Cardiovascular & hematological disorders drug targets最新文献

Sickle cell disease is a severe genetic blood disorder marked by the production of abnormal hemoglobin (HbS), leading to sickle-shaped red blood cells that obstruct blood flow and cause various problems, such as the increased risk of infection, persistent anemia, acute pain episodes, and organ damage. Roughly 100,000 Americans suffer from SCD, with approximately 40,000 of them being children. Black people have the highest frequency of the disease. There are six Food and Drug Administration (FDA)-approved drugs, hydroxyurea, L-glutamine, crizanlizumab- TMCA, voxelotor, Casgevy, and Lyfgenia, that are used for the prophylaxis and treatment of serious complications of sickle cell disease. Current treatment approaches focus on symptom management, including pain control, hydroxyurea to reduce pain crises, and transfusions for severe anemia. Based on the clinical trial results, L-glutamine and crizanlizumab-TMCA prevent cell damage and hemoglobin sickling by reducing the sickle cell crisis episodes. At the same time, voxelotor improves hemoglobin oxygen-binding capacity in patients with SCD. Novel therapies, such as gene therapy and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9) technology, aim to correct the genetic defect. At the same time, stem cell and bone marrow transplants offer potential cures but are limited by the availability of donors and side effects. Ongoing research seeks to enhance treatment options and develop potential cures for SCD. This review attempts to present a comprehensive overview of the current therapeutic approaches and newly developed innovative medicines to combat and potentially eradicate SCD with an emphasis on their mechanisms, efficacy, and clinical implications.

Introduction: In-stent restenosis (ISR) is a recurrence of a blockage in a section of the coronary artery that has previously been treated with a stent. Molecular/biochemical pathways underlying ISR are not fully understood, but inflammation and reactive oxygen species (ROS) induced oxidative stress play a significant role in the pathogenesis of restenosis. As blood cells are highly sensitive to oxidative stress and blood is readily accessible compared to other tissues, the current study flow cytometrically investigated intracellular ROS and cytokine profile of blood cells as possible markers of restenosis. Flow cytometry is commonly used for detecting ROS and analyzing oxidative stress but so far, it has not been utilized for prediction of ISR. So, the aim of the study was to explore the potential of flow cytometric assessment of ROS levels in the blood cells as predictor of ISR.

Methods: The study was carried out in a total of 60 patients who had previously undergone coronary artery stent implantation. They were categorized as Group I - Coronary stent implanted patients without restenosis (n=30) and Group II - Coronary stent implanted patients with restenosis (n=30). Sociodemographics, biochemical and angiographic characteristics were assessed. Intracellular ROS and cytokine estimation in blood cells was done by using flow cytometric analysis.

Results: Flow cytometric measurements demonstrated a 1.3-fold increase in ROS levels in red blood cells (RBCs) and 2-fold increase in ROS levels in leucocytes in group II as compared to group I. Mean serum concentrations of pro-inflammatory cytokines: tumor necrosis factor-α (33.54 ± 6.48 vs. 20.10 ± 5.61, p <0.001***), interferon-gamma (21.76 ± 4.46 vs. 20.10 ± 5.61, p <0.001***), interleukin 6 (152.56 ± 30.67 vs. 113.95 ± 23.38, p <0.001***) were found to be higher in restenotic patients as compared to the non-restenotic patients. Correlation analysis showed that intracellular ROS levels of RBCs exhibited a significant positive correlation with late lumen loss in restenotic (r=0.71, p <0.01) as well as non-restenotic patients (r=0.59, p <0.01). Similarly, intracellular ROS levels of WBCs exhibited a significant positive correlation with late lumen loss in restenotic (r=0.72, p <0.01) as well as non-restenotic patients (r=0.61, p <0.01).

Conclusion: This study highlights the role of increased levels of intracellular ROS in blood cells in the subsequent development of ISR, which can be detected flow cytometrically. The study suggests that intracellular ROS estimation in blood cells may serve as a potential marker for restenosis and their flow cytometric analysis may facilitate the prediction of ISR.

