The Role of Colchicine in the Prevention of Cerebrovascular Ischemia

2018 ◽  
Vol 24 (6) ◽  
pp. 668-674 ◽  
Author(s):  
Georgios Tsivgoulis ◽  
Aristeidis H. Katsanos ◽  
Georgios Giannopoulos ◽  
Vasiliki Panagopoulou ◽  
Dalius Jatuzis ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Lifestyle Modification ◽  
Recurrent Stroke ◽  
Inflammatory Cells ◽  
Lipid Lowering ◽  
Atheromatous Plaque ◽  
Vascular Events ◽  
Plaque Stabilization ◽  
Anti Inflammatory

Introduction: Despite the proven efficacy of anti-thrombotic, lipid-lowering, anti-hypertensive therapies and lifestyle modification changes for secondary ischemic stroke prevention, the risk of recurrent stroke, coronary events and vascular death remains substantial even for patients treated with high rates of established secondary preventive medications. Methods: In the present review, we summarize available literature data on the association between systemic inflammation and symptomatic atherosclerosis including recurrent cerebral ischemia. We also highlight the potential role of colchicine in the suppression of atherosclerosis-induced inflammation, plaque stabilization and thromboembolism prevention. Results: Accumulating evidence suggests that inflammation is of key importance in the pathophysiology of atherosclerotic plaque de-stabilization and thromboembolism, with inflammatory cells being involved in all stages of atherosclerosis development. Therefore, anti-inflammatory therapies targeting the atherosclerotic plaque inflammation may be important contributors in plaque stabilization and in the prevention of thromboembolic events. Colchicine is known to have multiple anti-inflammatory properties including inhibition of microtubule polymerization, leading to reduced secretion in monocyte-macrophages. Currently the randomized controlled CONVINCE trial is enrolling stroke patients to evaluate the effect of a daily low-dose of colchicine in reducing the rate of recurrent stroke and major vascular events. Conclusion: Inflammatory pathways seem to be key mediators in the development of atherosclerotic process, atheromatous plaque destabilization and thromboembolism. Colchicine as a novel therapeutic agent could be a safe and effective inhibitor of the inflammation cascade in patients with extra- or intracranial atherosclerosis or arteriolosclerosis, resulting in reduced vascular events.

Abstract WMP73: Peripheral T Cells From MCAO Mice Contribute to Microglial Polarization

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Dan Ye ◽  
Yun Xu
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Inflammatory Cells ◽  
Treg Cells ◽  
Experimental Stroke ◽  
Dual Roles ◽  
Microglial Polarization ◽  
Peripheral T Cells ◽  
Anti Inflammatory

Both resident microglia and infiltrated peripheral T cells have been proved to play important roles in the pathology of stroke. It is well accepted that activated microglia exert dual roles, including pro-inflammatory (M1) and anti-inflammatory (M2) functions. However, the mechanism regulating microglial polarization remains elusive. T cells are recruited into the ischemic area within 24 h after stroke, which also exhibit pro-inflammatory (Th1, Th17) and anti-inflammatory (Th2, Treg) functions. The interaction between microglia and T cells after stroke is barely understood, which may be served as modifiers of pathobiology in stroke. Here we described the role of T cells in the microglial polarization in mouse experimental stroke. We isolated T cells from spleens of MCAO mice at 24 h and 72 h, respectively, and then added to cultured microglia for 24 h. Our results indicated that splenic T cells obtained at 24 h after MCAO selectively promoted microglia polarize to a pro-inflammatory (M1) state, while T cells obtained at 72 h, favored microglia polarize to an anti-inflammatory (M2) state. The results of flow cytometry showed that Th1 and Th17 cells increased at 24 h after MCAO while Th2 and Treg cells increased at 72 h after MCAO. This study implicates that distinct subtypes of T cells contribute differentially to microglial polarization after stroke onset. Therefore, treatments aiming at modulating the ratios of T cells to anti-inflammatory cells have the potential to induce microglial polarize to M2 phenotype and improve the outcome of ischemic stroke.

scholarly journals Hydroxychloroquine: Looking into the Future

2017 ◽  
Vol 24 (4) ◽  
pp. 369-375 ◽  
Author(s):  
Saibal Chakravorty ◽  
Indranil Purkait ◽  
Anil Pareek ◽  
Avinash Talware
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
Systemic Inflammation ◽  
Cardiovascular Effects ◽  
Lipid Lowering ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractHydroxychloroquine, an antimalarial agent has also been found to possess antidiabetic action. Onset of type-2 diabetes (T2DM) and cardiovascular disease is now considered to be the outcome of systemic inflammation. Many clinical trials are targeting systemic inflammation to reduce cardiovascular risk. Anti-inflammatory drugs with cardiovascular effects may be valuable therapeutic intervention to reduce massive cardiovascular risk in T2DM. In this review, antidiabetic action and potential cardioprotective role of hydroxychloroquine has been discussed. By virtue of its antidiabetic, lipid lowering, anti-platelet, anticoagulant and anti-inflammatory properties, hydroxychloroquine can be a key therapeutic alternative to manage patients with T2DM.

