scholarly journals Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Lirong Xu ◽  
Yutong Liu ◽  
Qianyun Cheng ◽  
Yang Shen ◽  
Ye Yuan ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Clinical Stage ◽  
Life Quality ◽  
Limb Ischemia ◽  
Lipid Uptake ◽  
Circadian Gene ◽  
Advanced Clinical Stage ◽  
Cell Functions

Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1−/− mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.

scholarly journals Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pegah Nammian ◽  
Seyedeh-Leili Asadi-Yousefabad ◽  
Sajad Daneshi ◽  
Mohammad Hasan Sheikhha ◽  
Seyed Mohammad Bagher Tabei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Cell Therapy ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Limb Ischemia

Abstract Introduction Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment. Methods For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis. Results Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups. Conclusions Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

Does Deep Femoral Artery Revascularization as an Isolated Procedure Play a Role in Chronic Critical Limb Ischemia?

2004 ◽  
Vol 11 (2) ◽  
pp. 119-124 ◽  
Author(s):  
Nicolas Diehm ◽  
Hannu Savolainen ◽  
Felix Mahler ◽  
Jürg Schmidli ◽  
Do-Dai Do ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Limb Ischemia ◽  
Deep Femoral Artery ◽  
Chronic Critical Limb Ischemia

Isolated femoral artery revascularisation with or without iliac inflow improvement – a less invasive surgical option in critical limb ischemia

VASA ◽  
2021 ◽  
pp. 1-7
Author(s):  
Andreas S. Peters ◽  
Katrin Meisenbacher ◽  
Dorothea Weber ◽  
Theodosios Bisdas ◽  
Giovanni Torsello ◽  
...  
Keyword(s):  
Risk Factors ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Negative Impact ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Lesion Length ◽  
Vascular Intervention ◽  
Selection Of Variables ◽  
Surgical Option

Summary: Background: Isolated femoral artery revascularisation (iFAR) represents a well-established surgical method in the treatment of peripheral arterial disease (PAD) involving common femoral artery disease. Data for iFAR in multilevel PAD are inconsistent, particularly in patients with critical limb ischemia (CLI). The aim of the study was to evaluate the outcome of iFAR in CLI regarding major amputation and reintervention and to identify associated risk factors for this outcome. Patients and methods: The data used have been derived from the German Registry of Firstline Treatment in Critical Limb Ischemia (CRITISCH). A total of 1200 patients were enrolled in 27 vascular centres. This sub-analysis included patients, which were treated with iFAR with/without concomitant iliac intervention. For detection of risk factors for the combined endpoint of major amputation and/or reintervention, selection of variables for multiple regression was conducted using stepwise forward/backward selection by Akaike’s information criterion. Results: 95 patients were included (mean age: 72 years ± 10.82; 64.2% male). Of those, 32 (33.7%) participants reached the combined endpoint. Risk factor analysis revealed continued tobacco use (odds ratio [OR] 2.316, confidence interval [CI] 0.832–6.674), TASC D-lesion (OR: 2.293, CI: 0.869–6.261) and previous vascular intervention in the trial leg (OR: 2.720, CI: 1.037–7.381) to be associated with reaching the combined endpoint. Conclusions: iFAR provides a reasonable, surgical option to treat CLI. Lesion length (TASC D) seems to have a negative impact on outcome. Further research is required to better define the future role of iFAR for combined femoro-popliteal lesions in CLI – best in terms of a randomised controlled trial.

Antegrade vs Crossover Femoral Artery Access in the Endovascular Treatment of Isolated Below-the-Knee Lesions in Patients With Critical Limb Ischemia

2017 ◽  
Vol 24 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Yukun Li ◽  
Ali Esmail ◽  
Konstantinos P. Donas ◽  
Georgios Pitoulias ◽  
Giovanni Torsello ◽  
...  
Keyword(s):  
Endovascular Treatment ◽  
Success Rate ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Limb Ischemia ◽  
Technical Success ◽  
Femoral Access ◽  
Technical Success Rate ◽  
Below The Knee ◽  
Antegrade Approach

