Pathophysiology Of Sickle Cell Disease Research Articles

Novel Pathway and Recent Advances for Targeting Sickle Cell Anemia through Novel Drug Delivery System.

Red blood cells with sickle cell anemia (SCA) have an irregular shape, and it is a genetic blood condition that can cause several problems and shorten life expectancy. Traditional treatments have focused on symptom management, but recent advancements in drug delivery systems offer promising pathways for targeted therapies. This abstract explores novel approaches to combat SCA through innovative drug delivery systems, gene therapy, and new pharmaceutical interventions. One novel pathway for targeting SCA involves utilizing advanced drug delivery systems to enhance the effectiveness of therapeutic agents. Nanotechnology-based delivery systems, such as nanoparticles and liposomes, offer precise drug targeting, controlled release, and improved bioavailability. These systems can encapsulate anti-sickling agents, like hydroxyurea, and enable their specific delivery to affected cells, reducing side effects and enhancing therapeutic outcomes. Additionally, therapy has become a ground-breaking method of treating SCA. CRISPR/Cas9 technology presents a groundbreaking opportunity to correct the genetic mutation responsible for sickle hemoglobin production. By precisely editing the HBB gene, which encodes the abnormal hemoglobin, researchers aim to restore normal hemoglobin expression, potentially offering a curative treatment for SCA. Furthermore, recent advancements in drug development have led to the discovery of promising candidates targeting specific pathways involved in SCA pathophysiology. Experimental drugs, such as voxelotor and crizanlizumab focus on modifying hemoglobin properties or inhibiting cell adhesion, respectively, thereby preventing sickle cell-related complications and reducing vaso-occlusive crisis frequency.

EVALUATION OF GLUTATHIONE PEROXIDASE ACTIVITY, MALONYLALDEHYDE AND SELENIUM LEVELS IN SICKLE CELL ANAEMIA INDIVIDUALS ATTENDING NAUTH, NNEWI IN SOUTH-EASTERN NIGERIA.

Background: Oxidative stress is an imbalance between the production and clearance of toxic free radicals known as reactive oxygen species (ROS). It is associated with hemolysis, a hallmark of SCD. SCD has long been recognized as an inflammatory condition and oxidative stress play important role in pathophysiology of SCA. Imbalance between production and elimination of reactive oxygen species (ROS) damages cell structures, including lipids, membranes, proteins and nucleic acids resulting in cell death or altered cell function. Aim: The aim of this study was to measure the serum level of Glutathione peroxidase, Malonaldehyde and Selenium in SCA (HbSS) in their steady state, AA (Healthy adult) and AS (sickle cell carriers) Methods: This is a cross- sectional study. A total of one hundred and fifty aged matched participants were recruited for this study.50 SCA subjects with sickle cell anemia (SS). Glutathione peroxidase and Malonyaldehyde were measured using turbidometry and colorimetric methods respectively while Selenium was analysed using Atomic Absorption Spectrophotometry (AAS) Results: The result of analysis of variance (ANOVA) showed that the mean serum level of MDA concentration (2.97±0.29) was higher in the SS group and was statistically significant (p< 0.05). MDA concentration was lower in the AS group. In the post hoc analysis MDA was statistically significant between SS vs AS and AA vs AA. The glutathione peroxidase activity was significantly lower in the SS group (0.85±0.12) compare with the mean values obtained in the AA and AS group. The GPx activity among the three groups was statistically significant while the post hoc analysis among the three groups showed statistical difference and was significant (p < 0.005) The Selenium levels in the SS group is lower compared with the values observed between the AA and AS group. The Se levels in the SS group was statistically lower (5.73±1.34) (p < 0.05) and showed significant difference. The comparison study between AS vs SS and AA vs AA were statistically significant. Conclusion: The decrease in selenium level potentiates low and weakened antioxidant activity and capacity which also is a reflection of low level of glutathione peroxidase observed which is supposed to attack free radicals to prevent oxidative stress. The findings from this study are in tandem with other researches suggesting that the pathophysiology of sickle cell disease is associated with oxidative stress

