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Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients' outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: To compare advanced non-parallel transmission zoomed diffusion-weighted imaging (nonPTX zoom-DWI) to conventional DWI (conv-DWI) for the assessment of prostate cancer (PCa). Methods: This retrospective study included 98 patients who underwent conv-DWI, nonPTX zoom-DWI, and T2-weighted imaging of the prostate. The image qualities of the two DWI sets, including the distortion of the prostate and the existence of artifacts, were evaluated. To compare the overall PCa and clinically important PCa (ciPCa) detection ability between the sets, lesions were scored using the Prostate Imaging Reporting and Data System (PI-RADS) version 2. Apparent diffusion coefficient (ADC) values of the lesions were also measured and compared. The Mann–Whitney U test was used to compare continuous variables, and the χ2 test was used to compare categorical variables. Two-sided P values of < 0.05 were considered significant. Results: Non-PTX zoom-DWI yielded significantly better image quality and image analysis reproducibility than conv-DWI (all P < 0.001). Compared with conv-ADC, nonPTX zoom-ADC showed slightly better detection performance for overall PCa (AUC: 0.827 vs. 0.797; P = 0.55) and ciPCa (AUC: 0.822 vs. 0.749; P = 0.58). At a PI-RADS score of 4 as the cutoff value for PCa prediction, nonPTX zoom-DWI showed significantly higher diagnostic efficiency for overall PCa detection (sensitivity: 87.9% vs. 72.4%; specificity: 87.5% vs. 77.5%; both P < 0.05) and ciPCa detection (sensitivity: 86.3% vs. 74.5%; specificity: 72.3% vs. 63.8%; both P ≤ 0.001). Conclusion: Non-PTX zoom-DWI yields better image quality and higher PCa detection performance than Conv-DWI. [ABSTRACT FROM AUTHOR]

Abstract Background The present investigation was designed to elucidate the use of dynamic contrast enhanced perfusion MR imaging (DCE pMRI) in characterizing hyperemia, including microvessel changes, and to examine whether DCE pMRI can predict benign or malignant hyperemia. Methods Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) by intraluminal suture placement. All rats were randomized to 4 groups: MCAO for 0.5 hours followed by saline treatment (10 ml/kg; group 1); MCAO for 3 hours followed by treatment with saline (group 2) or urokinase (25000 IU/kg; group 3); and MCAO for 6 hours followed by urokinase treatment (group 4). Relative cerebral blood volume (rCBV) and relative maximum slope of increase of the signal intensity time curve (rMSI) were quantitatively analyzed from MRI. Microvessel diameter and blood-brain barrier disruption obtained by laser scanning confocal microscopy (LSCM) as well as transmission electron microscopy (TEM) were obtained for correlative study. Results Benign hyperemia was noticed only in group 1; malignant hyperemia was seen in group 3. Although the rCBV of malignant hyperemia was slightly higher than in benign hyperemia (P > 0.05), the rMSI, on the other hand, was significantly lower (P < 0.05). Fluoro-isothiocyanate dextran (FITC-dextran) extravasations, marked glial end-foot process swelling, and significant vasodilatation were seen in malignant hyperemia, while no or mild leakage of FITC-dextran and slight glial end-foot process swelling occurred in benign hyperemia. Conclusion Our findings indicate that DCE pMRI can characterize post-ischemic hyperemia and correlates well with microvascular damage.

