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Systemic vasculitis is diverse group of autoimmune disorders which are characterized by inflammation of blood vessel walls with deep aching and burning pain. Their underlying etiology and pathophysiology still remain poorly understood. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, are membrane vesicular structures that are released either during cell activation, or when cells undergo programmed cell death, including apoptosis, necroptosis, and pyroptosis. Although EVs were thought as cell dusts, but now they have been found to be potently active since they harbor bioactive molecules, such as proteins, lipids, nucleic acids, or multi-molecular complexes. EVs can serve as novel mediators for cell-to-cell communications by delivery bioactive molecules from their parental cells to the recipient cells. Earlier studies mainly focused on MVs budding from membrane surface. Recent studies demonstrated that EVs may also carry molecules from cytoplasm or even from nucleus of their parental cells, and these EVs may carry autoantigens and are important in vasculitis. EVs may play important roles in vasculitis through their potential pathogenic involvements in inflammation, autoimmune responses, procoagulation, endothelial dysfunction/damage, angiogenesis, and intimal hyperplasia. EVs have also been used as specific biomarkers for diagnostic use or disease severity monitoring. In this review, we have focused on the aspects of EV biology most relevant to the pathogenesis of vasculitis, discussed their perspective insights, and summarized the exist literature on EV relevant studies in vasculitis, therefore provides an integration of current knowledge regarding the novel role of EVs in systemic vasculitis.

Systemic vasculitis is a heterogeneous group of multisystem autoimmune disorders characterized by inflammation of blood vessels. Although many progresses in diagnosis and immunotherapies have been achieved over the past decades, there are still many unanswered questions about vasculitis from pathological understanding to more advanced therapeutics. Extracellular vesicles (EVs) are double-layer phospholipid membrane vesicles harboring various cargoes. EVs can be classified into exosomes, microvesicles (MVs), and apoptotic bodies depending on their size and origin of cellular compartment. EVs can be released by almost all cell types and may be involved in physical and pathological processes including, inflammation and autoimmune responses. In systemic vasculitis, EVs may have pathogenic involvement in inflammation, autoimmune responses, thrombosis, endothelium injury, angiogenesis and intimal hyperplasia. EV-associated redox reaction may also be involved in vasculitis pathogenesis by inducing inflammation, endothelial injury and thrombosis. Additionally, EVs may serve as specific biomarkers for diagnosis or monitoring of disease activity and therapeutic efficacy, i.e. AAV-associated renal involvement. In this review, we have discussed the recent advances of EVs, especially their roles in pathogenesis and clinical involvements in vasculitis.

Microvesicles (MVs) have been shown to be involved in pathophysiology of ischemic heart diseases. However, the underlying mechanisms are still unclear. Here we investigated the effects of MVs derived from ischemic preconditioning (IPC-MVs) on myocardial ischemic/reperfusion (I/R) injury in rats. Myocardial IPC model was elicited by three cycles of ischemia and reperfusion of the left anterior descending (LAD) coronary artery. IPC-MVs from the peripheral blood of the above animal model were isolated by ultracentrifugation and characterized by flow cytometry and transmission electron microscopy. IPC-MVs were administered intravenously (7 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min ischemia and 120-min reperfusion of LAD in rats. We found that total IPC-MVs and different phenotypes, including platelet-derived MVs (PMVs), endothelial cell-derived MVs (EMVs), leucocyte-derived MVs and erythrocyte-derived MVs (RMVs) were all isolated which were identified membrane vesicles (