Targeting ICAM1 to Ameliorate Vaso-Occlusion and Inflammation in Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary disorder characterized by vaso-occlusion, inflammation, and tissue damage. Intercellular adhesion molecule 1 (ICAM-1) plays a crucial role in the pathophysiology of SCD by promoting the adhesion of sickle cells to the endothelium, contributing to vaso-occlusion and tissue damage. The ICAM-1 gene encodes a glycoprotein that interacts with lymphocyte function-associated antigen 1 (LFA-1) and macrophage 1-antigen (Mac-1) receptors, perpetuating inflammation, and oxidative stress. The NF-κB signaling pathway regulates ICAM-1 expression, which is elevated in patients with SCD, leading to increased endothelial cell activation and damage. Targeting ICAM-1 and its interactions with sickle cells and the endothelium has emerged as a potential therapeutic strategy for managing SCD. This review highlights the complex interplay between ICAM-1, sickle cells, and the endothelium, and discusses the potential of ICAM-1-targeted therapies for mitigating VOC and improving the quality of life for patients with SCD.

Potassium dynamics in sickle cell anemia: clinical implications and pathophysiological insights

Potassium dynamics are critical in the pathophysiology of sickle cell anemia (SCA), a genetic disorder characterized by the presence of abnormally shaped red blood cells that lead to various complications such as vaso-occlusive crises and hemolytic anemia. This review focuses on the clinical implications and pathophysiological insights of potassium regulation in SCA, highlighting its impact on disease progression and potential therapeutic strategies. The dysregulation of potassium transport in SCA leads to significant K+ efflux and cellular dehydration, exacerbating the sickling process. Dehydrated sickle cells, due to potassium loss, become more rigid and prone to causing blockages in small blood vessels, leading to painful vaso-occlusive crises and ischemia. Furthermore, chronic hemolysis in SCA, aggravated by potassium imbalance, contributes to severe anemia and systemic complications. These insights underscore the importance of maintaining potassium homeostasis to mitigate disease severity and improve patient outcomes. Therapeutic strategies targeting potassium regulation show promise in managing SCA. Inhibitors of the Gardos channel, such as senicapoc, have demonstrated potential in reducing sickling and hemolysis. Additionally, hydration therapy plays a crucial role in maintaining electrolyte balance and preventing RBC dehydration. A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management.

Microbiome in sickle cell disease: Pathophysiology and therapeutic insights.

Sickle cell disease (SCD) is a complex genetic blood disorder characterized by abnormal haemoglobin, resulting in sickle-shaped red blood cells. While extensive research has concentrated on the genetic and physiological aspects of SCD, recent studies suggest a potential role of the human microbiome in SCD pathophysiology, adding new dimensions to its understanding. This review synthesizes current knowledge on the microbiome's involvement in SCD, focusing on alterations in the gut microbiome composition and diversity compared to healthy individuals, and their implications for disease pathogenesis. We explore how microbiome changes may contribute to vaso-occlusive crises and other complications, along with the possible associations of specific microbial taxa or markers with disease crises and clinical outcomes. Additionally, we discuss the potential of microbiome-targeted interventions, including probiotics, dietary modifications, and faecal microbiota transplantation, in managing SCD complications and improving patient outcomes. Understanding the intricate relationship between the microbiome and SCD could lead to innovative therapeutic strategies and personalized interventions for better managing the disease. This review underscores the importance of further microbiome research and its integration into holistic SCD care.

Stroke in sickle cell patients, epidemiology, pathophysiology, systemic and surgical treatment options and prevention strategies

AbstractBackgroundA hereditary haemoglobinopathy known as sickle cell disease (SCD) affects over 100 000 people in the United States severely. Cerebrovascular disease is a prominent consequence of SCD. By the age of 30, 53% of patients have silent cerebral infarcts (SCIs) (a stroke that occurs without any obvious symptoms because it damages a small part of the brain that isn't responsible for any essential functions), and by the age of 40, 3.8% have overt strokes.Main bodyThe multidimensional burden of cerebrovascular illness in SCD is reviewed in detail in this article, which includes both clinical strokes and the frequently asymptomatic SCIs. The intricate pathophysiology of SCD and stroke is explored. With SCD, there are currently very few methods for preventing primary and secondary stroke; the most common ones are hydroxyurea and blood transfusion. Nevertheless, not enough research has been done on the possible contributions of anticoagulation and aspirin to strokes linked to SCD. Promising evidence is also highlighted in the study, suggesting that new drugs intended to treat SCD may be able to alleviate leg ulcers and renal impairment in addition to reducing unusually high transcranial Doppler flow velocity – a crucial component of cerebrovascular events. Given that these novel medications specifically target haemolysis and vaso‐occlusion, the two main causes of strokes in this population, more research is desperately needed to determine whether they are effective in avoiding strokes in people with SCD. The literature review also emphasizes how common healthcare inequities are and how they hinder advancements in SCD research and management in the United States.ConclusionTo successfully address these inequities, the evaluation recommends more funding for both SCD management and research, as well as for patient and clinician education. This multimodal viewpoint highlights the intricate terrain of cerebrovascular problems associated with SCD and the urgent need for all‐encompassing and fair strategies to improve patient outcomes and advance research.