Background: Pulmonary embolism (PE) is a frequent cause of death. Acute PE may be treated either with full anticoagulation (AC) alone or thrombolytic therapy with systemic tissue-type-plasminogen-activator (tPA) based on risk assessment. Currently, AC is the standard of care for most patients with intermediate-high-risk PE, with low-dose tPA emerging as an effective alternative. However, studies directly comparing the efficacy and safety of low-dose tPA to AC are lacking in this patient population.

Objectives: The aim of this study was to retrospectively compare the efficacy and safety of low-dose tPA, compared to AC alone in regards to right ventricular function, in-hospital mortality and bleeding complications in patients presenting with intermediate-high risk PE.

Methods: This is a single-center, retrospective cohort trial conducted at a university hospital. A total of 148 patients were screened, and 88 patients qualified for this study. The primary endpoints were changes in right ventricular function on echocardiogram in 24 hours, in-hospital mortality, and major bleeding complications.

Results: Eighty-eight consecutive patients with intermediate high-risk PE were included. Twenty- six patients (29.5%) received low-dose systemic tPA administered via intravenous infusion, and 62 patients (70.4%) received standard full-dose anticoagulation. There were no significant differences in baseline vital signs or PESI scores between the low-dose tPA and the AC group. Patients in the low-dose tPA group had worse RV function and higher troponin levels at baseline but showed significant improvement in all RV parameters assessed during the 24-hour follow-up. In comparison, there was no significant improvement in RV function in the AC group. There were more bleeding events in the AC group. LOS was shorter in the low-dose tPA group.

Conclusion: Treatment with low-dose prolonged infusion of tPA may be an effective and safe therapy in patients with intermediate-risk PE. Compared to AC, low-dose tPA was effective in decreasing PASP and restoration of RV function.

The past decade has appreciated personalized medicine as a novel medical approach that deals with all practices that are tailored to individual patients. Personalized treatment or personalized cardiology for cardiovascular disorders is an emerging medicine system for related patients. Personalized cardiology is solely based on genomics and proteomics; molecular diagnostics and biomarkers of the cardiovascular system link diagnosis with therapy. Bioinformatics is useful in CVD risk stratification and might improve risk-estimating algorithms. Personalized cardiology involves 3D printing, pharmacotherapy, surgery, lifestyle modifications, and combinations thereof. Understanding the pathology of CVD and identifying causative factors at the individual level can provide opportunities for developing personalized medicine. Since it offers novel avenues for diagnosing, preventing, and treating CVD, molecular genetics has made a substantial contribution to the field of molecular cardiology. Nonetheless, there are still a lot of obstacles to overcome from the standpoints of science and policy. These obstacles can be avoided using evidence-based procedures, clinical applications, biomarker-based detection techniques, comprehensive concepts, and understanding. Targeted therapies may be developed as a result of improved disease classification and a better knowledge of the individual differences in pathology. Cardiovascular disorders, like hypertension, angina, or ischemic heart, a condition of reduced blood flow to the heart, coronary artery disease or damaged blood vessels, myocardial infarction or resisted blood flow to the myocardium, and cardiac arrhythmia or irregular cardiac cycles are the primary targets for personalized cardiology. The current review discusses various parameters for personalizing the treatment of cardiovascular disorders.

Background: Hematohidrosis is an extremely rare condition characterized by the spontaneous exudation of blood through intact skin, often linked to emotional stress and sympathetic nervous system activation. Due to its rarity, many aspects of its pathophysiology remain poorly understood. This case highlights the importance of considering hematohidrosis in the differential diagnosis of unexplained bleeding and emphasizes the role of psychological assessment in its management.

