The impacts of different embolization techniques on splenic artery embolization for blunt splenic injury: a systematic review and meta-analysis.

BACKGROUND: Splenic artery embolization (SAE) has been an effective adjunct to the Non-operative management (NOM) for blunt splenic injury (BSI). However, the optimal embolization techniques are still inconclusive. To further understand the roles of different embolization locations and embolic materials in SAE, we conducted this system review and meta-analyses. METHODS: Clinical studies related to SAE for adult patients were researched in electronic databases, included PubMed, Embase, ScienceDirect and Google Scholar Search (between October 1991 and March 2013), and relevant information was extracted. To eliminate the heterogeneity, a sensitivity analysis was conducted on two reduced study sets. Then, the pooled outcomes were compared and the quality assessments were performed using Newcastle-Ottawa Scale (NOS). The SAE success rate, incidences of life-threatening complications of different embolization techniques were compared by χ2 test in 1st study set. Associations between different embolization techniques and clinical outcomes were evaluated by fixed-effects model in 2nd study set. RESULTS: Twenty-three studies were included in 1st study set. And then, 13 of them were excluded, because lack of the necessary details of SAE. The remaining 10 studies comprised 2nd study set, and quality assessments were performed using NOS. In 1st set, the primary success rate is 90.1% and the incidence of life-threatening complications is 20.4%, though the cases which required surgical intervention are very few (6.4%). For different embolization locations, there was no obvious association between primary success rate and embolization location in both 1st and 2nd study sets (P > 0.05). But in 2nd study set, it indicated that proximal embolization reduced severe complications and complications needed surgical management. As for the embolic materials, the success rate between coil and gelfoam is not significant. However, coil is associated with a lower risk of life-threatening complications, as well as less complications requiring surgical management. CONCLUSIONS: Different embolization techniques affect the clinical outcomes of SAE. The proximal embolization is the best option due to the less life-threatening complications. For commonly embolic material, coil is superior to gelfoam for fewer severe complications and less further surgery management.

The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance.

Cellular repressor of E1A-stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte-specific CREG deletion dramatically exacerbates high-fat diet and leptin deficiency-induced (ob/ob) adverse effects such as obesity, hepatic steatosis, and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that c-Jun N-terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal-regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyperactivated JNK1 signaling was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. CONCLUSION: The results of our study provides evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1-JNK1 signaling. This study offers insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. (Hepatology 2017;66:834-854).

CREG1 ameliorates myocardial fibrosis associated with autophagy activation and Rab7 expression.

In cardiomyocytes subjected to stress, autophagy activation is a critical survival mechanism that preserves cellular energy status while degrading damaged proteins and organelles. However, little is known about the mechanisms that govern this autophagic response. Cellular repressor of E1A genes (CREG1) is an evolutionarily conserved lysosomal protein, and an important new factor in regulating tissues homeostasis that has been shown to antagonize injury of tissues or cells. In the present study, we aimed to investigate the regulatory role of CREG1 in cardiac autophagy, and to clarify autophagy activation mechanisms. First, we generated a CREG1 haploinsufficiency (Creg1(+/-)) mouse model, and identified that CREG1 deficiency aggravates myocardial fibrosis in response to aging or angiotensin II (Ang II). Conversely, exogenous infusion of recombinant CREG1 protein complete reversed cardiac damage. CERG1 deficiency in Creg1(+/-) mouse heart showed a market accumulation of autophagosome that acquired LC3II and beclin-1, and a decrease in autophagic flux clearance as indicated by upregulating the level of p62. Inversely, restoration of CREG1 activates cardiac autophagy, Furthermore, chloroquine, an inhibitor of lysosomal acidification, was used to confirm that CREG1 protected the heart tissue against Ang II-induced fibrosis by activating autophagy. Using adenoviral infection of primary cardiomyocytes, overexpression of CREG1 with concurrent resveratrol treatment significantly increased autophagy, while silencing CREG1 blocked the resveratrol-induced autophagy. These results suggest that CREG1-induced autophagy is required to maintain heart function in the face of stress-induced myocardiac damage. Both in vitro and in vivo studies identified that CREG1 deficiency influenced the maturation of lysosomes and reduced the espression of Rab7, which might be involved in CREG1-induced cardiomyocyte autophagy. These findings suggest that autophagy activation via CREG1 may be a viable therapeutic strategy autophagy for improving cardiac performance under pathologic conditions. This article is part of a Special Issue entitled: autophagy and protein quality control in cardiometabolic diseases.

Alginate-calcium microsphere loaded with thrombin: a new composite biomaterial for hemostatic embolization.

