Dioxide and Nitrogenous Small Molecules.

Carbon neutrality is one of the central topics of not only the scientific community but also the majority of human society. The development of highly efficient carbon dioxide (CO2) capture and utilization (CCU) techniques is expected to stimulate routes and concepts to go beyond fossil fuels and provide more economic benefits for a carbon-neutral economy. While various single-carbon (C1) and multi-carbon (C2+) products have been selectively produced to date, the scope of CCU can be further expanded to more valuable chemicals beyond simple carbon species by integration of nitrogenous reactants into CO2 reduction. In this Review, research progress toward sustainable production of high-value-added chemicals (urea, methylamine, ethylamine, formamide, acetamide, and glycine) from catalytic coupling of CO2 and nitrogenous small molecules (NH3, N2, NO3-, and NO2-) is highlighted. C-N bond formation is a key mechanistic step in N-integrated CO2 reduction, so we focus on the possible pathways of C-N coupling starting from the CO2 reduction and nitrogenous small molecules reduction processes as well as the catalytic attributes that enable the C-N coupling. We also propose research directions and prospects in the field, aiming to inspire future investigations and achieve comprehensive improvement of the performance and product scope of C-N coupling systems.

Involvement of endothelial progenitor cells in blood flow recovery through activation of the Wnt/ß-catenin signaling pathway and inhibition of high oxidative stress in diabetic hindlimb ischemic rats.

BACKGROUND: Diabetes mellitus (DM) often causes stenosis and occlusion of hindlimb blood vessels, which are also the main cause for hindlimb ischemia in elderly people. OBJECTIVES: To investigate the therapeutic effect of endothelial progenitor cell (EPC) transplantation on diabetic hindlimb ischemia. MATERIAL AND METHODS: Endothelial progenitor cells were separated, labeled with PKH-26 and transplanted into rat models (107 cells/100 g). Dichlorodihydrofluorescein diacetate (DCFH-DA) was used to detect any oxidative stress. Streptozotocin (STZ) was injected to establish a diabetic rat model and hindlimb ischemia model was established via operation. Western blotting was used to detect total ß-catenin (T-ß-catenin) and non-phospho-ß-catenin (NP-ß-catenin) levels. The malondialdehyde (MDA), superoxide dismutase (SOD), Wnt3a, Wnt5a and Wnt7a levels were detected using enzyme-linked immunosorbent assay (ELISA). Oxidative stress was measured using DCFH-DA and dihydroethidium (DHE). The endothelial biomarker CD31 was observed to highlight vessels, and PKH-26 to trace migration/adhesion of EPCs. RESULTS: Endothelial progenitor cells were successfully isolated and identified, and diabetic hindlimb ischemic rat models were created. Tempol remarkably improved blood flow in diabetic hindlimb ischemic rats compared to DM+EPCs rats at 14 days (p < 0.001) and 28 days post-operation (p < 0.001). High oxidative stress was observed in diabetic hindlimb ischemic rats. Tempol significantly inhibited oxidative stress levels in diabetic hindlimb ischemic rats. Furthermore, Tempol significantly promoted angiogenesis in diabetic hindlimb ischemic rats compared to DM+EPCs rats. The ß-catenin inhibitor, XAV (DM+EPCs+Tempol+XAV group), significantly suppressed blood flow recovery and angiogenesis in diabetic hindlimb ischemic rats when compared to the DM+EPCs+Tempol group at 14 days (p = 0.026) and 28 days (p < 0.001). The XAV remarkably reduced T-ß-catenin (p < 0.001) and N-ß-catenin (p = 0.030) levels in Tempol-treated diabetic hindlimb ischemic rats, as compared to the DM+EPCs+Tempol group. The Wnt5a participated in the pathology of diabetic hindlimb ischemia. CONCLUSIONS: There are high oxidative stress levels in both EPCs in high-glucose environments and diabetic hindlimb ischemia, which can lead to limited blood flow recovery. The high oxidative stress caused the inhibition of Wnt/ß-catenin signaling pathway, leading to limited blood flow recovery in diabetic hindlimb ischemia. At the same time, Wnt5a participated in the EPC-mediated blood flow recovery.

AGEs/RAGE Promote Osteogenic Differentiation in Rat Bone Marrow-Derived Endothelial Progenitor Cells via MAPK Signaling.