// Yao Wang 1 , Su Wei 1 , Yi-Lu Wang 1 , Miao Liu 1 , Man Shang 1 , Qi Zhang 4 , Yan-Na Wu 1 , Ming-Lin Liu 2, 3 , Jun-Qiu Song 1 and Yan-Xia Liu 1 1 Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China 2 Section of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA19140, USA 3 Section of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA 4 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Correspondence to: Yan-Xia Liu, email: liu_yanxia126@126.com Jun-Qiu Song, email: song_junqiu@126.com Keywords: microvesicles, ischemia/reperfusion, apoptosis, Bcl-2/Bax, GRP78 Received: October 17, 2016 Accepted: March 28, 2017 Published: April 26, 2017 ABSTRACT Objective: To investigate the effects of circulating microvesicles derived from myocardial ischemia (I-MVs) on apoptosis in myocardial ischemia/reperfusion (I/R) injury in rats. Methods: I-MVs from rats undergoing myocardial left anterior descending (LAD) coronary artery ligation were isolated by ultracentrifugation from circulating blood and characterized by flow cytometry. I-MVs were administered intravenously (4.8 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min of ischemia and 120-min of reperfusion of LAD in rats. Results: Treatment with I-MVssignificantly reduced the size of myocardial infarction, the activities of serum CK-MB and LDH, and the number of apoptotic cardiomyocytes. The activities of caspase 3, caspase 9 and caspase 12 in myocardium were also decreased significantly with I-MVs treatment. Moreover, the expression of Bax was decreased but Bcl-2 was increased. The expression of glucose regulated protein 78 (GRP78), sarco/endoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2) and phosphorylated phospholamban (p-PLB) were increased after being treated with I-MVs. Conclusion: I-MVs could protect hearts from I/R injury in rats through SERCA2 and p-PLB of calcium regulatory proteins to alleviate intrinsic myocardial apoptosis including mitochondrial and endoplasmic reticulum pathways.

Human insulin-like growth factor-1 (IGF-1) plays important roles in development and regeneration of skeletal muscles and bones but requires daily injections or surgical implantation. Current clinical IGF-1 lacks e-peptide and is glycosylated, reducing functional efficacy. In this study, codon-optimized Pro-IGF-1 with e-peptide (fused to GM1 receptor binding protein CTB or cell penetrating peptide PTD) was expressed in lettuce chloroplasts to facilitate oral delivery. Pro-IGF-1 was expressed at high levels in the absence of the antibiotic resistance gene in lettuce chloroplasts and was maintained in subsequent generations. In lyophilized plant cells, Pro-IGF-1 maintained folding, assembly, stability and functionality up to 31 months, when stored at ambient temperature. CTB-Pro-IGF-1 stimulated proliferation of human oral keratinocytes, gingiva-derived mesenchymal stromal cells and mouse osteoblasts in a dose-dependent manner and promoted osteoblast differentiation through upregulation of ALP, OSX and RUNX2 genes. Mice orally gavaged with the lyophilized plant cells significantly increased IGF-1 levels in sera, skeletal muscles and was stable for several hours. When bioencapsulated CTB-Pro-IGF-1 was gavaged to femoral fractured diabetic mice, bone regeneration was significantly promoted with increase in bone volume, density and area. This novel delivery system should increase affordability and patient compliance, especially for treatment of musculoskeletal diseases.

Lupus nephritis (LN) is a major cause for overall morbidity and mortality in patients with systemic lupus erythematosus (SLE), while its pathogenic mechanisms are still not well understood. Extracellular vesicles (EVs) are membrane vesicles that are released from almost all cell types. EVs can be subdivided into exosomes, microvesicles, and apoptotic bodies. Latest studies have shown that EVs can be released during several cellular events, including cell activation, autophagy, and several types of programed cell death, i.e. apoptosis, necroptosis, pyroptosis, and NETosis. Emerging evidence demonstrates that EVs harbor different bioactive molecules, including nucleic acids, proteins, lipids, cytokines, immune complexes (ICs), complements, and other molecules, some of which may contribute to pathogenesis of autoimmune diseases. EVs can serve as novel information shuttle to mediate local autocrine or paracrine signals to nearby cells, and distant endocrine signals to cells located far away. In LN, EVs may have pathogenic effects by transportation of autoantigens or complements, promotion of IC deposition or complement activation, and stimulation of inflammatory responses, renal tissue injury, or microthrombus formation. Additionally, EVs released from kidney cells may serve as specific biomarkers for diagnosis or monitoring of disease activity and therapeutic efficacy. In this review, we will summarize the latest progress about EV generation from basic research, their potential pathologic effects on LN, and their clinical implications. The cutting-edge knowledge about EV research provides insights into novel therapeutic strategy, new tools for diagnosis or prognosis, and evaluation approaches for treatment effectiveness in LN.