Prevalence, Risk Factors, and Complications of Sickle Cell Disease in Saudi Arabia: A Systematic Review.

This study examined sickle cell disease (SCD) in Saudi Arabia. A systematic search of relevant databases was conducted to identify studies investigating SCD in the Saudi population. Studies were then screened based on predefined criteria and critically appraised for methodological quality. Data was extracted and synthesized to provide an overall picture of the SCD burden in Saudi Arabia. The most commonly reported complications were vaso-occlusive crises (VOC), acute chest syndrome (ACS), acute painful crisis, splenic sequestration, osteomyelitis, aplastic crisis, hemolytic crisis, serious bacterial infections, chronic vascular occlusion (CVO), depression, sickle cell nephropathy (SCN), obstructive sleep apnea (OSA), and renal complications. Reduced blood levels of antioxidant trace elements (Cu, Zn, and Se) may encourage oxidative stress, which in turn may contribute to the pathophysiology of SCD. Infections and ACS were common among young children (<7 years) while pain attacks were common in older children (>7 years). The high rate of hospitalizations among SCD patients highlights the need for better management strategies. Future research should focus on understanding the underlying causes of SCD complications and developing new ways to control them.

A critical review of therapeutic interventions in sickle cell disease: Progress and challenges.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that occurs due to the point mutation in the β-globin gene, which results in the formation of sickle hemoglobin (HbS) in the red blood cells (RBCs). When HbS is exposed to an oxygen-depleted environment, it polymerizes, resulting in hemolysis, vaso-occlusion pain, and impaired blood flow. Still, there is no affordable cure for this inherited disease. Approved medications held promise but were met with challenges due to limited patient tolerance and undesired side effects, thereby inhibiting their ability to enhance the quality of life across various individuals with SCD. Progress has been made in understanding the pathophysiology of SCD during the past few decades, leading to the discovery of novel targets and therapies. However, there is a compelling need for research to discover medications with improved efficacy and reduced side effects. Also, more clinical investigations on various drug combinations with different mechanisms of action are needed. This review comprehensively presents therapeutic approaches for SCD, including those currently available or under investigation. It covers fundamental aspects of the disease, such as epidemiology and pathophysiology, and provides detailed discussions on various disease-modifying agents. Additionally, expert insights are offered on the future development of pharmacotherapy for SCD.

Nitric Oxide Dysregulation and Vaso-Occlusive Crisis in Sickle Cell Anemia: A Review

Sickle cell anemia (SCA) is a genetic disorder characterized by the production of abnormal hemoglobin S (HbS), leading to chronic hemolysis and recurrent vaso-occlusive crises (VOCs). VOCs are acute, painful episodes caused by the obstruction of blood flow due to sickled red blood cells (RBCs), resulting in tissue ischemia and organ damage. Nitric oxide (NO) plays a crucial role in vascular homeostasis, and its dysregulation is a significant factor in the pathophysiology of SCA, particularly in VOCs. In SCA, chronic hemolysis releases free hemoglobin into the plasma, which scavenges NO and reduces its bioavailability. Additionally, increased arginase activity depletes L-arginine, the substrate for NO synthesis, further diminishing NO production. Oxidative stress exacerbates NO degradation and endothelial dysfunction, amplifying the risk of VOCs. The interplay between NO deficiency, oxidative stress, and endothelial dysfunction creates a vicious cycle that perpetuates vascular damage and increases the frequency and severity of VOCs. This review explores the mechanisms underlying NO dysregulation in SCA and its impact on vascular function. It also discusses potential therapeutic interventions aimed at modulating NO pathways to prevent or reduce VOCs. These interventions include NO donors, L-arginine supplementation, phosphodiesterase inhibitors, antioxidant therapy, and arginase inhibitors. Keywords: Sickle cell anemia, vaso-occlusive crisis, nitric oxide dysregulation, hemolysis, endothelial dysfunction, oxidative stress, therapeutic interventions.