Aims: This study aimed to compare pancreatic volume and its clinical significance among patients with type 2 diabetes mellitus (DM), adult-onset type 1 DM and latent autoimmune diabetes in adults (LADA).Methods: This is a cross-sectional study. One hundred twenty-six outpatients (68 with LADA and 58 with type 1 DM) and 158 inpatients (71 with type 2 DM and 87 non-diabetic controls) were recruited during May-July 2013 in Shanghai Jiao Tong University Affiliated Sixth People's Hospital. All the patients underwent abdominal computerized tomography; pancreatic volume was then calculated.Results: The mean pancreatic volume was highest in the controls, followed by those in patients with type 2 DM, LADA and type 1 DM. The pancreatic volume in LADA was comparable with that in type 2 DM but significantly greater than that in type 1 DM (p < 0.05). The pancreatic volume in patients with LADA was significantly correlated with sex, waist circumference, body surface area, body mass index, diastolic blood pressure and high-density lipoprotein cholesterol (all p < 0.05). The correlation between pancreatic volume and fasting C-peptide was high in patients with LADA (r = 0.643, p < 0.001) and moderate in patients with type 2 DM (r = 0.467, p < 0.001). The area under the receiver operating characteristic curve for pancreatic volume predictive of absolute insulin deficiency (FCP < 0.9 ng/mL) was 0.85 (0.76-0.94) in LADA.Conclusions: Pancreatic atrophy in LADA was less marked than in type 1 DM. Pancreatic atrophy may suggest reduced level of fasting C-peptide in patients with LADA. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim: We retrospectively investigated the clinical profiles and neuroimaging data of patients with documented cerebral venous sinus thrombosis (CVST) to analyze the relationship between the sites of CVST and clinical manifestations. Methods: A total of 68 patients, who were examined and treated at our hospital, were identified after review and their data were retrospectively analyzed. Results: Initial non-contrast CT scan showed a definite spontaneous hyperdensity of one or several sinuses in 47 patients (69.1%) and was normal in the remaining patients (30.9%). Furthermore, the ?² test revealed a significant difference (p = 0.001) in the infarction or hemorrhage rate between the patients with straight sinus thrombosis (SST; 19 of 28, 67.8%) and other subjects (9 of 39, 23.1%). Moreover, patients with SST had a 6.33-fold (95% CI 2.18-18.4) increased risk of infarction or hemorrhage. Conclusion: Our data suggested that infarction and/or hemorrhage was more common in CVST patients with SST. [ABSTRACT FROM AUTHOR]

We investigated the relationship between serum cystatin C levels and the prognosis of diabetic foot ulcerations (DFU). A population-based cohort study involving 1018 patients with type 2 diabetes was conducted. These patients recruited and divided into two groups: nondiabetic foot ulcer group (NDF, n = 865, 85.5%) and diabetic foot ulcer group (DFU, n = 147, 14.5%).After a 1-year-follow-up, DFUs were grouped into healing ( n = 110, 74.8%) and nonhealing ( n = 37, 25.2%) group based on the clinical prognosis. Compared with the healing group, the nonhealing group were older, had long diabetic duration and had significantly increased serum cystatin C concentrations in DFU ( p < 0.01). After adjustments for age, diabetes duration, renal function and infection control, multiple logistical regression analysis revealed that cystatin C remained associated increased risk of undesirable DFU outcome (OR = 7.279, 95% CI: 1.299-40.784, p < 0.05). When divided into quartiles according to cystatin C levels, the healing rate of Quartile 4 was significantly lower (57.9%) compared with other groups ( p < 0.01). The odd is ratio (OR) analysis showed that the risk of undesirable DFU outcome in Quartile 4 was significantly higher (OR = 4.554, 95% CI: 3.14-5.12, p < 0.05) compared with that in Quartile 1. We concluded that there was a strong and independent association between serum cystatin C and diabetic foot ulceration prognosis, cystatin C > 1.35 mg/L predicts more than sixfold increased risk of incurable foot ulceration. [ABSTRACT FROM AUTHOR]

We chose hepcidin and its related factors as evaluating indicators to determine the degrees of iron overload in myelodysplastic syndromes (MDS) patients. A total of 73 patients and 28 healthy volunteers were enrolled in this study. We performed enzyme-linked immunosorbent assay to measure both bone marrow and peripheral blood serum hepcidin. Real-time quantitative polymerase chain reaction was used to determine the gene expression of growth differentiation factor 15 and twisted gastrulation 1. Serum ferritin (SF), C-reactive protein (CRP), and erythropoietin were measured by routine standard laboratory assays. CD4+ and CD19+ lymphocytes and Th polarization were detected by flow cytometry. Twenty-four MDS patients were measured their cardiac and liver iron deposition levels through magnetic resonance imaging (MRI) T2* examination. No significant difference was found between the bone marrow hepcidin levels and peripheral blood hepcidin levels (P = 0.134). Stratified according to different World Health Organization subtypes, refractory anemia with ringed sideroblasts patients had the lowest hepcidin levels (105.40 ± 5.13 ng/ml), while refractory anemia with excess blasts-1 had the highest levels (335.71 ± 25.16 ng/ml). Stratified according to International Prognostic Scoring System and WHO Classification-based Prognostic Scoring System, there was a significant difference of hepcidin levels between low-risk group and high-risk group in two systems, respectively (P = 0.033 and 0.009). The hepcidin levels of CD4+ high-expression group were demonstrated higher than the normal expression groups (P = 0.02), but the CD19+ high-expression group did not show the same result (P = 0.206). Meanwhile, patients with a Th1 polarization trend had a high level of hepcidin versus normal group (P < 0.001). Liver iron concentration (LIC) measured by MRI T2* had a closer correlation (r = 0.582, P < 0.001) to hepcidin than serum ferritin, by stepwise regression. C-reactive protein and LIC seemed to be the key determinants of hepcidin, by multivariate regression. Inflammation plays an important role in the regulation of hepcidin expression. T-lymphocyte activation and Th polarization trend might participate in the regulatory mechanism partly. The capability of organ iron load assessment of MRI T2* seems better than that of SF. It seems that hepcidin with CRP and LIC measured by MRI T2* are potential indicators of iron overload in MDS patients. [ABSTRACT FROM AUTHOR]