Microvesicles (MVs, also known as microparticles) are small vesicles that originate from plasma membrane of almost all eukaryotic cells during apoptosis or activation. MVs can serve as extracellular vehicles to transport bioactive molecules from their parental cells to recipient target cells, thereby serving as novel mediators for intercellular communication. Importantly, more and more evidence indicates that MVs could play important roles in early pathogenesis and subsequent progression of cardiovascular and metabolic diseases. Elevated plasma concentrations of MVs, originating from red blood cells, leukocytes, platelets, or other organs and tissues, have been reported in various cardiometabolic diseases. Circulating MVs could serve as potential biomarkers for disease diagnosis or therapeutic monitoring. In this review, we summarized recently-published studies in the field and discussed the role of MVs in the pathogenesis of cardiometabolic diseases. The emerging values of MVs that serve as biomarker for non-invasive diagnosis and prognosis, as well as their roles as novel therapeutic targets in cardiometabolic diseases, were also described. Keywords: Microvesicle, Microparticle, Exosome, Cardiometabolic disease, Biomarker

Microvesicles (MVs), also known as microparticles, are small membrane vesicles released from different cell types under different conditions. MVs have been detected in the circulation and in organs/tissues in various diseases, including diabetes. Patients with different types of diabetes and complications have different cellular MV patterns. Studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, and other pathological processes of the disease through their procoagulant, pro-inflammatory, pro-angiogenic, proteolytic, and other properties. Therefore, MVs contribute to the development of diabetic macrovascular and microvascular complications. In addition, clinical studies have indicated that changes in MV number and composition may reflect the pathophysiological conditions of disease, and therefore, may serve as potential biomarkers for diagnostic and prognostic use. Understanding MVs' involvement in the pathophysiological conditions may provide insight into disease mechanisms and would also be helpful for the development of novel therapeutic strategies in the future. Here, we review the latest publications from our group and other groups and focus on the involvement of MVs in diabetic complications.

We have read with great interest the article by Kato and colleagues regarding the ‘Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus’.1 However, we are concerned that the authors studied exclusively blood serum, that is, all blood samples from their patients with lupus and healthy controls were coagulated ex vivo before analysis. At least three major changes can occur to the population of membrane microvesicles (MVs) during coagulation in a test tube. First, a subset of circulating MVs participate in, and become consumed by, clotting. For example, studies from our group and others indicated that over half of the total membrane MVs in blood plasma …

The objectives of safety evacuation in the subway were directly related to the safety of Personal life. How to effectively ease the evacuation of the public crowded and prevent casualties had become a focus in the domain of current domestic and international public safety, as well as an important component of MRT design. Once emergency happened, the capability of emergency evacuation is the important factor to reduce the loss and ensure the life safety. Based on the analysis of characteristics of subway station emergency established on the basis of evaluation index system using fuzzy network analysis to subway station emergency evacuation capacity in comprehensive evaluation Based on the analysis of subway station emergency characteristics to established evaluation index system and used fuzzy network analysis to evaluate the subway station emergency evacuation capacity in comprehensive.

Diabetic retinopathy (DR) is a common complication of diabetes and has been recognized as the leading cause of blindness in adults. Several interrelated molecular pathways are involved in the development of DR. Microvesicles (MVs) are cell membrane vesicles, which carry many biologic molecules, such as mRNAs, microRNAs, transcription factors, membrane lipids, membrane receptors, and other proteins. They may be involved in intercellular communication that can promote inflammation, angiogenesis, and coagulation. Recent studies have indicated that changes in the number and composition of MVs may reflect the pathologic conditions of DR. At present, MVs are well recognized as being involved in the pathophysiological conditions of tumors and cardio-metabolic diseases. However, the roles of MVs in DR have yet to be investigated. In this review, we provide an overview of DR-induced microvascular injury that is caused by MVs derived from endothelial and circulating cells, and discuss the possible mechanisms by which MVs can lead to endothelial dysfunction, coagulation and inflammation. In addition, the protective effects of preconditioned MVs and stem cell-derived MVs are also described . Understanding the involvement of MVs in the pathophysiological conditions of DR may provide insight into the disease mechanisms and may suggest novel therapeutic strategies for DR in the future.