Purpose: To evaluate the safety and effectiveness of antegrade vs crossover femoral artery access in the endovascular treatment of isolated below-the-knee (BTK) lesions in patients with critical limb ischemia (CLI). Methods: Between January 2014 and December 2015, 224 high-risk patients (mean age 75.8±9.8 years; 151 men) with CLI underwent infragenicular interventions on 292 crural vessels in 3 European vascular centers. All patients had isolated TransAtlantic Inter-Society Consensus (TASC) C (n=26) or D (n=198) BTK lesions. Primary endpoints were freedom from access-related complications and technical success comparing the antegrade vs crossover access groups. Results: Balloon angioplasty was the most used treatment modality (169 vessels, 75.4%). The technical success rate was 88.4% in the entire cohort and 88.0% in the antegrade group vs 90.4% in the crossover group (p>0.99). In all patients, the technical success rate was higher for stenotic lesions (100%) vs occlusions (85.5%, p=0.002) and in patients with TASC C BTK lesions (100%) vs TASC D (86.9%, p=0.033). The overall freedom from access-related complications was 97.8%: 99% in the antegrade group and 90.6% in the crossover group (p=0.022). Larger sheath size (5/6-F vs 4-F) was associated with a significantly higher risk for access-related complications (7.1% vs 1.1%, respectively; p=0.047). Conclusion: The present multicenter study showed high technical success and a low incidence of access-related complications in the treatment of isolated BTK lesions using either antegrade or crossover femoral access. The antegrade approach with the use of a 4-F system seems to have a significantly lower rate of access-related complications.

scholarly journals Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Huanyu He ◽  
Xinmao Song ◽  
Zuozhang Yang ◽  
Yuchi Mao ◽  
Kunming Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Stereotactic Body Radiotherapy ◽  
Clinical Stage ◽  
Resistant Cell ◽  
Antitumor Effects ◽  
Large Tumor ◽  
Advanced Clinical Stage ◽  
Potential Strategy

Abstract Stereotactic body radiotherapy (SBRT) has emerged as a standard treatment for non-small-cell lung cancer. However, its therapeutic advantages are limited with the development of SBRT resistance. The SBRT-resistant cell lines (A549/IR and H1975/IR) were established after exposure with hypofractionated irradiation. The differential lncRNAs were screened by microarray assay, then the expression was detected in LUAD tumor tissues and cell lines by qPCR. The influence on radiation response was assessed via in vitro and in vivo assays, and autophagy levels were evaluated by western blot and transmission electron microscopy. Bioinformatics prediction and rescue experiments were used to identify the pathways underlying SBRT resistance. High expression of KCNQ1OT1 was identified in LUAD SBRT-resistant cells and tissues, positively associated with a large tumor, advanced clinical stage, and a lower response rate to concurrent therapy. KCNQ1OT1 depletion significantly resensitized A549/IR and H1975/IR cells to radiation by inhibiting autophagy, which could be attenuated by miR-372-3p knockdown. Furthermore, autophagy-related 5 (ATG5) and autophagy-related 12 (ATG12) were confirmed as direct targets of miR-372-3p. Restoration of either ATG5 or ATG12 abrogated miR-372-3p-mediated autophagy inhibition and radiosensitivity. Our data describe that KCNQ1OT1 is responsible for SBRT resistance in LUAD through induction of ATG5- and ATG12-dependent autophagy via sponging miR-372-3p, which would be a potential strategy to enhance the antitumor effects of radiotherapy in LUAD.

Beneficial Effects of VEGF Secreted from Stromal Cells in Supporting Endothelial Cell Functions: Therapeutic Implications for Critical Limb Ischemia

2010 ◽  
Vol 19 (11) ◽  
pp. 1425-1437 ◽  
Author(s):  
Gilda Cobellis ◽  
Ciro Maione ◽  
Chiara Botti ◽  
Antonietta Coppola ◽  
Andrea Silvestroni ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Critical Limb Ischemia ◽  
Stromal Cells ◽  
Limb Ischemia ◽  
Therapeutic Implications ◽  
Beneficial Effects ◽  
Cell Functions

scholarly journals High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4675-4686 ◽  
Author(s):  
Marco Herling ◽  
Kaushali A. Patel ◽  
Nicole Weit ◽  
Nils Lilienthal ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Advanced Clinical Stage ◽  
Therapy Regimen ◽  
Cell Counts

Abstract Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5+ B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70+ tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.

scholarly journals Endovascular Recanalization of Chronic Total Occlusions of the Native Superficial Femoral Artery After Failed Femoropopliteal Bypass in Patients with Critical Limb Ischemia.