Objective: Cystatin C is growing to be an ideal indicator for renal function and cardiovascular events. The aim of this study was to investigate the relationship between serum cystatin C levels and peripheral arterial disease and to explore its diagnostic value for lower limb ischemia (LLI) in type 2 diabetic population. Methods: A total of 1609 T2DM patients were included in this cross-sectional study. Their clinical and biochemical characteristics, ankle-brachial index (ABI), carotid and lower extremity arterial ultrasound were detected. LLI was defined by ABI <0.9 and lower extremity arterial stenosis >50% by ultrasound examination. Patients were divided to two groups: with LLI and without. The risk factors of LLI were explored by binary logistic regression analysis. Results: The serum concentrations of cystatin C were 1.53±0.60 and 1.08±0.30 mg/L in patients with and without LLI, respectively. Binary logistic regression analysis showed that the significant risk factors were cystatin C (P = 0.007, OR = 5.081), the presence of hypertension (P = 0.011, OR = 3.527), age (P<0.001, OR = 1.181), GA (P = 0.002, OR = 1.089) and diabetes duration (P = 0.008, OR = 1.074). The prevalence of coronary artery disease, cerebral infarction and LLI increased with cystatin C (P<0.01), and the prevalence of LLI in patients with cystatin C >1.2 mg/L was much higher than other three quartile groups. Receiver operating characteristic curve analysis revealed the cut point of cystatin C for LLI was 1.2 mg/L. The risk of LLI dramatically increased in patients with cystatin C >1.2 mg/L (OR = 21.793, 95% confidence interval 10.046−47.280, P<0.001). After adjusting for sex, age, duration, HbA1c, GA and hypertension, its OR still remained 3.395 (95% confidence interval 1.335–8.634). Conclusions: There was a strong and independent association between cystatin C and limb arterial disease in diabetic population, and cystatin C >1.2 mg/L indicated a great increased risk of LLI. [ABSTRACT FROM AUTHOR]

Poly-L-lysine (PLL) can be replaced successfully by quaternized chitosan to prepare alginate-Ca microcapsules. By changing the compontent of quaternized chitosan mixture, including N-trimethylated chitosan, octadecyl quaternized carboxymethyl chitosan (OQC) and Poly(ethylene glycol) (PEG) modified OQC (PEG-OQC), different alginate-Ca microcapsules as carriers of cell transplantation can be obtained with diverse properties. Compared with alginate-PLL (AP), the mechanical strength of the alginate-quaternized chitosan (AQC) microcapsules was encouraging, and there was no apparent difference between AQC and AP microcapsules ( P < 0.05). The permeability of both microcapsules was observed in the presence of fluorescein isothiocyanate (FITC), immunoglobulin and bovine serum albumin (BSA) by fluorescent microscopy. Both microcapsules membranes were permeable to FITC, part-permeable to IgG and impermeable to larger molecule proteins such as BSA. The AQC and AP microcapsules entrapping L929 cells were cultured properly. L929 cells were retrieved from microcapsules and grew well after being recultured for 3 days. [ABSTRACT FROM PUBLISHER]

