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Use of Marine Compounds to Treat Ischemic Diseases

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Abstract

The marine reservoir, with its massive biodiversity, likely harbors numerous human drug candidates. Polysaccharides of various marine origins have shown to be good alternatives to mammalian polysaccharides. One well‐known example is heparin, a sulfated polysaccharide used in the prevention of thrombosis and pulmonary embolism. The oldest use of marine polysaccharides concerns those produced by algae. These products form the basis for an economically important and expanding global industry. This chapter provides a historical background to the discovery of the therapeutic potential of these marine compounds, together with their medical and biotechnological applications. Peripheral arterial disease (PAD) is a progressive disorder due to atherosclerosis (narrowing of the peripheral arteries, especially in the legs). Arterial flow is reduced or discontinuous, causing oxygen deprivation in the underlying tissues and possible tissue necrosis. The primary aim of medical therapy is to increase arterial flow in the affected limb in order to relieve pain, heal trophic lesions, and avoid amputation. Anticoagulant, antithrombotic, and antiplatelet agents are used to reduce the risk of thrombus formation. Novel treatments such as therapeutic angiogenesis (promotion of new blood vessel growth) are in the development phase, with promising preclinical data. Fucoidan is a polysulfated l‐fucose endowed with biological activities closely related to its chemical composition (especially the distribution of sulfate groups along its polyfucose backbone) and to its molecular weight. Fucoidans are highly soluble in water, nontoxic, and non‐immunogenic. Details are provided below on its production and characterization and on the main chemical characteristics that influence their biological activities. Fucoidan exhibits venous and arterial antithrombotic properties in animal models. In animal experiments, fucoidan promoted the formation of new blood vessels, thereby preventing necrosis of ischemic tissue. It also recruits stem cells from bone marrow, further accelerating tissue healing. The cellular and molecular mechanisms underlying fucoidan's effects on angiogenesis are then addressed, beginning with a brief overview of blood vessel formation. Recent advances have been made in understanding how the interactions between these polyfucoses and adult stem cells contribute to new blood vessel formation after ischemic injury, notably via carbohydrates located mainly in the basement membrane and cell surface.

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Antiplatelet agents are recommended for the reduction of major adverse cardiovascular events among all patients with symptomatic peripheral artery disease. However, the optimal antiplatelet regimen and duration of therapy in peripheral artery disease (PAD) remains unclear, largely due to limited and conflicting data in this patient population. This article reviews current data on antithrombotic therapy in PAD and discusses the implications of this data for current practice and future research.
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The role of endothelial progenitor cells (EPCs) in peripheral artery disease (PAD) remains unclear. We hypothesized that EPC mobilization and function play a central role in the development of endothelial dysfunction and directly influence the degree of atherosclerotic burden in peripheral artery vessels. The number of circulating EPCs, defined as CD34(+)/KDR(+) cells, were assessed by flow cytometry in 91 subjects classified according to a predefined sample size of 31 non-diabetic PAD patients, 30 diabetic PAD patients, and 30 healthy volunteers. Both PAD groups had undergone endovascular treatment in the past. As a functional parameter, EPC colony-forming units were determined ex vivo. Apart from a broad laboratory analysis, a series of clinical measures using the ankle-brachial index (ABI), flow-mediated dilatation (FMD) and carotid intima-media thickness (cIMT) were investigated. A significant reduction of EPC counts and proliferation indices in both PAD groups compared to healthy subjects were observed. Low EPC number and pathological findings in the clinical assessment were strongly correlated to the group allocation. Multivariate statistical analysis revealed these findings to be independent predictors of disease appearance. Linear regression analysis showed the ABI to be a predictor of circulating EPC number (p=0.02). Moreover, the functionality of EPCs was correlated by linear regression (p=0.017) to cIMT. The influence of diabetes mellitus on EPCs in our study has to be considered marginal in already disease-affected patients. This study demonstrated that EPCs could predict the prevalence and severity of symptomatic PAD, with ABI as the determinant of the state of EPC populations in disease-affected groups.