scholarly journals Sneddon syndrome: a comprehensive clinical review of 53 patients

2021 ◽  
Author(s):  
N. L. P. Starmans ◽  
M. R. van Dijk ◽  
L. J. Kappelle ◽  
C. J. M. Frijns
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Clinical Features ◽  
Recurrent Stroke ◽  
Anticoagulation Therapy ◽  
Vascular Events ◽  
Median Period ◽  
Sneddon Syndrome

Abstract Background The presence of livedo reticularis in patients with ischaemic stroke is associated with Sneddon syndrome (SS). Our objective was to present the clinical features of SS patients and to assess the role of antiphospholipid antibodies (APL). Methods Consecutive patients, diagnosed with SS between 1996 and 2017, were retrospectively reviewed for their demographic, neurological, dermatological, cardiac and extracerebral vascular features. Diagnosis of SS was made only if other causes of stroke were excluded. Patients with and without APL were included and compared for their clinical features. Results Fifty-three patients (79% female) were included, of whom 14 patients were APL-positive. Median age at diagnosis was 40 years. Approximately 60% of the patients had ≥ 3 cardiovascular risk factors. There were 129 previous vascular events (66 ischaemic strokes, 62 TIAs and 1 amaurosis fugax) during a median period of 2 years between the first event and diagnosis of SS. Skin biopsy was positive for SS in 29 patients (67%), mostly showing a thickened vessel wall with neovascularization in the deep dermis. After a median follow-up of 28 months, 4 patients, either on antiplatelet or oral anticoagulation therapy, had a recurrent stroke. There were few statistically significant differences between APL-negative and APL-positive patients, including the number of vascular events before diagnosis. Conclusions SS predominantly affects young women with a relatively large number of cardiovascular risk factors. Clinical features of SS are comparable across different studies. We found no differences in the main clinical features between APL-positive and APL-negative patients.

scholarly journals Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) – study protocol for a randomised controlled trial

2021 ◽  
Vol 6 (2) ◽  
pp. 222-228
Author(s):  
Peter Kelly ◽  
Christian Weimar ◽  
Robin Lemmens ◽  
Sean Murphy ◽  
Francisco Purroy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Ischaemic Stroke ◽  
Usual Care ◽  
Artery Stenosis ◽  
Cardioembolic Stroke ◽  
Lipid Lowering ◽  
Large Artery ◽  
Vascular Events ◽  
Anti Inflammatory

Background Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events. Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. Design CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. Outcome The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). Summary CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. Schedule First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

scholarly journals Trends and predictors of myocardial infarction or vascular death after ischaemic stroke or TIA in China, 2007–2018: insights from China National Stroke Registries

2020 ◽  
pp. svn-2020-000503
Author(s):  
Long Li ◽  
Yuesong Pan ◽  
Mengxing Wang ◽  
Jing Jing ◽  
Xia Meng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischaemic Stroke ◽  
Proportional Hazards ◽  
Recurrent Stroke ◽  
Cox Proportional Hazards ◽  
Lipid Lowering ◽  
Stroke Management ◽  
Vascular Events ◽  
Vascular Death ◽  
Increased Risk

BackgroundAlthough stroke management, primary and secondary preventions have been improved in China last decades, the trends and predictors of major vascular events after ischaemic stroke or transient ischaemic attack (TIA) at national scale are less known.MethodsData were obtained from the three phases of China National Stroke Registry (CNSR), including CNSR-Ⅰ (years 2007–2008), CNSR-Ⅱ (years 2012–2013) and CNSR-III (years 2015–2018). For comparison, patients who were diagnosed as ischaemic stroke or TIA were included. Kaplan-Meier estimates of myocardial infarction (MI) or vascular death were calculated at 1 year. Independent predictors were further assessed with a Cox proportional hazards regression.ResultsFrom 2007 to 2018, a total of 50 284 patients with ischaemic stroke or TIA were enrolled in this study. A declining trend was found in 1-year MI or vascular death (p for trend <0.001), while recurrent stroke depicted a U-shape curve with a nadir in 2012–2013 cohort. A similar trend was also observed in patients who were admitted to 26 hospitals in all three CNSRs. In 2015–2018 cohort, only 251 (1.7%; 95% CI 1.5% to 1.9%) MI or vascular death had occurred at 1 year. Older age, previous stroke or TIA, history of coronary artery disease and the National Institutes of Health Stroke Scale >6 were associated with both an increased risk of MI or vascular death and recurrent stroke. While early antiplatelet therapy and lipid-lowering agents at discharge predicted a reduced risk.ConclusionA declining trend and current low incidence of MI or vascular death, rather than recurrent stroke, after ischaemic stroke or TIA were observed in China. Traditional factors were found as independent predictors. These findings suggested there is still much room to improve for stroke management.