Background Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM). Smokers exhibit low circulating levels of total adiponectin (ADPN) and high-molecular-weight (HMW) ADPN multimers. Blood concentrations of HMW ADPN multimers closely correlate with insulin sensitivity for handling glucose. How tobacco smoke exposure lowers blood levels of ADPN, however, has not been investigated. In the current study, we examined the effects of tobacco smoke exposure in vitro and in vivo on the intracellular and extracellular distribution of ADPN and its HMW multimers, as well as potential mechanisms. Findings We found that exposure of cultured adipocytes to tobacco smoke extract (TSE) suppressed total ADPN secretion, and TSE administration to mice lowered their plasma ADPN concentrations. Surprisingly, TSE caused intracellular accumulation of HMW ADPN in cultured adipocytes and in the adipose tissue of wild-type mice, while preferentially decreasing HMW ADPN in culture medium and in plasma. Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum. In addition, TSE down-regulated DsbA-L, a factor for ADPN secretion. Conclusions Tobacco smoke exposure traps HMW ADPN intracellularly, thereby blocking its secretion. Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers.

Objective— Oxidized low-density lipoprotein (Ox-LDL)is implicated in the pathogenesis of atherosclerosis. Circulating oxidation-specific epitopes on plasma Ox-LDL has been linked with coronary artery disease, but its determinants and its association with early development of atherosclerosis in familial combined hyperlipidemia (FCHL) has not been very well studied. This study aimed to investigate the determinants of the circulating Ox-LDL and the association between Ox-LDL and carotid intima-media thickness (IMT) in asymptomatic members of FCHL families. Methods and Results— Ox-LDL, susceptibility of LDL to oxidation in vitro, plasma 8-isoprostane and antioxidants, lipids and lipoproteins, LDL particle size, and carotid IMT were measured in 150 asymptomatic FCHL family members. Affected FCHL family members had reduced LDL particle size and lag time for LDL oxidation, increased plasma levels of Ox-LDL, increased plasma urate and α-tocopherol, and a trend for the increase of 8-isoprostane as compared with nonaffected FCHL. Ox-LDL was independently associated with serum LDL cholesterol, apoB, and 8-isoprostane in multivariate analysis but only univariately correlated with LDL particle size and lag time for LDL oxidation. In addition, Ox-LDL was significantly associated with carotid mean IMT independently of other clinical and biochemical variables in a multivariate model. Conclusion— Serum LDL cholesterol, apoB levels, and 8-isoprostane were the most important determinants of Ox-LDL. Ox-LDL is independently associated with carotid IMT in asymptomatic FCHL family members and can be used as a marker of early atherosclerosis in FCHL.

There is increasing evidence that oxidation of low-density lipoprotein (LDL) plays an important role in atherogenesis.To explore the LDL oxidizability and its determinants in familial combined hyperlipidemia (FCHL) patients with different phenotypes.The study included 59 FCHL family members with different lipid phenotypes, 39 non-affected relatives, and 30 spouses as healthy controls.The lag time for LDL oxidation was significantly shorter in FCHL patients with different lipid phenotypes as compared to healthy controls. There were no significant differences in the propagation rate and conjugated diene formation and alpha-tocopherol content in LDL between the FCHL groups and healthy controls. Plasma concentrations of alpha-tocopherol in all FCHL patients and uric acid in FCHL patients with IIB and IV phenotypes were significantly higher than in healthy controls. Plasma total peroxyl radical trapping capacity measured (TRAPmea) and TRAPcalc tended to be higher in affected FCHL groups, but the difference was significant only for IIB phenotype. The peak LDL particle size in the combined group of FCHL patients was significantly smaller than in healthy controls. The lag time for LDL oxidation correlated significantly with LDL size both in the group of FCHL family members (r = 0.477, P0.001) and in the healthy controls (r = 0.482, P0.01).LDL from FCHL patients irrespectively of lipid phenotypes is more susceptible to oxidation in vitro than LDL from healthy controls. This increased susceptibility of LDL to oxidation in vitro seems to be attributed to the abundance of small dense LDL particles and not to the defect of antioxidant capacity in FCHL

Microparticles are small membrane fragments shed primarily from blood and endothelial cells during either activation or apoptosis. There is mounting evidence suggesting that microparticles perform a large array of biological functions and contribute to various diseases. Of these disease processes, a significant link has been established between microparticles and venous thromboembolism. Advances in research on the role of microparticles in thrombosis have yielded crucial insights into possible mechanisms, diagnoses and therapeutic targets of venous thromboembolism. In this review, we discuss the definition and properties of microparticles and venous thromboembolism, provide a synopsis of the evidence detailing the contributions of microparticles to venous thromboembolism, and propose potential mechanisms, by which venous thromboembolism occurs. Moreover, we illustrate a possible role of microparticles in cancer-related venous thromboembolism.

