Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis.

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

Impact of prophylactic wound closure in colorectal ESD on postoperative wound complications: A meta-analysis.

Endoscopic submucosa dissection (ESD) has been applied extensively in the treatment of large intestine tumours due to its high total excision ratio. Nevertheless, there is a high incidence of adverse reactions in colon ESD, and the efficacy of prophylactic ESD following ESD in prevention of postoperative haemorrhage is still disputed. The purpose of this meta-analysis is to evaluate the effectiveness of prophylaxis of wound closure in large intestine ESD after operation. For eligibility, we looked through three databases: PubMed, Embase and Cochrane Library. Heterogenity was measured by means of a chi-square method of Q-statistic and an I2 test. Fixed or random effects models were used for data processing. Based on the retrieval policy, we found a total of 1286 papers, and then we collected nine papers to extract the data. Regarding postoperative haemorrhage, there was a significant reduction in the risk of wound haemorrhage in the wound closure group than in the control group (OR, 0.29; 95% CI, 0.19-0.44 p < 0.0001). No statistical significance was found in the incidence of perforation in the wound closure and the control group (OR, 0.45; 95% CI, 0.19-1.03 p = 0.06). There was a significant reduction in the incidence of postoperation fever among those in the wound closure group than in the control group (OR, 0.37; 95% CI, 0.15-0.93 p = 0.04). Preventive endoscopic closure decreased the rate of ESD in colon disease, but did not significantly decrease the rate of postoperation perforation and postoperative fever. Future research will be required to clarify the risk factors and classify high-risk individuals in order to formulate a cost-effective prevention strategy.

MCP-1-Loaded Poly(l-lactide-co-caprolactone) Fibrous Films Modulate Macrophage Polarization toward an Anti-inflammatory Phenotype and Improve Angiogenesis.

Tissue engineering approaches such as the electrospinning technique can fabricate nanofibrous scaffolds which are widely used for small-diameter vascular grafting. However, foreign body reaction (FBR) and lack of endothelial coverage are still the main cause of graft failure after the implantation of nanofibrous scaffolds. Macrophage-targeting therapeutic strategies have the potential to address these issues. Here, we fabricate a monocyte chemotactic protein-1 (MCP-1)-loaded coaxial fibrous film with poly(l-lactide-co-ε-caprolactone) (PLCL/MCP-1). The PLCL/MCP-1 fibrous film can polarize macrophages toward anti-inflammatory M2 macrophages through the sustained release of MCP-1. Meanwhile, these specific functional polarization macrophages can mitigate FBR and promote angiogenesis during the remodeling of implanted fibrous films. These studies indicate that MCP-1-loaded PLCL fibers have a higher potential to modulate macrophage polarity, which provides a new strategy for small-diameter vascular graft designing.

Editor's Choice - Clinical Efficacy of Venastent - A Novel Iliac Vein Stent for Non-Thrombotic Iliac Vein Lesions: A Multi-Centre Randomised Controlled Trial.

OBJECTIVE: To determine the efficacy of Venastent - a novel iliac vein stent for non-thrombotic iliac vein lesions (NIVLs). METHODS: From October 2018 to January 2021, 256 NIVL patients were recruited at 19 Chinese hospitals. A randomised controlled trial was conducted to compare the efficacy of the new iliac vein stent-Venastent (Tianhong China) with Zilver stent (Cook USA). All patients were allocated randomly to two groups: the experimental group patients used Venastent, while the control group received the Zilver stent. The trial was registered in Chinese Clinical Trial Registry (ChiCTR2200057851). RESULTS: A total of 123 patients in the experimental group and 122 patients in the control group had a full set of data collected (p = ns). The technical success rate was 100% (n = 245/245). The patency rate was 100% (n = 123/123) in the experimental group and 98.4% (n = 120/122) in control group one year after operation (p = ns). The lower extremity swelling remission rate was 79.1% (n = 87/110) in the experimental group and 78.4% (n = 91/116) in the control group (p = ns). The lower extremity pain relief rate was 68.8% (n = 50/80) in the experimental group and 77.2% (n = 71/92) in the control group (p = ns). The ulcer healing rate was 90% (n = 18/20) in the experimental group and 87% (n = 20/23) in the control group (p = ns). There was no difference in stent re-stenosis or clinical remission between the two groups. CONCLUSION: The new iliac vein stent, Venastent, had a comparable high patency rate and safety profile as the Zilver stent (Cook) in NIVLs patients. Venastent significantly reduced symptoms of chronic venous disease.