Intraprocedural aneurysm rupture during embolization is a rare but life-threatening event, may be taken to reduce and improve the outcome of this tragic occurrence. We report an unusual case of endovascular packing of ruptured aneurysm with balloon assistance, followed by subarachnoid contrast enhancement (SCE) on computed tomography (CT) imaging immediately after the procedure, mimicking procedure-related intracerebral hemorrhage, the management however, differed from the patient with procedure-related hemorrhage.Coil embolization of a ruptured aneurysm was carried out using the balloon remodeling technique with total occlusion of the aneurysm sac. During the procedure, there was no excursion of the microcatheter, coil mass, or microwire beyond the confines of the vascular compartment that would imply perforation. However, immediate postprocedural CT showed marked asymmetric enhancement that resembled procedure-related subarachnoid hemorrhage. This case showed that although a rare occurrence, temporary disruption of the blood-brain barrier can mimic procedure-related intracerebral hemorrhage. Agents (nimodipine and heparin) that prevent cerebral vasospasm and subsequent infarcts were continued regardless of appearance of SCE.We discuss the potential mechanisms of this phenomenon and review the literature on SCE after endovascular packing of ruptured aneurysm with balloon assistance, to raise the awareness of this event, so that appropriate measures must be taken to prevent procedure-related complication. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between ankle-branchial index (ABI) and cardiovascular disease in type 2 diabetes patients.Methods: A total of 634 inpatients with type 2 diabetes were recruited in this cross-sectional study. All patients were measured with ABI and computed tomography angiography (CTA) scan for coronary artery disease (CAD). According to ABI values, patients were divided into three groups: low-ABI group (ABI < 0.9, n = 259), normal-ABI group (ABI = 0.9-1.3, n = 272), and high-ABI group (ABI > 1.3, n = 103). According to the manifestation of coronary CTA, the patients were divided into CAD group (n = 348) and non-CAD group (n = 286). Their clinical data and biochemical parameters were compared and analysed.Results: The prevalence of CAD in low-ABI group (90%) was significantly higher than that of normal-ABI group (33%) and high-ABI group (25%) (both P < 0.01). Spearman correlation analysis showed that age, sex, duration, spontaneous bacterial peritonitis, total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C), serum creatinine, and glycosylated haemoglobin (HbA1c ) were positively correlated with CAD, and high-density lipoprotein cholesterol (HDL-C), glomerular filtration rate, and ABI were negatively correlated with CAD. Logistic regression analysis further revealed that age, sex, duration, TC, HDL-C, LDL-C, HbA1c , and ABI were independent risk factors of CAD. After all potential confounders is adjusted, the risk of CAD in low-ABI group still increased over four times than the normal-ABI group (odds ratio [OR], 5.32; 95% CI, 1.973-16.5; P < 0.001). In female patients, this risk increased more than nine times (OR, 10.63; 95% CI, 3.416-17.8; P < 0.001). Receiver-operating characteristic analysis indicated that ABI < 1.045 predicted the occurrence of CAD (sensitivity, 79.7%; specificity, 71.5%; P < 0.01).Conclusions: ABI is an independent risk factor for CAD and may be a potential simple screening instrument for CAD in Chinese type 2 diabetic patients, especially in elder women. [ABSTRACT FROM AUTHOR]

Aims: Wound healing is deeply dependent on neovascularization to restore blood flow. The neovascularization of endothelial progenitor cells (EPCs) through paracrine secretion has been reported in various tissue repair models. Exosomes, key components of cell paracrine mechanism, have been rarely reported in wound healing.Methods: Exosomes were isolated from the media of EPCs obtained from human umbilical cord blood. Diabetic rats wound model was established and treated with exosomes. The in vitro effects of exosomes on the proliferation, migration and angiogenic tubule formation of endothelial cells were investigated.Results: We revealed that human umbilical cord blood EPCs derived exosomes transplantation could accelerate cutaneous wound healing in diabetic rats. We also showed that exosomes enhanced the proliferation, migration and tube formation of vascular endothelial cells in vitro. Furthermore, we found that endothelial cells stimulated with these exosomes would increase expression of angiogenesis-related molecules, including FGF-1, VEGFA, VEGFR-2, ANG-1, E-selectin, CXCL-16, eNOS and IL-8.Conclusion: Taken together, our findings indicated that EPCs-derived exosomes facilitate wound healing by positively modulating vascular endothelial cells function. [ABSTRACT FROM AUTHOR]