Malnutrition in sickle cell anemia: Prevalence, impact, and interventions: A Review.

Sickle Cell Anemia (SCA) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive events, and a wide range of clinical complications. Malnutrition, often an underexplored aspect of this complex condition, plays a critical role in disease management and overall patient well-being. This publication provides a comprehensive review of the prevalence, impact, and interventions related to malnutrition in individuals with SCA. A thorough literature review reveals the multifaceted challenges faced by SCA patients in maintaining adequate nutrition. The pathophysiology of SCA, involving chronic inflammation, oxidative stress, and hypermetabolism, contributes to increased nutritional requirements and altered dietary patterns. Factors such as reduced appetite, nutrient malabsorption, dietary restrictions, and socioeconomic disparities further exacerbate the risk of malnutrition. Malnutrition is a prevalent issue among individuals with SCA, affecting patients of different age groups and disease severities. Nutritional deficiencies, including vitamins, minerals, and essential nutrients, are common in this population. The impact of malnutrition on disease outcomes is significant, with associations between nutrient status and complications such as pain crises, infections, and impaired quality of life. This paper also reviews nutritional interventions aimed at addressing malnutrition in SCA patients. While dietary counseling, supplementation, and personalized nutrition plans have shown promise in improving nutritional status, challenges such as patient adherence and access to healthcare must be addressed to optimize their effectiveness.

Eosinophilic dialogues: a molecular exploration of sickle cell anemia severity.

Sickle cell anemia (SCA) is a genetically inherited hemoglobinopathy characterized by the abnormal morphology of red blood cells, resulting in vaso-occlusive events and diverse clinical complications. Recent investigations have unveiled a novel dimension in understanding SCA severity through the lens of eosinophilic dialogues. This review article synthesizes current knowledge on the molecular intricacies of eosinophils in the context of SCA, exploring their biology, molecular markers, and interactions with other cellular components. Eosinophil-mediated inflammation and oxidative stress are dissected to elucidate their impact on the disease course. Furthermore, the review evaluates potential therapeutic interventions and outlines future directions in this burgeoning field. The term "Eosinophilic Dialogues" encapsulates the multifaceted molecular exchanges that influence SCA severity, presenting a promising avenue for targeted interventions and improved clinical outcomes. This review serves as a comprehensive resource for researchers, clinicians, and healthcare practitioners engaged in unraveling the complex pathophysiology of SCA and exploring novel therapeutic avenues.

Managing gastrointestinal challenges: Diarrhea in sickle cell anemia.

Sickle cell anemia (SCA), a hereditary hemoglobinopathy, is characterized by the presence of abnormal hemoglobin and has long been associated with a wide range of complications. While much attention has been given to the condition hematological aspects, gastrointestinal complications, particularly diarrhea, have been relatively understudied and often overlooked. This publication delves into the management of gastrointestinal challenges, with a focus on diarrhea, in individuals living with SCA. The pathophysiology of SCA is intrinsically linked to gastrointestinal complications, and diarrhea is a common manifestation of this condition. This abstract publication outlines the key elements discussed in the full-length work, which includes the clinical presentation of diarrhea in these patients, the diagnostic tools used to evaluate the condition, and various management strategies to alleviate symptoms and enhance the overall quality of life for affected individuals. The paper emphasizes the importance of patient education, offering healthcare professionals valuable insights into how to inform and support patients in managing their conditions effectively. It also highlights the need for continued research to further our understanding of gastrointestinal challenges in SCA and to identify potential areas for future therapeutic interventions. Ultimately, the comprehensive management of diarrhea in individuals with SCA is vital for their overall well-being. This publication serves as a valuable resource for healthcare providers, researchers, and caregivers in addressing the gastrointestinal challenges that accompany SCA, ultimately working toward a better quality of life for those affected by this condition.

TSH Receptor Reduces Hemoglobin S Polymerization and Increases Deformability and Adhesion of Sickle Erythrocytes.

