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Adhesion Molecules and Endothelial Dysfunction in Vaso-Occlusive Crisis

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Review Article | DOI: https://doi.org/10.31579/2639-4162/209

Adhesion Molecules and Endothelial Dysfunction in Vaso-Occlusive Crisis

  • Emmanuel Ifeanyi Obeagu

Department of Medical Laboratory Science, Kampala International University, Uganda.

*Corresponding Author: Emmanuel Ifeanyi Obeagu, Department of Medical Laboratory Science, Kampala International University, Uganda.

Citation: Emmanuel I. Obeagu, (2024), Adhesion Molecules and Endothelial Dysfunction in Vaso-Occlusive Crisis, J. General Medicine and Clinical Practice, 7(14); DOI:10.31579/2639-4162/209

Copyright: © 2024, Emmanuel Ifeanyi Obeagu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 29 July 2024 | Accepted: 12 August 2024 | Published: 22 August 2024

Keywords: adhesion molecules; endothelial dysfunction; vaso-occlusive crisis; sickle cell disease, vascular endothelium; icam-1; vcam-1; e-selectin, p-selectin

Abstract

Vaso-occlusive crisis (VOC) is a severe and painful complication of sickle cell disease (SCD) characterized by the obstruction of blood flow due to interactions between sickled erythrocytes, leukocytes, platelets, and the vascular endothelium. Central to the pathogenesis of VOC are adhesion molecules, such as ICAM-1, VCAM-1, E-selectin, and P-selectin, which facilitate the adhesion of blood cells to the endothelium, initiating inflammatory responses and promoting vascular occlusion. Endothelial dysfunction, a condition marked by impaired vasodilation, increased permeability, and a pro-inflammatory state, plays a pivotal role in VOC. The reduced bioavailability of nitric oxide (NO) due to hemolysis and the presence of oxidative stress further exacerbate endothelial activation and adhesion molecule expression. Elevated inflammatory cytokines in SCD contribute to these processes, creating a vicious cycle of endothelial injury and vaso-occlusion. Therapeutic strategies targeting these underlying mechanisms, such as inhibition of adhesion molecules, enhancement of NO bioavailability, antioxidant therapy, and anti-inflammatory agents, offer potential for reducing the frequency and severity of VOC. 

Introduction

Vaso-occlusive crisis (VOC) is a primary and debilitating complication of sickle cell disease (SCD), a genetic disorder characterized by the presence of abnormal hemoglobin S. This condition leads to the deformation of red blood cells (RBCs) into a sickle shape, which impedes their flow through blood vessels and causes recurrent episodes of acute pain and organ damage. The pathophysiology of VOC is complex, involving a cascade of events that begin with the adhesion of sickled RBCs to the vascular endothelium, followed by interactions with leukocytes and platelets, leading to vascular occlusion and ischemia.1-3 The endothelium, a thin layer of cells lining the blood vessels, plays a critical role in maintaining vascular homeostasis by regulating blood flow, vascular tone, and the balance between coagulation and fibrinolysis. In SCD, the integrity and function of the endothelium are severely compromised, contributing to the pathogenesis of VOC. Endothelial cells in patients with SCD exhibit increased expression of adhesion molecules, a hallmark of endothelial activation and dysfunction.4-6 Adhesion molecules are cell surface proteins that mediate the attachment of cells to each other and to the extracellular matrix. In the context of VOC, these molecules facilitate the adhesion of sickled RBCs, leukocytes, and platelets to the endothelium, promoting vascular inflammation and occlusion. Key adhesion molecules involved in this process include intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin.7-8 ICAM-1 is expressed on endothelial cells and is upregulated in response to inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). It binds to leukocyte function-associated antigen-1 (LFA-1) on leukocytes, facilitating their firm adhesion and transmigration across the endothelium. This interaction is crucial for the recruitment of leukocytes to sites of vascular injury and inflammation in VOC. [9-10]