Article
The age-adjusted prevalence of peripheral arterial disease in the US population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may successfully reperfuse the limbs of certain patients with peripheral arterial disease. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients, for many of whom amputation represents the only hope for alleviation of symptoms. The ultimate failure of medical treatment and procedural revascularization in significant numbers of patients has led to attempts to develop alternative therapies for ischemic disease. These strategies include administration of angiogenic cytokines, either as recombinant protein or as gene therapy, and more recently, to investigations of stem/progenitor cell therapy. The purpose of this review is to provide an outline of the preclinical basis for angiogenic and stem cell therapies, review the clinical research that has been done, summarize the lessons learned, identify gaps in knowledge, and suggest a course toward successfully addressing an unmet medical need in a large and growing patient population.
Article
Pharmacologic interventions are an integral component of peripheral artery disease (PAD) management, supported by high-quality clinical studies. Those affected by this potentially debilitating and life-threatening disease process often have multiple contributing conditions, such as tobacco abuse, diabetes, hypertension, and hyperlipidemia. In addition to medications aimed at improving claudication symptoms, risk factor modification and appropriate use of antiplatelet agents is essential to decreasing rates of major adverse clinical events and improving vessel patency following intervention. While lower extremity PAD is increasingly recognized as a prevalent condition, affected individuals remain undertreated with optimal pharmacotherapy. Novel approaches to treatment of PAD include stem cell therapy, which may play a beneficial role in those with minimal revascularization options but disease placing them at high risk for limb amputation. Additionally, timely initiation of optimal pharmacotherapy represents a cost-effective approach to management of this chronic condition. Copyright © 2014. Published by Elsevier Inc.
Article
Aim: We have designed ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles associated with fucoidan (USPOI-FUCO), a natural sulfated polysaccharide with high affinity for activated platelets, to visualize by MRI arterial thrombi. Materials & methods: USPIOs were prepared and sizes, zeta-potentials and relaxivities were measured. Elastase perfusion in the infrarenal aorta of Wistar rats induced intraluminal thrombus. They were scanned on 4.7 T MRI before and after injection of USPIO-FUCO or USPIO coated with anionic dextran. Results: Surface plasmon resonance evidenced that fucoidan and USPIO-FUCO bind in vitro to immobilized P-selectin. All intraluminal hyposignals detected by MRI after injection of USPIO-FUCO on animals (13 out of 13) were correlated by histology with thrombi, whereas none could be identified with control USPIOs (0 out of 7). No signal was seen in absence of thrombus. Thrombi by MRI were correlated with P-selectin immunostaining and USPIO detection by electron microscopy. Conclusion: In vivo thrombi can thus be evidenced by MRI with USPIO-FUCO.
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The isolation of the polysaccharide sulphate, fucoidin, from various species of Phœophycœ is described and the results of quantitative analyses are reported.
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With the recent advent of glycomics, many medically relevant glycans have been discovered. Sulfated fucans (SFs) and sulfated galactans (SGs) are one of these classes of glycans with increasing interest to both glycomics and medicine. Besides having very unique structures, some of these molecules exhibit a broad range of pharmacological actions. In certain cases, high levels of effectiveness may be reached when the proper structural requirements are found. Here, we cover the fundamental biochemical mechanisms of some of these medicinal properties. We particularly focus on the beneficial activities of SFs and SGs in inflammation, hemostasis, vascular biology, and cancer. In these clinical systems, intermolecular complexes directly driven by electrostatic interactions of SFs and SGs with P- and L-selectins, chemokines, antithrombin, heparin cofactor II, thrombin, factor Xa, bFGF, and VEGF, overall govern the resultant therapeutic effects. In spite of that, the structural features of SFs and SGs have shown to be essential determinants for formation and stability of those molecular complexes, which consequently account to the differential levels of the biomedical responses. Accurate structure-function relationships have mostly been achieved when SFs and SGs of well-defined structures are used for study. Therefore, these types of glycans have become of great usefulness to identify the chemical requirements needed to achieve satisfactory clinical responses.
Article
The predominant repeating structure of a fraction of the fucoidan from Ascophyllum nodosum prepared by acid hydrolysis and centrifugal partition chromatography (LMWF) was established as:by NMR spectroscopy and methylation analysis. The proton and carbon NMR spectra of this unit have been assigned and found to correspond with features in the spectra of the whole purified fucan from A. nodosum which account for most of the integrated intensity. The same structure has also been recognised in the fucoidan of Fucus vesiculosus. The fraction LMWF has in vitro anticoagulant activity, indicating that the above structure may be partly responsible for biological activity in the native fucoidan.