SCD is a hereditary disorder caused by genetic mutation in the beta-globin gene, resulting in abnormal hemoglobin, HbS that forms sickle-shaped erythrocytes under hypoxia. Patients with SCD have endocrine disorders and it was described that 7% of these patients have clinical hypothyroidism. Recent studies have shown that mature erythrocytes possess TSH receptors. Thus, we aimed to assess the effects of TSH on SCD erythrocytes. The experiments were conducted using different concentrations of TSH (1, 2, 3, and 5 mIU/L). In HbS polymerization assay, erythrocytes were exposed to TSH in hypoxia to induce polymerization, and measurements were taken for 30 minutes. The deformability assay was made using Sephacryl-S 500 columns to separate deformable from nondeformable cells. Static adhesion test utilized thrombospondin to assess erythrocyte adhesion in the presence of TSH. TSH at all contractions were able to reduce polymerization of HbS and increase deformability. The static adhesion of erythrocytes at the lowest concentrations of 1 and 2 mIU/L were increased, but at higher contractions of 3 and 5 mIU/L, static adhesion was not modulated. The results suggest that TSH has potential involvement in the pathophysiology of sickle cell disease by inhibiting HbS polymerization, positively modulating deformability and impacting static adhesion to thrombospondin.

Bidirectional Relationship Between Sickle Cell Disease and Food Insecurity: Scoping Review.

In the United States, sickle cell disease (SCD)-the homozygous inheritance of a point mutation within the beta-globin chain of hemoglobin-affects between 80,000 and 100,000 people. Adequate nutrition can influence the pathophysiology of SCD, and individuals with SCD who are undernourished are more likely to have impaired immune function and disease exacerbation. Undernourishment is often caused by food insecurity (FI), which is defined as "a household-level economic and social condition of limited or uncertain access to adequate food" by the USDA. FI disproportionately affects African Americans, a population disproportionately affected by SCD in the United States. We performed a scoping review to better understand the relationship between FI and SCD severity. A comprehensive search for peer-reviewed research articles and meeting abstracts was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Selected studies were reviewed for descriptive analysis by three independent reviewers. In total, 72 studies were identified, 62 were excluded for meeting inclusion criteria. The remaining 10 studies, 5 of which were meeting abstracts, were reviewed. Although limited evidence is available, the results of this scoping review suggest a bidirectional relationship between SCD and FI. Seven key themes were identified to help elucidate this relationship: 1) prevalence of FI among individuals with SCD, 2) child versus caregiver experiences of FI, 3) psychosocial factors, 4) food assistance benefits, 5) dietary intake, 6) external spending, 7) healthcare utilization. Findings from this scoping review suggest how SCD and FI work in tandem to exacerbate each other. Furthermore, the findings illustrate current gaps in the literature and opportunities for actions to address FI among individuals living with SCD.

DEPRESSIVE DISORDER AND SICKLE CELL DISEASE: A state of art

The connection between sickle cell disease and depression, although crucial, remains an inadequately explored field, calling for further investigation. This notably concerning health scenario demands more specialized attention from professionals in the field. The present study aims to meticulously analyze the relationship between sickle cell disease and depression, delving into the state of the art on this subject, incorporating sources such as articles, books, dissertations, and theses. Individuals with sickle cell disease show a propensity for elevated levels of depression compared to the general population. Additionally, it has been observed that patients with sickle cell disease and depression experience an intensification of pain compared to their counterparts without depression, suggesting an intrinsic correlation between pain and both conditions. The in-depth analysis of the pathophysiology of both sickle cell disease and depression played a fundamental role in understanding this interconnection. It is concluded that the quality of life for these individuals is compromised, not only in terms of pathophysiological aspects but also in the realms of mental health, highlighting a significant increase in morbidity associated with the presence of depression. In this context, seeking medical assistance proves crucial to mitigate the impacts on the mental health of individuals with sickle cell disease, emphasizing the need for a holistic and integrated approach to substantially improve their quality of life.

Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype

BackgroundConstitutive inflammation and hemostatic activation have been identified as key contributors to the pathophysiology of sickle cell disease (SCD), leading to clinical consequences such as vaso-occlusive crises and stroke. Patients with hemoglobin SS (HbSS) and hemoglobin SC (HbSC) genotypes are reported to have different symptoms, as do patients in steady-state and crisis situations. Differences among these groups remain unclear in pediatric patients. ObjectivesTo compare hemostatic activity in HbSS and HbSC pediatric patients during steady state, in crisis, and in clinical follow-up and compare HbSS and HbSC patients with normal healthy children. MethodsWhole-blood coagulation assay thromboelastography (TEG) was used to assess hemostatic activity. In parallel, flow cytometry was used to assess procoagulant surface expression of platelets and red blood cells. ResultsTEG results indicated no significant differences in clotting onset (R time), clot maximum amplitude, or maximum rate of thrombus generation among steady-state, crisis, and follow-up subgroups of HbSS and HbSC patients. TEG parameters did not differ significantly between HbSC patients and healthy children, while HbSS patients showed significantly shorter R time and greater maximum amplitude and maximum rate of thrombus generation, all indicative of a constitutive hypercoagulable state. Flow cytometry results did not detect increased platelet integrin αIIbβ3 activation or red blood cell procoagulant surface expression in SCD patients compared with unaffected children. ConclusionOur results indicate that pediatric SCD patients with the HbSS genotype have constitutively activated hemostasis relative to HbSC patients and healthy children. It remains to be determined how treatments that improve clinical outcomes in SCD patients affect this constitutively hypercoagulable state.