VCAM-1 is another critical adhesion molecule expressed on endothelial cells. It interacts with very late antigen-4 (VLA-4) on leukocytes and sickled RBCs, promoting their adhesion to the endothelium. This interaction is particularly significant in SCD, as it not only contributes to the recruitment of leukocytes but also to the adhesion of sickled RBCs, exacerbating vascular occlusion and ischemic injury. E-selectin and P-selectin are selectins expressed on activated endothelial cells and platelets. They mediate the initial rolling of leukocytes and sickled RBCs on the endothelial surface, a critical step in the adhesion cascade. P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes and RBCs binds to P-selectin, while E-selectin interacts with various glycoproteins on leukocytes. These interactions are essential for the recruitment of cells to sites of vascular injury and inflammation in VOC. [11-15] Endothelial dysfunction, a condition characterized by impaired endothelium-dependent vasodilation, increased endothelial permeability, and a pro-inflammatory and pro-thrombotic state, plays a pivotal role in the pathogenesis of VOC. In SCD, endothelial dysfunction is both a cause and consequence of the vaso-occlusive events. The reduced bioavailability of nitric oxide (NO) due to hemolysis and increased oxidative stress further exacerbates endothelial activation and the expression of adhesion molecules. Nitric oxide is a potent vasodilator produced by endothelial cells that plays a key role in maintaining vascular homeostasis. In SCD, hemolysis releases free hemoglobin into the bloodstream, which scavenges NO, reducing its availability. This results in vasoconstriction, increased endothelial activation, and upregulation of adhesion molecules, promoting VOC. [16-20] Oxidative stress, resulting from chronic hemolysis and ischemia-reperfusion injury, also contributes to endothelial dysfunction in SCD. Reactive oxygen species (ROS) generated during these processes damage endothelial cells, further reducing NO bioavailability and increasing the expression of adhesion molecules. This oxidative damage exacerbates the inflammatory response and promotes vascular occlusion. Inflammatory cytokines, such as TNF-α and IL-1β, are elevated in SCD and play a critical role in endothelial dysfunction. These cytokines upregulate the expression of adhesion molecules on endothelial cells, enhance leukocyte adhesion and transmigration, and contribute to the pro-inflammatory state in VOC. The interplay between these inflammatory mediators and endothelial cells creates a vicious cycle of endothelial injury and vascular occlusion. [21-25]

Adhesion Molecules in Vaso-Occlusive Crisis

Adhesion molecules are pivotal in the pathophysiology of vaso-occlusive crisis (VOC), playing a central role in the interaction between sickled red blood cells (RBCs), leukocytes, and the vascular endothelium. These molecules facilitate the adhesion and migration of cells across the endothelium, promoting vascular inflammation and occlusion. Key adhesion molecules involved in VOC include intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin. Intracellular Adhesion Molecule-1 (ICAM-1) is a transmembrane protein expressed on endothelial cells and various other cell types, including leukocytes. In the context of VOC, ICAM-1 expression is significantly upregulated in response to inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). This upregulation facilitates the firm adhesion of leukocytes to the endothelium through interactions with leukocyte function-associated antigen-1 (LFA-1) on leukocytes. The ICAM-1/LFA-1 interaction is crucial for leukocyte transmigration across the endothelium, contributing to vascular inflammation and endothelial damage in VOC. [26-30] Vascular Cell Adhesion Molecule-1 (VCAM-1) is another critical adhesion molecule expressed on endothelial cells, especially during inflammatory states. It interacts with very late antigen-4 (VLA-4) on leukocytes and sickled RBCs. The binding of VCAM-1 to VLA-4 promotes the adhesion of these cells to the endothelium, exacerbating vascular occlusion and ischemic injury in VOC. VCAM-1 plays a particularly significant role in the recruitment of leukocytes and the adhesion of sickled RBCs, making it a crucial target in understanding and potentially mitigating VOC. E-selectin and P-selectin are selectin family adhesion molecules expressed on activated endothelial cells and platelets. These molecules mediate the initial rolling of leukocytes and sickled RBCs on the endothelial surface, a critical step in the adhesion cascade leading to VOC. P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes and RBCs binds to P-selectin, while E-selectin interacts with various glycoproteins on leukocytes. The initial rolling mediated by selectins is followed by firm adhesion and transmigration, leading to vascular occlusion. [31-35]

P-selectin is stored in Weibel-Palade bodies of endothelial cells and alpha granules of platelets, P-selectin is rapidly translocated to the cell surface upon activation by inflammatory stimuli. P-selectin plays a critical role in the early stages of VOC by mediating the rolling and adhesion of sickled RBCs and leukocytes to the endothelium. E-selectin is induced on endothelial cells in response to inflammatory cytokines, E-selectin mediates the adhesion of leukocytes to the endothelium. It plays a complementary role to P-selectin in the recruitment of leukocytes to sites of vascular injury and inflammation. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), also known as CD31, is expressed on endothelial cells and plays a role in the transmigration of leukocytes through the endothelium. Although not as extensively studied in VOC as ICAM-1, VCAM-1, and selectins, PECAM-1 is involved in the inflammatory response and may contribute to endothelial dysfunction in SCD. [36-40] Integrins, such as LFA-1 and VLA-4, are expressed on leukocytes and sickled RBCs. These integrins interact with their respective ligands (ICAM-1 and VCAM-1) on endothelial cells, mediating firm adhesion and transmigration. The role of integrins in VOC highlights the importance of leukocyte and RBC-endothelial interactions in the pathogenesis of this condition. [41-42]