2021 ◽  
Author(s):  
Roberto Minici ◽  
Michele Ammendola ◽  
Marisa Talarico ◽  
Maria Luposella ◽  
Marco Minici ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Superficial Femoral Artery ◽  
Limb Ischemia ◽  
Secondary Patency ◽  
Femoropopliteal Bypass ◽  
Technical Success ◽  
Clinical Prognosis ◽  
Chronic Total Occlusions ◽  
Endovascular Recanalization

Abstract Background: The femoropopliteal bypass occlusion in patients with critical limb ischemia and chronic total occlusion of the native superficial femoral artery remains a significant problem, that hardly challenges vascular surgeons and interventional radiologists. Performing a secondary femoropopliteal bypass is still considered the standard of care, although it is associated with a higher complication rate and lower patency rate in comparison with primary bypass. Advanced age, lack of a good great saphenous vein, anastomosis’ pseudoaneurysms and high surgical risks make surgical approach not always suitable. Over the past few years, angioplasty has been commonly used, with the development in endovascular technologies, to treat chronic total occlusions of the native SFA, with a good technical success rate and clinical prognosis. Hence, the idea to recanalize the native SFA chronic total occlusions, in patients with critical limb ischemia (CLI) and femoro-popliteal bypass failure, has been born, limited to those patients unfit for surgery or refusing surgical reconstruction. Data regarding long-term outcomes of this approach in femoro-popliteal bypass failure are limited to few case-series studies.Results: Technical success was achieved in 51 (94.4%) of 54 limbs. Angiographically, 77.8% of the lesions were TASC II category D, while 22.2% TASC II category C. The average length of the native SFA lesions was 26.8 cm. Clinical success, with improved Rutherford classification staging, followed each case of technical success. The median follow-up value was 5.75 years (IQR, 1.5 – 7). By Kaplan-Meier survival analysis, primary patency rates were 61% (±0.07 SE) at 1 year and 46% (±0.07 SE) at 5 years. Secondary patency rates were 93% (±0.04 SE) at 1 year and 61% (±0.07 SE) at 5 years. Limb salvage rates were 94% (±0.03 SE) at 1 year and 88% (±0.05 SE) at 5 years.Conclusions: The endovascular recanalization of chronic total occlusions (CTO) of the native superficial femoral artery (SFA) after failed femoropopliteal bypass is a safe and effective therapeutic option in patients unfit for surgery with critical limb ischemia.

scholarly journals POOR PROGNOSTIC DETERMINANTS FOR PATIENTS UNDERGOING SUPERFICIAL FEMORAL ARTERY ANGIOPLASTY

2020 ◽  
Vol 8 (11) ◽  
pp. 828-831
Author(s):  
S. Maruthu Thurai ◽  
◽  
P. Mohan Raja ◽  
M. Murali ◽  
◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Superficial Femoral Artery ◽  
Lower Limb ◽  
Prospective Observational Study ◽  
Negative Impact ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
The Poor

Introduction: Aim is to study the poor prognostic determinants for patients undergoing superficial femoral artery angioplasty . Material and Methods: It is a Prospective observational study done in fifty patients who has undergone superficial femoral artery angioplasty for lower limb ischemia. Results: 22% had reocclusion of lesion, 10% required reintervention and 8% underwent major limb amputation .These three were considered major negative impact conditions. These were found in majority of patients with renal insufficiency, critical limb ischemia, smoker and drug defaulters. Conclusion: Thus poor prognostic determinants in the study were renal insufficiency, critical limb ischemia , smoker and drug defaulters.

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