NINJ1 Facilitates Abdominal Aortic Aneurysm Formation via Blocking TLR4-ANXA2 Interaction and Enhancing Macrophage Infiltration.

Abdominal aortic aneurysm (AAA) is a common and potentially life-threatening condition. Chronic aortic inflammation is closely associated with the pathogenesis of AAA. Nerve injury-induced protein 1 (NINJ1) is increasingly acknowledged as a significant regulator of the inflammatory process. However, the precise involvement of NINJ1 in AAA formation remains largely unexplored. The present study finds that the expression level of NINJ1 is elevated, along with the specific expression level in macrophages within human and angiotensin II (Ang II)-induced murine AAA lesions. Furthermore, Ninj1flox/flox and Ninj1flox/floxLyz2-Cre mice on an ApoE-/- background are generated, and macrophage NINJ1 deficiency inhibits AAA formation and reduces macrophage infiltration in mice infused with Ang II. Consistently, in vitro suppressing the expression level of NINJ1 in macrophages significantly restricts macrophage adhesion and migration, while attenuating macrophage pro-inflammatory responses. Bulk RNA-sequencing and pathway analysis uncover that NINJ1 can modulate macrophage infiltration through the TLR4/NF-κB/CCR2 signaling pathway. Protein-protein interaction analysis indicates that NINJ1 can activate TLR4 by competitively binding with ANXA2, an inhibitory interacting protein of TLR4. These findings reveal that NINJ1 can modulate AAA formation by promoting macrophage infiltration and pro-inflammatory responses, highlighting the potential of NINJ1 as a therapeutic target for AAA.

Application of 3D Printing Insole by Hemodynamics in Older Patients with Critical Limb Ischemia: Protocol for a Randomized Clinical Trial.

Introduction: Critical limb ischemia (CLI) is a severe condition characterized by inadequate blood flow to the lower extremities, often leading to tissue damage and amputation. CLI is characterized by microcirculatory dysfunction, muscle tissue necrosis, and inflammation. Patients may suffer from the traumatic pain and the increase of plantar pressure, and foot care for patients with CLI has become the "last mile" to improve their life quality. Traditional shoe insoles often lack individual customization, failing to address the unique anatomical needs and hemodynamic characteristics of patients. The study aims to investigate the effects of this innovative intervention on improving the clinical outcomes, and quality of life in CLI patients. Methods and Analysis: This Critical Limb Ischemia Hemodynamic Insole Study is a randomized controlled study performed to explore the effect of a 3D printing insole on foot care of CLI patients. This study recruitment began on November 1, 2021. Patients with CLI confirmed by clinical symptoms and imaging were recruited as the research objects. Participants will be randomly assigned to either the experimental group, which will receive 3D-printed insoles customized based on their hemodynamics, or the control group, which will receive traditionally manufactured insoles. Both groups were followed up for up to 24 months after surgery, including claudication distance, claudication time, pain score, rehospitalization, etc. Trial Registration Number: ChiCTR2100051857.

An H2 S-BMP6 Dual-Loading System with Regulating Yap/Taz and Jun Pathway for Synergistic Critical Limb Ischemia Salvaging Therapy.

Critical limb ischemia, the final course of peripheral artery disease, is characterized by an insufficient supply of blood flow and excessive oxidative stress. H2 S molecular therapy possesses huge potential for accelerating revascularization and scavenging intracellular reactive oxygen species (ROS). Moreover, it is found that BMP6 is the most significantly up-expressed secreted protein-related gene in HUVECs treated with GYY4137, a H2 S donor, based on the transcriptome analysis. Herein, a UIO-66-NH2 @GYY4137@BMP6 co-delivery nanoplatform to strengthen the therapeutic effects of limb ischemia is developed. The established UIO-66-NH2 @GYY4137@BMP6 nanoplatform exerts its proangiogenic and anti-oxidation functions by regulating key pathways. The underlying molecular mechanisms of UIO-66-NH2 @GYY4137@BMP6 dual-loading system lie in the upregulation of phosphorylated YAP/TAZ and Jun to promote HUVECs proliferation and downregulation of phosphorylated p53/p21 to scavenge excessive ROS. Meanwhile, laser-doppler perfusion imaging (LDPI), injury severity evaluation, and histological analysis confirm the excellent therapeutic effects of UIO-66-NH2 @GYY4137@BMP6 in vivo. This work may shed light on the treatment of critical limb ischemia by regulating YAP, Jun, and p53 signaling pathways based on gas-protein synergistic therapy.

Efficacy and safety of preoperative embolization in carotid body tumor treatment: A propensity score matching retrospective cohort study.

BACKGROUND: To assess the efficacy and safety of preoperative embolization (PE) in patients with carotid body tumor (CBTs). METHODS: In a single-center retrospective cohort study, 127 patients underwent surgical resection of CBTs from January 2003 to December 2019. One-to-one propensity score matching was conducted between patients with or without PE. RESULTS: Thirty-two (25.2%) patients received PE. After propensity score matching, no statistically significant differences were found in the baseline characteristics of 28 patients in each group. Compared with NPE group, operative time and estimated blood loss (EBL) were significantly reduced in the PE group. The incidence of stroke, perioperative complications, intraoperative blood transfusion, vascular reconstruction, hospital stay, tumor recurrence, and all-cause mortality were not different between the PE and NPE group. CONCLUSIONS: Preoperative embolization was efficient and safe with a reduction of intraoperative blood loss and operative time during CBT resection.

A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans.