scholarly journals The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways

2021 ◽  
Vol 22 (8) ◽  
pp. 3991
Author(s):  
Rosalba Siracusa ◽  
Ramona D’Amico ◽  
Marika Cordaro ◽  
Alessio Filippo Peritore ◽  
Tiziana Genovese ◽  
...  
Keyword(s):  
Methyl Ester ◽  
Inflammatory Cells ◽  
Blue Staining ◽  
Sod Activity ◽  
Inflammatory Microenvironment ◽  
Nfkb Activation ◽  
Fibronectin Expression ◽  
Gynecological Disease ◽  
Anti Inflammatory

Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways.

scholarly journals Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

2021 ◽  
Vol 23 (1) ◽  
pp. 77
Author(s):  
Khadija El Hadri ◽  
Rémy Smith ◽  
Eric Duplus ◽  
Chahrazade El Amri
Keyword(s):  
Oxidative Stress ◽  
Atherosclerotic Plaque ◽  
Therapeutic Option ◽  
Lipid Lowering ◽  
Antioxidant Systems ◽  
Blood Levels ◽  
Ldl Particles ◽  
Antioxidant Agents ◽  
Anti Inflammatory ◽  
The Impact

Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation.

scholarly journals Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Olga Tsave ◽  
Savvas Petanidis ◽  
Efrosini Kioseoglou ◽  
Maria P. Yavropoulou ◽  
John G. Yovos ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Chemical Reactivity ◽  
Inflammatory Cells ◽  
T Cell Signaling ◽  
Cell Immunotherapy ◽  
Molecular Immunology ◽  
Anti Inflammatory

Over the last decade, a diverse spectrum of vanadium compounds has arisen as anti-inflammatory therapeutic metallodrugs targeting various diseases. Recent studies have demonstrated that select well-defined vanadium species are involved in many immune-driven molecular mechanisms that regulate and influence immune responses. In addition, advances in cell immunotherapy have relied on the use of metallodrugs to create a “safe,” highly regulated, environment for optimal control of immune response. Emerging findings include optimal regulation of B/T cell signaling and expression of immune suppressive or anti-inflammatory cytokines, critical for immune cell effector functions. Furthermore, in-depth perusals have explored NF-κB and Toll-like receptor signaling mechanisms in order to enhance adaptive immune responses and promote recruitment or conversion of inflammatory cells to immunodeficient tissues. Consequently, well-defined vanadium metallodrugs, poised to access and resensitize the immune microenvironment, interact with various biomolecular targets, such as B cells, T cells, interleukin markers, and transcription factors, thereby influencing and affecting immune signaling. A synthetically formulated and structure-based (bio)chemical reactivity account of vanadoforms emerges as a plausible strategy for designing drugs characterized by selectivity and specificity, with respect to the cellular molecular targets intimately linked to immune responses, thereby giving rise to a challenging field linked to the development of immune system vanadodrugs.

scholarly journals PCSK9 Induces Rat Smooth Muscle Cell Proliferation and Counteracts the Pleiotropic Effects of Simvastatin

2021 ◽  
Vol 22 (8) ◽  
pp. 4114
Author(s):  
Maria Giovanna Lupo ◽  
Silvia Marchianò ◽  
Maria Pia Adorni ◽  
Francesca Zimetti ◽  
Massimiliano Ruscica ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Atherosclerotic Plaque ◽  
Regulatory Element ◽  
Smooth Muscle Actin ◽  
Cholesterol Biosynthesis ◽  
Lipid Lowering ◽  
Direct Role ◽  
Contractile Phenotype

Human atherosclerotic plaque contains smooth muscle cells (SMCs) negative for the contractile phenotype (α-smooth muscle actin) but positive for proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, we generated rat SMCs which overexpressed human PCSK9 (SMCsPCSK9) with the aim of investigating the role of PCSK9 in the phenotype of SMCs. PCSK9 overexpression in SMCsPCSK9 led to a significant downregulation of the low-density lipoprotein receptor (Ldlr) as well as transgelin (Sm22α), a marker of the contractile phenotype. The cell proliferation rate of SMCsPCSK9 was significantly faster than that of the control SMCs (SMCspuro). Interestingly, overexpression of PCSK9 did not impact the migratory capacity of SMCs in response to 10% FCS, as determined by Boyden’s chamber assay. Expression and activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) was significantly increased in the presence of PCSK9, both in SMCPCSK9 and after treatment with recombinant PCSK9. The transcriptional activity of sterol regulatory element-binding protein (SREBP) was also increased in the presence of PSCK9, suggesting a direct role of PCSK9 in the control of SRE-responsive genes, like HMGCR. We also observed that cholesterol biosynthesis is elevated in SMCPCSK9, potentially explaining the increased proliferation observed in these cells. Finally, concentration-dependent experiments with simvastatin demonstrated that SMCsPCSK9 were partially resistant to the antiproliferative and antimigratory effect of this drug. Taken together, these data further support a direct role of PCSK9 in proliferation, migration, and phenotypic changes in SMCs—pivotal features of atherosclerotic plaque development. We also provide new evidence on the role of PCSK9 in the pharmacological response to statins—gold standard lipid-lowering drugs with pleiotropic action.

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