Endothelial Dysfunction in Vaso-Occlusive Crisis

Endothelial dysfunction is a critical component of the pathophysiology of vaso-occlusive crisis (VOC) in sickle cell disease (SCD). It refers to a state of impaired endothelial function characterized by reduced vasodilatory capacity, increased permeability, and a pro-inflammatory and pro-thrombotic environment. The dysfunction of the endothelium plays a significant role in the initiation and perpetuation of VOC, contributing to the overall severity and frequency of these painful episodes. One of the primary roles of the endothelium is to regulate vascular tone through the production of vasodilators such as nitric oxide (NO). In SCD, endothelial dysfunction is marked by decreased bioavailability of NO due to the effects of hemolysis. When sickled RBCs undergo hemolysis, free hemoglobin is released into circulation. This free hemoglobin can scavenge NO, leading to reduced levels of this critical vasodilator. As a result, the ability of blood vessels to dilate is compromised, leading to increased vascular resistance and impaired blood flow. This lack of adequate vasodilation contributes to the development of VOC by promoting further sickling of RBCs and enhancing the risk of vascular occlusion. [43-47].  Endothelial dysfunction is also associated with increased permeability of the endothelial barrier. In SCD, inflammatory mediators, including cytokines such as TNF-α and IL-1β, induce the expression of adhesion molecules and increase the permeability of the endothelium. This heightened permeability allows for the extravasation of plasma proteins and leukocytes into the surrounding tissue, exacerbating inflammation and tissue injury. The infiltration of inflammatory cells further activates the endothelium, creating a vicious cycle of endothelial activation and dysfunction. Increased endothelial permeability can also contribute to edema and tissue ischemia, worsening the clinical presentation of VOC. Endothelial dysfunction in SCD is characterized by a shift toward a pro-inflammatory and pro-thrombotic state. In normal physiology, the endothelium maintains a delicate balance between pro-coagulant and anti-coagulant factors. However, in SCD, this balance is disrupted. The activated endothelium releases pro-inflammatory cytokines, chemokines, and adhesion molecules that promote leukocyte recruitment and activation. This inflammatory response is a significant contributor to the pathogenesis of VOC, as it leads to increased leukocyte adhesion to the endothelium and enhanced interactions between leukocytes, sickled RBCs, and the vascular wall. [48-52].

Moreover, the endothelium in SCD tends to produce more von Willebrand factor (vWF) and tissue factor (TF), both of which promote coagulation. The increased expression of vWF enhances platelet adhesion and aggregation, while TF is a potent pro-coagulant that initiates the extrinsic pathway of the coagulation cascade. This pro-thrombotic environment increases the risk of thrombus formation, which can further compromise blood flow and contribute to the development of VOC. Oxidative stress plays a crucial role in endothelial dysfunction in SCD. Chronic hemolysis and ischemia-reperfusion injury result in the generation of reactive oxygen species (ROS), which cause damage to endothelial cells. Oxidative stress leads to the oxidation of lipids, proteins, and DNA, impairing endothelial function and promoting inflammation. The oxidative environment also contributes to the depletion of NO, as ROS can react with NO to form peroxynitrite, further reducing its bioavailability. In addition, oxidative stress can upregulate the expression of adhesion molecules on endothelial cells, enhancing the adhesion of leukocytes and sickled RBCs and perpetuating the cycle of inflammation and endothelial dysfunction. The interplay between oxidative stress and endothelial dysfunction underscores the complexity of VOC pathophysiology in SCD. [53-57]. Inflammatory cytokines are central to the development of endothelial dysfunction in SCD. Elevated levels of TNF-α, IL-1β, and other cytokines promote the activation of endothelial cells, leading to increased expression of adhesion molecules and enhanced permeability. These cytokines also stimulate the production of reactive oxygen species, further exacerbating oxidative stress and endothelial injury. The persistent inflammation associated with SCD results in chronic endothelial activation, creating an environment that is conducive to the development of VOC [58].