Systemic vascular impairment is the most common complication of diabetes. Advanced glycation end products (AGEs) can exacerbate diabetes-related vascular damage by affecting the intima and media through a variety of mechanisms. In the study, we demonstrated that AGEs and their membrane receptor RAGE could induce the differentiation of EPCs into osteoblasts under certain circumstances, thereby promoting accelerated atherosclerosis. Differentiation into osteoblasts was confirmed by positive staining for DiI-acetylated fluorescently labeled low-density lipoprotein and FITC-conjugated Ulex europaeus agglutinin. During differentiation, expression of receptor for AGE (RAGE) was significantly upregulated. This upregulation was attenuated by transfection with RAGE-targeting small interfering (si)RNA. siRNA-mediated knockdown of RAGE expression significantly inhibited the upregulation of AGE-induced calcification-related proteins, such as runt-related transcription factor 2 (RUNX2) and osteoprotegerin (OPG). Additional experiments showed that AGE induction of EPCs significantly induced ERK, p38MAPK, and JNK activation. The AGE-induced upregulation of osteoblast proteins (RUNX2 and OPG) was suppressed by treatment with a p38MAPK inhibitor (SB203580) or JNK inhibitor (SP600125), but not by treatment with an ERK inhibitor (PD98059), which indicated that AGE-induced osteoblast differentiation from EPCs may be mediated by p38MAPK and JNK signaling, but not by ERK signaling. These data suggested that AGEs may bind to RAGE on the EPC membrane to trigger differentiation into osteoblasts. The underlying mechanism appears to involve the p38MAPK and JNK1/2 pathways, but not the ERK1/2 pathway.

Development of a Hepatic VX2 carcinoma model in rabbits using an improved minimally invasive method and evaluation with imaging examinations.

Context: The hepatic VX2 carcinoma model in rabbits has been widely used in interventional diagnosis and treatment research for hepatocellular carcinoma (HCC). However, traditional methods for developing this model all have their shortcomings. Aims: To develop an improved method to construct an animal model of hepatic VX2 carcinoma. Settings and Design: The puncture technique was used to obtain the VX2 tumor tissue. A tumor puncture-inoculation kit was designed and modified to implant the tumor tissue into the recipient rabbit's liver. Methods and Material: 18 New Zealand white rabbits were implanted with VX2 tumor tissue using the improved tumor puncture-inoculation kit under ultrasound guidance. Ultrasonography, contrast-enhanced computerized tomography, magnetic resonance imaging, and digital subtraction angiography were performed to evaluate tumor formation and imaging characteristics. Statistical Analysis: Statistical analysis was performed using SPSS software. Two groups were compared using Student's t-test analysis. Results: All rabbits tolerated VX2 tumor tissue implantation successfully. 17 out of the 18 experimental rabbits developed liver tumors, and one rabbit had abdominal tumor metastasis. The average volume of tumors was 39.47 mm3 and 460.1 mm3 (P < 0.001) on the 7th and 14th days after modeling, respectively. Imageological diagnosis showed that all tumors had abundant blood supply and typical imaging characteristics. Conclusions: This improved modeling method is easy to operate and less traumatic, with a high tumor formation rate, low metastasis rate, prominent tumor imaging characteristics, and high detection rate, which is expected to become a promising method for constructing rabbit liver tumor model.

AGEs-Induced Calcification and Apoptosis in Human Vascular Smooth Muscle Cells Is Reversed by Inhibition of Autophagy.

Vascular calcification (VC) in macrovascular and peripheral blood vessels is one of the main factors leading to diabetes mellitus (DM) and death. Apart from the induction of vascular calcification, advanced glycation end products (AGEs) have also been reported to modulate autophagy and apoptosis in DM. Autophagy plays a role in maintaining the stabilization of the external and internal microenvironment. This process is vital for regulating arteriosclerosis. However, the internal mechanisms of this pathogenic process are still unclear. Besides, the relationship among autophagy, apoptosis, and calcification in HASMCs upon AGEs exposure has not been reported in detail. In this study, we established a calcification model of SMC through the intervention of AGEs. It was found that the calcification was upregulated in AGEs treated HASMCs when autophagy and apoptosis were activated. In the country, AGEs-activated calcification and apoptosis were suppressed in Atg7 knockout cells or pretreated with wortmannin (WM), an autophagy inhibitor. These results provide new insights to conduct further investigations on the potential clinical applications for autophagy inhibitors in the treatment of diabetes-related vascular calcification.