Association of FIB-4 index and clinical outcomes in critically ill patients with acute kidney injury: a cohort study.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and clinical outcomes in patients with acute kidney injury (AKI) is unclear. We aimed to investigate the association between FIB-4 index and all-cause mortality in critically ill patients with AKI. METHODS: We used data from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database (v1.4). The FIB-4 score was calculated using the existing formulas. logistic regression model, and Cox proportional hazards model were used to assessed the relationship between the FIB-4 index and in-hospital,28-day and 90-day mortality, respectively. RESULTS: A total of 3592 patients with AKI included in the data analysis. 395 (10.99%) patients died during hospitalization and 458 (12.74%) patients died in 28-day. During the 90-day follow-up, 893 (22.54%) patients were dead. An elevated FIB-4 value was significantly associated with increased in-hospital mortality when used as a continuous variable (odds ratio [OR] 1.183, 95% confidence interval [CI] 1.072-1.305, P = 0.002) and as a quartile variable (OR of Q2 to Q4 1.216-1.744, with Q1 as reference). FIB-4 was positively associated with 28-day mortality of AKI patients with hazard ratio (HR) of 1.097 (95% CI 1.008, 1.194) and 1.098 (95% 1.032, 1.167) for 90-day mortality, respectively. CONCLUSION: This study demonstrated the FIB-4 index is associated with clinical outcomes in critically ill patients with acute kidney injury.

Efficacy and safety of rivaroxaban in patients with inferior vena cava filter placement without anticoagulation contraindications (EPICT): a prospective randomised controlled trial study protocol.

INTRODUCTION: Inferior vena cava (IVC) filters are commonly used in patients with venous thromboembolism to prevent fatal pulmonary embolism, but the thrombosis risk increases after filter placement. Warfarin is a widely anticoagulant, but long-term monitoring and dose adjustments are required. Anticoagulation with rivaroxaban is more straightforward as it dose not require laboratory monitoring. This study compares the efficacy and safety of rivaroxaban and warfarin as an in anticoagulation therapy for patients with IVC filter placement. METHODS AND ANALYSIS: This is a multicentre, randomised controlled trial. In total, 200 patients with deep vein thrombosis (DVT) with IVC filter implantation from 10 hospitals will be recruited. The patients will be randomised to the experimental group (rivaroxaban) or the control group (nadroparin overlapped with warfarin). The primary outcomes include death of any cause, pulmonary embolism (PE)-related death, bleeding and recurrent PE/DVT. The secondary outcomes include the percentage of other vascular events, IVC filter retrieval failure and net clinical benefits. This study aims to provide reliable, verification for the efficacy and safety of rivaroxaban antithrombotic therapy after IVC filter placement. ETHICS AND DISSEMINATION: The study was approved by the Human Research Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (approval number: (2019) 295). The results will be disseminated through presentations at scientific conferences and publications in peer-reviewed journals TRIAL REGISTRATION NUMBER: NCT04066764.

G protein-coupled receptor 39 activation alleviates oxidized low-density lipoprotein-induced macrophage inflammatory response, lipid accumulation and apoptosis by inducing A20 expression.

G protein-coupled receptor 39 (GPR39) agonist weakens oxidized low-density lipoprotein (ox-LDL)-induced attachment of monocytes to vascular endothelial cells and thus alleviates atherosclerosis. This study looks at whether GPR39 protects macrophages against ox-LDL-induced inflammation and apoptosis and ameliorates lipid accumulation in atherosclerosis and investigates its mechanism. Following inducement of ox-LDL, the expression of GPR39 and tumor necrosis factor alpha-induced protein 3 (TNFAIP3, also known as A20) in Raw 264.7 cells was detected by RT-qPCR and western blotting. The viability of macrophages treated with GPR39 agonist was detected by a cell counting kit 8 kit. GPR39 and A20 expression in ox-LDL-challenged macrophages was assayed by RT-qPCR and western blot with or without GPR30 agonist. After transfection of small interfering RNA (siRNA)-A20, the expression of pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6 and anti-inflammatory cytokine IL-10 as well as NF-κB p65 and COX2 was detected. Lipid accumulation was observed through Oil Red O Staining. Total cholesterol (TC) and free cholesterol (FC) in macrophages were detected by commercial kits. Lastly, macrophage apoptosis was observed through TUNEL, and apoptosis-related proteins were detected by western blotting . Results indicated that decreased expression of GPR39 and A20 was observed in ox-LDL-induced macrophages. GPR39 agonist significantly increased A20 expression in ox-LDL-treated macrophages. Furthermore, A20 interference reversed the inhibitory effect of GPR39 agonist on ox-LDL-induced inflammation, lipid accumulation, TC and FC overexpression as well as cell apoptosis. In conclusion, activating GPR39 alleviates ox-LDL-induced macrophage inflammation, lipid accumulation and apoptosis in an A20-dependent manner.