To date, transcatheter arterial embolization (TAE) has become a standard treatment to control intracavitary bleeding as an alternative to surgery. Due to excellent biocompatibility and no residual in vivo, biodegradable materials are preferred in TAE. However, gelfoam is the only commercially available biodegradable embolic material used to treat blunt trauma of solid abdominal viscera until now, and controversial on its stability and reliability never stopped in the past five decades. In this study, a new biodegradable macromolecule material (thrombin-loaded alginate-calcium microspheres, TACMs) was prepared using electrostatic droplet techniques and a special method was developed for hemostatic embolization. Thrombin was successfully loaded into microspheres with high encapsulation efficiency and drug loading capacity. A burst release of TACMs was observed at early stage and sustained release later on, with the activity of thrombin preserved well. The strength of TACMs mixed thrombus, which was used as embolic agent, increased in a dose-dependent manner after TACMs were added. In addition, the TACMs were verified to be of no cytotoxicity and systemic toxicity, and biodegradable in vivo. Finally, the results of preliminary applications revealed that the TACMs could serve as an effective and promising embolic material for blunt trauma and hemorrhage of solid abdominal viscera.

MicroRNA-495 regulates the proliferation and apoptosis of human umbilical vein endothelial cells by targeting chemokine CCL2.

INTRODUCTION: Endothelium dysfunction plays a critical role in atherosclerosis. MicroRNAs are endogenous non-coding RNAs that suppress gene expression by binding to the 3' untranslated regions of target genes. MiR-495 can regulate the proliferation and apoptosis of cancer cells, however, the roles of miR-495 in endothelial cells (ECs) remain unclear. Therefore, this study aims to investigate the roles and mechanisms of miR-495 on ECs proliferation and apoptosis. MATERIALS AND METHODS: MiR-495 and CCL2 expressions were examined using quantitative RT-PCR, ELISA assay and western blot. Bioinformatics analysis and luciferase reporter assay were used to examine the regulatory relationship between miR-495 and CCL2. CCK8 assay, BrdU incorporation assay and flow cytometry were used to analyze the roles of miR-495 and CCL2 on the proliferation of human umbilical vein endothelial cells (HUVECs). The effects of miR-495 and CCL2 on HUVECs apoptosis were examined by tunnel staining and western blot. RESULTS: MiR-495 was down-regulated in patients with coronary artery disease compared with healthy controls. CCL2 was a novel target gene of miR-495. MiR-495 significantly promoted HUVECs proliferation by altering cell cycle distribution, and it also inhibited HUVECs apoptosis by affecting the expression of cleaved caspase 3. Effects of miR-495 on HUVECs proliferation and apoptosis were significantly reversed by overexpression of CCL2. CONCLUSIONS: MiR-495 could affect HUVECs proliferation and apoptosis by directly targeting CCL2. This is the first report to disclose the roles and mechanisms of miR-495 on HUVECs proliferation and apoptosis, which may provide a theoretical basis for clarifying the mechanisms of atherosclerosis.

Purification and functional assessment of smooth muscle cells derived from mouse embryonic stem cells.

OBJECTIVE: To obtain a pure population of smooth muscle cells (SMC) derived from mouse embryonic stem cells (ESC) and further assess their functions. METHODS: A vector, expressing both puromycin resistance gene (puro(r) ) and enhanced green fluorescent protein (EGFP) gene driven by smooth muscle 22α (SM22α) promoter, named pSM22α-puro(r)-IRES2-EGFP was constructed and used to transfect ESC. Transgenic ESC (Tg-ESC) clones were selected by G418 and identified by PCR amplification of puro(r) gene. The characteristics of Tg-ESC were detected by alkaline phosphatase (ALP) staining, SSEA-1 immunofluorescence and teratoma formation test in vivo. After induction of SMC differentiation by all-trans retinoic acid, differentiated Tg-ESC were treated with 10 µg/mL puromycin for three days to obtain purified SMC (P-SMC). Percentage of EGFP(+) cells in P-SMC was assessed by flow cytometer. Expressions of smooth muscle specific markers were detected by immunostaining and Western blotting. Proliferation, migration and contractility of P-SMC were analyzed by growth curve, trans-well migration assay, and carbachol treatment, respectively. Finally, both P-SMC and unpurified SMC (unP-SMC) were injected into syngeneic mouse to see teratoma development. RESULTS: Tg-ESC clone was successfully established and confirmed by PCR detection of puro(r) gene in its genomic DNA. The Tg-ESC was positive for ALP staining, SSEA-1 staining and formed teratoma containing tissues derived from three germ layers. After retinoic acid induction, large amount of EGFP positive cells outgrew from differentiated Tg-ESC. Three days of puromycin treatment produced a population of P-SMC with an EGFP(+) percentage as high as 98.2% in contrast to 29.47% of unP-SMC. Compared with primary mouse vascular smooth muscle cells (VSMC), P-SMC displayed positive, but lowered expression of SMC-specific markers including SM α-actin and myosin heavy chain (SM-MHC) detected either, by immunostaining, or immunoblotting, accelerated proliferation, improved migration (99.33 ± 2.04 vs. 44.00 ± 2.08 migrated cells/field, P < 0.05), and decreased contractility in response to carbachol (7.75 ± 1.19 % vs. 16.50 ± 3.76 % in cell area reduction, P < 0.05). In vivo injection of unP-SMC developed apparent teratoma while P-SMC did not. CONCLUSIONS: We obtained a pure population of ESC derived SMC with less mature (differentiated) phenotypes, which will be of great use in research of vascular diseases and in bio-engineered vascular grafts for regenerative medicine.