Case presentation: A 7-year-old girl from a low-income background presented with a two-month history of recurrent blood oozing from the sweat glands at her elbows, knee joints, and forehead. The episodes, lasting 5-10 minutes, were more frequent during periods of emotional distress. Physical examination revealed no signs of trauma, purpura, or underlying skin lesions. Routine laboratory investigations, including hemogram, platelet count, clotting time, prothrombin time, and activated partial thromboplastin time, were within normal limits. Microscopic analysis of the secreted fluid confirmed the presence of erythrocytes, supporting the diagnosis of hematohidrosis. Given the suspected psychogenic trigger, the patient was referred for psychiatric evaluation and stress management therapy, leading to a gradual reduction in symptom frequency over a four-month follow- up period.

Conclusion: This case reinforces the multidisciplinary approach required for diagnosing and managing hematohidrosis, which lacks definitive diagnostic markers. Early psychological intervention is crucial in mitigating symptom severity, as evidenced by this patient's clinical improvement. Increased awareness of hematohidrosis among clinicians can prevent unnecessary invasive testing, facilitate timely recognition, and optimize patient outcomes.

Introduction: Myocardial ischemia/reperfusion injuries (MI/RI) are responsible for fatal cardiovascular diseases. Myocardial infarction may lead to ischemic cardiomyopathy (ICM). Thereby, illustrating the MI/RI molecular basis could lead to the emergence of novel therapeutic options. PIM1/ASK1 (MAP3K5) pathway is well-known in renal ischemia/ reperfusion. PIM1 protein can promote autophagy after hypoxia.

Materials and methods: We selected the dataset GSE46224 from the National Center of Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database for evaluation. This dataset was analyzed using tools such as the Kyoto Encyclopedia of Genes and Genomes, Gene- Codis, and BioGRID. Three groups of patients were selected from the dataset. ICM group (n=8), non-failing (NF) group (n=8), and non-ischemic cardiomyopathy (NICM) group (n=8) evaluated for 15 genes expression levels. P-value <0.05 is statistically significant.

Results: JAK1 showed significantly lower gene expression in the ICM group compared to the NF group (p-value = 0.012, difference = -6.24). ASK1 was also significantly down-regulated in the ICM group compared to the NF group (p-value =0.0159, difference = -1.478). In contrast, STAT5B and NF-κB were significantly up-regulated in the ICM group (STAT5B: p-value = 0.0238, difference = 2.388; NF-κB: p-value = 0.0158, difference = 1.11). The analysis of differences and the volcano plot confirmed these findings, highlighting key dysregulated genes in ICM.

Conclusion: In conclusion, ICM patients have altered ASK1 expression compared to NF individuals. The significant down-regulation of ASK1 and JAK1, along with the up-regulation of STAT5B and NF-κB, suggests that targeting ASK1 could be an important strategy to ameliorate ischemia-related cardiomyocyte damage.

Background: Autoimmune hemolytic anemia (AIHA) is a rare disorder in hematology, with an incidence of 1-3 per 100,000 per year. The current data available on open-heart procedures in patients with AIHA is limited. Despite presenting periprocedural challenges, multidisciplinary efforts enabled the successful performance of surgical atrial septal defect (ASD) closure in a patient with warm-reactive AIHA.

Case presentation: A 56-year-old woman with a large elliptical ASD was planned for surgical closure. The patient has never received a blood transfusion or experienced any previous hematological issues. During the surgical preparation, the patient's immunoglobulin G Coombs test result was positive for the presence of immunoglobulin G. The patient was diagnosed with a remission state of warm AIHA. A challenge arose when surgical ASD closure needed a cardiopulmonary bypass (CPB), which increased the risk of hemolysis. The patient also needed to be hypothermic to reduce metabolism, which may interact with the pathophysiology of AIHA. Several approaches were taken, and the procedure was conducted successfully without noteworthy obstacles.

Conclusion: A successful surgical ASD closure was performed in a patient with complete remission of warm-reactive AIHA. Considering the different hemolytic mechanisms between CPB and AIHA, determining whether AIHA is cold or warm reactive is crucial for managing temperature in the heart-lung machine. Several approaches, such as utilizing a roller pump, a heparin-coated circuit, and administering steroids, can be implemented to prevent hemolysis.