An efficacy and safety study of rivaroxaban for the prevention of deep vein thrombosis in patients with left iliac vein compression treated with stent implantation (PLICTS): study protocol for a prospective randomized controlled trial.

BACKGROUND: Balloon dilatation with stent implantation has been proved to be an effective option for left iliac vein compression syndrome (LIVCS), but thrombosis may still occur after the operation. Currently, warfarin is used for anticoagulant therapy, but long-term monitoring is required, while rivaroxaban does not need laboratory monitoring, which can simplify treatment. Therefore, this study aimed to compare the efficacy and safety of rivaroxaban and warfarin in anticoagulation. METHODS: This study is a multicenter, randomized controlled trial. We will recruit 224 patients with thrombotic LIVCS from 9 hospitals. Moreover, these patients will be randomized to either the experimental group (rivaroxaban) or the control group (warfarin plus nadroparin). The primary outcome is stent occlusion rate. Secondary outcomes are quality of life scale survey results, all-cause mortality, anticoagulation-related mortality, and the proportion of participants with stent displacement/fracture, thrombosis, hemorrhage, and other vascular events. DISCUSSION: This study will provide reliable, evidence-based clinical evidence for the efficacy and safety of rivaroxaban antithrombotic therapy after stent implantation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04067505 . Registered on August 26, 2019.

CTRP6 inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration.

Vascular smooth muscle cell (VSMC) proliferation and migration play critical roles in the development and progression of atherosclerosis. C1q/tumor necrosis factor-related protein 6 (CTRP6), a member of CTRPs family, was involved in cardiovascular diseases, inflammatory reaction and adipogenesis. However, the role of CTRP6 in VSMCs remains largely unknown. The purpose of this study is to investigate the effects of CTRP6 on VSMC proliferation and migration and explore the possible mechanism. Our results indicated that CTRP6 expression was dramatically down-regulated in human atherosclerotic tissues and in cultured VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB). In addition, CTRP6 overexpression significantly inhibited the proliferation and migration of VSMCs exposed to PDGF-BB, as well as increased expression of α-SMA and SM22α in PDGF-BB-stimulated VSMCs. Furthermore, CTRP6 overexpression efficiently prevented the activation of PI3K/Akt/mTOR in VSMCs in response to PDGF-BB. In conclusion, these findings showed that CTRP6 inhibits PDGF-BB-induced VSMC proliferation and migration, at least in part, through suppressing the PI3K/Akt/mTOR signaling pathway. Therefore, CTRP6 may be a potential target for the treatment of atherosclerosis.

Characteristics of immunogenic and tolerogenic dendritic cells within the arterial wall in atherosclerosis and in vitro.

AIM: To investigate the characteristic of mature dendritic cell (mDC) and tolerogenic dendritic cell (TDC) in human lower limb atherosclerosis occlusion syndrome (ASO) and diabetic foot and in vitro. METHODS: 58 human ASO and diabetic foot arterial specimens were collected from surgical operation and autopsy. Immunohistochemical and Western blotting method were used to examine the distribution and the content of CD83 and CD1a positive reaction mDC and CD11b and DC-SIGN positive reaction TDC. Furthermore, bone marrow-derived DCs were induced by rmGM-CSF and rmIL-4 in the presence or absence of LPS in vitro. The percent of CD11c(+)CD11b(+)TDC and CD11c(+)CD83(+)mDC were analyzed by flow cytometry. The effects of TDC and mDC on T lymphocytes were analyzed by the IL-17 level, the percent of Th17, and IL-17 mRNA expression. RESULTS: Immunogenicity mDC was heavily found in intima plaque and around the small vessel of adventitia on artherosclerosis aorta of lesion group, and was positively correlated to the progress of the disease. However, there were low expression of TDC and was negatively correlated to the progress of the disease. Meanwhile, we found that there is a close relationship between high glucose and disease progression. TDC expressed high levels of IL-10 and TGF-ß1 and down-regulated the percent of CD4(+)IL-17(+) Th17, IL-17 mRNA and the level of IL-17 in vitro. CONCLUSION: TDC and mDC are assembled in the process of ASO, and the progression of the disease might be aggravated by DC-maturation. High glucose might closely relate to the progression of atherosclerosis.