Aim: The association between thyroid stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to diabetic peripheral neuropathy (DPN) has not been studied. The aim of this study was to explore the relationship between TSH and DPN in Chinese patients with T2DM.Methods: In this cross-sectional study, 605 patients with T2DM were enrolled. Subclinical hypothyroidism (SCH) was defined as an elevated TSH level (>4.0mIU/L) and a normal free thyroxine level. DPN was evaluated by neurological symptoms, neurological signs, and electromyogram.Results: Serum TSH levels were significantly higher in DPN and signs of DPN compared with non-DPN T2DM patients (both P<0.01).The prevalence of DPN and signs of DPN in SCH subjects was higher than that in euthyroid subjects (both P<0.01). Spearman's correlation analysis showed that the serum TSH level was positively associated with DPN (r=0.172, P<0.01). A significant independent association between TSH and DPN was found by multiple logistic regression analysis after adjusting for potential confounding variables [odds ratio (OR)=1.365, P<0.01]. The patients were sequentially assigned to quartiles according to TSH level. Compared with quartile 1, patients in quartile 2 (P<0.01), quartile 3 (P=0.01), and quartile 4 (P<0.01) had a higher risk of DPN. Receiver-operating characteristic curve analysis revealed that the optimal cutoff point of TSH to indicate DPN was 3.045mIU/L in men and 2.94mIU/L in women.Conclusion: TSH level is independently associated with DPN in Chinese population with T2DM. A high serum TSH level may be a potential risk factor for DPN. [ABSTRACT FROM AUTHOR]

Aims: To assess the effects of plerixafor on function and endothelial regeneration of endothelial progenitor cells (EPCs).Methods: The proliferation and adhesion capacity of EPCs were evaluated in vitro. Furthermore, the expression levels of CXC chemokine receptor-7 (CXCR7) were detected before and after treatment with plerixafor. The CXCR7 expression of EPCs was knocked-down by RNA interference to evaluate the role of CXCR7 in regulating function of EPCs. A rat carotid artery injury model was established to assess the influences of plerixafor on endothelial regeneration.Results: Plerixafor stimulated adhesion capacity of EPCs, associating with upregulation of CXCR7 and activation of LFA-1 and VLA-4 molecules. Knockdown of CXCR7 slightly impaired proliferation capacity but significantly attenuated adhesion capacity of EPCs. Plerixafor facilitated endothelial repair at 7 days, while reduced neointimal hyperplasia at 7 and 14 days via recruiting more EPCs participating in endothelial reparation.Conclusions: Plerixafor can positively regulate adhesion capacity of EPCs to HUVECs via elevating the expression level of CXCR7 and stimulating LFA-1 and VLA-4 molecules activation. Treatment with plerixafor accelerated re-endothelialization and inhibited neointimal hyperplasia after endoth elial injury, indicating that it can to be used for endothelial regeneration. [ABSTRACT FROM AUTHOR]

Purpose To develop an MRI-based model for clinically significant prostate cancer (csPCa) diagnosis that can resist rectal artifact interference. Materials and Methods This retrospective study included 2203 male patients with prostate lesions who underwent biparametric MRI and biopsy between January 2019 and June 2023. Targeted adversarial training with proprietary adversarial samples (TPAS) strategy was proposed to enhance model resistance against rectal artifacts. The automated csPCa diagnostic models trained with and without TPAS were compared using multicenter validation datasets. The impact of rectal artifacts on the diagnostic performance of each model at the patient and lesion levels was compared using the area under the receiver operating characteristic curve (AUC) and the area under the precision-recall curve (AUPRC). The AUC between models was compared using the DeLong test, and the AUPRC was compared using the bootstrap method. Results The TPAS model exhibited diagnostic performance improvements of 6% at the patient level (AUC: 0.87 vs 0.81, P < .001) and 7% at the lesion level (AUPRC: 0.84 vs 0.77, P = .007) compared with the control model. The TPAS model demonstrated less performance decline in the presence of rectal artifact-pattern adversarial noise than the control model (ΔAUC: -17% vs -19%, ΔAUPRC: -18% vs -21%). The TPAS model performed better than the control model in patients with moderate (AUC: 0.79 vs 0.73, AUPRC: 0.68 vs 0.61) and severe (AUC: 0.75 vs 0.57, AUPRC: 0.69 vs 0.59) artifacts. Conclusion This study demonstrates that the TPAS model can reduce rectal artifact interference in MRI-based csPCa diagnosis, thereby improving its performance in clinical applications. Keywords: MR-Diffusion-weighted Imaging, Urinary, Prostate, Comparative Studies, Diagnosis, Transfer Learning Clinical trial registration no. ChiCTR23000069832 Supplemental material is available for this article. Published under a CC BY 4.0 license.

Insulin release index (IRI) based on 72-h fasting test has been used for the definitive diagnosis of insulinoma; however, hospitalization and subsequent costs contribute to the disadvantage of IRI. Therefore, a simple and cost-effective screening procedure for the diagnosis of insulinoma for outpatients are crucially needed. Continuous glucose monitoring (CGM) has been widely used for monitoring high level of glucose in diabetic patients. The aim of the study is to determine the potential contribution or implementation of CGM in the screening of the insulinoma. We performed a single-center prospective study with the demographics and laboratory data including 28 patients with the pathological diagnosis of insulinoma and 25 patients with functional hypoglycemia as control group. The analysis showed that areas under the receiver operating characteristic (ROC) curve of coefficient of variation (CV) was 0.914. The CV cutoff point was 19% with the Youden 62.1%, the corresponding sensitivity and specificity were 82.1 and 80%, respectively. In patients with CV greater than the median, more than 60% of insulinomas were located in the head of the pancreas; most Ki-67 values were more than 2% and when compared with the group with CV smaller than the median, the average tumor size was 2.7 times larger. In conclusion, CGM can be used as a valuable tool in not only monitoring high glucose levels in diabetic patients but also identifying the etiology of insulinoma. CV greater than 19% can be highly effective for the screening of insulinoma in outpatients.

The present study was conducted to assess the effects of AMD3100 and stromal cell-derived factor 1 (SDF-1) on cellular functions and endothelial regeneration of endothelial progenitor cells (EPCs). The cell proliferation and adhesion capacity of EPCs were evaluated in vitro following treatment with AMD3100 and SDF‑1 using a Cell Counting Kit‑8 assay. Furthermore, the expression levels of C‑X‑C motif chemokine receptor 4 (CXCR4) and C‑X‑C motif chemokine receptor 7 (CXCR7) were detected before and after treatment with AMD3100 and SDF‑1 to elucidate their possible role in regulating the cellular function of EPCs. A rat carotid artery injury model was established to assess the influences of AMD3100 and SDF‑1 on endothelial regeneration. AMD3100 reduced the proliferation and adhesion capacity of EPCs to fibronectin (FN), whereas it increased the adhesion capacity of EPCs to human umbilical vein endothelial cells (HUVECs). However, SDF‑1 stimulated the proliferation and cell adhesion capacity of EPCs to HUVECs and FN. Additionally, the expression levels of CXCR7 but not CXCR4 were upregulated following AMD3100 treatment, whereas the expression levels of both CXCR4 and CXCR7 were upregulated after SDF‑1 treatment. In vivo results demonstrated that AMD3100 increased the number of EPCs in the peripheral blood and facilitated endothelial repair at 7 days after treatment. However, local administration of SDF‑1 alone did not enhance reendothelialization 7 and 14 days after treatment. Importantly, the combination of AMD3100 with SDF‑1 exhibited superior therapeutic effects compared with AMD3100 treatment alone, accelerated reendothelialization 7 days after treatment, and attenuated neointimal hyperplasia at day 7 and 14 by recruiting more EPCs to the injury site. In conclusion, AMD3100 could positively regulate the adhesion capacity of EPCs to HUVECs via elevation of the expression levels of CXCR7 but not CXCR4, whereas SDF‑1 could stimulate the proliferation and adhesion capacity of EPCs to FN and HUVECs by elevating the expression levels of CXCR4 and CXCR7. AMD3100 combined with SDF‑1 outperformed AMD3100 alone, promoted early reendothelialization and inhibited neointimal hyperplasia, indicating that early reendothelialization attenuated neointimal hypoplasia following endothelial injury.

Background: Our previous studies observed that administration of exosomes from endothelial progenitor cells (EPC) facilitated vascular repair in the rat model of balloon injury. However, the molecular events underlying this process remain elusive. Here, we aim to interrogate the key miRNAs within EPC-derived exosomes (EPC-exosomes) responsible for the activation of endothelial cell (EC) repair. Methods: The efficacy of EPC-exosomes in re-endothelialization was examined by Evans Blue dye and histological examination in the rat model of balloon-induced carotid artery injury. The effects of EPC-exosomes on human vascular EC (HUVEC) were also studied by evaluating the effects on growth, migratory and tube formation. To dissect the underlying mechanism, RNA-sequencing assays were performed to determine miRNA abundance in exosomes and mRNA profiles in exosome-treated HUVECs. Meanwhile, in vitro loss of function assays identified an exosomal miRNA and its target gene in EC, which engaged in EPC-exosomes-induced EC repair. Results: Administration of EPC-exosomes potentiated re-endothelialization in the early phase after endothelial damage in the rat carotid artery. The uptake of exogenous EPC-exosomes intensified HUVEC in proliferation rate, migration and tube-forming ability. Integrative analyses of miRNA-mRNA interactions revealed that miR-21-5p was highly enriched in EPC-exosomes and specifically suppressed the expression of an angiogenesis inhibitor Thrombospondin-1 (THBS1) in the recipient EC. The following functional studies demonstrated a fundamental role of miR-21-5p in the pro-angiogenic activities of EPC-exosomes. Conclusions: The present work highlights a critical event for the regulation of EC behavior by EPC-exosomes, which EPC-exosomes may deliver miR-21-5p and inhibit THBS1 expression to promote EC repair., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Timely endothelial repair after intervention-associated vascular injury is critical to prevent restenosis and thrombosis. Compared to living cell therapies, exosomes may be a better alternative. Thus, we aimed to compare the role of exosomes derived from human umbilical vein endothelial cells (HUVECs) versus those derived from endothelial progenitor cells (EPCs) in vascular endothelial repair., Material/methods: Exosomes secreted from HUVECs and EPCs were isolated and characterized respectively. In vitro, the effects of the two types of exosomes on migration and proliferation of endothelial cells were studied. In vivo, rats were systemically treated with the two exosome groups respectively after carotid artery endothelial injury induced by a balloon. The efficacy in promoting re-endothelialization was measured by Evans blue dye and histological examination., Results: Both types of exosomes, sized from 30 nm to 100 nm, had sphere-shaped or cupped morphology, and expressed CD63, CD9, and CD81; but the total yield of exosomes (particles/mL) based on number of cells, was 4.2 times higher from EPCs than HUVECs. Compared with control treatment, both exosome treated groups manifested significant enhancement of migration and proliferation in vitro and vascular recovery at an early stage in vivo. The two exosome-treated groups, however, did not statistically significantly differ., Conclusion: In conclusion, our results indicated that exosomes derived from HUVECs and EPCs had similar morphology, size distributions and characteristics, but those derived from EPCs were more abundant with comparable biologic activity. Therefore, EPCs may be a robust source of exosomes to promote vascular repair., Competing Interests: None., (IJCEP Copyright © 2019.)

Background: Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism, and it is still unclear whether FGF21 is related to atherosclerosis. Here, we explored the potential link between FGF21 and lower extremity atherosclerotic disease (LEAD) in type 2 diabetic patients., Methods: A cross-sectional study was conducted on 504 type 2 diabetic patients (283 men, 221 women). LEAD was defined by Ankle-brachial index (ABI) <0.9 and lower extremity arterial plaque evaluated by color Doppler ultrasound. Serum FGF21 concentrations were quantified by a sandwich enzyme-linked immunosorbent assay., Results: The total FGF21 levels of male and female patients had no significant differenence ((299.14(177.31-534.49) vs 362.50(214.01-578.73), P=0.516). Serum FGF21 levels in LEAD group were significantly higher than non-LEAD group in females (385.34(243.89-661.54) vs 313.13(156.38-485.79), P=0.006), while not in male patients (295.52(177.09-549.64) vs 342.09 (198.70-549.87), P=0.613). In diabetic women, subjects with LEAD had significantly higher serum FGF21 regardless of non-alcoholic fatty liver disease (NAFLD) (P < 0.05). And serum FGF21 levels were positively correlated with waist circumference and systolic blood pressure after adjusted for age and BMI (r=0.198, P=0.004; r=0.152, P=0.027; respectively). Moreover, FGF21 was independently tied to femoral intima-media thickness (FIMT) (β=0.208, P=0.031). After adjusted for other LEAD risk factors, FGF21 was demonstrated to be an independent risk factor for LEAD in type 2 diabetic women (OR, 1.106; 95%CI 1.008-1.223; P=0.028). In addition, FGF21 was negatively correlated with estradiol in premenopausal diabetic women (r=-0.368, P=0.009). After adjusted for estradiol, serum FGF21 levels were still positively associated with FIMT in premenopausal diabetic women (r=0.381, P=0.007). In diabetic men, serum FGF21 levels were correlated with triglyceride and C-reactive protein even after adjusted for age and BMI (r=0.204, P=0.001; r=0.312, P < 0.001; respectively). However, serum FGF21 was not an independent impact factor for LEAD in men (P > 0.05)., Conclusions: Serum FGF21 level independently and positively links LEAD in Chinese women with type 2 diabetes. The gender difference may be due to different estrogen levels.