Background: Chronic myeloid leukemia (CML) is a common hematological malignancy where patients present with varied clinical symptoms and are usually diagnosed with incidentally detected elevated total leucocyte counts in hemogram. The presence of pelvic hematoma at the presentation of CML is an uncommon finding.

Case presentation: Two male young adults presented with massive splenomegaly and pelvic hematoma. On evaluation for anemia and leukocytosis with massive splenomegaly, diagnosis of CML chronic phase (CML-CP) was made on peripheral smear, bone marrow examination including cytogenetic study and molecular methods (peripheral blood quantitative BCR: ABL1 by real- time PCR). The first patient underwent aspiration of hematoma, and the second patient presented late where the hematoma organized into a solid mass and no intervention could be possible. A basic available coagulation study revealed no abnormalities and was managed with tyrosine kinase inhibitors.

Conclusion: Initial manifestation of CML with pelvic hematoma is uncommon and should undergo aspiration or drainage to avoid organization of hematoma and compressive symptoms locally.

Background: Diabetic Cardiomyopathy (DCM) remains a significant health concern, necessitating innovative therapeutic approaches. This study explores the potential of a polyherbal combination (PHC) in mitigating DCM and delves into the underlying molecular mechanisms.

Methods: Rat models with induced diabetes and cardiomyopathy were administered the polyherbal combination. Molecular analyses included the assessment of ICAM-1, VCAM-1, and NF- κB expression in cardiac tissue. Histopathological and functional evaluations of cardiac health were performed.

Results and discussion: The polyherbal-treated group showed a significant reduction in blood glucose levels and improved cardiac function, as indicated by increased ejection fraction and cardiac output. Cardiac injury markers, CK-MB and hs-CRP, were significantly reduced by 66.6% and 50% respectively. Lipid profile improvements included lower total cholesterol and triglycerides by 28.5% and 31.1%, respectively. TGF-┘ levels were markedly reduced, suggesting an anti-fibrotic effect. Additionally, NF-κB, ICAM-1, and VCAM-1 expression were significantly downregulated, confirming the polyherbal formulation's anti-inflammatory potential. These findings highlight its cardioprotective effects, making it a promising therapeutic approach for mitigating diabetic cardiomyopathy.

Conclusion: The study unveils a promising therapeutic strategy for DCM, characterized by the PHC's ability to modulate ICAM-1, VCAM-1, and NF-κB expression. This molecular insight underscores the potential for innovative interventions in managing DCM and offers hope for improved cardiac health in individuals with diabetes.

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease marked by inflammation and fibrosis, stemming from non-alcoholic fatty liver disease (NAFLD). Despite its rising predominance, current therapeutic medications are limited in efficacy and safety. Recent attention has shifted towards herbal therapies as potential adjuncts or alternatives in NASH management, given their anti-inflammatory, antioxidant, and phospholipid-controlling characteristics. This research study attempted to assess critically existing literature on the efficacy of herbal interventions while managing NASH. The main goal was to assess the possible medicinal advantages of different herbs, highlight their mechanisms of action, and identify gaps in current research to guide future studies. A systematic review of peer-reviewed articles using databases, like PubMed, Scopus, and Google Scholar, was conducted. It included studies that investigated the effects of herbal extracts (e.g., silymarin, curcumin, berberine) on NASH-related outcomes, such as liver function, fibrosis, lipid metabolism, and inflammatory markers. The review identified several herbs with promising therapeutic effects on NASH. Silymarin showed consistent improvements in liver enzymes and fibrosis markers. Curcumin and berberine were effective in reducing inflammation of the liver and oxidative damage. However, the heterogeneity in research designs, dosages, and outcome measures has limited the generalizability of findings. Herbal therapies hold potential as complementary treatments for NASH, with evidence supporting their role in improving liver function and reducing inflammation. To prove their safety and effectiveness, however, greater sample numbers and longer follow-up times are required in standardised clinical studies.