Soluble guanylate cyclase stimulators and activators: new horizons in the treatment of priapism associated with sickle cell disease.

Priapism, defined as a prolonged and often painful penile erection occurring without sexual stimulation or desire, is a common complication in sickle cell disease (SCD), affecting up to 48% of male patients. This condition presents significant clinical challenges and can lead to erectile dysfunction if not properly managed. Current pharmacological treatments for SCD-related priapism are primarily reactive rather than preventative, highlighting a gap in effective medical intervention strategies. A critical factor in developing priapism is the reduced basal bioavailability of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in erectile tissues. New prevention strategies should ideally target the underlying pathophysiology of the disease. Compounds that stimulate and activate soluble guanylate cyclase (sGC) emerge as potential therapeutic candidates since these compounds have the property of inducing cGMP production by sGC. This review explores the potential of sGC stimulators and activators in treating priapism associated with SCD. We discuss the advantages of these agents in the face of the challenging pathophysiology of SCD. Additionally, the review underscores the impact of intravascular hemolysis and oxidative stress on priapism pathophysiology in SCD, areas in which sGC stimulators and activators may also have beneficial therapeutic effects.

Red Blood Cells as Therapeutic Target to Treat Sickle Cell Disease.

Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

Sickle cell disease (SCD) affects millions worldwide, yet there are few therapeutic options. To develop effective treatments, preclinical models that recapitulate human physiology and SCD pathophysiology are needed. SCD arises from a single Glu-to-Val substitution at position 6 in the β subunit of hemoglobin (Hb), promoting Hb polymerization and subsequent disease. Sheep share important physiological and developmental characteristics with humans, including the same developmental pattern of fetal to adult Hb switching. Herein, we investigated whether introducing the SCD mutation into the sheep β-globin locus would recapitulate SCD’s complex pathophysiology by generating high quality SWISS-MODEL sheep Hb structures and performing MD simulations of normal/sickle human (huHbA/huHbS) and sheep (shHbB/shHbS) Hb, establishing how accurately shHbS mimics huHbS behavior. shHbS, like huHbS, remained stable with low RMSD, while huHbA and shHbB had higher and fluctuating RMSD. shHbB and shHbS also behaved identically to huHbA and huHbS with respect to β2-Glu6 and β1-Asp73 (β1-Asn72 in sheep) solvent interactions. These data demonstrate that introducing the single SCD-causing Glu-to-Val substitution into sheep β-globin causes alterations consistent with the Hb polymerization that drives RBC sickling, supporting the development of a SCD sheep model to pave the way for alternative cures for this debilitating, globally impactful disease.

Oxidative Stress and Redox Signaling in the Pathophysiology of Sickle Cell Disease: A Review

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy characterized by the aberrant hemoglobin S, resulting in the formation of sickle-shaped red blood cells and a cascade of clinical complications. While the molecular aspects of SCD are well-elucidated, recent investigations underscore the critical influence of oxidative stress and redox signaling in the disease’s pathophysiology. This comprehensive review synthesizes current knowledge on the interplay between oxidative stress, redox signaling, and SCD, providing insights into potential therapeutic targets. Discussions encompass the generation of reactive oxygen species (ROS), antioxidant defense mechanisms, and the activation of redox-sensitive signaling pathways. The consequences of oxidative stress, such as vaso-occlusion, inflammation, and endothelial dysfunction, are examined in detail. Furthermore, the review evaluates existing antioxidant therapies, explores potential strategies targeting redox signaling pathways, and discusses emerging therapeutic targets. By elucidating the intricate relationship between oxidative stress and SCD, this review aims to advance our understanding of the disease’s complexity and pave the way for innovative therapeutic interventions, offering renewed hope for enhanced patient care and management.