Knockdown of LncRNA-H19 Ameliorates Kidney Fibrosis in Diabetic Mice by Suppressing miR-29a-Mediated EndMT.

Diabetic nephropathy is the leading cause of kidney fibrosis. Recently, altered expressed or dysfunction of some long non-coding RNAs (lncRNAs) has been linked to kidney fibrosis; however, the mechanisms of lncRNAs in kidney fibrosis remain unclear. We have shown that the DPP-4 inhibitor linagliptin can inhibit endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with DPP-4 protein levels via the induction of miR-29. Here, we found that expression of the lncRNA H19 was significantly up-regulated in TGF-ß2-induced fibrosis in human dermal microvascular endothelial cells (HMVECs) in vitro, and in kidney fibrosis of streptozotocin-induced diabetic CD-1 mice. We also detected up-regulated H19 expression and down-regulated miR-29a expression in the early and advanced mouse models of diabetic kidney fibrosis. H19 knockdown significantly attenuated kidney fibrosis in vitro and in vivo, which was associated with the inhibition of the EndMT-associated gene FSP-1. We also found that the up-regulation of H19 observed in fibrotic kidneys associated with the suppression of miR-29a in diabetic mice. H19, miR-29a, and EndMT contribute to a regulatory network involved in kidney fibrosis, and are associated with regulation of the TGF-ß/SMAD3 singling pathway. This study indicates that inhibition of LncRNA H19 represents a novel anti-fibrotic treatment for diabetic kidney diseases.

Activation of CREB Protein With Tabersonine Attenuates STAT3 During Atherosclerosis in Apolipoprotein E-Deficient Mice.

OBJECTIVE: Atherosclerosis is a pathological condition of fat deposition in the arteries, which causes cardiovascular disorders. Management of atherosclerosis remains a challenge and conventional drugs used for its management have several limitations. This study evaluated the protective effect of tabersonine against atherosclerosis and assessed its molecular mechanism of action. METHODS: Atherosclerosis was induced by feeding apolipoprotein E (ApoE)-deficient mice a high-fat diet. Mice were treated with 20 or 40 mg/kg of tabersonine intraperitoneally for the 12-week duration of the study. Atherosclerosis markers and nitric oxide were measured in the sera of ApoE-deficient mice. Mediators of inflammation and markers of oxidative stress were assessed using enzyme-linked immunosorbent assays. Western blotting, quantitative reverse transcriptase polymerase chain reaction, and immunohistochemistry analyses were conducted to determine the protein expression in aortic tissue. RESULTS: The tabersonine-treatment groups had an improved lipid profile and enhanced liver function, compared to the ApoE treatment group. Tabersonine treatment resulted in reduced levels of nitric oxide, cytokines, and oxidative stress, compared to the ApoE group. The altered expression levels of protein inhibitor activated STAT-3 (PIAS3), signal transducer and activator of transcription-3 (STAT-3), and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα) in ApoE-deficient mice were ameliorated by tabersonine treatment. Moreover, cAMP-response-element-binding (CREB) expression was elevated in aortic tissue of tabersonine treatment groups, compared to the ApoE group. CONCLUSION: These results suggested that tabersonine ameliorates the expression of STAT-3 by activating CREB protein in atherosclerotic ApoE-deficient mice.

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis.

Atherosclerosis is a multifactorial disease of the vasculature, and shear stress is a crucial regulator of its process. Disturbed flow promotes atherosclerotic effects, while laminar flow has a protective action on the endothelium. Hippo/YAP is a major cascade that senses various mechanical cues and mediates the expression of pro-inflammatory genes. However, the mechanism modulating the transcription factor YAP in response to different patterns of blood flow remains unclear. In this study, we provide evidence that shear stress modulates YAP activity via autophagy in endothelial cells. Laminar flow promoted the expression of the autophagic markers BECLIN 1 and LC3II/LC3I. Autophagy blockade using a chemical inhibitor repressed YAP degradation under laminar flow. Conversely, the induction of autophagy under disturbed flow partially antagonized the nuclear import and transcriptional activation of YAP. In parallel, laminar flow led to the increased expression of SIRT1 protein, a NAD+-dependent deacetylase. Further investigation showed that SIRT1-mediated YAP deacetylation. The forced expression of SIRT1 under disturbed flow effectively attenuated YAP activation and nuclear accumulation, thereby downregulating the expression of pro-inflammatory genes. In atheroprone vessels of mice receiving rapamycin to induce autophagy, the enhanced expression of SIRT1 was observed together with YAP repression. Altogether, these results show that endothelial autophagy and SIRT1 expression induced by laminar flow contribute to the inhibition of Hippo/YAP signaling and interrupt atherosclerotic plaque formation.

The active components derived from Penthorum chinensePursh protect against oxidative-stress-induced vascular injury via autophagy induction.

Oxidative stress-induced damage has been proposed as a major risk factor for cardiovascular disease and is a pathogenic feature of atherosclerosis. Although autophagy was reported to have a protective effect against atherosclerosis, its mechanism for reducing oxidative stress remains un-elucidated. In this study, we have identified 4 novel autophagic compounds from traditional Chinese medicines (TCMs), which activated the AMPK mediated autophagy pathway for the recovery of mitochondrial membrane potential (MMP) to reduce the production of reactive oxygen species (ROS) in Human umbilical vein endothelial cells (HUVECs). In this study, 4 compounds (TA, PG, TB and PG1) identified from Penthorum chinense Pursh (PCP) were demonstrated for the first time to possess binding affinity to HUVECs cell membranes via cell membrane chromatography (CMC) accompanied by UHPLC-TOF-MS analysis, and the 4 identified compounds induce autophagy in HUVECs. Among the 4 autophagic activators identified from PCP, TA (Thonningianin A, Pinocembrin dihydrochalcone-7-O-[3″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-glucoside) is the major chemcial component in PCP, which possesses the most potent autophagy effect via a Ca2+/AMPK-dependent and mTOR-independent pathways. Moreover, TA efficiently reduced the level of ROS in HUVECs induced by H2O2. Additionally, the expression of pro- and cleaved-IL-1ß in the aortic artery of ApoE-KO mice were also alleviated at the transcription and post-transcription levels after the administration of TA, which might be correlated to the reduction of oxidative-stress induced inflammasome-related Nod-like receptor protein3 (NLRP3) in the aortic arteries of ApoE-KO mice. This study has pinpointed the novel autophagic role of TA in alleviating the oxidative stress of HUVECs and aortic artery of ApoE-KO mice, and provided insight into the therapeutic application of TA in treatment of atherosclerosis or other cardiovascular diseases.

Bavachin Protects Human Aortic Smooth Muscle Cells Against ß-Glycerophosphate-Mediated Vascular Calcification and Apoptosis via Activation of mTOR-Dependent Autophagy and Suppression of ß-Catenin Signaling.

Vascular calcification is a major complication of cardiovascular disease and chronic renal failure. Autophagy help to maintain a stable internal and external environment that is important for modulating arteriosclerosis, but its pathogenic mechanism is far from clear. Here, we aimed to identify the bioactive compounds from traditional Chinese medicines (TCM) that exhibit an anti-arteriosclerosis effect. In ß-glycerophosphate (ß-GP)-stimulated human aortic smooth muscle cells (HASMCs), the calcium level was increased and the expression of the calcification-related proteins OPG, OPN, Runx2, and BMP2 were all up-regulated, followed by autophagy induction and apoptosis. Meanwhile, we further revealed that ß-GP induced apoptosis of human osteoblasts and promoted differentiation of osteoblasts through Wnt/ß-catenin signaling. Bavachin, a natural compound from Psoralea corylifolia, dose-dependently reduced the level of intracellular calcium and the expression of calcification-related proteins OPG, OPN, Runx2 and BMP2, thus inhibiting cell apoptosis. In addition, bavachin increased LC3-II and beclin1 expression, along with intracellular LC3-II puncta formation, which autophagy induction is Atg7-dependent and is regulated by suppression of mTOR signaling. Furthermore, addition of autophagy inhibitor, wortmannin (WM) attenuated the inhibitory effect of bavachin on ß-GP-induced calcification and apoptosis in HASMCs. Collectively, the present study revealed that bavachin protects HASMCs against apoptosis and calcification by activation of the Atg7/mTOR-autophagy pathway and suppression of the ß-catenin signaling, our findings provide a potential clinical application for bavachin in the therapy of cardiovascular disease.

Downregulation of MicroRNA-4463 Attenuates High-Glucose- and Hypoxia-Induced Endothelial Cell Injury by Targeting PNUTS.

BACKGROUND/AIMS: Vascular complications are the main reasons for disability and mortality associated with type 2 diabetes mellitus (T2DM) and numerous microRNAs (miRNAs) are involved in this process. Our previous study demonstrated that miR-4463 was increased in the plasma of T2DM patients combined with arteriosclerosis of low extremity artery (ASO). However, the role of miR-4463 remains unclear. METHODS: miR-4463 expression in the vascular tissues of patients with ASO and T2DM and in human umbilical vein endothelial cells (HUVECs) was detected by qPCR. Cell survival and apoptosis was analyzed via Cell Counting Kit-8 and flow cytometry assays, respectively. Protein expression was determined by Western blot and protein subcellular localization was detected with immunofluorescence. A dual-luciferase assay was used to elucidate the target gene of miR-4463. RESULTS: miR-4463 was elevated in the vascular tissues of patients with T2DM and ASO. In HUVECs, both 25 mmol/L glucose (high glucose, HG) and hypoxia induced miR-4463 expression. Downregulation of miR-4463 promoted HUVEC survival and reduced cell apoptosis under HG and/or hypoxic conditions by facilitating the expression of protein phosphatase-1 nuclear targeting subunit (PNUTS), X-linked inhibitor of apoptosis protein (XIAP), p-AKT, p-Bad, increased the Bcl-2/Bax ratio, as well as downregulated cleaved caspase 3 expression. Mechanistically, we identified PNUTS as a direct target gene of miR-4463. Both the inhibition of AKT phosphorylation and silencing of PNUTS diminished the effect of miR-4463 on HUVEC apoptosis. Moreover, downregulation of miR-4463 enhanced PNUTS to enable PTEN nuclear localization, which resulted in AKT phosphorylation. CONCLUSION: Our results suggest that downregulation of miR-4463 attenuates cell apoptosis by directly enhancing PNUTS expression to promote PTEN nuclear localization, subsequently activating AKT signaling pathway in HUVECs under HG and/ or hypoxic conditions.

MiR-4463 inhibits the migration of human aortic smooth muscle cells by AMOT.

Aberrant vascular smooth muscle cell (VSMC) migration has been implicated in a variety of vascular disorders, while the signal pathways governing this process remain unclear. Here, we investigated whether miRNAs, which are strong post-transcriptional regulators of gene expression, could alter VSMC migration. We detected the expression of miR-4463 in the plasma of patients with atherosclerosis and in human aortic smooth muscle cells under hypoxia-ischemia condition, and investigated the migration effect and its downstream pathways. The results have shown that whether in clinical AS patients or hypoxic cells, the expression of miR-4463 was lower than that of normal group, then the number of migrating cells in the miR-4463 mimic intervention group was significantly decreased compared with the normal group and miR-4463 inhibitor instead. Furthermore, the expression of angiomotin (AMOT) in gastrocnemius muscle and femoral artery of patients was significantly higher than that of the control group. The protein level of AMOT in miR-4463 mimic intervention group was significantly decreased, and its level was reversed by inhibiting miR-4463. In summary, these results indicate that miR-4463 is a novel modulator of VSMC migration by targetting AMOT expression. Regulating miR-4463 or its specific downstream target genes in VSMCs may represent an attractive approach for the treatment of vascular diseases.

MiR-146a protects small intestine against ischemia/reperfusion injury by down-regulating TLR4/TRAF6/NF-κB pathway.