Functional endothelial cells derived from embryonic stem cells labeled with HIV transactivator peptide-conjugated superparamagnetic nanoparticles.

BACKGROUND: The development of regenerative therapies using derivatives of embryonic stem (ES) cells would be facilitated by a non-invasive method to monitor transplanted cells in vivo, for example, magnetic resonance imaging of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Although ES cells have been labeled with SPIO particles, the potential adverse effects of the label have not been fully examined. The objective of this study was to determine whether SPIO labeling affects murine ES cell viability, proliferation, or ability to differentiate into functional endothelial cells (ECs). METHODS: Cross-linked iron oxide (CLIO, an SPIO) was conjugated with human immunodeficiency virus transactivator of transcription (HIV-Tat) peptides, and murine ES cells were labeled with either CLIO-Tat, CLIO, or HIV-Tat. After labeling, ES cells were cultured for 4 days and Flk-1(+) ES cells identified and sorted by immunocytochemistry and fluorescence activated cell sorting (FACS). Flk-1(+) cells were replated on fibronectin-coated dishes, and ECs were obtained by culturing these for 4 weeks in endothelial cell growth medium supplemented with vascular endothelial growth factor (VEGF). ES cell viability was determined using trypan blue exclusion, and the proportion of SPIO(+) cells was evaluated using Prussian blue staining and transmission electron microscopy. After differentiation, the behavior and phenotype of ECs were analyzed by reverse transcription-polymerase chain reaction, flow cytometry, immunocytochemistry, DiI-labeled acetylated low-density lipoprotein (AcLDL) uptake, and Matrigel tube formation assay. RESULTS: CLIO-Tat was a highly effective label for ES cells, with > 96% of cells incorporating the particles, and it did not alter the viability of the labeled cells. ECs derived from CLIO-Tat(+) ES cells were very similar to murine aortic ECs in their morphology, expression of endothelial cell markers, ability to form vascular-like channels, and scavenging of AcLDL from the culture medium. CONCLUSIONS: CLIO-Tat is a highly effective label for ES cells and does not adversely affect cell viability, differentiation, or behavior. CLIO-Tat could be a useful marker for the non-invasive monitoring of transplanted stem cells.

Drug-carrier/hydrogel scaffold for controlled growth of cells.

In this work, a novel functional drug-carrier/hydrogel scaffold was prepared to control the growth of cells for tissue engineering. The drug-carrier/hydrogel scaffold was constructed from a micelle/Ca-alginate microparticles (Alg-MPs)/poly(vinyl alcohol) (PVA) hydrogel composite. In such a system, paclitaxel (PTX) is encapsulated in the micelles formed by poly(L-glutamic acid)-b-poly(propylene oxide)-b-poly(L-glutamic acid) (GPG), while human vascular endothelial growth factor-165 (VEGF(165)) is loaded in the Alg-MPs. The designed function of this scaffold is to encourage the fast growth of cells such as endothelial cells (ECs) in the early period to reduce the rejection and inhibit the growth of cells such as smooth muscle cells (SMCs) in late period to prevent the vascular intimal hyperplasia. The effect of VEGF(165) is to encourage the growth of ECs, while PTX is used to inhibit the growth of smooth muscle cells (SMCs). Structure characterizations show that the drug carriers are well dispersed in the PVA hydrogel. Independent release behaviors of the two drugs are observed. VEGF(165) shows a short-term release behavior, while PTX shows a long-term release behavior from the drug-carrier/hydrogel scaffolds. Further study shows a controllable cell growth behavior on this functional drug-carrier/hydrogel scaffold via the MTT assay.