Article
Vascular rejection after organ transplantation is characterized by an arterial occlusive lesion, resulting from intimal proliferation occurring in response to arterial wall immune aggression. Our hypothesis is that an early endothelial repair may prevent vascular graft rejection. The aim of the current study was to compare different pharmacologic progenitor cell mobilizing treatments for their protective effects against vascular rejection. Aortic transplants were made from balb/c donor to C57Bl/6 recipient mice. Three different mobilizing pharmacologic agents were used: low molecular weight fucoidan (LMWF), simvastatin, and AMD3100. The circulating levels of progenitor cells were found to be increased by all three treatments, as determined by flow cytometry. For each treatment, the design was: treated allografts, nontreated allografts, treated isografts, and nontreated isografts. After 21 d, morphometric and immunohistochemical analyses were performed. We found that the three treatments significantly reduced intimal proliferation, compared with nontreated allografts. This was associated with intimal re-endothelialization of the grafts. Further, in chimeric mice that had previously received GFP-transgenic bone marrow transplantation, GFP-positive cells were found in the vascular allograft intima, indicating that re-endothelialization was, at least partly, due to the recruitment of bone marrow-derived, presumably endothelial progenitor circulating cells. In this aortic allograft model, three different mobilizing treatments were found to partially prevent vascular transplant rejection. Bone marrow-derived progenitor cells mobilized by the three treatments may play a direct role in the endothelial repair process and in the suppression of intimal proliferation.
Article
The discovery of endothelial progenitor cells in the 1990s challenged the paradigm of angiogenesis by showing that cells derived from hematopoietic stem cells are capable of forming new blood vessels even in the absence of a pre-existing vessel network, a process termed vasculogenesis. Since then, the majority of studies in the field have found a strong association between circulating endothelial progenitor cells and cardiovascular risk. Several studies have also reported that inflammation influences the mobilization and differentiation of endothelial progenitor cells. In this review, we discuss the emerging role of endothelial progenitor cells as biomarkers of cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology. We will also review the challenges in the field of endothelial progenitor cell-based therapy.
Article
Endothelial progenitor cells (EPCs) have been isolated and shown to be effective in animal models of ischemia, and many groups involved in clinical trials have demonstrated that EPC therapy is safe and feasible for the treatment of critical limb ischemia and cardiovascular diseases. However, many issues in the field of EPC biology, especially in regards to the proper and unambiguous molecular characterization of these cells still remain unresolved, hampering not only basic research but also the effective therapeutic use and widespread application of these cells. In this review, we introduce the recent concept of EPC identification in terms of hematopoietic and nonhematopoietic EPCs along with the development of EPC biology research. Furthermore, we define the role of circulating EPCs in postnatal neovascularization to illustrate the future direction of EPC therapeutic applications. Next, we review on-going medical applications of EPC for cardiovascular and peripheral vascular diseases, introduce the practical example of therapeutic application of EPCs to patients with ischemic disease, and discuss about the feedback of clinical researches.
Article
The aim of this study was to identify the clinical parameters of absolutely poor-prognosis patients with chronic critical limb ischemia (AP-CLI). Sixteen no-option CLI patients with arteriosclerosis obliterans: ASO (nine) and non-ASO patients (seven) treated with bone marrow-mononuclear cell implantation (BMI) were analyzed. There were three AP-CLI patients (all ASO). The mRNA expression of several angiogenic factors in the implanted cells was analyzed in comparison with normal donor bone marrow. To observe the response of bone marrow components to hypoxia, normal bone marrow cells were cultured for 24 h in 2.5% O(2), and mRNA expression of angiogenic factors were measured. AP-CLI patients exhibited extraordinary low bone marrow cellularity as well as the percentage of CD34-positive cells. Among angiogenic factors, only VEGF expression was maintained in response to HIF-1, while other factors such as HGF, Ang-1, PLGF, and SDF-1 decreased in the implanted bone marrow cells of the patients with CLI compared to normal bone marrow cells. HIF-1 and all of the five angiogenic factors increased in vitro in response to hypoxia. Thus it is highly likely that angiogenic factors except VEGF do not respond to chronic ischemia in bone marrow in vivo. An organ-protection system against tissue ischemia may be applied for acute hypoxia, but it may be insufficient for chronic ischemia.