Therapeutic Implications

These strategies focus on modulating the inflammatory response, improving endothelial function, and inhibiting the pathological interactions that lead to vascular occlusion. Below are key therapeutic implications based on the pathophysiological mechanisms underlying VOC. Targeting adhesion molecules presents a promising approach to reduce the adhesion of sickled red blood cells (RBCs) and leukocytes to the endothelium, thereby mitigating VOC. Agents such as anti-P-selectin and anti-VCAM-1 antibodies can disrupt the interactions between these adhesion molecules and their ligands, effectively reducing cell adhesion and preventing vascular occlusion. Clinical trials exploring these agents are essential to determine their efficacy and safety in SCD patients.59 Small molecules that interfere with the signaling pathways that upregulate adhesion molecules on endothelial cells could help prevent their expression and subsequent cell adhesion. Research into these compounds is necessary to identify candidates that can be effective in clinical settings. Restoring the balance of nitric oxide (NO) is crucial for maintaining endothelial function and promoting vasodilation in SCD. Pharmacological agents that release NO, such as nitroglycerin or other NO donors, can be used to improve endothelial function and promote vasodilation. These agents may provide symptomatic relief during VOC episodes and help prevent future crises. Medications that inhibit phosphodiesterase, thereby increasing the levels of cyclic guanosine monophosphate (cGMP), may enhance NO signaling and improve endothelial function. This approach could also help alleviate the vasoconstriction associated with VOC. L-arginine is the precursor for NO synthesis. Supplementing with L-arginine may improve NO production and bioavailability, thereby supporting endothelial function and reducing the risk of VOC. Reducing oxidative stress is critical in restoring endothelial function and preventing the damage caused by reactive oxygen species (ROS). Potential antioxidant therapies include: N-acetylcysteine (NAC) is an antioxidant that has shown promise in reducing oxidative stress in SCD. It can replenish intracellular glutathione levels, thereby enhancing the body’s antioxidant defenses and protecting endothelial cells from oxidative damage. As a fat-soluble antioxidant, vitamin E can help neutralize free radicals and reduce oxidative stress in SCD. Studies investigating its role in improving endothelial function and reducing VOC severity could provide valuable insights. This medication has been widely used in SCD to increase fetal hemoglobin levels and reduce leukocyte counts. Hydroxyurea decreases the frequency of VOC by modulating inflammation and reducing the expression of adhesion molecules on endothelial cells. Although they are not commonly used in chronic management, corticosteroids may be beneficial during acute crises due to their potent anti-inflammatory effects. Their use should be carefully considered, balancing potential benefits with risks.60-61

Targeting specific inflammatory cytokines, such as TNF-α or IL-1β, with monoclonal antibodies may help reduce the inflammatory response in SCD. This approach could provide a more precise intervention in managing VOC. Low Molecular Weight Heparin (LMWH) can reduce the risk of thrombus formation during VOC. Its use in prophylactic or therapeutic settings should be explored to determine its impact on VOC frequency and severity. Emerging evidence suggests that DOACs may have a role in managing thrombosis in SCD. Clinical studies are needed to evaluate their safety and efficacy in this patient population. Incorporating these therapeutic strategies into a comprehensive care plan for SCD patients is essential. A multidisciplinary approach involving hematologists, primary care physicians, and supportive care specialists can optimize patient outcomes. Educating patients about recognizing early signs of VOC and the importance of hydration, pain management, and adherence to treatment regimens can empower them to manage their condition effectively. Regular monitoring of patients for early signs of VOC and evaluating treatment responses is crucial for adjusting therapies and preventing complications.61

Conclusion

Vaso-occlusive crisis (VOC) is a significant and painful complication of sickle cell disease (SCD), arising from a complex interplay of factors involving sickled red blood cells, leukocytes, platelets, and the vascular endothelium. Adhesion molecules and endothelial dysfunction are central to the pathophysiology of VOC, facilitating the adhesion and migration of cells, leading to vascular inflammation and obstruction. Key adhesion molecules, such as ICAM-1, VCAM-1, E-selectin, and P-selectin, play critical roles in mediating the interactions between sickled RBCs, leukocytes, and the endothelium, driving the inflammatory response that precipitates VOC.

Endothelial dysfunction, characterized by impaired vasodilation, increased permeability, and a pro-inflammatory and pro-thrombotic state, is a fundamental aspect of VOC. The reduced bioavailability of nitric oxide due to hemolysis, coupled with oxidative stress and elevated inflammatory cytokines, exacerbates endothelial activation and promotes the adhesion of blood cells to the vascular wall. This dysfunction creates a vicious cycle that not only contributes to the occurrence of VOC but also intensifies the severity of the episodes.

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Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

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Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

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Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

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Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

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Mina Sherif Soliman Georgy

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

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Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

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Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

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Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

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S Munshi

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Tania Munoz

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner