Liraglutide Attenuates Restenosis After Vascular Injury in Rabbits With Diabetes Via the TGF-ß/Smad3 Signaling Pathway.

Background: Lower limb ischemia due to arterial stenosis is a major complication in patients with diabetes mellitus (DM). Liraglutide is a long-acting analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist used for lowering blood glucose in patients with DM, and is believed to possess cardiovascular protective effects. The aim of this study was to investigate whether liraglutide has a protective effect on blood vessels and alleviates vascular intimal hyperplasia in streptozotocin (STZ)-induced rabbits with DM and its molecular mechanism. Methods: Rabbits with DM were induced by STZ, and a lower limb ischemia model was established. The animals were divided into a control group, DM-injury group and liraglutide treatment group. Pathological staining was used to observe the intimal growth, analyze the oxidation levels of malondialdehyde (MDA), superoxide dismutase (SOD) and plasma glutathione peroxidase (GSH-Px), and analyze the changes in expression of marker proteins and signaling pathway proteins by Western blotting. A hyperglycemia (HG)-injured vascular smooth muscle cells (VSMCs) model was established to analyze reactive oxygen species (ROS) levels, Cell-Counting Kit-8 (CCK-8) was used to analyze cell proliferation, scratch assay and Transwell Migration Assay to analyze cell migration, flow cytometry to analyze apoptosis and Western blotting was used to analyze changes in the expression of marker and signaling pathway proteins. Results: The results of pathological staining showed that intimal hyperplasia was severe after diabetes-induced lower limb ischemia in rabbits at 4 weeks, and liraglutide treatment reduced symptoms. Liraglutide treatment significantly decreased MDA content, increased SOD, GSH-Px content, and augmented total antioxidant capacity levels in tissues. The results of Western blotting analysis showed that E-cadherin, mitochondrial membrane potential 9 (MMP-9), proliferating cell nuclear antigen (PCNA), and type I collagen protein expression levels were significantly decreased after liraglutide treatment compared with the DM injury group. The results indicated that liraglutide inhibited epithelial-mesenchymal transition (EMT) progression, vascular cell proliferation and migration and collagen production. Liraglutide inhibits transforming growth factor beta 1 (TGF-ß1)/Smad3 signaling pathway protein expression. In vitro assays have shown that liraglutide reduces cellular ROS levels, inhibits cell proliferation and migration and promotes apoptosis. Liraglutide down-regulated the expression of E-cadherin, MMP-9, PCNA, type I collagen protein as well as the TGF-ß1/Smad3 signaling pathway, but this effect could be reversed by tumor necrosis factor alpha (TNF-α). Conclusion: Liraglutide can significantly improve tissue antioxidant capacity, reduce vascular cell proliferation and migration via the TGF-ß1/Smad3 signaling pathway, inhibit the EMT and collagen production processes, and alleviate hyperglycemia(HG)-induced lower limb ischemia and intimal hyperplasia.

Efficacy and safety of therapeutic anticoagulation for the treatment of isolated calf muscle vein thrombosis - a systematic review and meta-analysis.

BACKGROUND: Diverse treatment suggestions range from monitoring with duplex examinations to therapeutic anticoagulation (TA) for managing isolated calf muscle vein thrombosis (ICMVT). However, the small sample sizes and low-level evidence provided by most studies in the literature mean that the benefits of promising new treatment protocols are unclear. Hence, this meta-analysis is intended to assess the efficacy and safety of TA for patients with ICMVT. PATIENTS AND METHODS: Articles comparing TA with no anticoagulation (NA) or no therapeutic anticoagulation (NTA) in patients with ICMVT were collected from PubMed, the Cochrane Library, EMBASE, and Web of Science. The risk ratio (RR) and 95 % confidence interval (95 % CI) were generated for each outcome of interest. The data were pooled using a random-effects or fixed-effects model to evaluate differences in outcomes between the TA and control groups. RESULTS: Five of 377 initially identified papers were included. One randomized controlled trial, one non-randomized controlled trial and three retrospective cohort studies (a total of 744 patients, 390 in the TA group and the remaining 354 in the NA or NTA group) were included in this meta-analysis. The occurrence of thrombosis progression was significantly less frequent in those who received TA compared with those receiving NTA (RR = 0.33, 95 % CI 0.20 to 0.54, p < 0.01). The rate of complete recanalization was higher, albeit not significantly, in the TA group than in the NTA group (RR = 1.96, 95 % CI 1.01 to 3.80, p = 0.05). None of the pooled outcomes were significantly different when comparing the TA and NA groups. CONCLUSIONS: This study suggests that TA may result in a significant reduction in the rate of thrombosis progression and a marginally significant increase in the rate of complete recanalization for patients with ICMVT. Further studies are needed to confirm these findings and clarify whether the benefits of TA outweigh the potential harm.

Effect of umbilical cord blood stem cell transplantation on restenosis after endovascular interventional therapy for diabetic hindlimb vascular disease.

This study aimed to investigate the mechanism of human umbilical cord blood stem cell (HUCBSC) transplantation on restenosis after percutaneous transluminal angioplasty (PTA) for diabetic hindlimb vascular disease in rabbits. After successfully preparing a rabbit model of diabetic hindlimb vascular disease, 16 rabbits were randomly assigned to two groups. Of these, 8 rabbits received PTA surgery alone (PTA group), and the other 8 rabbits received PTA and HUCBSC (PTA+HUCBSC group) treatments. Five more healthy rabbits were set as healthy control (HC group). Samples were collected after 4 weeks of treatment. The expressions of regulator of calcineurin 1 (RCAN1) and calcineurin A (CnA) in the diseased artery were detected by immunofluorescence staining. The distribution of HUCBSCs was observed by pathological examination in transplanted artery, distal artery, and liver. Cytology experiments were applied to assess the levels of JAK and STAT3, and the migration and proliferation of human aortic vascular smooth muscle cells (HA-VSMC). In the rabbit model of diabetic vascular lesions in the hindlimbs, we found the stenosis of the femoral artery became more and more serious with time, and the expression level of PCNA positive cells was also gradually increased. The expression levels of RCAN1 and CnA in the PTA+HUCBSC group were significantly lower than those in PTA group. HUCBSC inhibited the migration and proliferation of HA-VSMC via JAK/STAT3 pathway. After HUCBSC local transplantation, HUCBSC had no distal tissue distribution. HUCBSC transplantation may prevent restenosis after PTA of diabetic hindlimb vascular disease through JAK/STAT3 pathway.

Five-year follow-up observation of interventional therapy for lower extremity vascular disease in type 2 diabetes and analysis of risk factors for restenosis.

BACKGROUND: The high incidence of type 2 diabetes, the low rate of compliance, and the complex mechanism of vascular disease caused by diabetes make its complications increase year by year. Our study aimed to investigate the clinical characteristics of lower extremity vascular diseases in type 2 diabetes and evaluate the long-term efficacy of vascular intervention for these diseases. METHODS: From 2007 to 2014, 362 patients who underwent vascular intervention in our hospital due to lower extremity vascular diseases in type 2 diabetes were followed up for 5 years and their clinical characteristics were analyzed in this retrospective study. RESULTS: Compared with those before treatment, the values of blood pressure, fasting blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride Ester (TG), and low density lipoprotein-cholesterol (LDL-C) of patients were significantly lower 5 years after intervention (P < 0.01). We found that the levels of fibrinogen, blood glucose, HbA1c, TC, TG, LDL-C, and small dense low-density lipoprotein (sdLDL) in the vascular restenosis group were significantly higher than those in the vascular patency group (P < 0.001), whereas the level of HDL-C in the vascular restenosis group was significantly lower compared with the vascular patency group. CONCLUSIONS: Vascular intervention can significantly improve a series of biochemical indicators in patients with lower extremity vascular diseases caused by type 2 diabetes. Postoperative restenosis may be related to hypertension, duration of diabetes, rate of inferior knee disease, fibrinogen, and sdLDL. Good survival and limb salvage were achieved in the patients in this series with interventions and medical treatment provided by endocrinologists.

A comparison of diagnostic performance of vacuum-assisted biopsy and core needle biopsy for breast microcalcification: a systematic review and meta-analysis.

BACKGROUND: Core needle biopsy (CNB) and vacuum-assisted biopsy (VAB) are both popularly used breast percutaneous biopsies. Both of them have become reliable alternatives to open surgical biopsy (OSB) for breast microcalcification (BM). AIMS: It is controversial that which biopsy method is more accurate and safer for BM. Hence, we conducted this meta-analysis to compare the diagnostic performance between CNB and VAB for BM, aiming to find out the better method. METHODS: Articles according with including and excluding criteria were collected from the databases, PubMed, Embase, and the Cochrane Library. Preset outcomes were abstracted and pooled to find out the potential advantages in CNB or VAB. RESULTS: Seven studies were identified and entered final meta-analysis from initially found 138 studies. The rate of ductal carcinoma in situ (DCIS) underestimation was significantly lower in VAB than CNB group [risk ratio (RR) = 1.83, 95% confidence interval (CI) 1.40 to 2.40, p < 0.001]. The microcalcification retrieval rate was significantly higher in VAB than CNB group (RR = 0.89, 95% CI 0.81 to 0.98, p = 0.02), while CNB owned a significantly lower complication rate than VAB (RR = 0.18, 95% CI 0.03 to 0.93, p = 0.04). The atypical ductal hyperplasia (ADH) underestimation rates were not compared for the limited number of studies reporting this outcome. CONCLUSIONS: Compared with CNB, VAB shows better diagnostic performance in DCIS underestimation rate and microcalcification retrieval rate. However, CNB shows a significantly lower complication rate. More studies are needed to verify these findings.

A bioactive implant in situ and long-term releases combined drugs for treatment of osteoarticular tuberculosis.

Anti-tuberculosis chemotherapy with a long duration and adequate dosing is the mainstay for treatment of osteoarticular tuberculosis (TB). However, it is difficult for systemic administration to reach adequate local drug concentrations and achieve effective treatment. Herein, a hydroxyapatite (HA) scaffold implant combined with a drug-releasing system was designed to achieve in situ and long-term anti-TB drug release and highly efficient therapeutic activity in vitro and in vivo. The clinical anti-TB drugs hydrophilic isoniazid (INH) and hydrophobic rifampicin (RFP) were molecularly dispersed into polyvinyl alcohol (PVA) through immersion-curing techniques and were steadily adhered onto the surfaces of HA scaffolds (HA-drug@PVA). The HA-drug@PVA scaffolds showed a long-term, sustained drug release profile and killed proliferating Mycobacterium in vitro. In vivo experimental results revealed that the HA-drug@PVA scaffolds provided over 10- and 100-fold higher concentrations in muscles and bones, respectively, as well as a much lower concentration (<0.025) in blood. Furthermore, the HA-drug@PVA scaffold implanted in an osteoarticular TB rabbit model showed obvious bone regeneration and fusion due to the inhibition of TB-associated inflammatory changes. The excellent therapeutic effects indicate that in situ implant materials combined with a long-term drug release system are promising for the treatment of osteoarticular TB and other osteoarticular infections.