Objective: Serum cystatin C (CysC) is a sensitive marker of kidney function and recent studies have shown that CysC plays a critical role in degenerative diseases in both the central and the peripheral nervous systems. The aim of this study was to explore the relationship between serum CysC and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes., Methods: In total, 937 type 2 diabetic patients were enrolled in this cross-sectional study. Serum CysC concentration was measured by immunoturbidimetry. DPN was evaluated by neurological symptoms, neurological signs, neurothesiometer, and electromyogram., Results: Serum CysC levels were significantly higher in DPN patients (1.3 (1.1-1.5) mg/l) compared with patients with signs of DPN (1.1 (0.9-1.3) mg/l, P<0.001) and non-DPN patients (1.0 (0.9-1.3) mg/l, P<0.001). Multiple regression analysis revealed that DPN was associated with age, diabetes duration, HbA1c, and serum CysC. Spearman's correlation analysis showed that serum CysC was closely related with age, sex, diabetes duration, hypertension, glomerular infiltration rate, and serum creatinine (Cr) level. The patients were divided into quartiles according to the serum CysC levels. Compared with quartile 1 (referent), the risk of DPN was significantly higher in quartile 2 (odds ratio (OR), 1.753; 95% CI, 1.055-2.912; P<0.05), quartile 3 (OR, 2.463; 95% CI, 1.445-4.917; P<0.01), and quartile 4 (OR, 5.867; 95% CI, 2.075-16.589; P<0.01). Receiver-operating characteristic analysis revealed that the optimal cutoff point of serum CysC to indicate DPN was 1.25 mg/l in male patients and 1.05 mg/l in female patients. High serum CysC level indicated a onefold higher risk of DPN., Conclusions: High serum CysC level is closely associated with DPN and may be a potential biomarker for DPN in type 2 diabetic patients., (© 2014 European Society of Endocrinology.)

Background: The present investigation was designed to elucidate the use of dynamic contrast enhanced perfusion MR imaging (DCE pMRI) in characterizing hyperemia, including microvessel changes, and to examine whether DCE pMRI can predict benign or malignant hyperemia., Methods: Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) by intraluminal suture placement. All rats were randomized to 4 groups: MCAO for 0.5 hours followed by saline treatment (10 ml/kg; group 1); MCAO for 3 hours followed by treatment with saline (group 2) or urokinase (25000 IU/kg; group 3); and MCAO for 6 hours followed by urokinase treatment (group 4). Relative cerebral blood volume (rCBV) and relative maximum slope of increase of the signal intensity time curve (rMSI) were quantitatively analyzed from MRI. Microvessel diameter and blood-brain barrier disruption obtained by laser scanning confocal microscopy (LSCM) as well as transmission electron microscopy (TEM) were obtained for correlative study., Results: Benign hyperemia was noticed only in group 1; malignant hyperemia was seen in group 3. Although the rCBV of malignant hyperemia was slightly higher than in benign hyperemia (P > 0.05), the rMSI, on the other hand, was significantly lower (P < 0.05). Fluoro-isothiocyanate dextran (FITC-dextran) extravasations, marked glial end-foot process swelling, and significant vasodilatation were seen in malignant hyperemia, while no or mild leakage of FITC-dextran and slight glial end-foot process swelling occurred in benign hyperemia., Conclusion: Our findings indicate that DCE pMRI can characterize post-ischemic hyperemia and correlates well with microvascular damage.