OBJECTIVE: Atherosclerosis obliterans (ASO) is a chronic occlusive arterial disease and the most common type of peripheral arterial disease. Current treatment options like medication and vascularization have limited effects for "no-option" patients, and stem cell therapy is considered a viable option, although its application and efficacy have not been standardized. The objective of this review was to assess the safety and efficacy of autologous stem cell therapy in patients with ASO. METHODS: We performed a literature search of published randomized controlled trials (RCTs) for patients with ASO receiving stem cell therapy without a revascularization option. PubMed, Embase, and the Cochrane Library were searched. This study was conducted by a pair of authors independently and audited by a third author. Data were synthesized with a random-effects model. RESULTS: A total of 630 patients in 12 RCTs were included. The results showed that cell therapy significantly improved total amputation (relative risk [RR], 0.64; 95% confidence interval [CI], 0.47-0.87; P = .004), major amputation (RR, 0.69; 95% CI, 0.50-0.94; P = .02), ankle-brachial index (mean difference [MD], 0.08; 95% CI, 0.02-0.13; P = .004), transcutaneous oxygen tension (MD, 11.52; 95% CI, 3.60-19.43; P = .004), and rest pain score (MD, -0.64; 95% CI, -1.10 to -0.17; P = .007) compared with placebo or standard care. However, current studies showed cell therapy was not superior to placebo or standard care in all-cause death (RR, 0.75; 95% CI, 0.41-1.36; P = .34) and ulcer size (MD, -8.85; 95% CI, -29.05 to 11.36; P = .39). The number of trials included was limited. Moreover, most trials were designed for "no-option" patients, and thus the results should be applied with caution to other patients with peripheral arterial disease. CONCLUSIONS: Patients with ASO can benefit from autologous cell therapy in limb salvage, limb blood perfusion, and rest pain alleviation.

Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia.

BACKGROUND: Diabetic limb ischemia is a clinical syndrome and refractory to therapy. Our previous study demonstrated that adipose-derived stem cells (ADSCs) overexpressing glyoxalase-1 (GLO-1) promoted the regeneration of ischemic lower limbs in diabetic mice, but low survival rate, difficulty in differentiation, and tumorigenicity of the transplanted cells restricted its application. Recent studies have found that exosomes secreted by the ADSCs have the advantages of containing parental beneficial factors and exhibiting non-immunogenic, non-tumorigenic, and strong stable characteristics. METHODS: ADSCs overexpressing GLO-1 (G-ADSCs) were established using lentivirus transfection, and exosomes secreted from ADSCs (G-ADSC-Exos) were isolated and characterized to coculture with human umbilical vein endothelial cells (HUVECs). Proliferation, apoptosis, migration, and tube formation of the HUVECs were detected under high-glucose conditions. The G-ADSC-Exos were injected into ischemic hindlimb muscles of type 2 diabetes mellitus (T2DM) mice, and the laser Doppler perfusion index, Masson's staining, immunofluorescence, and immunohistochemistry assays were adopted to assess the treatment efficiency. Moreover, the underlying regulatory mechanisms of the G-ADSC-Exos on the proliferation, migration, angiogenesis, and apoptosis of the HUVECs were explored. RESULTS: The G-ADSC-Exos enhanced the proliferation, migration, tube formation, and anti-apoptosis of the HUVECs in vitro under high-glucose conditions. After in vivo transplantation, the G-ADSC-Exo group showed significantly higher laser Doppler perfusion index, better muscle structural integrity, and higher microvessel's density than the ADSC-Exo and control groups by Masson's staining and immunofluorescence assays. The underlying mechanisms by which the G-ADSC-Exos protected endothelial cells both in vitro and in vivo might be via the activation of eNOS/AKT/ERK/P-38 signaling pathways, inhibition of AP-1/ROS/NLRP3/ASC/Caspase-1/IL-1ß, as well as the increased secretion of VEGF, IGF-1, and FGF. CONCLUSION: Exosomes derived from adipose-derived stem cells overexpressing GLO-1 protected the endothelial cells and promoted the angiogenesis in type 2 diabetic mice with limb ischemia, which will be a promising clinical treatment in diabetic lower limb ischemia.

Atherectomy Combined with Balloon Angioplasty versus Balloon Angioplasty Alone for de Novo Femoropopliteal Arterial Diseases: A Systematic Review and Meta-analysis of Randomised Controlled Trials.

OBJECTIVE: The efficacy and cost effectiveness of atherectomy for femoropopliteal (FP) arterial diseases have not been determined yet. A systematic review and meta-analysis were performed to compare the efficacy and safety between atherectomy combined with balloon angioplasty (BA) and BA alone for patients with de novo FP steno-occlusive lesions. METHODS: The Cochrane Library, Medline, and Embase were used to search for studies evaluating outcomes of atherectomy combined with BA compared with BA alone in FP arterial diseases from inception to July 2020. The methodological quality of the included studies was evaluated with the Cochrane Risk of Bias Tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the level of evidence for each outcome. The fixed effects model was chosen to combine the data when I2 < 50%; otherwise, the random effects model was used. Subgroup and sensitivity analyses were performed to further analyse the results. RESULTS: Four RCTs were included. The meta-analysis showed that atherectomy combined with BA was associated with improved technical success rate (risk ratio [RR] 0.22, 95% confidence interval [CI] 0.13-0.38, p < .001; I2 = 0; high quality), reduced bailout stenting (RR 0.15, 95% CI 0.07-0.32, p < .001; I2 = 16%; high quality), and flow limiting dissection (RR 0.24, 95% CI 0.13-0.47, p < .001; I2 = 0; high quality). No statistically significant difference was found in target lesion revascularisation (TLR), primary patency, mortality, major adverse event (MAE), or ankle brachial index (ABI) after one year follow up. CONCLUSION: Compared with BA alone, atherectomy combined with BA may not improve primary patency, TLR, mortality rate, or ABI, but may reduce the need for bailout stenting and the incidence of flow limiting dissection and increase the technical success rate in FP arterial diseases. More studies are warranted to further confirm the conclusion.