OBJECTIVE: To search for determinants of endothelial dysfunction in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comprehensive analysis of cardiovascular risk markers and measured blood flow responses to endothelium-dependent (acetylcholine [ACh] and NG-monomethyl-L-arginine) and -independent (sodium nitroprusside [SNP]) vasoactive agents in 30 nonsmoking men with type 2 diabetes (age 51 +/- 1 years, BMI 27.8 +/- 0.4 kg/m2, HbA1c 7.4 +/- 0.3%) and 12 matched normal control men. RESULTS: ACh-induced vasodilation was 37% lower in type 2 diabetic (6.1 +/- 0.5) than in normal subjects (9.7 +/- 1.5 ml.dl-1.min-1, P < 0.01), while flows during SNP were similar (9.1 +/- 0.6 vs. 9.9 +/- 1.3 ml.dl-1.min-1, NS). The ratio of endothelium-dependent vs. -independent flow (ACh:SNP ratio) was 31% lower in type 2 diabetic (0.70 +/- 0.05) than in normal subjects (1.10 +/- 0.18, P < 0.01). Total (2.2 +/- 0.4 vs. 1.3 +/- 0.2 mmol/l, P < 0.05), VLDL, and intermediate-density lipoprotein triglycerides were significantly higher, and the mean LDL particle diameter was significantly smaller in type 2 diabetic than in normal subjects. The lag times for LDL oxidation by Cu2+ in vitro were similar in patients with type 2 diabetes (183 +/- 7) and in normal subjects (183 +/- 9 min, NS). Measured and calculated (sum of concentration of individual antioxidants in serum) total peroxyl radical-trapping capacities (TRAPs) were comparable between the groups. In the patients with type 2 diabetes, LDL size was significantly correlated with endothelium-dependent vasodilation (r = 0.43, P < 0.05), serum triglycerides (r = -0.75, P < 0.001), and the lag time for LDL oxidation in vitro (r = 0.38, P < 0.05). HbA1c was inversely correlated with the lag time for LDL oxidation in vitro (r = -0.41, P < 0.05) and TRAP. CONCLUSIONS: In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.

Background and Purpose — In addition to low-density lipoprotein (LDL) cholesterol, small, dense LDL particles and oxidative modification of LDL have been linked to the pathogenesis of atherosclerosis. The present study was aimed at investigating the association between carotid artery intima-media thickness (IMT) and LDL particle size and susceptibility of LDL to oxidation in vitro in asymptomatic members of familial combined hyperlipidemia (FCHL) families. Methods — LDL particle size, susceptibility of LDL to oxidation in vitro, and carotid IMT were measured in 148 asymptomatic FCHL family members. Results — LDL particle size and lag time for LDL oxidation were reduced in hyperlipidemic compared with normolipidemic family members. LDL particle size, serum total cholesterol, and α-tocopherol in LDL were independently associated with lag time for LDL oxidation in multivariate analysis. LDL particle size was associated with carotid mean IMT independently of clinical, lipid, and antioxidant variables in multivariate analysis. Although the susceptibility of LDL to oxidation in vitro was correlated with mean IMT, it did not have a significant independent contribution to variation in mean IMT in the multivariate model. Conclusions — We conclude that LDL particle size but not susceptibility of LDL to oxidation in vitro is independently associated with carotid IMT in asymptomatic FCHL family members. These results imply that small, dense LDL as an inherent feature of FCHL is an important diagnostic indicator for coronary artery disease risk in FCHL.

We thank Drs. Lieske and Birkenfeld (1) for their comments. We agree that in our article (2) we did not address the question of whether or not the activating effects of insulin on endoplasmic reticulum …