Previous studies reported that miR-146a was involved in small intestine ischemia-reperfusion (I/R) injury, but the mechanism is largely vague. Here, we aimed to identify the change of miR-146a in patients with mesenteric ischemia and explore the potential regulatory mechanism of miR-146a in intestine epithelial cells survival under ischemia and I/R injury. The plasma of 20 patients with mesenteric ischemia and 25 controls was collected to examine the miR-146a expression by qPCR. Rat intestinal epithelial cells (IEC-6) and 24 male Sprague-Dawley rats were included to build ischemia and I/R model in vitro and in vivo. The qPCR results showed that miR-146a decreased both in the plasma of patients with mesenteric ischemia and in IEC-6 cells and rat small intestine tissues in ischemia and I/R model compared to controls. Both the in vitro and in vivo results showed that I/R resulted in more severe apoptotic injury than ischemia. Cleaved-caspase 3, TLR4, TRAF6, and nuclear NF-κB p65 were up-regulated accompanying reduced XIAP and SOCS3 expression in intestinal ischemia and I/R injury. After up-regulation of miR-146a in IEC-6 cells, increased cell survival and decreased cell apoptosis were observed, concomitant with decreased cleaved-caspase 3 and down-regulated TLR4/TRAF6/NF-κB pathway. What is more, this protective effect was blocked by TRAF6 overexpression and increased nuclear NF-κB p65 nuclear. Taken together, this study revealed that miR-146a expression was decreased in small intestine ischemia and I/R injury. And miR-146a improves intestine epithelial cells survival under ischemia and I/R injury through inhibition TLR4, TRAF6, and p-IκBα, subsequently leading to decreased NF-κB p65 nuclear translocation.

Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling.

The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome have been implicated in the initiation or progression of atherosclerosis. Recent research showed that irisin, a newly discovered adipomiokine, alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses, suggesting that irisin may be a promising candidate for the treatment of vascular complications of diabetes. However, the association between irisin and NLRP3 inflammasome in the pathogenesis of atherosclerosis remains unclear. In the present study, we cultured human umbilical vein endothelial cells (HUVECs) in advanced glycation end products (AGEs) medium; exogenous irisin (0.01, 0.1, 1 µg/ml) were used as an intervention reagent. siRNA and adenoviral vector were constructed to realize silencing and over-expression of NLRP3 gene. Our data showed that irisin significantly reversed AGEs-induced oxidative stress and NLRP3 inflammasome signaling activation (p < 0.05), and increased the endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production in a dose-dependent manner (p < 0.05). siRNA-mediated knockdown NLRP3 facilitated the irisin-mediated anti-inflammatory and antiatherogenic effects (p < 0.05). However, these irisin-mediated effects were reversed by over-expression NLRP3 (p < 0.05). Taken together, our results reveal that irisin alleviates AGEs-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling, suggest a likely mechanism for irisin-induced therapeutic effect in vascular complications of diabetes.

A Single-Center Retrospective Analysis of the Efficacy of a New Balloon Catheter in Autogenous Arteriovenous Fistula Dysfunction Resistant to Conventional Balloon Angioplasty.

PURPOSE: The purpose of the study was to present a new alternative balloon catheter option for autogenous arteriovenous fistula (AVF) dysfunction with a stiff constriction resistant to conventional balloon angioplasty. METHODS: Our first series of 51 patients with autogenous AVF dysfunction who were simultaneously treated with VascuTrak™ balloon catheter, following failed conventional balloon therapy (failure was defined as residual stenosis of >30%), were retrospectively observed and analyzed. The indices that were used to evaluate the clinical efficacy of VascuTrak balloon catheter included the immediate technical success rate, residual stenosis, successful dilation times, degree of pain assessed using the Visual Analog Scale, complications, and follow-up patency rate. RESULTS: The stenotic or occlusive lesions of all 51 cases resistant to conventional balloon angioplasty were promptly eliminated or alleviated (residual stenosis rate ≤ 30%), with a 100% immediate technical success rate. VascuTrak balloon catheters were successful in achieving full dilation under working pressure, of which 44 cases required a 1-time dilation (86.3%) and 7 cases required 2 dilations, which differed significantly from the average of 2.4 dilations required by the preceding conventional balloon therapy (P < 0.0001). A statistically significant improvement in the degree of pain experienced by patients who received VascuTrak balloon dilation was observed compared to that of the preceding conventional balloon dilation (P < 0.0001). One case of a brachial artery pseudoaneurysm complication occurred in the perioperative period. The primary patency rate was 88.2% at 6 months and 74.5% at 12 months. CONCLUSION: The use of VascuTrak balloon catheter to treat autogenous AVF dysfunction resistant to conventional balloon angioplasty appears to be safe and effective, although further, large randomized controlled trials are necessary.